A transcriptome-wide association study identifies susceptibility genes for Parkinson's disease.

Genome-wide association study (GWAS) has seen great strides in revealing initial insights into the genetic architecture of Parkinson's disease (PD). Since GWAS signals often reside in non-coding regions, relatively few of the associations have implicated specific biological mechanisms. Here, we aimed to integrate the GWAS results with large-scale expression quantitative trait loci (eQTL) in 13 brain tissues to identify candidate causal genes for PD. We conducted a transcriptome-wide association study (TWAS) for PD using the summary statistics of over 480,000 individuals from the most recent PD GWAS. We identified 18 genes significantly associated with PD after Bonferroni corrections. The most significant gene, LRRC37A2, was associated with PD in all 13 brain tissues, such as in the hypothalamus (P = 6.12 × 10-22) and nucleus accumbens basal ganglia (P = 5.62 × 10-21). We also identified eight conditionally independent genes, including four new genes at known PD loci: CD38, LRRC37A2, RNF40, and ZSWIM7. Through conditional analyses, we demonstrated that several of the GWAS significant signals on PD could be driven by genetically regulated gene expression. The most significant TWAS gene LRRC37A2 accounts for 0.855 of the GWAS signal at its loci, and ZSWIM7 accounts for all the GWAS signals at its loci. We further identified several phenotypes previously associated with PD by querying the single nucleotide polymorphisms (SNPs) in the final model of the identified genes in phenome databases. In conclusion, we prioritized genes that are likely to affect PD by using a TWAS approach and identified phenotypes associated with PD.

An E3 Ubiquitin Ligase RNF139 Serves as a Tumor-Suppressor in Glioma.

Glioma is highly lethal because of its high malignancy. Ubiquitination, a type of ubiquitin-dependent protein modification, has been reported to play an oncogenic or tumor-suppressive role in glioma development, depending on the targets. Ring finger protein 139 (RNF139) is a membrane-bound E3 ubiquitin ligase serving as a tumor suppressor by ubiquitylation-dependently suppressing cell growth. Herein, we firstly confirmed the abnormal downregulation of RNF139 in glioma tissues and cell lines. In glioma cells, ectopic RNF139 overexpression could inhibit, whereas RNF139 knockdown could aggravate the aggressive behaviors of glioma cells, including hyperproliferation, migration, and invasion. Moreover, in two glioma cell lines, RNF139 overexpression inhibited, whereas RNF139 knockdown enhanced the phosphorylation of phosphatidylinositol 3-kinase (PI3K) and AKT serine/threonine kinase 1 (AKT). In a word, we demonstrate the aberration in RNF139 expression in glioma tissue samples and cell lines. RNF139 serves as a tumor-suppressor in glioma by inhibiting glioma cell proliferation, migration, and invasion and promoting glioma cell apoptosis through regulating PI3K/AKT signaling.

Chaihu-Longgu-Muli Decoction exerts an antiepileptic effect in rats by improving pyroptosis in hippocampal neurons.

ETHNOPHARMACOLOGICAL RELEVANCE: Chaihu-Longgu-Muli Decoction (CLMD) is a classic prescription created by Zhong-jing Zhang, a famous ancient Chinese medical scientist, to harmonize uncontrollable body activities and calm the minds. Now Traditional Chinese Medicine (TCM) physicians often apply it to treat psychiatric diseases such as epilepsy. AIM OF THE STUDY: This study investigated the mechanism of the effect of Chaihu-Longgu-Muli Decoction (CLMD) on hippocampal neurons pyroptosis in rats with Temporal Lobe Epilepsy (TLE). MATERIALS AND METHODS: The lithium chloride-pilocarpine-induced TLE rat model was established. The behavioral testing was performed and, the expression of IL-1ß and TNF-α in serum was detected by ELISA, qRT-PCR was used to detect the mRNA expression of NLRP3, Caspase-1, IL-1ß and TNF-α in hippocampus. The expression of NLRP3 and Caspase-1 in hippocampal dentate gyrus was detected by immunofluorescence assay. RESULTS: CLMD could significantly suppress the frequency and duration time of epileptic seizures, reduce the expression of NLRP3, Caspase-1 TNF-α and IL-1ß. CONCLUSIONS: CLMD exerted an obvious antiepileptic effect by improving pyroptosis in hippocampal neurons of TLE rats.

Successful Treatment of Psychiatric Symptoms after Traumatic Brain Injury Using Deep Brain Stimulation to the Anterior Limb of Internal Capsule-Nucleus Accumbens.

Psychiatric symptoms are common after traumatic brain injury (TBI), and some patients have poor drug therapeutic efficacy. We report a successfully treated case of psychiatric symptoms after TBI using deep brain stimulation (DBS) to the anterior limb of internal capsule (ALIC)-nucleus accumbens (NAc) in a 76-year-old woman. The patient suffered from auditory hallucination, mood changes, and insomnia caused by TBI. Psychological test assessment showed the scores of Hamilton Anxiety Scale, Hamilton Depression Scale and Positive and Negative Syndrome Scale were 30, 35, and 96 respectively. Head magnetic resonance imaging scan showed right temporal lobe encephalomalacia. Head magnetic resonance spectroscopy (MRS) showed bilateral basal ganglia choline increased relatively. After DBS to the ALIC-NAc, the target parameters were adjusted. The psychiatric symptoms were completely improved and the result of head MRS was normal in the end. The current report declares that DBS is reversible, adjustable and safe in the treatment of psychiatric symptoms caused by TBI. DBS to the ALIC-NAc should be considered as a possible treatment choice once a patient showed psychiatric symptoms after TBI.

microRNA-200a functions as a tumor suppressor by targeting FOXA1 in glioma.

microRNAs (miRs) serve primary roles in certain human malignancies; however, the detailed regulatory mechanism of miR-200a in glioma progression is yet to be fully elucidated. The current study aimed to assess the expression of miR-200a in glioma as well as the regulatory mechanism of miR-200a in glioma cell proliferation, survival and invasion. RT-qPCR and western blotting were performed to examine mRNA and protein expression. An MTT assay, an EdU incorporation cell proliferation assay and a transwell assay were utilized to assess cell survival, proliferation and invasion. The results indicated that the miR-200a levels were significantly reduced in glioma tissues compared with normal brain tissues. Levels were also downregulated in glioma cell lines when compared with those in normal human astrocyte cells. Furthermore, low miR-200a expression was associated with advanced progression of glioma. The overexpression of miR-200a inhibited glioma cell proliferation, survival and invasion. Results also identified that FOXA1 was a target gene of miR-200a in glioma cells and that the increased expression of FOXA1 was negatively correlated to the decreased expression of miR-200a in glioma tissues. Furthermore, FOXA1 expression was negatively mediated by miR-200a in glioma cells and the overexpression of FOXA1 eliminated the inhibitory effects of miR-200a on the survival, proliferation and invasion of glioma cells. In conclusion, the current study demonstrated that miR-200a functions acts as a tumor suppressor in glioma by directly targeting FOXA1 and may thus be a potential candidate for the treatment of glioma.

Effect of postoperative systemic antipsychotic therapy on psychiatric recurrence in patients with meningiomas.

A number of patients with meningiomas and psychiatric disorders will suffer psychiatric symptom recurrence following tumorectomies. The present study reported a retrospective analysis regarding 42 cases of patients with meningiomas using complete clinical follow-up data from June 2005 to June 2013. The patients were divided into the systemic antipsychotic (SP) group (n=20) following 6months of postoperative SP therapy and the none-SP (NSP) group (n=22), who did not receive postoperative antipsychotic treatment. Patients were assessed using the Positive and Negative Syndrome Scale (PANSS) and Brief Psychiatric Rating Scale (BPRS) at the time points of prior to surgery, immediately following surgery, and 6 months, 12 months and 3 years following surgery. The effective rate, recurrence rate, rehospitalization rate and survival analysis were calculated. The BPRS score and PANSS scores (including PANSS positive, PANSS negative, PANSS general psychopathology and PANSS overall) in the SP group at 6 months, 12 months and 3 years following surgery were significantly decreased compared with the NSP group (P<0.05). The effective rate was 95, 90 and 90% at 6 months, 12 months and 3 years, respectively, in the SP group, whilst it was 68.2, 63.6 and 59%, respectively, in the NSP group, which was statistically significant (χ2=4.89, χ2=4.01 and χ2=5.12; P<0.05). The recurrence rate of the SP group was 0, 5 and 10% at 6 months, 12 months and 3 years, respectively, whilst in the NSP group it was 22.7, 31.8 and 54.5%, respectively, which was statistically significant (χ2=5.16, χ2=4.89 and χ2=9.34; P<0.05). The rehospitalization rate of the SP group was 0, 0 and 5% at 6 months, 12 months and 3 years, respectively, whilst in the NSP group it was 13.6, 22.7 and 36.4%, respectively, and the data at 12 months and 3 years was statistically significant (χ2=5.16 and χ2=6.12; P<0.05). Kaplan-Meier survival analysis indicated that the accumulative survival rates of recurrence and rehospitalization in the SP group were improved compared with the NSP group. The log-rank of recurrence was χ2=9.369 (P=0.002) and the log-rank of rehospitalization was χ2=6.330 (P=0.012). In conclusion, postoperative SP therapy is of great importance to the consolidation of mental symptoms in patients with meningiomas and psychiatric symptoms, and it may significantly reduce the recurrence and rehospitalization rates.

Knockdown of RWD domain containing 3 inhibits the malignant phenotypes of glioblastoma cells via inhibition of phosphoinositide 3-kinase/protein kinase B signaling.

Glioblastoma is the most common and malignant primary brain tumor. RWD domain containing 3 (RWDD3) has been previously reported to serve a promoting role in pituitary tumors. However, the exact role of RWDD3 in glioblastoma remains unclear. Therefore, the present study aimed to investigate the expression levels of RWDD3 in human glioblastoma tissues and cell lines, as well as to examine the regulatory mechanism of RWDD3 underlying glioblastoma growth and metastasis. The results revealed that RWDD3 was significantly upregulated in glioblastoma tissues compared with normal brain tissues, while high expression of RWDD3 was associated with a shorter survival time of glioblastoma patients. The expression levels of RWDD3 were also higher in the glioblastoma cell lines compared with the normal human astrocyte cell line. Subsequent to knockdown of RWDD3, the proliferation of glioblastoma U87 and U251 cells was significantly decreased, possibly due to the cell cycle arrest at G1 phase, as well as the increased cell apoptosis. Furthermore, downregulation of RWDD3 also suppressed U87 and U251 cell invasion by inhibiting the expression levels of matrix metalloproteinase 2 (MMP2) and MMP9. Molecular mechanism investigation demonstrated that knockdown of RWDD3 significantly downregulated the activity of the phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) signaling pathway. Activation of PI3K/AKT signaling prevented the suppressive effects of RWDD3 downregulation on glioblastoma cell proliferation and migration, concurrent with increased protein levels of MMP2 and MMP9. In conclusion, the current study demonstrated for the first time that inhibition of RWDD3 expression inhibited glioblastoma progression, at least partly, via suppressing the PI3K/AKT signaling activity, and thus RWDD3 may be a novel potential therapeutic target for glioblastoma.

Advanced research on deep brain stimulation in treating mental disorders.

Deep brain stimulation is a method that involves using an electric stimulus on a specific target in the brain with stereotaxis. It is a minimally invasive, safe, adjustable and reversible nerve involvement technology. At present, this technique is widely applied to treat movement disorders and has produced promising effects on mental symptoms, including combined anxiety and depression. Deep brain stimulation has therefore been employed as a novel treatment for depression, obsessive-compulsive disorder, habituation, Tourette's syndrome, presenile dementia, anorexia nervosa and other refractory mental illnesses. Many encouraging results have been reported. The aim of the present review was to briefly describe the mechanisms, target selection, side effects, ethical arguments and risks associated with deep brain stimulation. Although deep brain stimulation is a developing and promising treatment, a large amount of research is still required to determine its curative effect, and the selection of patients and targets must be subjected to strict ethical standards.

Intracranial multiple germ cell tumors: a case report and review of literature.

Intracranial multiple germ cell tumors (GCTs) are rare. In this article, we reported a case of intracranial multiple GCTs in an 18-year-old boy with symptoms of psychosis for 8 months also. Tumors in the pineal, sellar region, corpus callosum, bilateral lateral ventricles and fourth ventricle were confirmed by enhanced magnetic resonance imaging (MRI) and stereotactic biopsy. Immunohistochemical analysis results demonstrated that the tumor cells were positive for CD117 and placental alkaline phosphatase (PLAP). The patient was treated by radiotherapy and the prescribed radiation doses were 18 Gy. After near 24 months of follow-up, no local recurrence and distant metastasis has been found.

[Clinical characteristics and cognitive function of unipolar and bipolar depression].

OBJECTIVE: To determine the clinical characteristics and cognitive dysfunction of bipolar depression and unipolar depression. METHODS: Fifty patients with unipolar depression, 48 bipolar depression, and 50 normal controls were assessed with Hamilton Depression Scale, Hamilton Anxiety Scale, Life Events Scale, and The Wisconsin Card Sorting Test. General demographic data, clinical data, and the scores of recognitive function in the 3 groups were compared. RESULTS: The patients with bipolar depression occured at young age and had obvious family history compared with those with unipolar depression. The patients with bipolar or unipolar disorders had lower scores in most neuropsychological tests than those in the control group (P<0.05). The patients with bipolar depression in understanding memory and Wisconsin card sorting test were worse than those with unipolar depression (P<0.05). CONCLUSION: There is cognitive dysfunction in patients with bipolar or unipolar disorder. Understanding memory and executive function damage may be cognitive features in bipolar disorder.

[Follow-up study on refractory schizophrenia with brain stereotaxis therapy].

OBJECTIVE: To determine the long-term effect and security of refractory schizophrenia with brain stereotaxis multi-target therapy technique. METHODS: A total of 87 patients with refractory schizophrenia were treated with brain stereotaxis multi-target therapy and were followed up over 2 years. The scores of Clinical Global Impression, Brief Psychiatric Rating Scale, Positive and Negative Symptom Scale, Wechsler Adult Intelligence Scale, Wechsler Memory Scale, Actives of Daily Living, and Social Disability Screening Schedule were compared before and after the operation. RESULTS: Of the 87 patients, 40 obviously improved, 24 improved, 12 improved little, 7 did not change. None grew worse, 1 died, and 3 shed. There was a significant difference in the scales before and after the operation (P<0.01). No severe complications and sequelae occurred. CONCLUSION: Stereotaxic multi-target therapy is effective and safe for refractory schizophrenia. After the operation, drug therapy should be maintained and recovery of social function is helpful.