Pathophysiology characterization of Alzheimer's disease in South China's aging population: for the Greater-Bay-Area Healthy Aging Brain Study (GHABS).

INTRODUCTION: The Guangdong-Hong Kong-Macao Greater-Bay-Area of South China has an 86 million population and faces a significant challenge of Alzheimer's disease (AD). However, the characteristics and prevalence of AD in this area are still unclear due to the rarely available community-based neuroimaging AD cohort. METHODS: Following the standard protocols of the Alzheimer's Disease Neuroimaging Initiative, the Greater-Bay-Area Healthy Aging Brain Study (GHABS) was initiated in 2021. GHABS participants completed clinical assessments, plasma biomarkers, genotyping, magnetic resonance imaging (MRI), ß-amyloid (Aß) positron emission tomography (PET) imaging, and tau PET imaging. The GHABS cohort focuses on pathophysiology characterization and early AD detection in the Guangdong-Hong Kong-Macao Greater Bay Area. In this study, we analyzed plasma Aß42/Aß40 (A), p-Tau181 (T), neurofilament light, and GFAP by Simoa in 470 Chinese older adults, and 301, 195, and 70 had MRI, Aß PET, and tau PET, respectively. Plasma biomarkers, Aß PET, tau PET, hippocampal volume, and temporal-metaROI cortical thickness were compared between normal control (NC), subjective cognitive decline (SCD), mild cognitive impairment (MCI), and dementia groups, controlling for age, sex, and APOE-ε4. The prevalence of plasma A/T profiles and Aß PET positivity were also determined in different diagnostic groups. RESULTS: The aims, study design, data collection, and potential applications of GHABS are summarized. SCD individuals had significantly higher plasma p-Tau181 and plasma GFAP than the NC individuals. MCI and dementia patients showed more abnormal changes in all the plasma and neuroimaging biomarkers than NC and SCD individuals. The frequencies of plasma A+/T+ (NC; 5.9%, SCD: 8.2%, MCI: 25.3%, dementia: 64.9%) and Aß PET positivity (NC: 25.6%, SCD: 22.5%, MCI: 47.7%, dementia: 89.3%) were reported. DISCUSSION: The GHABS cohort may provide helpful guidance toward designing standard AD community cohorts in South China. This study, for the first time, reported the pathophysiology characterization of plasma biomarkers, Aß PET, tau PET, hippocampal atrophy, and AD-signature cortical thinning, as well as the prevalence of Aß PET positivity in the Guangdong-Hong Kong-Macao Greater Bay Area of China. These findings provide novel insights into understanding the characteristics of abnormal AD pathological changes in South China's older population.

A novel pathogenic variant in TDP2 causes spinocerebellar ataxia autosomal recessive 23 accompanied by pituitary tumor and hyperhidrosis: a case report.

TDP2 gene encodes tyrosyl DNA phosphodiesterase 2, an enzyme required for effective repair of the DNA double-strand breaks (DSBs). Spinocerebellar ataxia autosomal recessive 23 (SCAR23) is a rare disease caused by the pathogenic mutation of TDP2 gene and characterized by intellectual disability, progressive ataxia and refractory epilepsy. Thus far, merely nine patients harboring five different variants (c.425 + 1G > A; c.413_414delinsAA, p. Ser138*; c.400C > T, p. Arg134*; c.636 + 3_ 636 + 6 del; c.4G > T, p. Glu2*) in TDP2 gene have been reported. Here, we describe the tenth patient with a novel variant (c.650del, p. Gly217GlufsTer7) and new phenotype (pituitary tumor and hyperhidrosis).

Scalp ripple rates for rapid epilepsy differentiation and seizure activity assessment: Applicability and influential factors.

OBJECTIVE: We aim to determine whether automatically detected ripple rate (ADRR) of 10-min scalp electroencephalography (EEG) during slow-wave sleep can be a useful tool for rapid epilepsy differentiation and seizure activity assessment, and we analyze the clinical factors that may affect the scalp ripple rates. METHODS: We retrospectively included 336 patients who underwent long-term video-EEG with a sampling rate ≥1000 Hz, and three groups were established based on their final clinical diagnosis (non-epilepsy; non-active epilepsy [epilepsy being seizure-free for at least 1 year]; and active epilepsy [epilepsy with one or more seizures in the past year]). ADRRs between groups were compared and diagnostic thresholds set according to the maximum of Youden index with the receiver-operating characteristic curve. RESULTS: The 336 patients comprised 49 non-epilepsy and 287 epilepsy patients (95 non-active epilepsy and 192 active epilepsy). The median ADRR of the epilepsy group was significantly greater than in the non-epilepsy group, with a diagnostic threshold of 4.25 /min (specificity 89.8%, sensitivity 47.74%, p<.001). Following stratification by age, the area under the curve was greatest in the 0-20 year subgroup, threshold 4.10 /min (specificity 100%, sensitivity 52.47%, p<.001). Regarding distinguishing active epilepsy from non-active epilepsy patients, the area under the curve was also greatest in patients 0-20 years of age, threshold 13.05/min (specificity 98.36%, sensitivity 35.64%, p<.001). Following stratification by epilepsy type, the diagnostic efficiency was best in children with developmental and epileptic encephalopathies/epileptic encephalopathies (DEEs/EEs) (threshold 5.20/min, specificity 100%, sensitivity 100%) and self-limited focal epilepsies (SeLFEs) (threshold 5.45/min, specificity 80%, sensitivity 100%). Multivariate analysis revealed that the influential factors of ADRRs were age, depth of epileptogenic lesion, and seizure frequency. SIGNIFICANCE: ADRR of scalp EEG can be a rapid and specific method to differentiate epilepsy and evaluate seizure activity. This method is especially suitable for young patients.

[Corrigendum] HSP90 inhibits apoptosis and promotes growth by regulating HIF-1α abundance in hepatocellular carcinoma.

Subsequently to the publication of the above paper, the authors contacted the Editorial Office to explain that they had found several mistakes in Figs. 1B, 2B, 6B and 7B in their paper. The PCR results shown in Fig. 1B, the flow cytometric results in Figs. 2B and 6B, and the immunohistochemistry results in Fig. 7B were inadvertently chosen incorrectly when these images were selected from the pool of raw data. However, the authors retained access to their original data, and were able to re-assemble the data in these figures as they had intended. Consequently, the corrected versions of Figs. 1, 2, 6 and 7, containing the replacement data for Figs. 1B, 2B, 6B, and 7B, are shown below and on the next two pages. It should be emphasized that the errors that were made in assembling Figs. 1B, 2B, 6B and 7B did not have a major effect on either the results reported or the conclusions reached in this article. The authors are grateful to the Editor of International Journal of Molecular Medicine for allowing them the opportunity to publish this Corrigendum, and all of the authors agree to the publication of this Corrigendum. The authors sincerely apologize for their mistakes and regret any inconvenience that these errors may have caused. [International Journal of Molecular Medicine 37: 825­835, 2016; DOI: 10.3892/ijmm.2016.2482].

Molecular and clinical characteristics of ATP1A3-related diseases.

Objective: With detailed studies of ATP1A3-related diseases, the phenotypic spectrum of ATP1A3 has greatly expanded. This study aimed to potentially identify the mechanisms by which ATP1A3 caused neurological dysfunction by analyzing the clinical features and phenotypes of ATP1A3-related diseases, and exploring the distribution patterns of mutations in the subregions of the ATP1A3 protein, thus providing new and effective therapeutic approaches. Methods: Databases of PubMed, Online Mendelian Inheritance in Man, and Human Gene Mutation Database, Wanfang Data, and Embase were searched for case reports of ATP1A3-related diseases. Following case screening, we collected clinical information and genetic testing results of patients, and analyzed the disease characteristics on the clinical phenotype spectrum associated with mutations, genetic characteristics of mutations, and effects of drug therapy. Results: We collected 902 clinical cases related to ATP1A3 gene. From the results of previous studies, we further clarified the clinical characteristics of ATP1A3-related diseases, such as alternating hemiplegia of childhood (AHC), rapid-onset dystonia-parkinsonism; cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss syndrome, and relapsing encephalopathy with cerebellar ataxia, frequency of mutations in different phenotypes and their distribution in gene and protein structures, and differences in mutations in different clinical phenotypes. Regarding the efficacy of drug treatment, 80 of the 124 patients with AHC were treated with flunarizine, with an effectiveness rate of ~64.5%. Conclusions: Nervous system dysfunction due to mutations of ATP1A3 gene was characterized by a group of genotypic-phenotypic interrelated disease pedigrees with multiple clinical manifestations. The presented results might help guide the diagnosis and treatment of ATP1A3-related diseases and provided new ideas for further exploring the mechanisms of nervous system diseases due to ATP1A3 mutations.

Identification of Ion Channel-Related Genes and miRNA-mRNA Networks in Mesial Temporal Lobe Epilepsy.

Objective: It aimed to construct the miRNA-mRNA regulatory network related to ion channel genes in mesial temporal lobe epilepsy (mTLE), and further identify the vital node in the network. Methods: Firstly, we identified ion channel-related differentially expressed genes (DEGs) in mTLE using the IUPHAR/BPS Guide to Pharmacology (GTP) database, neXtProt database, GeneCards database, and the high-throughput sequencing dataset. Then the STRING online database was used to construct a protein-protein interaction (PPI) network of DEGs, and the hub module in the PPI network was identified using the cytoHubba plug-in of Cytoscape software. In addition, the Single Cell Portal database was used to distinguish genes expression in different cell types. Based on the TarBase database, EpimiRBase database and the high-throughput sequencing dataset GSE99455, miRNA-mRNA regulatory network was constructed from selected miRNAs and their corresponding target genes from the identified DEGs. Finally, the rats were selected to construct chronic li-pilocarpine epilepsy model for the next stage experimental verification, and the miR-27a-3p mimic was used to regulate the miRNA expression level in PC12 cells. The relative expression of miR-27a-3p and its targeting mRNAs were determined by RT-qPCR. Results: 80 mTLE ion channel-related DEGs had been screened. The functional enrichment analysis results of these genes were highly enriched in voltage-gated channel activation and ion transport across membranes. In addition, the hub module, consisting of the Top20 genes in the protein-protein interaction (PPI) network, was identified, which was mainly enriched in excitatory neurons in the CA3 region of the hippocampus. Besides, 14 miRNAs targeting hub module genes were screened, especially the miR-27a-3p deserving particular attention. miR-27a-3p was capable of regulating multiple mTLE ion channel-related DEGs. Moreover, in Li-pilocarpine-induced epilepsy models, the expression level of miR-27a-3p was increased and the mRNAs expression level of KCNB1, SCN1B and KCNQ2 was decreased significantly. The mRNAs expression level of KCNB1 and KCNQ2 was decreased significantly following PC12 cells transfection with miR-27a-3p mimics. Conclusion: The hub ion channel-related DEGs in mTLE and the miRNA-mRNA regulatory networks had been identified. Moreover, the network of miR-27a-3p regulating ion channel genes will be of great value in mTLE.

Red blood cell distribution width predicts in-hospital mortality in patients with a primary diagnosis of seizures in the ICU: a retrospective database study.

PURPOSE: The aim of this study was to determine the predictive value of red blood cell distribution width (RDW) in patients with a primary diagnosis of seizures admitted to the intensive care unit (ICU) in terms of in-hospital mortality. METHODS: This was a retrospective study of the eICU Collaborative Research Database of adult patients (aged 18-88 years) with a primary diagnosis of seizures in 2014 and 2015. The prognostic value of RDW was investigated using a receiver operating characteristic (ROC) curve, multiple logistic regression model, and net reclassification index (NRI). RESULTS: We identified 1568 patients who met the inclusion criteria. High RDW was significantly correlated with in-hospital mortality after adjusting for potential confounders with an odds ratio (OR) of 3.513 (95% confidence interval [CI]:1.699-7.266). The area under the ROC curve of RDW for in-hospital mortality was 0.7225. Compared with the prediction of in-hospital mortality using APACHE IV score alone, the continuous NRI with the RDW variable was 0.3507 (95%CI: 0.0584-0.6431, p < 0.05). The length of stay in the ICU of patients with an RDW >14.65% was significantly increased compared to those with normal RDW (log-rank test, p < 0.0001). CONCLUSION: RDW width can be useful for prediction of in-hospital mortality in patients with seizures admitted to the ICU, and it provides additional prognostic value beyond the APACHE IV score alone.

Peroxisomal Dysfunction Contributes to White Matter Injury Following Subarachnoid Hemorrhage in Rats via Thioredoxin-Interacting Protein-Dependent Manner.

BACKGROUND AND PURPOSE: White matter injury (WMI) exists in the early stage of subarachnoid hemorrhage (SAH) and has not been well addressed so far. METHODS: We utilized short hairpin RNA (shRNA) and clustered regularly interspaced short palindromic repeats (CRISPR) to verify the role of peroxisomes in WMI following SAH. We evaluated short- and long-term neurobehavior after SAH. Western blotting, immunofluorescence, and Golgi staining techniques were performed to assess the changes in protein levels. RESULTS: Catalase (CAT) CRISPR treatment significantly attenuated neurological deficits and reduced long-term spatial learning and memory impairments after SAH by increasing the level of myelin basic protein (MBP) while decreasing the levels of amyloid precursor protein (APP), interleukin 6 (IL-6), and tumor necrosis factor (TNF)-α. The use of thioredoxin-interacting protein (TXNIP) shRNA significantly offset the effects of CAT shRNA, and the use of glycerone phosphate acyl transferase (GNPAT) shRNA significantly reversed the effects of CAT CRISPR by decreasing the levels of plasmalogens and reactive oxidative species (ROS). CONCLUSION: Peroxisomal dysfunction induced by SAH reversely exacerbated cerebral WMI following SAH, which was at least partly mediated by TXNIP and GNPAT pathways.

Risk of seizure recurrence from antiepileptic drug withdrawal among seizure-free patients for more than two years.

OBJECTIVE: The aim of this study was to determine the outcome of antiepileptic drug (AED) withdrawal in patients who were seizure-free for more than two years. METHODS: Patients with epilepsy who were seizure-free for at least two years and decided to stop AED therapy gradually were followed up every two months for seizure relapse. The inclusion criteria were as follows: (1) diagnosis of epilepsy, defined as the following conditions: ① at least two unprovoked (or reflex) seizures occurring >24 h apart; ② one unprovoked (or reflex) seizure and a probability of further seizures similar to the general recurrence risk (at least 60%) after two unprovoked seizures, occurring over the next 10 years; ③ diagnosis of an epilepsy syndrome; (2) patients remained seizure-free for at least 24 consecutive months during AED therapy; and (3) patients expressed a desire to discontinue AED therapy gradually and agreed to return for regular follow-ups. The time to a seizure relapse and predictive factors were analyzed by survival methods, including sex; age at seizure onset; number of episodes; seizure-free period before AED withdrawal; duration of follow-up after AED withdrawal; AED tapering off period (taper period); results from brain magnetic resonance (MRI); electroencephalogram (EEG) after drug withdrawal; EEG before drug withdrawal; seizure type (classified as generalized, partial, or multiple types based on history); and the number of AEDs administered for long-term seizure control. A log-rank test was used for univariate analysis, and a Cox proportional hazard model was used for multivariate analysis. RESULTS: We selected 94 patients (58 men, 36 women). The relapse ratio was 29.8%. Univariate analysis and multivariate Cox regression analysis indicated that withdrawal times and multiple AEDs, as well as the seizure-free period before withdrawal and abnormal EEG after drug withdrawal were significantly correlated with seizure recurrence and were significant independent predictive factors, with a hazard ratio of 0.839 and 3.971, 0.957, and 3.684, respectively. SIGNIFICANCE: The relapse rate in our study was similar to commonly reported overall rates for epilepsy. Distinguishing variables, such as withdrawal times, multiple AEDs, seizure-free period before withdrawal, and abnormal EEG after drug withdrawal, need to be considered when choosing to withdraw from AEDs. Therefore, our recommendation is that after two years of seizure-free survival, patients could consider withdrawal unless they have hippocampal sclerosis (HS).

Minocycline Attenuates Experimental Subarachnoid Hemorrhage in Rats.

BACKGROUD: The aim of this study was to evaluate the therapeutic effect of minocycline on treating experimental subarachnoid hemorrhage (SAH) in rats and to explore its possible molecular mechanism. METHODS: SAH was induced in male Sprague-Dawley rats by endovascular perforation. The rats were treated with minocycline (25 mg/kg or 50 mg/kg) or saline at 2 hand 12 h post SAH. Neurological function, cerebral hemorrhage, and edema were scored at 48 h post SAH. Cell death and P2X4 receptor (P2X4R) expression were observed in the prefrontal cortex (PFC). RESULTS: Treatment with a highdose of minocycline significantly improved the neurological function score, and attenuated cerebral hemorrhage and edema. Low-dose minocycline could reduce hemorrhage, but the effect on neurological deficits and brain edema was not obvious. Minocycline treatment could alleviate neuronal apoptosis in the PFC, which was related to reduced expression of inflammatory cytokines. Immunofluorescence showed that P2X4R on microglia was activated after SAH. Minocycline treatment inhibited P2X4R activation and further suppressed the phosphorylation of downstream p38 MAPK. CONCLUSIONS: Minocycline plays a neuroprotective role by attenuating early brain injury after experimental SAH. The therapeutic mechanism of minocycline may be mediated by the inhibition of P2X4R on microglia.

Tumor Tissue Detection using Blood-Oxygen-Level-Dependent Functional MRI based on Independent Component Analysis.

Accurate delineation of gliomas from the surrounding normal brain areas helps maximize tumor resection and improves outcome. Blood-oxygen-level-dependent (BOLD) functional MRI (fMRI) has been routinely adopted for presurgical mapping of the surrounding functional areas. For completely utilizing such imaging data, here we show the feasibility of using presurgical fMRI for tumor delineation. In particular, we introduce a novel method dedicated to tumor detection based on independent component analysis (ICA) of resting-state fMRI (rs-fMRI) with automatic tumor component identification. Multi-center rs-fMRI data of 32 glioma patients from three centers, plus the additional proof-of-concept data of 28 patients from the fourth center with non-brain musculoskeletal tumors, are fed into individual ICA with different total number of components (TNCs). The best-fitted tumor-related components derived from the optimized TNCs setting are automatically determined based on a new template-matching algorithm. The success rates are 100%, 100% and 93.75% for glioma tissue detection for the three centers, respectively, and 85.19% for musculoskeletal tumor detection. We propose that the high success rate could come from the previously overlooked ability of BOLD rs-fMRI in characterizing the abnormal vascularization, vasomotion and perfusion caused by tumors. Our findings suggest an additional usage of the rs-fMRI for comprehensive presurgical assessment.

Early post-haemorrhagic stroke testosterone and oestradiol levels and long-term risk of death.

OBJECTIVE: The influence of oestrogen and testosterone replacement on stroke risk has been examined, as well as mechanisms by which oestrogen may protect from post-stroke damage. However, whether testosterone levels in the early time period after haemorrhagic stroke influence long-term mortality has not previously been investigated. We examined whether these concentrations were predictive of risk of death. SETTING: University hospital. DESIGN: Prospective study. MAIN MEASURES: Testosterone and oestrogen levels in the week after haemorrhagic stroke were measured, and the predictive value of these levels and other clinical parameters such as the size, location and severity of the stroke on mortality during the three-year length of the study were assessed. RESULTS: Glasgow Coma Scale and low testosterone/oestradiol ratio on post-stroke day 7 were independent predictors of mortality. Stroke location and hematoma volume had no predictive power. CONCLUSION: The testosterone/oestradiol ratio on day 7 after a haemorrhagic stroke is an independent predictor of mortality during later months.

Pluronic P85-coated poly(butylcyanoacrylate) nanoparticles overcome phenytoin resistance in P-glycoprotein overexpressing rats with lithium-pilocarpine-induced chronic temporal lobe epilepsy.

P-glycoprotein (Pgp) overexpression in the blood brain barrier (BBB) is hypothesized to lower brain drug concentrations and thus inhibit anticonvulsant effects in drug-resistant epilepsy. Recently, the poly(butylcyanoacrylate) (PBCA) nanoparticle system was shown to overcome the obstacle of the BBB to deliver drugs into the brain. To determine whether pluronic P85-coated phenytoin poly(butylcyanoacrylate) nanoparticles (P85-PHT-PBCA-NPs) target PHT to the brain, PHT-resistant rats overexpressing Pgp in the BBB were screened by response to PHT treatment after chronic temporal lobe epilepsy induced by lithium-pilocarpine, followed by direct verification of PHT transport via measurement of brain PHT concentrations using microdialysis. Thereafter, the PHT-resistant rats were divided into three groups, which were treated with PHT, PHT + tariquidar (TQD), or P85-PHT-PBCA-NPs. PHT + TQD and P85-PHT-PBCA-NPs showed anticonvulsant activity in the PHT-resistant rats and increased the ratio of the area under the curve of the PHT concentrations in the brain/plasma in comparison with that observed in animals subjected to PHT treatment. However, the ratios of the PHT concentrations in the liver/plasma and kidney/plasma following P85-PHT-PBCA-NPs treatment were much lower than those measured following PHT + TQD treatment. Thus, Pgp overexpression decreases therapeutic drug concentrations in the brains of subjects with drug-resistant epilepsy and P85-PHT-PBCA-NPs could increase these drug concentrations.

PreSurgMapp: a MATLAB Toolbox for Presurgical Mapping of Eloquent Functional Areas Based on Task-Related and Resting-State Functional MRI.

The main goal of brain tumor surgery is to maximize tumor resection while minimizing the risk of irreversible postoperative functional sequelae. Eloquent functional areas should be delineated preoperatively, particularly for patients with tumors near eloquent areas. Functional magnetic resonance imaging (fMRI) is a noninvasive technique that demonstrates great promise for presurgical planning. However, specialized data processing toolkits for presurgical planning remain lacking. Based on several functions in open-source software such as Statistical Parametric Mapping (SPM), Resting-State fMRI Data Analysis Toolkit (REST), Data Processing Assistant for Resting-State fMRI (DPARSF) and Multiple Independent Component Analysis (MICA), here, we introduce an open-source MATLAB toolbox named PreSurgMapp. This toolbox can reveal eloquent areas using comprehensive methods and various complementary fMRI modalities. For example, PreSurgMapp supports both model-based (general linear model, GLM, and seed correlation) and data-driven (independent component analysis, ICA) methods and processes both task-based and resting-state fMRI data. PreSurgMapp is designed for highly automatic and individualized functional mapping with a user-friendly graphical user interface (GUI) for time-saving pipeline processing. For example, sensorimotor and language-related components can be automatically identified without human input interference using an effective, accurate component identification algorithm using discriminability index. All the results generated can be further evaluated and compared by neuro-radiologists or neurosurgeons. This software has substantial value for clinical neuro-radiology and neuro-oncology, including application to patients with low- and high-grade brain tumors and those with epilepsy foci in the dominant language hemisphere who are planning to undergo a temporal lobectomy.

Bortezomib-induced severe pulmonary complications in multiple myeloma: A case report and literature review.

The proteasome inhibitor bortezomib is indicated for use in the treatment of multiple myeloma (MM) patients. The most common side effects are neurological and gastrointestinal, while severe pulmonary complications are rarely described. The present study reports the case of a 62-year-old man with immunoglobulin (Ig)G-type MM who was treated with bortezomib, thalidomide and dexamethasone. Subsequent to the administration of chemotherapy, the patient developed an acute respiratory distress syndrome. High-resolution computed tomography of the chest showed bilateral diffuse alveolar infiltrations and multiple subpleural lesions. A diagnosis of bortezomib-induced severe pulmonary complications was formed. Systemic corticosteroid therapy led to a rapid improvement in clinical conditions and radiological findings. In addition, the present study reviewed the characteristics, including medical history, clinical manifestations, treatment strategies and outcomes, of all 16 MM patients with bortezomib-induced severe pulmonary complications reported previously in Pubmed. It was indicated that patients who were male, of IgG type, with a relapse status and a previous history of auto-PBSCT had a higher possibility of developing bortezomib-induced severe pulmonary complications. Additionally, a relatively low dose rather than a high dose of corticosteroids could obtain a better outcome.

HSP90 inhibits apoptosis and promotes growth by regulating HIF-1α abundance in hepatocellular carcinoma.

Heat shock protein (HSP)90 functions as a general oncogene by targeting several well-known oncoproteins for ubiquination and proteasomal degradation. However, the clinical significance of HSP90, as well as the mechanisms responsible for the tumor-promoting effects of HSP90 in hepatocellular carcinoma (HCC) remain unclear. In this study, HSP90 and hypoxia-inducible factor (HIF)-1α expression in 60 samples of HCC tissues and matched normal tumor-adjacent tissue were assessed using immunohistochemistry (IHC) or western blot analysis. Flow cytometry, BrdU cell proliferation assay, caspase-3/7 activity assay and MTT assay were used to detect the apoptosis and proliferation of the HCC cells. The regulatory effect of HSP90 on HIF-1α in the HCC cells was confirmed by immunofluorescence staining, western blot analysis and RT-qPCR. The interaction between HIF-1α and HSP90 was analyzed by co-immunoprecipitation. A subcutaneous tumor xenograft model in nude mice was established and TUNEL assay was performed to evaluate cancer cell apoptosis and growth in vivo. We found that HSP90 expression was higher in the HCC tissues than in the normal tissues and that a high HSP90 expression correlated with poor clinicopathological characteristics, including venous infiltration, an advanced TNM stage and high pathological grading. Furthermore, we confirmed that patients with a negative expression of HSP90 had an improved 3-year survival, and that HSP90 was an independent factor for predicting the prognosis of patients with HCC. We demonstrated that HSP90 promoted HCC by inhibiting apoptosis and promoting cancer cell growth. Pearson's correlation coefficient analysis indicated that HSP90 expression positively correlated with HIF-1α protein expression in the HCC tissues. Furthermore, we found that HSP90 regulated HIF-1α protein abundance by inhibiting the ubiquitination and proteasomal degradation of HIF-1α in HCC cells. Additionally, the upregulation of HIF-1α expression partially abrogated HSP90 siRNA-induced HCC cell growth arrest and apoptosis in vitro and in vivo. These results indicate that HSP90 may be used as a prognostic marker and that HIF-1α may be one of the potential therapeutic targets of HSP90 in HCC.

One-stage operation for rare multiple mirror intracranial aneurysms: a case report and literature review.

Although intracranial multiple aneurysms are not uncommon, multiple mirror aneurysms are relatively rare. A few isolated cases have been described. However, to the best of our knowledge, 3 pairs of pure symmetrical mirror aneurysms in one patient have not been reported yet. We present a case of multiple mirror aneurysms involving the bilateral middle cerebral artery (MCA) bifurcations and posterior communicating arteries (P-com A) confirmation by one-stage operation. The possibility of one-stage treatment must be considered before surgery. Missed diagnosis and misdiagnosis must be avoided before one-stage operation for multiple mirror aneurysms.

STE20/SPS1-related proline/alanine-rich kinase is involved in plasticity of GABA signaling function in a mouse model of acquired epilepsy.

The intracellular concentration of chloride ([Cl(-)]i) determines the strength and polarity of GABA neurotransmission. STE20/SPS1-related proline/alanine-rich kinase (SPAK) is known as an indirect regulator of [Cl(-)]i for its activation of Na-K-2 Cl(-)co-transporters (NKCC) and inhibition of K-Cl(-)co-transporters (KCC) in many organs. NKCC1 or KCC2 expression changes have been demonstrated previously in the hippocampal neurons of mice with pilocarpine-induced status epilepticus (PISE). However, it remains unclear whether SPAK modulates [Cl(-)]i via NKCC1 or KCC2 in the brain. Also, there are no data clearly characterizing SPAK expression in cortical or hippocampal neurons or confirming an association between SPAK and epilepsy. In the present study, we examined SPAK expression and co-expression with NKCC1 and KCC2 in the hippocampal neurons of mice with PISE, and we investigated alterations in SPAK expression in the hippocampus of such mice. Significant increases in SPAK mRNA and protein levels were detected during various stages of PISE in the PISE mice in comparison to levels in age-matched sham (control) and blank treatment (control) mice. SPAK and NKCC1 expression increased in vitro, while KCC2 was down-regulated in hippocampal neurons following hypoxic conditioning. However, SPAK overexpression did not influence the expression levels of NKCC1 or KCC2. Using co-immunoprecipitation, we determined that the intensity of interaction between SPAK and NKCC1 and between SPAK and KCC2 increased markedly after oxygen-deprivation, whereas SPAK overexpression strengthened the relationships. The [Cl(-)]i of hippocampal neurons changed in a corresponding manner under the different conditions. Our data suggests that SPAK is involved in the plasticity of GABA signaling function in acquired epilepsy via adjustment of [Cl(-)]i in hippocampal neurons.