Tubridge flow diverter for the treatment of small and medium aneurysms.

Background: Tubridge flow diverter is a widely used device aimed at reconstructing parent arteries and occluding complex aneurysms in China. The experience of Tubridge in treating small and medium aneurysms is still limited. In this study, we aimed to evaluate the safety and efficacy of the Tubridge flow diverter for the treatment of the two types of aneurysms. Methods: We reviewed the clinical records of aneurysms treated with a Tubridge flow diverter between 2018 and 2021 in a national cerebrovascular disease center. Cases were divided into small and medium aneurysms according to aneurysm size. The therapeutic process, occlusion rate, and clinical outcome were compared. Results: In total, 57 patients and 77 aneurysms were identified. The patients were divided into two groups: small aneurysms (39 patients, 54 aneurysms) and medium aneurysms (18 patients, 23 aneurysms). There were 19 patients with tandem aneurysms (a total of 39 aneurysms) in the two groups, among which 15 patients (30 aneurysms) were in the small aneurysm group and four patients (nine aneurysms) were in the medium aneurysm group. The results show that the mean maximal diameter/neck in the small and medium aneurysms was 3.68/3.25 and 7.61/6.24 mm, respectively. In total, 57 Tubridge flow diverters were successfully implanted without unfolding failure, and there were six patients with new mild cerebral infarction in the small aneurysm group. The complete occlusion rate on the last angiographic follow-up was achieved in 88.46% of the small aneurysms group and 81.82% of the medium aneurysms group. The complete occlusion rate of patients with tandem aneurysms in the last angiographic follow-up was 86.67% (13/15) of the small aneurysms group and 50% (2/4) of the medium aneurysm group. Intracranial hemorrhage was nonencountered in the two groups. Conclusion: Our preliminary experience suggests that the Tubridge flow diverter might be a safe and effective treatment for small and medium aneurysms along the internal carotid artery. Long stents may increase the risk of cerebral infarction. Adequate evidence is required to clarify the definite indications and complications in a multicenter randomized controlled trial with a long-term follow-up.

Tubridge Flow Diverter for the Treatment of Unruptured Dissecting Cerebral Aneurysms.

BACKGROUND: The Tubridge flow diverter is a device widely used in China aimed at reconstructing parent artery and occluding complex aneurysm. The experience of the Tubridge in treating unruptured vertebrobasilar artery dissecting aneurysms is still limited. In this study, we aimed to evaluate the safety and efficacy of the Tubridge flow diverter for the treatment of vertebrobasilar artery dissecting aneurysms. METHODS: We reviewed the clinical records of aneurysms treated with the Tubridge flow diverter between 2019 and 2021 in a national cerebrovascular disease center. Therapeutic process, occlusion rate, and clinical outcome were compared. RESULTS: Twenty-three patients with 23 vertebrobasilar artery aneurysms were identified. The results showed that the mean length and mean maximal width were 15.14 and 9.14 mm, respectively, in the vertebrobasilar artery. Twenty-four Tubridge flow diverters were successfully implanted without unfold failure. A complete occlusion rate at the last angiographic follow-up was achieved in 78.26% of vertebrobasilar artery aneurysms. Fifteen branch arteries were covered, and only 1 branch artery disappeared at follow-up. Mild asymptomatic cerebral infarction occurred in 3 patients (13.04%); intracranial hemorrhage was not found in the patients. CONCLUSIONS: Our preliminary experience suggests that the Tubridge flow diverter might be a safe and effective tool for dissecting cerebral aneurysms. Branch arteries were well protected and mild asymptomatic cerebral infarction occurred in some patients. Adequate evidence is required to clear the definite indications and complications in a multicenter randomized controlled trial with a long-term follow-up.

Proton pump inhibitors-induced psychiatric symptoms.

Proton pump inhibitors are widely used in cure of digestive tract diseases and drug-induced psychiatric symptoms are rare. In this study, we aim to investigate the presentations, diagnostic approaches, treatments and prognosis. We present one case of proton pump inhibitors-induced motor hallucination underwent drug withdrawal and recovery subsequently. Delirium Rating Scale and Hamilton Anxiety Scale examinations showed transient delirium and anxiety. Proton pump inhibitors-induced psychiatric symptoms are benign and affect patients' prognosis. No standard treatment exists, and the strategies contain discontinuing proton pump inhibitors and/or antipsychotics drugs. Overall prognosis is usually good and recurrence seems to be rare.

A novel NF2 splicing mutant causes neurofibromatosis type 2 via liquid-liquid phase separation with large tumor suppressor and Hippo pathway.

Neurofibromatosis type 2 is an autosomal dominant multiple neoplasia syndrome and is usually caused by mutations in the neurofibromin 2 (NF2) gene, which encodes a tumor suppressor and initiates the Hippo pathway. However, the mechanism by which NF2 functions in the Hippo pathway isn't fully understood. Here we identified a NF2 c.770-784del mutation from a neurofibromatosis type 2 family. MD simulations showed that this mutation significantly changed the structure of the F3 module of the NF2-FERM domain. Functional assays indicated that the NF2 c.770-784del variant formed LLPS in the cytoplasm with LATS to restrain LATS plasma membrane localization and inactivated the Hippo pathway. Besides, this deletion partly caused a skipping of exon 8 and reduced the protein level of NF2, collectively promoting proliferation and tumorigenesis of meningeal cells. We identified an unrecognized mechanism of LLPS and splicing skipping for the NF2-induced Hippo pathway, which provided new insight into the pathogenesis of neurofibromatosis type 2.

Mesenteric Panniculitis Can Be Diagnosed by Examination and Cured by Comprehensive Therapy.

Mesenteric panniculitis is a rare, slowly progressive, benign, and chronic fibrous inflammatory disease that affects the adipose tissue of the mesentery. In the present study, we aim to investigate its clinical presentations, computed tomography/sonography scan features, effectiveness of the treatment, and overall prognosis. We investigated various presentations, etiologies, diagnostic approaches, potential treatment modalities, and overall prognosis of mesenteric panniculitis. We present one case of mesenteric panniculitis with abdominal pain, which underwent steroid treatment regimens subsequently and gained weight moderately. An abdomen and pelvis cavity computed tomography scan showed misty mesentery, an ill-defined increase in the density of the peritoneal fat at the base of the mesentery with few small associated lymph nodes. The appearance is that of a panniculitis. His symptoms gradually decreased in intensity and disappeared totally within 1 month after oral prednisone 40 mg per day and moderate gain weight. Computed tomography scan features of the disease have recently been delineated clearly. Standard treatment strategy does not exist, and the current ways mainly consist of immunosuppressor or anti-inflammation agents. Overall prognosis is usually good and recurrence seems to be rare.

Targeting the TR4 nuclear receptor with antagonist bexarotene can suppress the proopiomelanocortin signalling in AtT-20 cells.

Drug options for the life-threatening Cushing's disease are limited, and surgical resection or radiation therapy is not invariably effective. Testicular receptor 4 (TR4) has been identified as a novel drug target to treat Cushing's disease. We built the structure model of TR4 and searched the TR4 antagonist candidate via in silico virtual screening. Bexarotene was identified as an antagonist of TR4 that can directly interact with TR4 ligand binding domain (TR4-LBD) and induces a conformational change in the secondary structure of TR4-LBD. Bexarotene suppressed AtT-20 cell growth, proopiomelanocortin (POMC) expression and adrenocorticotropin (ACTH) secretion. Mechanism dissection revealed that bexarotene could suppress TR4-increased POMC expression via promoting the TR4 translocation from the nucleus to the cytoplasm. This TR4 translocation might then result in reducing the TR4 binding to the TR4 response element (TR4RE) on the 5' promoter region of POMC. Results from in vivo mouse model also revealed that oral bexarotene administration markedly suppressed ACTH-secreting tumour growth, adrenal enlargement and the secretion of ACTH and corticosterone in mice with already established tumours. Together, these results suggest that bexarotene may be developed as a potential novel therapeutic drug to better suppress Cushing's disease.

Single Versus Double Burr Hole Craniostomy in Surgical Treatment of Chronic Subdural Hematoma: A Meta-Analysis.

BACKGROUND: Chronic subdural hematoma (cSDH) is one of the most common illnesses seen in neurosurgery departments worldwide. For surgical treatment, some neurosurgeons prefer single burr hole craniostomy (SBHC), whereas others prefer double burr hole craniostomy (DBHC). We performed a meta-analysis to investigate whether DBHC is associated with increased risks of recurrence, complications and mortality compared with SBHC in patients with cSDH. METHODS: Retrospective observational trial or randomized controlled trial (RCT) studies concerning burr hole craniostomy to treat cSDH were systematically identified through a search of electronic databases: PubMed, Web of Science, Embase, and Cochrane. Inclusion and exclusion criteria were defined for the eligible studies. The random fixed-effects model was used when heterogeneity was indicated; otherwise, a fixed-effects model was adopted. RESULTS: This meta-analysis included 12 studies, 3 of which were RCTs. Our findings can be summarized as follows. First, SBHC did not increase the risk of recurrence compared with DBHC in patients with cSDH (odds ratio [OR], 1.28; 95% confidence interval [CI], 0.92-1.78; P =0.07). Second, DBHC was not associated with an increased complication rate compared with SBHC in patients with cSDH (OR, 0.74; 95% CI, 0.20-2.76; P = 0.11). Third, DBHC did not increase mortality compared with SBHC in patients with cSDH (OR, 1.38; 95% CI, 0.55-3.46; P = 0.58). CONCLUSIONS: This meta-analysis demonstrates that there are no significant differences in recurrence rate, complication rate, and morbidity between SBHC and DBHC in the treatment of patients with cSDH.

The Comparison Between Surgical Procedure and Conservative Treatment in the Management of Traumatic Subdural Effusion.

AIM: Traumatic subdural effusion (TSE) occurs following traumatic brain injury and may be treated by either conservative methods or surgical procedure commonly according to the patients' clinical information. We aimed to compare the effective rate of effusion removal and the standardized morbidity ratio of poor prognosis of the two different treatments, and to discuss the future treatment methods possible. MATERIAL AND METHODS: We reviewed the clinical records of patients who were divided into two groups according to the treatment choices in our center, and the effective rate of effusion removal and the standardized morbidity ratio of poor prognosis were compared. RESULTS: Eighty patients were identified, and divided into two groups: conservative treatment and surgical procedure group. The mean CRASH-CT predicted risk of mortality in two weeks and unfavorable outcome at six months was higher in the surgical procedure group compared with the conservative treatment group. Effective rate of effusion removal was observed in 57.1 % of conservative treatment group versus 88.5% of surgical procedure group (p=0.002). The standardized morbidity ratio of poor prognosis (observed/expected poor prognosis) was 0.56 (95 % CI: 0.32-0.80) for the conservative treatment group versus 0.25 (95 % CI: 18 0.08-0.42) for the surgical procedure group. CONCLUSION: Conservative treatment and surgical procedure are used for the management of traumatic subdural effusion, and the former is used more commonly to treat the mildly affected patients than the latter one, but a surgical procedure may be more effective for the patients in poor clinical condition. Adequate evidence is required to clear the indications.

Clinical characteristics of 15 cases of chronic subdural hematomas due to spontaneous intracranial hypotension with spinal cerebrospinal fluid leak.

The etiology of chronic subdural hematoma (CSDH) in patients is diverse. The primary objective of this article was to discuss one of the causes, spontaneous intracranial hypotension with spinal cerebrospinal fluid (CSF) leak, which is usually neglected by the neurosurgeon. All the consecutive 15 patients who underwent operation for CSDHs between June 2012 and June 2014 at Sir Run Run Shaw Hospital of Zhejiang University were included in this retrospective cohort study. The clinical and imaging data of these patients with CSDHs due to spinal CSF leak were retrospectively studied. Fifteen patients, with a mean age of 53.8 ± 8.3 years, underwent operations for CSDH. Hematomas were unilateral in 4 patients and bilateral in 11 patients. Among these patients, eight patients had recurrence of hematomas after operation due to neglect of spinal CSF leak. All patients had fully recovery. Spinal CSF leak is a cause of cSDH, which is overlooked by the doctor.

Norcantharidin blocks Wnt/ß-catenin signaling via promoter demethylation of WIF-1 in glioma.

Glioma is one of the most common primary intracranial tumors, and the prognosis is poor even though much treatment management is employed. Wnt/ß-catenin signaling has been reported to be associated with glioma. Norcantharidin (NCTD) is the demethylated analog of cantharidin isolated from blister beetles, and it is reported to possess anticancer activity but less nephrotoxicity than cantharidin. Accordingly, we aimed to investigate NCTD as an anti-neoplastic drug that inhibits the Wnt/ß­catenin pathway via promoter demethylation of Wnt inhibitory factor-1 (WIF-1) in glioma growth in vitro. In the present study, we report that NCTD inhibited cell proliferation, induced apoptosis and cell cycle arrest, and suppressed cell migration and invasion in vitro. Moreover, we observed that the expression levels of WIF-1 mRNA and protein in the NCTD-treated cells were increased significantly compared with these levels in the negative control (NC) cells. Promoter demethylation was observed in the NCTD­treated cells. In contrast, aberrant methylation was observed in the NC cells. Additionally, more investigation revealed that NCTD suppressed activity of Wnt/ß-catenin signaling and transcription of ß-catenin/TCF-4. Furthermore, the expression of apoptosis-related proteins Bcl-2 and cleaved caspase-3 indicated significant cell apoptosis. We provide initial evidence that NCTD reactivates WIF-1 from a methylation state, and downregulates canonical Wnt/ß-catenin signaling. Our findings revealed that NCTD is effective for glioma in vitro and may be a new therapeutic option in vivo.

Neuroendocrine dysfunction and insomniain in mild traumatic brain injury patients.

Mild traumatic brain injury (mTBI) has been a growing public health concern in the worldwide. To investigate the subjective and objective characteristics of insomnia following mTBI and the association between insomnia and hypothalamic-pituitary-adrenal (HPA) function of mTBI patients, 59 patients with mTBI (mTBI group) were compared with 50 healthy participants (control group) in the present study. The subjective and objective measures of insomnia were respectively obtained from Pittsburgh Sleep Quality (PSQI) and polysomnography (PSG). HPA function was measured with low-dose short synacthen test (LDSST). According to the comparative and correlation analysis of the two groups, for PSQI, the scores of sleep syndrome, sleep latency, sleep efficiency, overall sleep quality and daytime dysfunction of mTBI patients were all higher, however only sleep efficiency and daytime dysfunction of mTBI patients were related with peak cortisol on lDSST; while for PSG, sleep efficiency (SE) was lower and wake after sleep onset (WASO) was longer in mTBI patients, moreover SE and WASO of mTBI patients were correlated with peak cortisol on LDSTT; for HPA function indexes, only peak cortisol on LDSST was lower in mTBI patients. These findings suggested that mTBI patients experienced more serious subjective insomnia symptoms than objective measurement, which were associated with HPA dysfunction. This study may contribute to identifying better treatment for mTBI patients with insomnia.

DNMT1 mediates chemosensitivity by reducing methylation of miRNA-20a promoter in glioma cells.

Although methyltransferase has been recognized as a major element that governs the epigenetic regulation of the genome during temozolomide (TMZ) chemotherapy in glioblastoma multiforme (GBM) patients, its regulatory effect on glioblastoma chemoresistance has not been well defined. This study investigated whether DNA methyltransferase (DNMT) expression was associated with TMZ sensitivity in glioma cells and elucidated the underlying mechanism. DNMT expression was analyzed by western blotting. miR-20a promoter methylation was evaluated by methylation-specific PCR. Cell viability and apoptosis were assessed using the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) and TdT-mediated dUTP-biotin nick end labeling assays, respectively. The results showed that compared with parental U251 cells, DNMT1 expression was downregulated, miR-20a promoter methylation was attenuated and miR-20a levels were elevated in TMZ-resistant U251 cells. Methyltransferase inhibition by 5-aza-2'-deoxycytidine treatment reduced TMZ sensitivity in U251 cells. In U251/TM cells, DNMT1 expression was negatively correlated with miR-20a expression and positively correlated with TMZ sensitivity and leucine-rich repeats and immunoglobulin-like domains 1 expression; these effects were reversed by changes in miR-20a expression. DNMT1 overexpression induced an increase in U251/TM cell apoptosis that was inhibited by the miR-20a mimic, whereas DNMT1 silencing attenuated U251/TM cell apoptosis in a manner that was abrogated by miR-20a inhibitor treatment. Tumor growth of the U251/TM xenograft was inhibited by pcDNA-DNMT1 pretreatment and boosted by DNMT1-small hairpin RNA pretreatment. In summary, DNMT1 mediated chemosensitivity by reducing methylation of the microRNA-20a promoter in glioma cells.

MiR-27a regulates Wnt/beta-catenin signaling through targeting SFRP1 in glioma.

Glioma is one of the most common intracranial tumors, and the prognosis is poor, although more and more treatments are employed. Wnt/beta-catenin signaling has been reported to be associated with glioma. SFRP1 acts as an antagonist and inhibits Wnt signaling by binding to Wnt molecules. In the present study, we aimed to investigate miRNA-27a as an antineoplastic factor that inhibits the Wnt/beta-catenin pathway by binding to the SFRP1 3'-UTR in glioma in vitro. We first showed that the expression of miR-27a was elevated in both glioma samples and cell lines. Furthermore, downregulation of miR-27a induced growth inhibition, cycle arrest, and apoptosis, and suppressed invasion/migration in glioma cell lines. Quantitative real-time PCR, western blot, and luciferase assay analysis showed that SFRP1 is a direct target of miR-27a. Overexpression of SFRP1 inhibited the malignancy of glioma cell lines. Our investigation showed that downregulation of miR-27a suppressed beta-catenin/TCF-4 transcription activity by targeting SFRP1. Our findings identify a role for miR-27a in glioma cell viability, cycle, apoptosis, and invasion/migration after activation of Wnt/beta-catenin signaling through SFRP1.

miR-20a mediates temozolomide-resistance in glioblastoma cells via negatively regulating LRIG1 expression.

AIMS: Resistance to temozolomide (TMZ) is a major obstacle in the treatment of glioblastoma multiforme (GBM). MiRNAs is considered as an important modulator of drug resistance in many cancers. Here, we aimed to elucidate the relationship between miR-20a, its predicted target genes leucine-rich repeats and immunoglobulin-like domains 1 (LRIG1) and TMZ resistance in GBM. MAIN METHODS: Real-time PCR or western blot was used to measure the levels of miR-20a and LRIG1. The cell viability was obtained to investigate the sensitivity of U251 cells and TMZ-resistant U251 (U251/TMZ) cells to TMZ. MiR-20a inhibitor or miR-20a mimic was used to down-regulate or up-regulate miR-20a expression. The interaction between miR-20a and its predicted target gene LRIG1 was confirmed by 3'-UTR dual-luciferase reporter assay. pcDNA-LRIG1 was used to overexpress LRIG1 [corrected]. A xenograft tumor model was used to investigate the in vivo antitumor activity. KEY FINDINGS: MiR-20a was highly expressed and LRIG1 lowly expressed in U251/TMZ cells. Knockdown of miR-20a by treatment with miR-20a inhibitor restored sensitivity of U251/TM cells to TMZ in vivo and in vitro, whereas overexpression of miR-20a by treatment with miR-20a mimic resulted in increased TMZ resistance. The levels of LRIG1 were inversely related to miR-20a levels. And the luciferase reporter assays showed that miR-20a directly targeted the 3'UTR of LRIG1. In addition, functional knock-down of LRIG1 by gene specific siRNA reversed the effect of miR-20a inhibitor. SIGNIFICANCE: MiR-20a mediated TMZ-resistance in glioblastoma cells through negatively regulating LRIG1 expression, which suggesting that miR-20a and LRIG1 would be potential therapeutic targets for glioma therapy.

LRIG1 dictates the chemo-sensitivity of temozolomide (TMZ) in U251 glioblastoma cells via down-regulation of EGFR/topoisomerase-2/Bcl-2.

In the current study, we aimed to understand the potential role of leucine-rich repeats and immunoglobulin-like domains 1 (LRIG1) in TMZ-resistance of U251 glioma cells. We established TMZ-resistant U251 clones (U251/TMZ cells), which expressed low level of LRIG1, but high levels of epidermal growth factor receptor (EGFR), topoisomerase-2 (Topo-2) and Bcl-2. Depletion of LRIG1 by the targeted RNA interference (RNAi) upregulated EGFR/Topo-2/Bcl-2 in U251 cells, and the cells were resistant to TMZ. Reversely, over-expression of LRIG1 in U251 cells downregulated EGFR/Topo-2/Bcl-2 expressions, and cells were hyper-sensitive to TMZ. Our data suggested EGFR-dependent mammalian target of rapamycin (mTOR) activation was important for Topo-2 and Bcl-2 expressions in U251/TMZ cells. The EGFR inhibitor and the mTOR inhibitor downregulated Topo-2/Bcl-2 expressions, both inhibitors also restored TMZ sensitivity in U251/TMZ cells. Finally, inhibition of Topo-2 or Bcl-2 by targeted RNAi(s) knockdown or by the corresponding inhibitor re-sensitized U251/TMZ cells to TMZ, indicating that both Topo-2 and Bcl-2 were important for TMZ resistance in the resistant U251 cells. Based on these results, we concluded that LRIG1 inhibits EGFR expression and the downstream signaling activation, interferes with Bcl-2/Topo-2 expressions and eventually sensitizes glioma cells to TMZ.