The role of atorvastatin in collateral circulation formation induced by encephaloduroarteriosynangiosis: a prospective trial.

OBJECTIVE: This prospective study was designed to confirm the role of atorvastatin in collateral circulation formation induced by encephaloduroarteriosynangiosis (EDAS) in patients with moyamoya disease (MMD). METHODS: Patients who were diagnosed with MMD at the Department of Neurosurgery in the Fifth Medical Center of Chinese PLA General Hospital, Beijing, China, between June 2017 and May 2018 were included. Blood samples were obtained from an antecubital vein and were analyzed using flow cytometry. Endothelial progenitor cells (EPCs) were defined as CD34brCD133+CD45dimKDR+. All patients included in the study underwent EDAS. Patients voluntarily chose whether to undergo atorvastatin treatment after EDAS. The correlation between atorvastatin and good postoperative collateral circulation was evaluated. RESULTS: A total of 106 patients with MMD were included in this study. Fifty-three patients (50%) received atorvastatin treatment. The baseline characteristics did not display statistically significant differences between the atorvastatin-treated and non-atorvastatin groups. Seventy-eight (42.9%) of the 182 hemispheres investigated postoperatively were classified as grade A collateral circulation, 47 (25.8%) as grade B, and 57 (31.3%) as grade C. Multivariate analysis revealed that only atorvastatin was significantly correlated with good collateral circulation after EDAS (p = 0.041). CONCLUSIONS: The results of this prospective clinical trial have indicated that atorvastatin administered at 20 mg daily is safe and effective for the formation of postoperative collateral induced by EDAS.

SPZ1 promotes glioma aggravation via targeting CXXC4.

PURPOSE: The purpose of this study was to detect the expression pattern of SPZ1 in glioma samples and to clarify its biological functions in the malignant progression of glioma. Our results provide a novel molecular target for glioma. METHODS: SPZ1 levels in 40 pairs of glioma and non-tumoral ones were detected by quantitative real-time polymerase chain reaction (qRT-PCR). The differences in clinical indicators and prognosis between glioma patients expressing high and low levels of SPZ1 were compared. After knockdown of SPZ1 by transfection of sh-SPZ1, migratory and invasive abilities of A172 and U251 cells were examined by transwell migration and invasion assays. The interaction between SPZ1 and its target gene CXXC4 was finally explored by Western blot and dual-luciferase reporter assay. RESULTS: SPZ1 was upregulated in glioma tissues than non-tumoral ones, and the difference was statistically significant. Cell function experiments showed that knockdown of SPZ1 weakened the migratory and invasive abilities of A172 and U251 cells. CXXC4 was identified as the target gene binding to SPZ1. Knockdown of CXXC4 abolished the role of SPZ1 knockdown in inhibiting glioma progression. CONCLUSIONS: SPZ1 stimulates glioma's malignant progression via targeting CXXC4.

Endothelial Progenitor Cells Induce Angiogenesis: a Potential Mechanism Underlying Neovascularization in Encephaloduroarteriosynangiosis.

Encephaloduroarteriosynangiosis (EDAS) is one of the most commonly used indirect vascular reconstruction methods. EDAS aids in the formation of collateral vessels from the extracranial to the intracranial circulation in patients with moyamoya disease (MMD). However, the underlying mechanism of collateral vessel formation is not well understood. Endothelial progenitor cells (EPCs) differentiate to form the vascular endothelial cells and play a very important role in angiogenesis. We designed this prospective clinical trial to investigate the presence of EPCs in patients with MMD and to explore the neovascularization mechanism mediated by the EPCs in EDAS. The patients who were diagnosed with MMD were recruited between February 5, 2017, and January 7, 2018. The blood samples were obtained from an antecubital vein and were analyzed using flow cytometry. EPCs were defined as CD34brCD133+CD45dimKDR+. All the patients enrolled in the study underwent EDAS. Cerebral arteriography was performed 6 months post-EDAS to assess the efficacy of synangiosis. The correlation between EPC count and good collateral circulation was evaluated. Among the 116 patients with MMD enrolled in this study, 73 were women and 43 were men. The average age of the patients was 33.8 ± 15.2 years. The EPC count of the patients with MMD was 0.071% ± 0.050% (expressed as percentage of the peripheral blood mononuclear cells). The EPC count in the good postoperative collateral circulation group was significantly higher (0.085% ± 0.054%) than that in the poor collateral circulation group (0.048% ± 0.034%) (P = 0.000). The age, modified Suzuki-Mugikura grade, and EPC count were significantly correlated with the good collateral circulation post-EDAS in the multivariate analysis (P = 0.018, P = 0.007, and P = 0.003, respectively). The formation of collateral vessels by EDAS is primarily driven by angiogenesis. The EPC count may be the most critical factor for collateral circulation. The therapeutic effect of EDAS is more likely to benefit younger or severe ischemic patients with MMD.

Metabolic profiling of acromegaly using a GC-MS-based nontargeted metabolomic approach.

PURPOSE: Acromegaly is a rare disease caused by chronic hypersecretion of growth hormone, which leads to multiple comorbidities and reduced life expectancy. The objective of this study was to characterize the serum metabolic profiles of acromegaly patients and identify metabolic biomarkers using metabolomics. METHODS: Twenty-nine active acromegaly patients and age- and sex-matched normal controls were recruited. Serum samples were collected, and serum metabolites were analyzed using gas chromatography-mass spectrometry coupled with a series of multivariate statistical analyses. RESULTS: The orthogonal projections to latent structures-discriminate analysis (OPLS-DA) model identified and validated significant metabolic differences between individuals with acromegaly and normal controls (R2Y = 0.908 and Q2Y = 0.601). Compared with normal controls, acromegaly patients had elevated levels of 5-aminovaleric acid, glyceric acid, L-dithiothreitol, dihydrocoumarin, N-acetyl-L-glutamic acid, gluconic acid, and monoolein (P < 0.05) and reduced serum levels of D-erythronolactone, taurine, carbamoyl-aspartic acid, and mucic acid (P < 0.01). Furthermore, glyceric acid and taurine possessed higher area under the receiver operating characteristic curve values (AUC values, 0.914 and 0.931, respectively), suggesting an excellent clinical ability to distinguish acromegaly patients from normal controls. Pathway analysis revealed that the pentose phosphate pathway and the taurine and hypotaurine metabolic pathway are significant pathways (P = 0.002 and 0.004, respectively). CONCLUSIONS: Metabolic activity is significantly altered in the serum of individuals with active acromegaly. Glyceric acid and taurine may be considered potential biomarkers for distinguishing acromegaly patients from normal controls.

Image Fusion: A Novel Approach in Gamma Knife Surgery Treating Trigeminal Neuralgia.

OBJECTIVE: Finding accurate locations for radiosurgical targets in trigeminal neuralgia (TN) remains challenging. This study provides a novel approach of image fusion used in locating radiosurgical targets for gamma knife surgery (GKS) in the treatment of TN. METHODS: Magnetic resonance imaging (MRI) scans were performed before frame fixation, and computed tomography (CT) scans were performed following frame fixation. Fusion of the CT and MRI images was performed to locate the treatment target. The therapeutic effects were evaluated following GKS. RESULTS: The CT image ensures precise imaging for defining the fiducial localizers. Multi-modality medical imaging allows the trigeminal nerve (CN V) to be distinguished from the adjacent corresponding vessels. Thus, image fusion makes isocenter positioning more accurate. Significant changes in the frequency, intensity, and length of pain attacks following GKS were achieved. CONCLUSION: Diagnostic MRI co-registered with stereotactic CT can be used for accurate target location. The therapeutic effects of image fusion for GKS treatment of TN are satisfactory.

Contribution of Spinal PKCγ Expression to Short- and Long-lasting Pain Behaviors in Formalin-induced Inflamed Mice.

BACKGROUND: Over-expression of spinal protein kinase Cγ(PKCγ) contributes to the induction of persistent bilateral hyperalgesia following inflammatory injury, yet the role of spinal PKCγ in short- and long-lasting pain behavior is poorly understood. OBJECTIVE: This study aimed to characterize the contribution of spinal PKCγ to spontaneous pain and long-lasting bilateral hyperalgesia in formalin-induced inflamed mice using pharmacological inhibition. STUDY DESIGN: Laboratory animal study. SETTING: The study was performed in the Department of Human Anatomy and K.K. Leung Brain Research Centre, Preclinical School of Medicine, the Fourth Military Medical University (Xi'an, China) and the Department of Anesthesiology, Fuzhou General Hospital (Fuzhou, China). METHODS: Male mice were unilaterally intraplantarly injected with formalin to induce inflammatory pain. Spontaneous pain behaviors, including flinches and lickings, were recorded by off-line video during the first hour post-injection and counted. Using von Frey tests, long-lasting bilateral mechanical paw withdrawal thresholds were determined before injection and at indicated time points thereafter. Temporal expression of spinal PKCγ was observed by immunohistochemical staining. For pharmacological inhibition, mice were treated daily with intrathecal Tat carrier or selective PKCγ inhibitor KIG31-1, from 1 hour prior to 10 days after formalin injection. Spontaneous pain behaviors and long-lasting bilateral mechanical hyperalgesia were assessed. Spinal PKCγ expression was also observed by using immunohistochemical staining and western blot. RESULTS: The number of PKCγ-immunoreactive (ir) spinal neurons was significantly higher at 10 days, but not 2 hours, after formalin intraplantar injection, and accompanied by long-lasting bilateral hyperalgesia. Furthermore, long-lasting bilateral hyperalgesia could be reversed by pharmacological inhibition of over-expressed spinal PKCγ; however, pretreating with intrathecal KIG31-1 showed no antinociceptive effects on short-term spontaneous pain behaviors. LIMITATIONS: All results were obtained from the mice and no PKCγ inhibitors were available through clinical practice. Therefore, it remains difficult to draw definitive connections between animal research and human application. CONCLUSION: Our findings suggest that spinal PKCγ plays a predominant role in long-lasting bilateral hyperalgesia, but not in the spontaneous pain behaviors induced by formalin. KEY WORDS: Formalin, spontaneous pain, mechanical hyperalgesia, protein kinase C gamma, KIG31-1, mice.

Birth weight and type 2 diabetes: A meta-analysis.

The prevalence of T2DM is increasing around the world on a yearly basis. A meta-analysis was conducted to analyze the association between birth weight and incidence of type 2 diabetes mellitus (T2DM). A literature search was performed from January 1990 to June 2016 in PubMed, ScienceDirect, SpringerLink, China National Knowledge Infrastructure and Chinese Biomedical Literature Database. After reviewing characteristics of all the included studies systematically, a meta-analytical method was employed to calculate the pooled odds ratios (ORs) and associated 95% confidence intervals (CI) from random-effects models. Heterogeneity was assessed by Q-statistic test. Funnel plot, Begg's and Egger's linear regression tests were applied to evaluate publication bias. A sensitivity analysis was also performed to assess the robustness of results. According to inclusion and exclusion criteria, 8 studies were selected to be included in the meta-analysis. Compared with normal birth weight (2,500-4,000 g), low birth weight (<2,500 g) was associated with an increased risk of T2DM (OR, 1.55; 95% CI, 1.39-1.73; P<0.001). No significant difference was observed between high birth weight (>4,000 g) and normal birth weight in terms of the risk of T2DM (OR, 0.98; 95% CI, 0.79-1.22). Compared with high birth weight, low birth weight was associated with an increased risk of diabetes mellitus (OR, 1.58; 95% CI, 1.30-1.93; P<0.001). These findings indicated that there may be an inverse linear association between birth weight and T2DM.

The Analgesic Effects of Celecoxib on the Formalin-induced Short- and Long-term Inflammatory Pain.

The non-steroidal anti-inflammatory drug celecoxib has long been used for reducing pain, in spite of moderate gastrointestinal side effects. In previous studies, it has been shown that celecoxib can inhibit formalin-induced spontaneous pain and secondary hyperalgesia. Injecting formalin into a rodent's hind paw not only induces acute pain behaviors, but also produces long-lasting hyperalgesia. Whether celecoxib can also have long-lasting effects is still unknown. Our results show that pretreatment with an intraperitoneal injection of celecoxib at one hour before formalin injection induced inhibition on the spontaneous flinch and licking behaviors in the second phase but not the first phase. Meanwhile, FOS expressions were also reduced with celecoxib pretreatment. Consecutive administration of celecoxib also protects the hind paw from hypoalgesia and relieves formalin-induced, long-lasting hyperalgesia in the ipsilateral hind paw. These analgesic effects may be related to suppression of the activation of neurons and astrocytes indicated by FOS and GFAP expressions. Based on the above findings, celecoxib demonstrated analgesic effects not only on acute spontaneous pain behavior but also on long-lasting hyperalgesia induced by formalin injection. The inhibition of neurons and astrocytes by celecoxib may be possible reasons for its analgesia.

Different analgesic effects of intrathecal endomorphin-2 on thermal hyperalgesia and evoked inflammatory pain in ovariectomized rats.

Hormone replacement remains one of the common therapies for menopause-related pain but is associated with risk of orofacial or back pain. Spinal endomorphin-2 (EM-2) is involved in varied pain and its release is steroid-dependent, but whether increasing spinal EM-2 can inhibit thermal hyperalgesia and inflammatory pain in ovariectomized (OVX) female rats, an animal model mimicking menopause, is not clear, nor is the potential involvement of spinal mu-opioid receptor (MOR). In the current study, we revealed that the temporal decrease of spinal EM-2 is accompanied with OVX-induced thermal hyperalgesia that was dose-dependently attenuated by intrathecal (IT) delivery of EM-2. The subcutaneous injection of formalin-induced inflammatory pain in OVX rats was exacerbated and IT delivery of EM-2 dose-dependently inhibited the inflammatory pain. However, the ED50 for IT delivery of EM-2 on thermal hyperalgesia is smaller than that on inflammatory pain in OVX rats, suggesting different contributions of the EM-2 system to these 2 pain modalities in OVX rats. IT pretreatment with MOR antagonist, beta-funaltrexamine (ß-FNA), attenuated IT EM-2 analgesia on both thermal hyperalgesia and inflammatory pain in OVX rats. Furthermore, IT delivery of EM-2 did not affect the animals' locomotion or anxiety status. Our findings suggested that IT EM-2 might be a safer analgesia strategy than hormone replacement therapy in reducing risk of orofacial or back pain. However, a long-lasting form of EM-2 with less tolerance is needed to induce sustained analgesia.

Identification of miRNAs as potential new biomarkers for nervous system cancer.

Several recent studies have indicated the possibility of detecting dysregulated microRNAs (miRNAs) to diagnose nervous system cancer (NSC). Our study was conducted to explore the clinical applicability of miRNAs as potential ideal biomarkers for the diagnosis of NSC. For this meta-analysis, a systematic literature search was conducted in the Embase, Medline, Cochrane, Wangfang, and Sinomed databases. A standard quality tool-quality assessment of diagnostic accuracy studies was employed to assess the quality of the included studies. Specificity, sensitivity, diagnostic odds ratio (DOR), and area under curve (AUC) were pooled to assess overall test accuracy. In total, 25 studies from 7 articles, including 388 patients with NSC and 435 controls (healthy controls and patients with neurologic disorders), were included in this meta-analysis. For the studied miRNAs, the pooled sensitivity, specificity, and DOR for predicting NSC were 85% (95% confidence interval [CI] 80-89%), 85% (95% CI 80-89%), and 32 (95% CI 19-55), respectively. The pooled AUC for miRNAs identifying NSC was 0.92. In addition, results from subgroup analyses indicated that using miRNA panels yield a much better diagnostic accuracy when compared with using a particular miRNA. The current evidence suggests that miRNAs, especially miRNA panels on body fluids, may be suitable for use as diagnostic biomarkers for NSC patients. However, more prospective studies using larger cohorts should be conducted to confirm their degree of accuracy.

Glatiramer acetate, an anti-demyelination drug, reduced rats' epileptic seizures induced by pentylenetetrazol via protection of myelin sheath.

Glatiramer acetate (GA) is a clinically prescribed immunomodulator drug used to treat demyelinating disease like multiple sclerosis (MS). Persistent down-regulation in the expression of myelin sheath proteins has been observed in both rats with pentylenetetrazol (PTZ) induced chronic epilepsy and some clinical epilepsy patients. Hypothetically, protection of myelin sheath by pharmaceutical means in the process of epilepsy might, to some extent, be helpful to control epileptic seizures. Therefore, we tried to use GA to treat PTZ-induced epilepsy rats. GA treatment successfully protected rats' myelin sheath from demyelination in the process of PTZ-induced epileptic seizures. Notably, electroencephalogram (EEG) monitoring demonstrated that GA-treated epilepsy rats showed significantly lowered epileptiform discharges. Correspondingly, behavioral recording showed reduced frequency of seizures in GA-treated epilepsy rats. The results indicate that epilepsy associated demyelination may be a contributing factor in seizures behavior, and early intervention with anti-demyelination drugs may be beneficial to reduce the severity of seizures behavior.

Expression of FSH and its co-localization with FSH receptor and GnRH receptor in rat cerebellar cortex.

The expression of follicle-stimulating hormone (FSH) and its receptor in extrapituitary and non-HPG axis tissues has been demonstrated and their non-reproductive functions in these tissues have been found. However, there have been no reports concerning the expression and function of FSH and its receptor in the cerebellum. In our study, immunofluorescence staining and in situ hybridization were used to detect the expression of FSH, double-labeled immunofluorescence staining was used to detect co-localization of FSH and its receptor and co-localization of FSH and gonadotropin-releasing hormone (GnRH) receptor in the rat cerebellar cortex. Results showed that some cells of the Purkinje cell layer, granular layer, and molecular layer of the cerebellar cortex showed both FSH immunoreactivity and FSH mRNA positive signals; not only for FSH and FSH receptor, but also for FSH and GnRH receptor co-localized in some cells throughout the Purkinje cell layer, granular layer, and molecular layer of the cerebellar cortex. These suggested that rat cerebellum could express FSH; cerebellum is a target tissue of FSH; FSH may exert certain functions through FSH receptor in a paracrine or autocrine manner; GnRH may regulate FSH positive cells through GnRH receptor in the cerebellum. Our study provides morphological evidence for further functional research on FSH and related hormones in the cerebellum.

Off-line analysis of single-unit neuronal discharge in the globus pallidus region in Parkinson's disease.

BACKGROUND: The accuracy of microelectrode-guided localization can make the operation safe and effective, but only experienced neurosurgeons are capable of performing this operation. A good index to identify neuronal discharges between globus pallidus interna and globus pallidus externa is needed. The aim of this research was to establish a good and practical electrophysiologic index to distinguish neuronal discharge in the interior globus pallidus from neuronal discharge in the exterior globus pallidus region of the brain in Parkinson's disease. The effect of neurons having an atypical discharge on successful surgical localization was also quantitatively evaluated. METHODS: The study included 30 patients with primary Parkinson's disease who underwent pallidotomy between September 2000 and October 2002. During each pallidotomy, the neuronal discharges in the pallidum and its vicinity were recorded. The recorded spikes were used to calculate the frequency, burst index, pause index, and pause ratio of the single-unit discharge. The interior and exterior globus pallidus regions were compared in terms of frequency, burst index, pause index, and pause ratio. The sensitivity, specificity, false-negative ratio, false-positive ratio, and accuracy of those indices were then evaluated. RESULTS: The values of frequency, burst index, pause index, and pause ratio in the interior globus pallidus were (96 +/- 43) Hz, 2.31 +/- 1.81, 0.05 +/- 0.05, and 0.27 +/- 0.28, respectively, and in the exterior globus pallidus were (59 +/- 27) Hz, 0.88 +/- 0.63, 0.20 +/- 0.14, and 1.54 +/- 1.17, respectively. Use of the four indices to distinguish the two neuron types produced a sensitivity of 0.84, 0.78, 0.77, and 0.93 with a specificity of 0.64, 0.79, 0.88, and 0.87, respectively. The false-positive ratio was 0.36, 0.21, 0.12, and 0.13 and the false-negative ratio was 0.16, 0.22, 0.23, and 0.07 while the accuracy was 0.72, 0.79, 0.80, and 0.90, respectively. CONCLUSIONS: Pause ratio is a relatively reliable index to distinguish neuronal discharges between the interior and exterior globus pallidus regions in Parkinson's disease. The effect of neurons with atypical discharge on the successful surgical localization would be reduced to 10% when the pause ratio is used as the index.

Clinical study for alleviating opiate drug psychological dependence by a method of ablating the nucleus accumbens with stereotactic surgery.

The aim of this study was to explore a new way of treating drug addiction by ablating the nucleus accumbens (NAC), which has a close relationship with drug-induced psychological dependence, using stereotactic surgery, blocking the mesocorticolimbic dopamine circuit, alleviating craving for drugs and lowering the relapse rate after detoxification. On the basis of animal experiments, stereotactic surgery was performed in 28 patients by making a lesion in the NAC bilaterally to treat opiate drug dependence. Indications, the criterion of therapeutic effect, treatment process and the therapeutic and safety evaluation index of the surgery were formulated particularly. The mean follow-up period was 15 months. Relapse has not occurred in 11 cases up till now. Drug-free time in these patients has been more than half a year in 4 cases (more than a year in 3 cases), and less than half a year in 7 cases. Relapse occurred in 15 cases after surgery. Drug-free time in these patients was more than half a year in 3 cases, between 1 month and half a year in 10 cases and less than 1 month in 2 cases. The therapeutic effect was excellent in 7 cases (26.9%), good in 10 cases (38.5%) and poor in 2 cases (7.7%). Another 7 cases were still under investigation at the time of writing. Relapse rates after surgery were 7.7, 38.5 and 57.5% within 1 month, between 1 month and half a year and after more than half a year, respectively. There were no common complications of surgery such as intracranial hematoma or infection in these patients after operation. Character type was changed slightly in 2 cases, and 4 cases suffered temporary memory loss, which did not affect their daily lives and learning function. They all recovered within 1 month. There were different degrees of effectiveness of treating drug addicts' psychological dependence by making lesions in the NAC bilaterally with stereotactic surgery. No particular complications occurred. The operation is safe and feasible. The mean follow-up time in this study was 15 months. The effectiveness was satisfactory. The relapse rate of drug addicts after detoxification was clearly reduced.