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Infiltrative non-GBM gliomas are common primary intracranial malignancies, and postoperative adjuvant radiotherapy is recommended for most adult patients diagnosed with this disease to enhance local control and prolong intracranial progression-free survival (PFS). However, RT-related neurocognitive function (NCF) consequences should not be ignored. Early neurocognitive decline principally includes episodic memory, associated significantly with functions of the hippocampus. This prospective study aims to investigate the impact of adjuvant brain irradiation on neurocognitive performances and relevant oncological outcomes.Twenty-five patients with intracranial infiltrative non-GBM gliomas were enrolled when postoperative adjuvant RT was recommended. All recruited patients should receive baseline brain magnetic resonance imaging, and neuropsychological assessments before and 4 months after the RT course. A battery of neuropsychological measures, mainly including executive functions, memory, psychomotor speed and visuoconstructive ability, was used to evaluate NCFs of interest.Analyzing the delta values between post-irradiation and baseline NCF scores, we observed a robust trend reflecting cognitive stabilization rather than deterioration in almost all NCF. Both verbal and visual memory functions exhibited significant differences in the corresponding scaled scores (

Objective To assess the predictive value of swab cultures of cryopreserved skull flaps during cranioplasties for surgical site infections (SSIs). Methods A retrospective review was conducted of consecutive patients who underwent delayed cranioplasties with cryopreserved autografts between 2009 and 2017. The results of cultures obtained from swabs and infected surgical sites were assessed. The accuracy, sensitivity, and specificity of swab cultures for SSIs were evaluated. Results The study included 422 patients categorized into two groups, swab and nonswab, depending on whether swab cultures were implemented during cranioplasties. The overall infection rate was 7.58%. No difference was seen in infection rates between groups. There were 18 false-positive and no true-positive swab culture results. All bacteria between swab cultures and SSI cultures were discordant. Meanwhile, there were 19 false-negative swab cultures. The results showed high specificity but low sensitivity for swab cultures to predict SSI occurrence and the pathogens. Conclusions Owing to low accuracy and sensitivity, swab cultures of cryopreserved autografts should not be routinely performed during delayed cranioplasties.

Our study aimed to investigate whether changes in brain function measured with functional magnetic resonance imaging (fMRI) can be detected among individuals with depressive disorders and suicidal ideation. The association between depression severity and brain images is also discussed. Our study recruited 111 participants in three groups: 35 depressive patients with suicidal ideation (SI), 32 depressive patients without suicidal ideation (NS), and 44 healthy controls (HCs). All participants were scanned using 3T MRI to obtain resting-state functional images, and functional connectivity (FC), amplitude of low-frequency fluctuation (ALFF), regional homogeneity (ReHo), and graph theoretical analysis (GTA) were performed. We found functional activity differences, such as the hippocampus and thalamus, in the SI group compared with the NS group. We also concluded lower activity in the thalamus and cuneus regions were related to suicidal ideation. We also found several functional connectivity of the brain areas, such as hippocampus, cuneus, and frontal regions, in the SI group correlated with Hamilton Depression Rating Scale (HAM-D) and Hospital Anxiety and Depression Scale (HADS). A graph theoretical analysis (GTA) and network-based statistical (NBS) analysis revealed different topological organization and slightly better local segregation of the brain network in healthy participants compared with those in depressive patients with suicidal ideation. We suggest that brain functional connectivity may be affected in depressive patients with suicidal ideation.

Conventional treatment for treating primary central nervous system lymphoma (PCNSL) has consisted of either whole-brain radiotherapy (WBRT) or methotrexate (MTX)-based combined modality therapy. However, delayed cognitive sequelae have emerged as a significant debilitating complication in PCNSL patients. A prospective observational case-series study with prospective assessments of neurocognitive functions (NCFs), neuroimaging, and activities of daily living in newly-diagnosed PCNSL patients was undertaken. A battery of neuropsychological measures, used to evaluate NCFs, is composed of ten standardized NCF tests, representing four domains sensitive to disease and treatment effects (executive function, attention, verbal memory, psychomotor speed), and activities of daily living. A total of 15 patients with newly-diagnosed PCNSL were consecutively enrolled in this study. Comparing the NCF scores between the baseline (before WBRT) and post-treatment (after combined chemoradiation therapy) intervals (Mean = 122.33 days, SD = 34.49, range = 77-196), neurobehavioral outcomes consistently remained improving or stable in almost each domain of NCF. Specifically, the scores on Paced Auditory Serial Addition Test-Revised (PASAT-R) were significantly improved between the baseline and post-chemoradiation assessment. Under the multidisciplinary treatment guidelines for treating patients with newly-diagnosed PCNSL, multi-domain NCF become stabilized and even improved after the course of conformal WBRT combined with or without MTX-based chemotherapy.

A dural substitute is frequently used to repair dura mater during neurosurgical procedures. Although autologous or commercially available dural substitutes matched most of the requirements; difficulties during dural repair, including insufficient space for suturing, insufficient mechanical strength, easy tear and cerebrospinal fluid leakage, represent major challenges. To meet this need, a photo-crosslinked hydrogel was developed as a dural substitute/anti-adhesion barrier in this study, which can show sol-to-gel phase transition in situ upon short-time exposure to visible light. For this purpose, hyaluronic acid (HA) and carboxymethyl cellulose (CMC), materials used in abdominal surgery for anti-adhesion purposes, were reacted separately with glycidyl methacrylate to form hyaluronic acid methacrylate (HAMA) and carboxymethyl cellulose methacrylate (CMCMA). The HA/CMC (HC) hydrogels with different HA compositions could be prepared by photo-crosslinking HAMA and CMCMA with a 400 nm light source using lithium phenyl-2,4,6-trimethylbenzoylphosphinate as a photo-initiator. From studies of physico-chemical and biological properties of HC composite hydrogels, they are bio-compatible, bio-degradable and mechanically robust, to be suitable as a dural substitute. By drastically reducing attachment and penetration of adhesion-forming fibroblasts in vitro, the HC hydrogel can also act as an anti-adhesion barrier to prevent adhesion formation after dural repair. From in vivo study in rabbits, the HC hydrogel can repair dural defects as well as protect the dura from post-operative adhesion, endorsing the possible application of this hydrogel as a novel dural substitute.

Initial tumor enlargement (or pseudoprogression) instead of true tumor progression is a common phenomenon in patients with acoustic neuromas who are treated with stereotactic radiosurgery (SRS). This phenomenon can affect clinical decision-making and patient management. This study assessed the correlation between initial tumor enlargement and magnetic resonance imaging characteristics in patients with acoustic neuromas who were treated with linear accelerator (LINAC)-based SRS. The long-term tumor control outcomes were also analyzed.In total, 330 patients with sporadic acoustic neuromas who were treated with LINAC SRS between March 2006 and March 2020 were retrospectively evaluated to assess their initial tumor enlargement. The tumors were divided into homogeneously enhanced, heterogeneously enhanced, and cystic types based on the morphological characteristics noted on magnetic resonance images. Tumor control was assessed in 275 patients with a follow-up duration of more than 2 years.Initial enlargement was observed in 137 of 330 (41.5%) tumors as early as 3 months after LINAC SRS. Data analysis revealed that postoperative tumors with a residual volume lower than 2.5 cmInitial enlargement can occur as early as 3 months after SRS. Postoperative residual tumors with a volume lower than 2.5 cm

Glioma is a severe disease with a poor prognosis despite aggressive surgical resection and traditional chemotherapies. Therefore, new anti-neoplastic drugs are urgently needed. Bioactive compounds from natural products are potential sources of antiproliferative molecules, among which manzamine compounds extracted from the Formosan marine sponge Haliclona sp. have shown considerable promise as anticancer drugs. In the present study, the anti-neoplastic effect and mechanism of the manzamine derivative 1-(9’-propyl-3’-carbazole)-1, 2, 3, 4-tetrahydro-β-carboline (PCTC) were investigated using in vitro cell lines and an in vivo subcutaneous animal model. Both cytotoxic and anti-proliferative effects were shown in human and murine glioma cell lines (A172, U87MG, and GL261), together with enhanced expressions of apoptotic enzymes and intracellular reactive oxygen species, and blockage of the G1/S phase of the cell cycle. In addition, combined treatment of GL261 cells with PCTC and temozolomide had a synergic antiproliferative effect. Significant safety, efficacy, and survival benefits were also demonstrated with PCTC treatment in the murine subcutaneous GL261 model. In conclusion, PCTC could effectively promote cell death through apoptosis and cell cycle arrest in glioma cell lines, and provide survival benefits in the animal model. Therefore, PCTC may be a clinically beneficial therapy for glioblastoma.

Background Glioblastoma (GBM) is a malignant human brain tumor that has an extremely poor prognosis. Classic mutations such as IDH (isocitrate dehydrogenase) mutations, EGFR (epidermal growth factor receptor) alternations, and MGMT (O6-methylguanine-methyltransferase) promoter hypermethylation have been used to stratify patients and provide prognostic significance. Epigenetic perturbations have been demonstrated in glioblastoma tumorigenesis. Despite the genetic markers used in the management of glioblastoma patients, new biomarkers that could predict patient survival independent of known biomarkers remain to be identified. Methods ATAC-seq (assay for transposase accessible chromatin followed by sequencing) and RNA-seq have been used to profile chromatin accessible regions using glioblastoma patient samples with short-survival versus long-survival. Cell viability, cell cycle, and Western blot analysis were used to characterize the cellular phenotypes and identify signaling pathways. Results Analysis of chromatin accessibility by ATAC-seq coupled with RNA-seq methods identified the GSTM1 (glutathione S-transferase mu-1) gene, which featured higher chromatin accessibility in GBM tumors with short survival. GSTM1 was confirmed to be a significant prognostic marker to predict survival using a different GBM patient cohort. Knockdown of GSTM1 decreased cell viability, caused cell cycle arrest, and decreased the phosphorylation levels of the NF-kB (nuclear factor kappa B) p65 subunit and STAT3 (signal transducer and activator of transcription 3) (pSer727). Conclusions This report demonstrates the use of ATAC-seq coupled with RNA-seq to identify GSTM1 as a prognostic marker of GBM patient survival. Activation of phosphorylation levels of NF-kB p65 and STAT3 (pSer727) by GSTM1 is shown. Analysis of chromatin accessibility in patient samples could generate an independent biomarker that can be used to predict patient survival.

OBJECTIVEDespite intensive medical treatment, patients with glioblastoma (grade IV glioma [GBM]) have a low 5-year survival rate of 5.5%. In this study, the authors tried to improve currently used therapies by identification of a therapeutic target, IGFBP3, for glioma treatment.METHODSIGFBP3 RNA expression in 135 patients newly diagnosed with glioma was correlated with clinicopathological factors. Immunohistochemical analysis was performed to determine IGFBP3 protein expression in glioma specimens. The effect of IGFBP3 depletion on cell proliferation was examined using IGFBP3 knockdown glioma cells. Intracranial infusion of IGFBP3 siRNAs was performed to evaluate the effect of IGFBP3 depletion in mouse intracranial xenograft models.RESULTSWe demonstrated higher IGFBP3 expression in GBM than in tumor margin and grade II glioma. IGFBP3 expression was not only positively correlated with tumor grades but also associated with tumor histology and IDH1/2 mutation status. Additionally, higher IGFBP3 expression predicted shorter overall survival in glioma and GBM proneural subgroup patients. In vitro cell culture studies suggested IGFBP3 knockdown suppressed cell proliferation and induced cell cycle G2/M arrest as well as apoptosis in glioma cells. Also, accumulation of DNA double-strand breaks and γH2AX was observed in IGFBP3 knockdown cells. IGFBP3 knockdown delayed in vivo tumor growth in mouse subcutaneous xenograft models. Furthermore, convection-enhanced delivery of IGFBP3 siRNA to mouse brain suppressed intracranial tumor growth and prolonged survival of tumor-bearing mice.CONCLUSIONSOur findings suggest IGFBP3 predicts poor outcome of glioma patients and is a potential therapeutic target for which depletion of its expression suppresses tumor growth through inducing apoptosis and accumulation of DNA damage in glioma cells.

Background and Aims: Subjects with diabetes are prone to a rapid decline in renal function and major adverse cardiovascular events when they reach chronic kidney disease (CKD) stage 3. This study aimed to identify modifiable risk factors associated with the progression of CKD in this population. Settings and Design: An observational cohort study. Methods and Materials: A total of 320 type 2 diabetic patients with CKD stage 3 registered in the shared-care-system in our hospital in 2010 were regularly followed up for 7 years. Demographic, laboratory, medication, and fundus examination data of these subjects were collected and analyzed. Statistical Analysis Used: Cox regression was used to identify factors associated with changes in CKD stage. Results: During the 7-year follow-up period, 204 cases (63.7%) remained at CKD stage 3 while 79 cases (24.7%) progressed to stage 4 or 5 and 37 cases (11.6%) improved to stage 1 or 2. The change in estimated glomerular filtration rate (eGFR) in the first 2 years and variations in glycated hemoglobin (HbA1c) over 7 years were independent factors of both progression (hazard ratio (HR) 1.098 and 1.710, respectively) and improvement (HR 0.919 and 0.231, respectively) of CKD stage. Variations in systolic blood pressure (SBP) was also found as an independent factor for progression of renal function (HR 1.052). Conclusions: Our results demonstrated that fluctuations in HbA1c and SBP, and changes in eGFR during the first 2 years of treatment were associated with the long-term renal outcomes in type 2 diabetic patients with CKD stage 3.

This study aimed to explore RGS2 as a regulator of melanoma cell growth.Effect of RGS2 over-expression was analyzed in three melanoma cell lines, and Rgs2 knockdown was performed in zebrafish.RGS2 was differentially expressed among the cell lines. In B16F10 cells, RGS2 over-expression inhibited MAPK and AKT activation, and prevented cell growth. A similar outcome was observed in A375 cells, but the MAPK signals were not suppressed. In A2058 cells, RGS2 repressed AKT activation, but without affecting cell growth. Moreover, MAPK and AKT constitutive activation abolished the RGS2 inhibitory effect on B16F10 cell growth. Rgs2 knockdown caused ectopic melanocyte differentiation, and promoted MAPK and AKT activation in zebrafish embryos.RGS2 prevents melanoma cell growth by inhibiting MAPK and AKT, but this effect depends on the overall cell genetic landscape. Further studies are warranted to investigate the anticancer therapeutic potential of RGS2 for melanoma.

Background The aim of this study was to assess the relationship between the atlantodental interval (ADI) on dynamic flexion/extension cervical radiographs and functional outcomes of posterior spinal fixation by the Harms technique for atlantoaxial subluxation (AAS).Dynamic flexion/extension on cervical radiographs is a standard assessment for evaluation of C1/2 instability in AAS patients. Most studies focused on postoperative ADI and functional outcome, including pain and fusion rate; only few studies compared dynamic ADI change pre- to post-operatively. Material and methods Retrospectively, we reviewed the medical records of 16 patients who underwent posterior spinal fixation in our center from 2018 to 2019. We used dynamic cervical flexion/extension radiographs to assess the pre- to postoperative change at 12 months in ADI of flexion (ADIf), ADI of extension (ADIe), ADI between flexion/extension (ADIΔ), C1/2 fusion rate and functional outcomes measured by the modified Japanese Orthopaedic Association scale (mJOA scale). Postoperative CT at 3∼12 months assessed screw positioning on the Gertzbein and Robbins classification. Results In the 16 patients included in this study, ADIf, ADIe and ADIΔ were significantly reduced, from respectively 8.0mm, 5.0mm and 3.0mm preoperatively to 4.6mm, 3.8mm and 0.8mm at 12 months' follow-up. The fusion rate was 81% and the mJOA score recovery rate was 34.9±14.7%. Although the screw malposition rate was higher than in other studies in C1(10%) and C2(20%), there were no new neurologic deficits or worsening of symptoms at follow-up. Conclusions The ADIΔ showed significant reduction, showing that the Harms technique of posterior spinal fixation can effective in maintaining the stability of the atlantoaxial joint and improving functional outcome.

Parkinson's disease (PD), the most common neurodegenerative motor disorder, is currently incurable. Although many studies have provided insights on the substantial influence of genetic factors on the occurrence and development of PD, the molecular mechanism underlying the disease is largely unclear. Previous studies have shown that point mutations in the phospholipase A2 group VI gene (PLA2G6) correlate with young-onset dystonia-parkinsonism type 14 (PARK14). However, limited information is available regarding the pathogenic role of this gene and the mechanism underlying its function. To study the role of PLA2G6 mutations, we first used zebrafish larvae to screen six PLA2G6 mutations and revealed that injection of D331Y, T572I, and R741Q mutation constructs induced phenotypes such as motility defects and reduction in dopaminergic neurons. The motility defects could be alleviated by treatment with L-3, 4-dihydroxyphenylalanine (L-dopa), indicating that these mutations are pathological for PARK14 symptoms. Furthermore, the injection of D331Y and T572I mutation constructs reduced phospholipase activity of PLA2G6 and its lipid metabolites, which confirmed that these two mutations are loss-of-function mutations. Metabolomic analysis revealed that D331Y or T572I mutation led to higher phospholipid and lower docosahexaenoic acid (DHA) levels, indicating that reduced DHA levels are pathological for defective motor functions. Further, a dietary DHA supplement relieved the motility defects in PLA2G6D331Y/D331Y knock-in mice. This result revealed that the D331Y mutation caused defective PLA2G6 phospholipase activity and consequently reduced the DHA level, which is the pathogenic factor responsible for PARK14. The results of this study will facilitate the development of therapeutic strategies for PARK14.

Background Spinal cord injury (SCI) and spinal fracture are major complications in patients with ankylosing spondylitis (AS) who sustain spinal trauma. The purpose of this study was to investigate the incidence, predictors, and sequelae of spinal trauma in patients with AS. Methods This retrospective study included patients with AS who were admitted for spinal trauma between January 1, 2006, and June 30, 2016. The study compared clinical outcomes of patients between group 1: SCI alone, group 2: spinal fracture alone (no SCI), and group 3: both SCI and spinal fracture. Results Of the 6285 patients with AS admitted during the retrospective study period, only 105 suffered from spinal trauma and were enrolled in the study. Case number in group 1, 2, and 3 was 11(10.48%), 45(42.85%), and 49(46.67%), respectively. Among the patients with spinal fractures, 52.1% had SCI. Bamboo spine was significantly more prevalent in the fracture group than in the nonfracture group (78.7% vs. 36.4%; P = 0.006). Patients with SCI had more instances of subluxation or dislocation (48.3% vs. 8.9%; P P = 0.003) than patients without SCI. The rate of delayed diagnosis for spinal fracture was 31.4%, with one-third of patients developing delayed SCI. Among the patients with incomplete SCI, 58.3% achieved neurological improvement after treatment (P = 0.004). Conclusions Patients with AS and bamboo spine at radiograph had a higher rate of spinal fracture, which may be an important factor in SCI in patients with AS. Spinal fractures involving the C3–C7 region, subluxation or dislocation, severe spinal fracture, and SEH were found to be predictive of SCI, and SCI in patients with AS resulted in higher mortality and complication rates.

Background: Parkinson’s disease (PD) is the most common neurodegenerative motor disorder, which is currently incurable. Mutations in many genes have been demonstrated to be the primary risk factors associated with the familial or idiopathic PD; however, the mechanisms underlying these genetic mutations resulting in parkinsonism remains unclear. Phospholipase A2 group VI (PLA2G6) has been shown to regulate lipid metabolism and homeostasis in the nervous system. Previous studies have shown that point mutations in PLA2G6 might be the risk factors associated with the young–onset of dystonia–parkinsonism type 14 (PARK14). However, limited information is available regarding its pathogenic role and the mechanism underlying its function.

Spinal cord injury (SCI) is associated with disability and a drastic decrease in quality of life for affected individuals. Previous studies support the idea that docosahexaenoic acid (DHA)-based pharmacological approach is a promising therapeutic strategy for the management of acute SCI. We postulated that a nanostructured material for controlled delivery of DHA at the lesion site may be well suited for this purpose. Toward this end, we prepare drug-loaded fibrous mats made of core-shell nanofibers by electrospinning, which contained a polylactic acid (PLA) shell for encapsulation of DHA within the core, for delivery of DHA in situ. In vitro study confirmed sustained DHA release from PLA/DHA core-shell nanofiber membrane (CSNM) for up to 36 days, which could significantly increase neurite outgrowth from primary cortical neurons in 3 days. This is supported by the upregulation of brain-derived neurotropic factor (BDNF) and neurotrophin-3 (NT-3) neural marker genes from qRT-PCR analysis. Most importantly, the sustained release of DHA could significantly increase the neurite outgrowth length from cortical neuron cells in 7 days when co-cultured with PLA/DHA CSNM, compared with cells cultured with 3 &mu, M DHA. From in vivo study with a SCI model created in rats, implantation of PLA/DHA CSNM could significantly improve neurological functions revealed by behavior assessment in comparison with the control (no treatment) and the PLA CSNM groups. According to histological analysis, PLA/DHA CSNM also effectively reduced neuron loss and increased serotonergic nerve sprouting. Taken together, the PLA/DHA CSNM may provide a nanostructured drug delivery system for DHA and contribute to neuroprotection and promoting neuroplasticity change following SCI.

Our study aimed to investigate whether changes in brain function measured with functional magnetic resonance imaging (fMRI) can be detected among individuals with depressive disorders and suicidal ideation. The association between depression severity and brain images is also discussed. Our study recruited 111 participants in three groups: 35 depressive patients with suicidal ideation (SI), 32 depressive patients without suicidal ideation (NS), and 44 healthy controls (HCs). All participants were scanned using 3T MRI to obtain resting-state functional images, and functional connectivity (FC), amplitude of low-frequency fluctuation (ALFF), regional homogeneity (ReHo), and graph theoretical analysis (GTA) were performed. We found functional activity differences, such as the hippocampus and thalamus, in the SI group compared with the NS group. We also concluded lower activity in the thalamus and cuneus regions were related to suicidal ideation. We also found several functional connectivity of the brain areas, such as hippocampus, cuneus, and frontal regions, in the SI group correlated with Hamilton Depression Rating Scale (HAM-D) and Hospital Anxiety and Depression Scale (HADS). A graph theoretical analysis (GTA) and network-based statistical (NBS) analysis revealed different topological organization and slightly better local segregation of the brain network in healthy participants compared with those in depressive patients with suicidal ideation. We suggest that brain functional connectivity may be affected in depressive patients with suicidal ideation.

Background Awake craniotomy (AC) with intraoperative stimulation mapping is the standard treatment for gliomas, especially those on the eloquent cortex. Many studies have reported survival benefits with the use of AC in patients with glioma, however most of these studies have focused on low-grade glioma. The aim of this study was to evaluate the experience of one treatment center over 10 years for resection of left hemispheric eloquent glioblastoma. Methods This retrospective analysis included 48 patients with left hemispheric eloquent glioblastoma who underwent AC and 61 patients who underwent surgery under general anesthesia (GA) between 2008 and 2018. Perioperative risk factors, extent of resection (EOR), preoperative and postoperative Karnofsky Performance Score (KPS), progression-free survival (PFS) and overall survival (OS) were assessed. Results The postoperative KPS was significantly lower in the GA patients compared to the AC patients (p=0.002). The EOR in the GA group was 90.2% compared to 94.9% in the AC group (p=0.003). The mean PFS was 18.9 months in the GA group and 23.2 months in the AC group (p=0.001). The mean OS was 25.5 months in all patients, 23.4 months in the GA group, and 28.1 months in the AC group (p

Background: Parkinson’s disease (PD) is the most common neurodegenerative motor disorder, which is currently incurable. Mutations in many genes have been demonstrated to be the primary risk factors associated with the familial or idiopathic PD; however, the mechanisms underlying these genetic mutations resulting in parkinsonism remains unclear. Phospholipase A2 group VI (PLA2G6) has been shown to regulate lipid metabolism and homeostasis in the nervous system. Previous studies have shown that point mutations in PLA2G6 might be the risk factors associated with the young–onset of dystonia–parkinsonism type 14 (PARK14). However, limited information is available regarding its pathogenic role and the mechanism underlying its function. Methods: To study the role of PLA2G6 mutations in zebrafish PARK14 models, we injected different mutation constructs of human PLA2G6 genes and zebrafish pla2g6 deletion constructs in the zebrafish larvae. We analyzed the locomotion behavior, performed immunohistochemistry to examine the formation of dopaminergic neurons, and identified the defective metabolites affected by PLA2G6 mutations through metabolomics analysis. Results: Injection of human PLA2G6 mutations and zebrafish pla2g6 deletion constructs induced symptoms such as motility defects and reduced number of dopaminergic neurons, and these symptoms resembled those observed in PARK14. These phenotypes could be rescued by treatment with L-dopa. Furthermore, the injection of two PLA2G6 mutation constructs, D331Y and T572I, led to a decrease in the phospholipase activity of PLA2G6 and its lipid metabolites, indicating that these two mutations are the loss-of-function mutations. We further performed metabolomics analysis to identify which lipids are majorly affected by the overexpression of PLA2G6 and PLA2G6 mutants. We found that injecting D331Y or T572I mutation constructs led to higher phospholipid and lower DHA levels. Conclusions: D331Y and T572I injections in zebrafish were sufficient to create a PD phenotypes. In addition, D331Y and T572I are loss of function mutations and cause defective phospholipase activity and reduced the level of DHA. These results have helped us elucidate the role of PLA2G6 mutations in PARK14 and further led to a deeper understanding of the molecular mechanisms underlying PD. The results of this study may also facilitate the development of therapeutic strategies for PD.

Background Many molecules and signaling pathways involved in neural development play a role in neurodegenerative diseases and brain tumor progression. Peroxisome proliferator-activated receptor (PPAR) proteins regulate the differentiation of tissues and the progression of many diseases. However, the role of these proteins in neural development is unclear. Results We examined the function of Pparα in the neural development of zebrafish. Two duplicate paralogs for mammalian PPARA/Ppara, namely pparaa and pparab, are present in the zebrafish genome. Both pparaa and pparab are expressed in the developing central nervous system in zebrafish embryos. Inhibiting the function of Pparα by using either the PPARα/Pparα antagonist GW6471 or pparaa or pparab truncated constructs produced identical phenotypes, which were sufficient to reduce the proliferation of neuronal and glial precursor cells without affecting the formation of neural progenitors. Conclusions We demonstrated that both Pparαa and Pparαb proteins are essential regulators of the proliferation of neuronal and glial precursors. This study provides a better understanding of the functions of PPARα/Pparα in neural development and further expands our knowledge of the potential role of PPARα/Pparα in neurological disorders and brain tumors. Developmental Dynamics 247:1264-1275, 2018. © 2018 Wiley Periodicals, Inc.

We report the first nationwide population-based cohort study using Taiwan's National Health Insurance Research Database on the association between enterovirus (EV) infection and the incidence of sleep disorders in a pediatric population.Two matched groups of children under 18 years of age were included in the analyses for nonapneic sleep disorder and obstructive sleep apnea (OSA). Among them, 316 subjects were diagnosed with OSA during the surveillance period, including 182 in the EV infection group and 134 in the non-EV infection group.Hospitalization because of EV infection was associated with OSA after adjusting for age, sex, urbanization atopic disease and perinatal complications (adjusted hazard ratio: 1.62, 95% confidence interval: 1.18-2.21; P = 0.003). An additional factor significantly associated with sleep apnea was allergic rhinitis (hazard ratio: 4.82, 95% confidence interval: 3.45-6.72).Children with severe EV infection (ie, requiring hospitalization) carry a significantly higher risk of developing OSA, particularly in those with allergic rhinitis. As pediatric obstructive sleep apnea is a treatable sleep disorder, we emphasize regular follow-up and early detection in children with EV infection.

Normal pressure hydrocephalus (NPH) was the first type of dementia ever described that can be treated using ventriculoperitoneal shunting surgery. Three typical clinical symptoms of NPH include gait disturbance, progressive cognitive dysfunction, and urinary incontinence. Although there are articles that have discovered several cerebrospinal fluid (CSF) protein biomarkers associated with NPH; however, studies examining individual and total protein concentrations from the ventricular CSF before and after shunting surgery are lacking. This study used proteomics to calculate the CSF individual and total protein concentrations before, and one week, one month and three months after the shunting surgery. Parameters of cadence, step length, walking speed, and percentages of single- and double-limb support in a gait cycle were measured. Protein concentrations associated with anti-oxidation, aging, and in the prevention of neurotoxic agent production increased by at least 2-folds after the surgery, indicating that the brain may become less susceptible to neurodegeneration. These proteins were alpha-1B-glycoprotein, apolipoproteins A-1 & A-IV, prostaglandin-H2 D-isomerase, alpha-1-antitrypsin, and serotransferrin. In gait analysis, lower cadence, decreased double-limb support, longer step length, and increased single-limb support were observed after the surgery, indicating a more stable walking balance. These changes lasted for a period of at least 3 months. As a result, shunting surgery may be recommended for geriatric patients with confirmed diagnosis of normal pressure hydrocephalus.

// Ching-Chi Chiu 1, 2, 3, * , Tu-Hsueh Yeh 1, 2, 4, 5, * , Chin-Song Lu 1, 2, 6, 7 , Yin-Cheng Huang 7, 8 , Yi-Chuan Cheng 9 , Ying-Zu Huang 1, 2, 6, 7, 10 , Yi-Hsin Weng 1, 2, 6, 7 , Yu-Chuan Liu 11 , Szu-Chia Lai 1, 2, 6, 7 , Ying-Ling Chen 3 , Yu-Jie Chen 1 , Chao-Lang Chen 1 , Hsin-Yi Chen 1, 6 , Yan-Wei Lin 1, 6 and Hung-Li Wang 1, 2, 6, 12 1 Neuroscience Research Center, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan 2 Healthy Aging Research Center, Chang Gung University College of Medicine, Taoyuan, Taiwan 3 Department of Nursing, Chang Gung University of Science and Technology, Taoyuan, Taiwan 4 Department of Neurology, Taipei Medical University Hospital, Taipei, Taiwan 5 School of Medicine, Taipei Medical University, Taipei, Taiwan 6 Division of Movement Disorders, Department of Neurology, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan 7 College of Medicine, Chang Gung University, Taoyuan, Taiwan 8 Department of Neurosurgery, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan 9 Graduate Institute of Biomedical Sciences, Chang Gung University College of Medicine, Taoyuan, Taiwan 10 Institute of Cognitive Neuroscience, National Central University, Taoyuan, Taiwan 11 Division of Sports Medicine, Taiwan Landseed Hospital, Taoyuan, Taiwan 12 Department of Physiology and Pharmacology, Chang Gung University College of Medicine, Taoyuan, Taiwan * These authors have contributed equally to this work Correspondence to: Hung-Li Wang, email: hlwns@mail.cgu.edu.tw Keywords: Parkinson’s disease, PARK14, PLA2G6, rotenone, mitochondrial dysfunction Received: March 01, 2017 Accepted: August 17, 2017 Published: September 15, 2017 ABSTRACT Mutations in the gene encoding Ca 2+ -independent phospholipase A 2 group 6 (PLA2G6) cause the recessive familial type 14 of Parkinson’s disease (PARK14). Mitochondrial dysfunction is involved in the pathogenesis of Parkinson’s disease (PD). PLA2G6 is believed to be required for maintaining mitochondrial function. In the present study, rotenone-induced cellular model of PD was used to investigate possible molecular pathogenic mechanism of PARK14 mutant PLA2G6-induced PD. Overexpression of wild-type (WT) PLA2G6 ameliorated rotenone-induced apoptotic death of SH-SY5Y dopaminergic cells. PARK14 mutant (D331Y), (G517C), (T572I), (R632W), (N659S) or (R741Q) PLA2G6 failed to prevent rotenone-induced activation of mitochondrial apoptotic pathway and exert a neuroprotective effect. WT PLA2G6, but not PARK14 mutant PLA2G6, prevented rotenone-induced mitophagy impairment. In contrast to WT PLA2G6, PARK14 mutant PLA2G6 was ineffective in attenuating rotenone-induced decrease in mitochondrial membrane potential and increase in the level of mitochondrial superoxide. WT PLA2G6, but not PARK14 PLA2G6 mutants, restored enzyme activity of mitochondrial complex I and cellular ATP content in rotenone-treated SH-SY5Y dopaminergic cells. In contrast to WT PLA2G6, PARK14 mutant PLA2G6 failed to prevent rotenone-induced mitochondrial lipid peroxidation and cytochrome c release. These results suggest that PARK14 PLA2G6 mutants lose their ability to maintain mitochondrial function and are defective inpreventing mitochondrial dysfunction, ROS production and activation of mitochondrial apoptotic pathway in rotenone-induced cellular model of PD.

Glioblastomas are among the most fatal brain tumors; however, the molecular determinants of their tumorigenic behavior are not adequately defined. In this study, we analyzed the role of KMT2A in the glioblastoma cell line U-87 MG. KMT2A knockdown promoted cell proliferation. Moreover, it increased the DNA methylation of NOTCH1 and NOTCH3 and reduced the expression of NOTCH1 and NOTCH3. NOTCH1 or NOTCH3 activation inhibited U-87 MG cell proliferation, whereas NOTCH1 and NOTCH3 inhibition by shRNAs induced cell proliferation, thus demonstrating the tumor-suppressive ability of NOTCH1 and NOTCH3 in U-87 MG cells. The induced cell proliferation caused by KMT2A knockdown could be nullified by using either constitutively active NOTCH1 or constitutively active NOTCH3. This result demonstrates that KMT2A positively regulates NOTCH1 and NOTCH3 and that this mechanism is essential for inhibiting the U-87 MG cell proliferation. The role of KMT2A knockdown in promoting tumor growth was further confirmed in vivo by transplanting U-87 MG cells into the brains of zebrafish larvae. In conclusion, we identified KMT2A-NOTCH as a negative regulatory cascade for glioblastoma cell proliferation, and this result provides important information for KMT2A- or NOTCH-targeted therapeutic strategies for brain tumors.

Background Awake craniotomy (AC) with intraoperative stimulation mapping is the standard treatment for glioma, especially when present on the eloquent cortex. The purpose of this study was to investigate whether functional preservation after AC compromises patient survival as compared with craniotomy under general anesthesia (GA). Methods The medical records of 339 patients who underwent tumor resection surgery for gliomas from January 2010 to December 2014 were retrospectively reviewed. Among these patients, 62 underwent AC with intraoperative stimulation mapping. The primary outcome was the Eastern cooperative oncology group (ECOG) performance score at 3 months postoperatively. Secondary outcomes were the progression-free survival (PFS) and overall survival (OS). A generalized linear model and the Cox proportional hazard model were used to evaluate potential factors influencing general functional status and progression-free survival.Results The newly-diagnosed disease AC and repeat-surgery groups were comparable in terms of sex, age, pathologic grade, extent of resection (EOR) and preoperative Karnofsky Performance Status (KPS). Among the patients with newly-diagnosed disease, the postoperative ECOG score of the AC group was significantly better than that of the GA group. Pathologic grade and the EOR determined the PFS and OS in both the AC and GA groups.Conclusion AC with intraoperative stimulation mapping is safe and allows maximal removal of lesions around the eloquent cortex. Greater preservation of neurologic function may have resulted in a better postoperative general functional status in the AC group.

Neural crest cells are multipotent progenitors that migrate extensively and differentiate into numerous derivatives. The developmental plasticity and migratory ability of neural crest cells render them an attractive model for studying numerous aspects of cell progression. We observed that zebrafish rgs2 was expressed in neural crest cells. Disrupting Rgs2 expression by using a dominant negative rgs2 construct or rgs2 morpholinos reduced GTPase-activating protein activity, induced the formation of neural crest progenitors, increased the proliferation of nonectomesenchymal neural crest cells, and inhibited the formation of ectomesenchymal neural crest derivatives. The transcription of pparda (which encodes Pparδ, a Wnt-activated transcription factor) was upregulated in Rgs2-deficient embryos, and Pparδ inhibition using a selective antagonist in the Rgs2-deficient embryos repaired neural crest defects. Our results clarify the mechanism through which the Rgs2–Pparδ cascade regulates neural crest development; specifically, Pparδ directly binds to the promoter and upregulates the transcription of the neural crest specifier sox10. This study reveals a unique regulatory mechanism, the Rgs2–Pparδ–Sox10 signaling cascade, and defines a key molecular regulator, Rgs2, in neural crest development.

Background Depression happens commonly in cancer patients. However, there is limited literature on uterine cancer. In this study, we aimed to evaluate the association between uterine cancer and depression as well as the moderating effect of age and hormone replacement therapy (HRT). Methods This was a population-based study using Taiwan's National Health Insurance Research Database. We conducted a matched cohort study and identified 6526 patients with uterine cancer and 65 260 controls. We adopted the competing risk analysis model as the statistical method and adjusted for potential confounding factors. Results From 1997 to 2008, 71 786 patients were included (6526 patients with uterine cancer and 65 260 controls). In the study, uterine cancer was not linked to depression. However, when we stratified the different age groups, those cancer patients aged

A new naphthol derivative, [F-18]FEONM, has been designed to be a new Tau protein PET imaging molecule for detecting Tau tangle status of Alzheimer's disease in a transgenic mouse model. In order to synthesize this molecule, 2-acetyl-6-methoxynaphthalene was the starting compound and needed five steps preparation to bonding functional and leaving group for preparing the precursor. Radiofluorination on the precursor was carried out by a modified [F-18]FDG autosynthesizer. After half an hour processing, it yielded more than 99% chemical and radiochemical purity product at up to 60% yield. Radiofluorination kinetic study showing 80% [F-18]FEONM would be produced within the first 5 min. The radiofluorination gap function factor is 0.122 for 150 min reaction. Recovery yield of crude [F-18]FEONM could be up to 60% by semi-preparative HILIC HPLC column purification with 95% ethanol elution. Brain glioma tumor mice PET imaging were performed after tail vein injecting [F-18]FEONM. Binding in mice brain tumor reached steady state after 30 min injection and shows 30–70% higher uptake compared to normal mouse. The static brain tumor uptake showed the summation accumulation binding rate was 60% faster than normal mouse. In vitro postmortem AD patient brain slice binding showed 70% higher uptake than normal brain. The uptake of spherical stem cells also showed higher association with neuronal differentiation and PET imaging of Tau and ABeta transgenic mice also showed visualized difference. The specific binding ratio of hippocampus to cerebellum of control mouse is 46.56%, cortex to cerebellum is 11.08% in a 12-month-old P301S Tau transgenic mouse; hippocampus to cerebellum is 106.66%, cortex to cerebellum is 82.48%. Relative ratio of hippocampus to cerebellum of a P301S mouse to control mouse is 2.29, cortex to cerebellum is 7.44.

Cerebral infarction is a common cause of disability. Malignant large infarction (MLI) is a catastrophic event, and there is no effective medical treatment. This study aimed to assess the outcome predictors of MLI and to analyze the impact of decompressive craniectomy (DC) on the functional outcome of survivors.This study comprised 213 MLI cases. Outcome was evaluated with modified Rankin Scale (mRS) at 1-year follow-up, and various parameters were tested for MLI outcome predictors. The impact of DC on functional outcome was examined after being further stratified into good survival (mRS score = 0, 1, 2, 3), poor survival (mRS score = 4, 5), and mortality (mRS score = 6) groups.Standard medical treatment only was used in 106 cases, and both medical treatment and DC were used in 107 cases. With multiple logistic regression analysis, age, motor response at deterioration/operation, and DC were identified as independent outcome predictors of MLI (P = 0.027, P0.001, P0.001). Compared with the sole standard medical treatment, additional DC resulted in a better outcome (odds ratio [OR] =19.95; 95% confidence interval [CI], 7.61-52.27; P0.001). Further analysis of functional outcome revealed that DC significantly increased the chance of good survival as opposed to poor survival (OR = 20.04; 95% CI, 6.05-66.32; P0.001) and death (OR = 43.72; 95% CI, 13.21-144.72; P0.001).In this study, DC performed on a young patient with motor response of localizing pain or better was linked with a better outcome. DC not only reduced mortality and increased the number of good survivals but also, most importantly, decreased the number of poor functional outcome survivals.

Background Lesional and symptomatic causes of epilepsy are the most common neurological disorders of the brain. Topiramate effectively controls newly diagnosed epilepsy and refractory focal seizures, but high-dose topiramate does not improve seizure control. This study aimed to evaluate the clinical efficacy and safety of dose-escalated topiramate as first-line monotherapy and add-on therapy in patients with neurosurgery-related epilepsy. Material and methods A total of 55 neurosurgical patients with epilepsy were divided into monotherapy and add-on therapy groups and both groups received topiramate via the dose-escalation method. The primary efficacy outcomes were seizure-free rate and seizure response rate. Adverse events and seizure frequency were recorded. Results The seizure response rate in the first month of monotherapy was significantly better than that of add-on therapy (89% vs 65%, P 24. Dizziness (25.5%) and headache (16.4%) were the most common adverse events. No severe adverse event such as cognitive impairment was observed. Conclusions Dose-escalated topiramate monotherapy and add-on therapy demonstrate good efficacy and safety, with fewer adverse events in seizure control in neurosurgical patients.

Cranioplasty is a technically simple procedure intended to repair defects of the skull to provide protection after craniectomy, improve functional outcomes, and restore cosmesis. Several materials have been used for the restoration of skull defects, including autologous bone grafts (AGs), polymethyl methacrylate (PMMA) flaps, and titanium mesh (T-mesh). However, the long-term results of cranioplasty after use of these materials are controversial.Medical records of 596 patients who underwent cranioplasty at our medical center between 2009 and 2015 with at least 2.5 years of follow-up were retrospectively reviewed. Patients were classified into 3 groups according to the materials used: AG, three-dimensional PMMA, and T-mesh. Demographic and clinical characteristics and postoperative complications were analyzed.Cranioplasty with AG had the highest bone flap depression rate (4.9%; P = 0.02) and was associated with a 26% long-term bone flap resorption. Younger age was a risk factor for bone flap resorption. T-mesh had a higher risk of postoperative skin erosion and bone exposure (17%; P = 0.004). Patients with diabetes, previous craniotomy, or hydrocephalus showed a higher risk of postoperative skin erosion. PMMA was associated with the highest rate of postoperative infection (14.4%3 months, 28.1%3 months; P0.05), and previous craniotomy may increase the infection risk after cranioplasty with PMMA.Complications after cranioplasty are high, and the various types of cranioplasty materials used are associated with different complications. Surgeons need to be aware of these potential complications and should choose the appropriate material for each individual patient.

Background Awake craniotomy is an effective method by which to reduce postoperative neurologic deficit in newly-diagnosed glioma patients. However, the level of functional preservation in patients undergoing resection of recurrent glioma remains unknown. Therefore, this study aimed to evaluate functional outcomes in patients with recurrent glioma undergoing awake craniotomy as compared with conservative general anesthesia craniotomy for tumor resection. Material and methods We retrospectively reviewed 225 patients who had recurrent gliomas from May 2013 to January 2016 in our institution. New-onset neurological deficits were evaluated on postoperative day 7 (early) and at 3 months (late). General performance was assessed both preoperatively and at 3 months postoperatively. Results The early neurological deficit rate was 3.8% in the awake craniotomy group and 21.6% in the general anesthesia group (P = 0.032), while the late neurological deficit rates were 3.8% and 11.5%, respectively (P = 0.231). Moreover, 46.1% of patients in the awake craniotomy group and 12.6% in the general anesthesia group demonstrated an improvement in the Karnofsky performance status (KPS) score (P Conclusions Awake craniotomy is an effective and safe method by which to perform recurrent glioma surgery. The neurological outcomes and general performance after awake craniotomy in recurrent glioma patients were better than those in patients undergoing general anesthesia craniotomy.

In managing patients with brain metastasis in the disciplines of neuro-oncology, neurosurgery, and radiation oncology, intracranial control and care. Of note, the controversies and problems associated with delayed radiation-related cognitive dysfunction cannot be ignored, particularly in patients who have undergone whole-brain radiation therapy (WBRT). Concerning neurocognitive consequences related to cranial irradiation, previous studies have shown that impaired hippocampal neurogenesis may be responsible for such cognitive impacts resulting from the delivery of WBRT. Therefore, it has been hypothesized that conformal hippocampal sparing during the course of WBRT (HS-WBRT) would contribute to meaningful preservation with regard to neurocognitive functions (NCFs).