Long-term follow-up and comparison of programmable and non-programmable ventricular cerebrospinal fluid shunts among adult patients with different hydrocephalus etiologies: a retrospective cohort study.

BACKGROUND: Programmable valve (PV) has been shown as a solution to the high revision rate in pediatric hydrocephalus patients, but it remains controversial among adults. This study is to compare the overall revision rate, revision cause, and revision-free survival between PV and non-programmable valve (NPV) in adult patients with different hydrocephalus etiologies. METHOD: We reviewed the chart of all patients with hydrocephalus receiving index ventricular cerebrospinal fluid (CSF) shunt operations conducted at a single institution from January 2017 to December 2017. Patients included in the study were followed up for at least 5 years. Statistical tests including independent t-test, chi-square test, and Fisher's exact test were used for comparative analysis, and Kaplan-Meier curve using log-rank test was performed to compare the revision-free survival between the PV and NPV groups. RESULTS: A total of 325 patients were included in the study, of which 181 patients were receiving PVs and 144 patients receiving NPV. There were 23 patients (12.8%) with PV and 22 patients (15.3%) with NPV receiving initial revision. No significant statistical difference in the initial revision rate was observed between the two groups (p = 0.52). No survival difference was found between the PV and NPV groups. However, better revision-free survival was noted in the PV group among idiopathic normal pressure hydrocephalus (iNPH) (p = 0.0274) and post-traumatic hydrocephalus (p = 0.017). CONCLUSIONS: The combination of the different etiologies of hydrocephalus and the features of PV and NPV results in different outcomes-revision rate and revision-free survival. PV use might be superior to NPV in iNPH and post-traumatic hydrocephalus patients. Further studies are needed to clarify the indications of PV use in adult hydrocephalus patients.

Rathke's cleft cyst classification and outcomes after endoscopic endonasal approach.

BACKGROUND: Rathke's cleft cyst is rare, with variable characteristics and no unified categorization system. This study aimed to evaluate long-term outcomes, based on different categorizations, of symptomatic Rathke's cleft cysts treated with endoscopic endonasal approach. METHODS: This retrospective study of 38 patients with symptomatic Rathke's cleft cyst treated with endoscopic endonasal approach from 2006/06-2021/08 recorded pre- and post-operative clinical presentation, endocrine and visual tests, radiological findings, and resection status. Rathke's cleft cysts were categorized by both cyst consistency and radiological features and clinical characteristics were analyzed. RESULTS: The most common pre-operative symptoms were visual field deficit (65.8%) and hypopituitarism (39.5 %). Visual field deficit improved in 84% of affected patients, and hyperprolactinemia improved in 80% of affected patients. Pre-operative hypothyroidism and hypogonadism were associated with radiological type 3 cysts, while headache was more common in type B and C. Type 3 cysts were also associated post-operative hypogonadism and hypothyroidism. Permanent Diabetes insipidus was found in 3 patients (7.9%). Cyst height was a significant factor related to pre-operative visual field deficit and post-operative Diabetes insipidus. Residual cysts were found in 11 cases (30.6%) and 9 patients experienced regrowth/recurrence. Residual cysts were a significant factor in regrowth/recurrence. Recurrence rate and post-operative complications were not correlated with different subtypes. CONCLUSIONS: Endoscopic endonasal approach for removal of Rathke's cleft cyst is a safe and effective intervention. It leads to significant improvement in visual field deficit and recovery of hyperprolactinemia. Although the incidence of post-operative Diabetes insipidus is high, it is usually temporary. Although different categorizations are not correlated to recurrence rate, they could help predict the status of hormone deficit.

Etv5a Suppresses Neural Progenitor Cell Proliferation by Inhibiting sox2 Transcription.

Neural progenitor cells are self-renewable, proliferative, and multipotent cell populations that generate diverse types of neurons and glia to build the nervous system. Transcription factors play critical roles in regulating various cellular processes; however, the transcription factors that regulate the development of neural progenitors are yet to be identified. In the present study, we demonstrated that zebrafish etv5a is expressed in the neural progenitor cells of the neuroectoderm. Downregulation of endogenous Etv5a function by etv5a morpholino or an etv5a dominant-negative variant increased the proliferation of sox2-positive neural progenitor cells, accompanied by inhibition of neurogenesis and gliogenesis. These phenotypes in Etv5a-depleted embryos could be rescued by a co-injection with etv5a cRNA. Etv5a overexpression reduced sox2 expression. Direct binding of Etv5a to the regulatory elements of sox2 was affirmed by chromatin immunoprecipitation. These data revealed that Etv5a directly suppressed sox2 expression to reduce the proliferation of neural progenitor cells. In addition, the expression of foxm1, a putative target gene of Etv5a and a direct upstream transcription factor of sox2, was upregulated in Etv5a-deficient embryos. Moreover, the suppression of Foxm1 function by the foxm1 dominant-negative construct nullified the phenotype of upregulated sox2 expression caused by Etv5a deficiency. Overall, our results indicated that Etv5a regulates the expression of sox2 via direct binding to the sox2 promoter and indirect regulation by inhibiting foxm1 expression. Hence, we revealed the role of Etv5a in the transcriptional hierarchy that regulates the proliferation of neural progenitor cells.

Middle cerebral artery infarction, A rare complication of intracranial cryptococcoma in an immunocompetent patient: A case report and literature review.

Background: This report presents the first case of intracranial cryptococcoma arising from the right frontal lobe causing right middle cerebral artery infarction. Intracranial cryptococcomas usually occur in the cerebral parenchyma, basal ganglia, cerebellum, pons, thalamus, and choroid plexus; they may mimic intracranial tumors, but seldom cause infarction. Of the 15 cases of pathology-confirmed intracranial cryptococcomas in the literature, no case has been complicated by middle cerebral artery (MCA) infarction. Here, we discuss a case of intracranial cryptococcoma with an ipsilateral middle cerebral artery infarction. Case Description: A 40-year-old man was referred to our emergency room due to progressive headaches and acute left hemiplegia. The patient was a construction worker with no history of avian contact, recent travel, or human immunodeficiency virus (HIV) infection. Brain computed tomography (CT) showed an intra-axial mass, and subsequent magnetic resonance imaging (MRI) delineated a large mass of 53 mm in the right middle frontal lobe and a small lesion of 18 mm in the right caudate head, with marginal enhancement and central necrosis. A neurosurgeon was consulted in view of the intracranial lesion, and the patient underwent en-bloc excision of the solid mass. The pathology report later identified a Cryptococcus infection rather than malignancy. The patient underwent 4 weeks of postoperative treatment with amphotericin B plus flucytosine; he then received subsequent oral antifungal treatment for 6 months, and had neurologic sequelae that manifested as left side hemiplegia. Conclusion: Diagnosis of fungal infections in the CNS remains challenging. This is especially true of Cryptococcus CNS infections that present as a space-occupying lesion in an immunocompetent patient. A Cryptococcus infection should be considered in the differential diagnoses in patients with brain mass lesions, as this infection can be misdiagnosed as a brain tumor.

Correlation between initial tumor enlargement and magnetic resonance imaging characteristics following linear accelerator-based stereotactic radiosurgery for acoustic neuromas.

BACKGROUND: 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. MATERIALS AND METHODS: 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. RESULTS: 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 cm3 had a lower incidence of initial enlargement (p = 0.039). No correlation was noted between the initial enlargement and morphological characteristics of tumors. In patients with a mean follow-up duration of 82.8 ± 37.2 months, heterogeneously enhanced tumors exhibited a lower control rate than homogeneously enhanced and cystic tumors (p = 0.045). No correlation was noted between initial enlargement and tumor control. CONCLUSION: Initial enlargement can occur as early as 3 months after SRS. Postoperative residual tumors with a volume lower than 2.5 cm3 exhibit a lower incidence of initial enlargement. Heterogeneously enhanced tumors have a lower local control rate.

Outcome predictors and clinical presentation of syringomyelia.

BACKGROUND: The prognosis of syringomyelia is not yet established. Syringomyelia derived from different etiologies contributes to similar symptoms. OBJECTIVE: Assess the syringomyelia in our medical institutes and describe the etiologies and clinical appearance of the disorder. And identify the predictors of a good outcome and to find the most suitable timing of surgical intervention according to our results. METHODS: This retrospective cohort study used databases in our hospitals to analyze 70 cases of syringomyelia between 1997 and 2014. All available information was obtained from medical records and radiological reports. We used American Spinal Injuries Association disability scores (ASIA scores), the modified Nurick classification system, and recorded the number of days the patient was hospitalized, for neurological and functional assessment. Univariate and multivariate analyses were used to evaluate the relationship between clinical factors and outcomes. RESULTS: Non-communicating syringomyelia was the most common type of syringomyelia. In univariate analysis, autonomic dysfunction and motor impairment were strong predictors of poor neurological and functional outcomes. In addition to the above factors, syrinxes at the cervical level predicted better functional outcomes than at any spinal level in multivariate analysis. CONCLUSIONS: Motor impairment, which is commonly seen in patients with syringomyelia in Taiwan, is a strong predictor to poor neurological and functional outcomes. Our study indicates that patients without autonomic dysfunction or motor impairment should receive timely surgical intervention to prevent symptomatic deterioration. We also found that cervical syringomyelia in particular has the potential for good functional recovery after adequate intervention.

Gross Total Resection Promotes Subsequent Recovery and Further Enhancement of Impaired Natural Killer Cell Activity in Glioblastoma Patients.

Glioblastoma is the most common primary malignant brain tumor, and median survival is relatively short despite aggressive standard treatment. Natural killer (NK) cell dysfunction is strongly associated with tumor recurrence and metastasis but is unclear in glioblastoma. NK activity (NKA) represents NK cell-secreted interferon-γ (IFN-γ), which modulates immunity and inhibits cancer progression. This study aimed to analyze NKA in glioblastoma patients to obtain a clearer overview of immunity surveillance. From 2020 to 2021, a total of 20 patients and six healthy controls were recruited. Peripheral blood samples were collected preoperatively and on postoperative days (POD) 3 and 30. Then, NKA was measured using the NK VUE kit. Although NKA decreased on POD3, it recovered and further significantly enhanced on POD30, with a nearly five-fold increase compared to baseline (p = 0.004). Furthermore, the percentage of CD56brightCD16- NK cells decreased significantly on POD3 (p = 0.022) and further recovered on PO30. Subgroup analysis of extent surgical resection further revealed that the recovery of impaired NKA was attributable to gross total resection (GTR) rather than subtotal resection (STR). In conclusion, NKA is significantly impaired in glioblastoma, and GTR has demonstrated superior benefit in improving the suppressed NKA and increased CD56brightCD16- NK subset in glioblastoma patients, which may be associated with subsequent patients' prognosis. Therefore, the goal of performing GTR for glioblastoma should be achieved when possible since it appears to increase NKA cell immunity.

Photo-Crosslinked Hyaluronic Acid/Carboxymethyl Cellulose Composite Hydrogel as a Dural Substitute to Prevent Post-Surgical Adhesion.

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.

A manzamine-derived compound as a potential therapeutic agent for glioma by inducing apoptosis and cell cycle arrest.

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-ß-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.

Spinal cord injury and spinal fracture in patients with ankylosing spondylitis.

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 < 0.001) and more cases of spinal epidural hematoma (SEH; 21.7% vs. 2.2%; 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.

Neuropsychological performances in patients with infiltrative non-GBM gliomas after postoperative adjuvant photon or proton radiotherapy: A prospective and preliminary investigation.

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 (Z = -2.722, p = .006, regarding verbal memory; Z = -2.246, p = .025, concerning non-verbal memory). Moreover, patients' neuropsychological performances associated with psychomotor speed and executive functions also disclosed a tendency toward stabilization/improvement.This prospective study demonstrated that patients with infiltrative non-GBM exhibited a marked tendency toward neurocognitive stabilization after receiving postoperative adjuvant RT. Clinical trial registration: Trial Registration with ClinicalTrials.gov identifier: NCT03534050.

Co-Delivery of Docosahexaenoic Acid and Brain-Derived Neurotropic Factor from Electrospun Aligned Core-Shell Fibrous Membranes in Treatment of Spinal Cord Injury.

To restore lost functions while repairing the neuronal structure after spinal cord injury (SCI), pharmacological interventions with multiple therapeutic agents will be a more effective modality given the complex pathophysiology of acute SCI. Toward this end, we prepared electrospun membranes containing aligned core-shell fibers with a polylactic acid (PLA) shell, and docosahexaenoic acid (DHA) or a brain-derived neurotropic factor (BDNF) in the core. The controlled release of both pro-regenerative agents is expected to provide combinatory treatment efficacy for effective neurogenesis, while aligned fiber topography is expected to guide directional neurite extension. The in vitro release study indicates that both DHA and BDNF could be released continuously from the electrospun membrane for up to 50 days, while aligned microfibers guide the neurite extension of primary cortical neurons along the fiber axis. Furthermore, the PLA/DHA/BDNF core-shell fibrous membrane (CSFM) provides a significantly higher neurite outgrowth length from the neuron cells than the PLA/DHA CSFM. This is supported by the upregulation of genes associated with neuroprotection and neuroplasticity from RT-PCR analysis. From an in vivo study by implanting a drug-loaded CSFM into the injury site of a rat suffering from SCI with a cervical hemisection, the co-delivery of DHA and BDNF from a PLA/DHA/BDNF CSFM could significantly improve neurological function recovery from behavioral assessment, as well as provide neuroprotection and promote neuroplasticity changes in recovered neuronal tissue from histological analysis.

Maintenance of multi-domain neurocognitive functions in patients with newly-diagnosed primary CNS lymphoma after primary cranial radiotherapy combined with methotrexate-based chemotherapy: A preliminary case-series study.

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.

Predictive Value of Swab Cultures for Cryopreserved Flaps During Delayed Cranioplasties.

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.

The surgical strategy for multilevel massive ossification of the posterior longitudinal ligaments.

Purpose: Creating enough decompression, favorable outcome, less complication, and maintain adequate lordosis and stability in the patients with cervical myelopathy due to multilevel massive ossification of the posterior longitudinal ligament (OPLL) still poses a challenge for surgeons. The aim of our study is to retrospectively evaluate our patients and try to seek a better surgical strategy. Methods: Between 2015 and 2019, 55 consecutive patients with multilevel massive OPLL underwent surgical treatment. Among these, 40 patients were treated with cervical laminectomy and then anterior decompression, fusion, and fixation (ADF), which was defined as group 1, and 15 patients were treated with cervical laminectomy and fixation simultaneously, which was defined as group 2. The patient's radiographic characteristics and postoperative outcomes were evaluated. Results: Better postoperative cervical sagittal lordosis and less long-term axial pain was achieved in group 1 (p < 0.001), though the functional outcome had no significant difference. In the multivariable analysis, anterior fixation accounts for independent factors for better cervical sagittal alignment (p < 0.001). No complications directly associated with cervical laminectomy were observed. Conclusion: In patients with cervical multilevel massive OPLL, laminectomy at compression level and then ADF depended on the severity and range of compression, but corpectomy of not more than two vertebral bodies is suggested, except K-line (+) and long-segment massive OPLL majorly involving the C2 and posterior laminectomy above and below the OPLL-affected levels with posterior fixation simultaneously.

RGS2 Suppresses Melanoma Growth via Inhibiting MAPK and AKT Signaling Pathways.

BACKGROUND/AIM: This study aimed to explore RGS2 as a regulator of melanoma cell growth. MATERIALS AND METHODS: Effect of RGS2 over-expression was analyzed in three melanoma cell lines, and Rgs2 knockdown was performed in zebrafish. RESULTS: 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. CONCLUSION: 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.

Chromatin accessibility analysis identifies GSTM1 as a prognostic marker in human glioblastoma patients.

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.

PLA2G6 mutations cause motor dysfunction phenotypes of young-onset dystonia-parkinsonism type 14 and can be relieved by DHA treatment in animal models.

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.

Incidence and Factors Associated with Postoperative Delayed Hyponatremia after Transsphenoidal Pituitary Surgery: A Meta-Analysis and Systematic Review.

INTRODUCTION: Postoperative delayed hyponatremia is a complication associated with transsphenoidal pituitary surgery. Due to a wide spectrum of symptoms, the reported incidence and predictors of postoperative delayed hyponatremia vary among studies, and this deserves to be reviewed systematically. METHODS: PubMed, EMBASE, and CENTRAL databases were searched until September 1, 2020. Studies were included when (1) the event number of delayed hyponatremia after transsphenoidal pituitary surgery was reported, or (2) the associated factors of such complication were evaluated. RESULTS: A total of 27 studies were included for meta-analysis. The pooled incidence of overall and symptomatic delayed hyponatremia was 10.5% (95% confidence interval (CI) = 7.4-14.7%) and 5.0% (95% CI = 3.6-6.9%), respectively. No overt variations of the pooled estimates were observed upon subgroups stratified by endoscopic and microscopic procedure, publication year, and patients' age. In addition, 44.3% (95% CI = 29.6-60.2%) of unplanned hospital readmissions within 30 days were caused by delayed hyponatremia. Among the predictors evaluated, older age was the only significant factor associated with increased delayed hyponatremia (odds ratio = 1.16, 95% CI = 1.04-1.29, P = 0.006). CONCLUSION: This meta-analysis and systematic review evaluated the incidence of postoperative delayed hyponatremia and found it as a major cause of unplanned readmissions after transsphenoidal pituitary surgery. Older patients are more prone to such complications and should be carefully followed. The retrospective nature and heterogeneity among the included studies and the small number of studies used for risk factor evaluation might weaken the corresponding results. Future prospective clinical studies are required to compensate for these limitations.

Resting-State Functional Connectivity and Brain Network Abnormalities in Depressive Patients with Suicidal Ideation.

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.