BioMed Research International: Neurology The latest articles from Hindawi © 2017 , Hindawi Limited . All rights reserved. Autologous Bone Marrow-Derived Stem Cells for Treating Diabetic Neuropathy in Metabolic Syndrome Sun, 01 Oct 2017 08:52:03 +0000 Diabetic neuropathy is one of the most common and serious complications of diabetes mellitus and metabolic syndrome. The current therapy strategies, including glucose control and pain management, are not effective for most patients. Growing evidence suggests that infiltration of inflammation factors and deficiency of local neurotrophic and angiogenic factors contribute significantly to the pathologies of diabetic neuropathy. Experimental and clinical studies have shown that bone marrow-derived stem cells (BMCs) therapy represents a novel and promising strategy for tissue repair through paracrine secretion of multiple cytokines, which has a potential to inhibit inflammation and promote angiogenesis and neurotrophy in diabetic neuropathy. In this review, we discuss the clinical practice in diabetic neuropathy and the therapeutic effect of BMC. We subsequently illustrate the functional impairment of autologous BMCs due to the interrupted bone marrow niche in diabetic neuropathy. We anticipate that the functional restoration of BMCs could improve their therapeutic effect and enable their wide applications in diabetic neuropathy. Wei Liu, Fengchun Yu, Zhenghong Zhou, Yi-Chen Li, Dongsheng Fan, and Kai Zhu Copyright © 2017 Wei Liu et al. All rights reserved. Response to: Comment on “Controversies about Interspinous Process Devices in the Treatment of Degenerative Lumbar Spine Diseases: Past, Present, and Future” Mon, 18 Sep 2017 00:00:00 +0000 Roberto Gazzeri, Marcelo Galarza, and Alex Alfieri Copyright © 2017 Roberto Gazzeri et al. All rights reserved. Relationship between Interferon Beta-1A Administration and Intracranial Vascular Tone Regulation in Patients with Relapsing-Remitting Multiple Sclerosis: A Pilot Study Wed, 13 Sep 2017 00:00:00 +0000 Interferon beta (IFN-β) therapy is one of the most commonly prescribed immunomodulatory therapies in relapsing-remitting multiple sclerosis (RRMS). A reversible cerebral vasoconstriction syndrome (RCVS), associated with IFN-β use, has been recently described. For this reason, we tested the effect of once a week intramuscular administration of IFN-β-1A on the function of cerebral vessels in a cohort of RRMS patients. Using transcranial Doppler (TCD) ultrasound, we measured the mean blood flow velocity (MFV) in intracranial vessels 10 h after IFN-β administration. Measurements showed a significant increase in MFV compared to the baseline values in some vessels. Vincenzo Dattola, Lilla Bonanno, Antonino Naro, Antonino Chillura, Anna Lisa Logiudice, Edoardo Sessa, Fausto Famà, Angelo Quartarone, Rocco Salvatore Calabrò, Silvia Marino, and Margherita Russo Copyright © 2017 Vincenzo Dattola et al. All rights reserved. Overexpression of MicroRNA-145 Ameliorates Astrocyte Injury by Targeting Aquaporin 4 in Cerebral Ischemic Stroke Wed, 13 Sep 2017 00:00:00 +0000 Cerebral ischemic stroke, which affects the global population, is a major disease with high incidence, mortality, and disability. Accumulating evidence has indicated that abnormal microRNA (miRNA) expression plays essential roles in the pathologies of ischemic stroke. Yet, the underlying regulatory mechanism of miRNAs in cerebral ischemic stroke remains unclear. We investigated the role of miR-145 in cerebral ischemic stroke and its potential mechanism in a model using primary cultured astrocytes. We detected the expression levels of miR-145 and its target gene AQP4 and assessed the role of miR-145 in cell death and apoptosis caused by oxygen-glucose deprivation (OGD). Bioinformatics analysis was used to explore the targets of miR-145. miR-145 expression levels were significantly decreased in primary astrocytes subjected to OGD. miR-145 overexpression promoted astrocyte health and inhibited OGD-induced apoptosis. AQP4 was a direct target of miR-145, and miR-145 suppressed AQP4 expression. Moreover, AQP4 enhanced astrocyte injury in ischemic stroke, and AQP4 knockdown diminished the miR-145-mediated protective effect on ischemic injury. Taken together, our results show that miR-145 plays an important role in protecting astrocytes from ischemic injury by downregulating AQP4 expression. These findings may highlight a novel therapeutic target in cerebral ischemic stroke. Lifang Zheng, Wei Cheng, Xijia Wang, Zhigang Yang, Xiangling Zhou, and Chunlian Pan Copyright © 2017 Lifang Zheng et al. All rights reserved. Lesion Pattern, Mechanisms, and Long-Term Prognosis in Patients with Monoparetic Stroke: A Comparison with Nonmonoparetic Stroke Tue, 12 Sep 2017 00:00:00 +0000 Background. Monoparetic stroke is rare but could be misdiagnosed as peripheral neuropathy. We investigated the prevalence, lesion pattern, stroke mechanism, and long-term prognosis in patients with monoparetic stroke. Methods. 586 acute ischemic stroke patients (including 31 with monoparesis) were studied. Monoparetic stroke was defined as a motor deficit in either an arm or a leg but without facial weakness or speech disturbance. Median follow-up period was 32.0 months. Kaplan-Meier survival curves, log-rank tests, logistic regressions, and Cox proportional hazards models were used for clinical outcome analyses. Results. The mean age (313 men and 273 women) was 67.6 years. Among monoparetic patients, most had cortical (80.6%) and multiple (64.5%) lesions. The main stroke mechanisms were cardioembolism (38.7%) and large artery atherosclerosis (29.0%). Precentral gyrus with additional regions was most frequently involved in monoparesis (45.2%). Upper motor neuron signs were found in only 11 patients (35.5%). Compared with the nonmonoparetic group, these patients had better functional outcomes (6-month modified Rankin scale ≤2) and long-term survival but had comparable risks for further vascular events, including stroke recurrences. Conclusions. Although monoparetic stroke may have a better functional outcome, the risk of the further vascular event seems similar to nonmonoparetic stroke. Seung-Jae Lee, Dong-Geun Lee, Hye-Jin Moon, and Tae-Kyeong Lee Copyright © 2017 Seung-Jae Lee et al. All rights reserved. Computer-Assessed Preference-Based Quality of Life in Patients with Spinal Cord Injury Wed, 30 Aug 2017 00:00:00 +0000 Objectives. Our aims were to (1) measure quality of life (QoL) in spinal cord injury (SCI) patients using different methods and analyze differences; (2) enable targeted treatments by identifying variables that affect QoL; and (3) provide decision-makers with useful data for cost-utility analyses in SCI population. Methods. Seventy-one participants were enrolled. The computer-based tool UceWeb was used to elicit QoL in terms of utility coefficients, through the standard gamble, time trade-off, and rating scale methods. The SF36 questionnaire was also administered. Statistical analyses were performed to find predictors of QoL among collected variables. Results. Median values for rating scale, time trade-off, and standard gamble were 0.60, 0.82, and 0.85, respectively. All scales were significantly correlated. Rating scale and SF36 provided similar values, significantly lower than the other methods. Impairment level, male gender, older age, living alone, and higher education were correlated with lower QoL but accounted for only 20% of the variation in utility coefficients. Conclusions. Demographic and clinical variables are useful to predict QoL but do not completely capture utility coefficients variability. Therefore, direct preference-based utility elicitation should be strengthened. Finally, this is the first study providing data that can be used as a reference for cost-utility analyses in the Italian SCI population. Enea Parimbelli, Caterina Pistarini, Gabriella Fizzotti, Carla Rognoni, Giampiero Olivieri, and Silvana Quaglini Copyright © 2017 Enea Parimbelli et al. All rights reserved. Adequate Platelet Function Inhibition Confirmed by Two Inductive Agents Predicts Lower Recurrence of Ischemic Stroke/Transient Ischemic Attack Thu, 24 Aug 2017 07:18:13 +0000 Background. The correlation between platelet function and recurrent ischemic stroke or TIA remains uncertain. Objective. To investigate two inductive agents to detect platelet functions and assess associations with recurrent ischemic stroke/TIA. Method. The study included 738 ischemic stroke/TIA patients. On days 0, 3, and 9 after antiplatelet therapy, platelet function tests were determined by maximum aggregation rate (MAR) using a PL-11 platelet function analyzer and phase matching reagents. Two induction agents were used: arachidonic acid (AA) and adenosine diphosphate (ADP). At 3-month follow-up, recurrence of stroke/TIA was recorded. Result. Cut-off values of adequate platelet function inhibition were MARADP < 35% and MARAA < 35%. Data showed that antiplatelet therapy could reduce the maximum aggregation rate. More importantly, adequate platelet function inhibition of either MARADP or MARAA was not associated with the recurrence of stroke/TIA, but adequate platelet function inhibition of not only MARADP but also MARAA predicts lower recurrence (0/121 (0.00%) versus 18/459 (3.92%), P = 0.0188). Conclusion. The platelet function tested by PL-11 demonstrated that adequate inhibition of both MARADP and MARAA could predict lower risk of ischemic stroke/TIA recurrence. Lulu Zhang, Xiaowei Hu, Juehua Zhu, Xiuying Cai, Yan Kong, Hui Wang, Shanshan Diao, Hongru Zhao, Jianhua Jiang, Dapeng Wang, Quanquan Zhang, Yiren Qin, Wei Yue, and Qi Fang Copyright © 2017 Lulu Zhang et al. All rights reserved. Neuronal Regeneration after Electroacupuncture Treatment in Ischemia–Reperfusion-Injured Cerebral Infarction Rats Thu, 24 Aug 2017 00:00:00 +0000 Adult neuronal cells which can regenerate have been reported. The present study investigated whether acupuncture enhances neuronal regeneration in ischemic stroke rats. We established an ischemic stroke rat model by occluding the cerebral blood flow of the right middle cerebral artery for 15 minutes and then allowing reperfusion in Sprague–Dawley rats. The results indicated that, in these rats, 2 Hz electroacupuncture (EA) at both Zusanli (ST36) and Shangjuxu (ST37) acupoints reduced the infarction/hemisphere ratio 8 days after reperfusion and reduced the modified neurological severity score (mNSS) and increased the rotarod test time 4 and 8 days after reperfusion, respectively. In addition, 2 Hz reduced nestin immunoreactive cells in the penumbra area and the ischemic core area; 2 Hz EA also reduced Ki67 immunoreactive cells and increased glial fibrillary acidic protein immunoreactive cells in the penumbra area. These findings suggest that 2 Hz EA at the ST36 and ST37 acupoints has a neuroprotective role. However, additional studies are needed to further investigate these preliminary results. Shiang-Lin Liao, Yi-Wen Lin, and Ching-Liang Hsieh Copyright © 2017 Shiang-Lin Liao et al. All rights reserved. Predictive Value of CTA Spot Sign on Hematoma Expansion in Intracerebral Hemorrhage Patients Wed, 09 Aug 2017 06:31:38 +0000 Hematoma expansion (HE) occurs in approximately one-third of patients with intracerebral hemorrhage and leads to high rates of mortality and morbidity. Currently, contrast extravasation within hematoma, termed the spot sign on computed tomography angiography (CTA), has been identified as a strong independent predictor of early hematoma expansion. Past studies indicate that the spot sign is a dynamic entity and is indicative of active hemorrhage. Furthermore, to enhance the spot sign’s accuracy of predicting HE, spot parameters observed on CTA or dynamic CTA were used for its quantification. In addition, spot signs detected on multiphase CTA and dynamic CTA are shown to have higher sensitivity and specificity when compared with simple standardized spot sign detection in recent studies. Based on the spot sign, novel methods such as leakage sign and rate of contrast extravasation were explored to redefine HE prediction in combination with clinical characteristics and spot sign on CTA to assist clinical judgment. The spot sign is an accepted independent predictor of active hemorrhage and is used in both secondary intracerebral hemorrhage and the process of surgical assessment for hemorrhagic risk in patients with ischemic stroke. Spot sign predicts patients at high risk for hematoma expansion. Wen-Jie Peng, Cesar Reis, Haley Reis, John Zhang, and Jun Yang Copyright © 2017 Wen-Jie Peng et al. All rights reserved. Serum Butyrylcholinesterase Activity: A Biomarker for Parkinson’s Disease and Related Dementia Thu, 03 Aug 2017 08:00:18 +0000 Objective. This study aim to determine changes of serum butyrylcholinesterase (BChE) activity in PD patients and related dementia. Patients and Methods. Consecutive PD patients and healthy controls were included and clinical data were collected. Fast serum BChE activity was determined and compared between healthy controls and PD patients. Independent risk factors were performed for BChE activity, PD, and related dementia. The relationship between BChE activity and disease severity was also evaluated. Receiver operating characteristic (ROC) curves were obtained to explore serum BChE activity in distinguishing PD patients and related dementia. Results. Serum BChE activity mainly independently correlated with gender, albumin, triglyceride, body mass index, and PD. Serum BChE activity decreased in PD patients compared with healthy controls. Based on the ROC curve, the optimal cut-off point was 6864.08 IU/L for distinguishing PD patients, and the sensitivity and specificity values were 61.8% and 72.1%. It inversely correlated with Unified Parkinson’s Disease Rating Scale score. BChE activity decreased in PD-related dementia compared with those without dementia. The sensitivity and specificity values were 70.6% and 76.3%, respectively, with an optimal cut-off point of 6550.00 IU/L. Conclusions. Serum BChE activity can be regarded as a biomarker for PD and related dementia. Mei-Xue Dong, Xiao-Min Xu, Ling Hu, Yang Liu, Yuan-Jun Huang, and You-Dong Wei Copyright © 2017 Mei-Xue Dong et al. All rights reserved. Clinical and Pathological Variation of Charcot-Marie-Tooth 1A in a Large Chinese Cohort Tue, 01 Aug 2017 07:27:36 +0000 Charcot-Marie-Tooth 1A (CMT1A) caused by peripheral myelin protein 22 (PMP22) gene duplication is the most common form of hereditary polyneuropathy. Twenty-four genetically confirmed CMT1A patients with sural nerve biopsies were enrolled in this study. The clinical picture included a great variability of phenotype with mean onset age of years (1–55 years). Pathologically, we observed a severe reduction in myelinated fiber density showing three types of changes: pure onion bulb formation in 3 cases (12.5%), onion bulb formation with axonal sprouts in 10 cases (41.7%), and focally thickened myelin with onion bulb formation or/and axonal sprouts in 11 cases (45.8%). We observed no significant correlation between nerve fiber density and disease duration. There was no significant difference between the 3 pathological types in terms of clinical manifestations, nerve fiber density, and -ratio. Our study indicates that there is marked variability in the age of onset of CMT1A, as well as significant pathological changes without deterioration with the development of the disease. Focally thickened myelin is another common morphological feature of demyelination. Rui Wu, He Lv, Wei Zhang, Zhaoxia Wang, Yuehuan Zuo, Jing Liu, and Yun Yuan Copyright © 2017 Rui Wu et al. All rights reserved. Spinal Cord Injury due to Tumour or Metastasis in Aragón, Northeastern Spain (1991–2008): Incidence, Time Trends, and Neurological Function Tue, 25 Jul 2017 00:00:00 +0000 Purpose. Understanding the presentation of spinal cord injury (SCI) due to tumours considering population distribution and temporal trends is key to managing SCI health services. This study quantified incidence rates, function scores, and trends of SCI due to tumour or metastasis over an 18-year time period in a defined region in Spain. Methods. A retrospective cohort study included in-and outpatients with nontraumatic SCI due to tumour or metastasis admitted to a metropolitan hospital in Spain between 1991 and 2008. Main outcome measures were crude and age- and sex-adjusted incidence rates, tumour location and type, distribution by spinal level, neurological level of injury, and impairment ASIA scores. Results. Primary tumour or metastasis accounted for 32.5% of nontraumatic SCI with an incidence rate of 4.1 per million population. Increasing rates with age and over time were observed. Major pathology groups were intradural-extramedullary masses from which meningiomas and neurinomas accounted for 40%. Lesions were mostly incomplete with predominant ASIA Grade D. Conclusions. Increasing incidence rates of tumour-related SCI over time in the middle-aged and the elderly suggest a growing need for neurooncology health resources in the future. Maayken Elizabeth Louise van den Berg, Juan M. Castellote, Jose Ignacio Mayordomo, Ignacio Mahillo-Fernandez, and Jesus de Pedro-Cuesta Copyright © 2017 Maayken Elizabeth Louise van den Berg et al. All rights reserved. CD36 Gene Polymorphisms Are Associated with Intracerebral Hemorrhage Susceptibility in a Han Chinese Population Wed, 19 Jul 2017 00:00:00 +0000 The CD36 gene encodes a membrane glycoprotein (type B scavenger receptor, SR-B2) that plays a crucial role in lipid sensing, innate immunity, atherogenesis, and glycolipid metabolism. In this study, we aimed to investigate the association between CD36 gene polymorphisms and intracerebral hemorrhage (ICH) in a Han Chinese population. We performed genotype and allele analyses for eleven single nucleotide polymorphisms (SNPs) of CD36 in a case-controlled study involving 292 ICH patients and 298 control participants. Eleven SNPs were genotyped by the Improved Multiple Ligase Detection Reaction (iMLDR) method. The results indicated that the SNP rs1194182 values were significantly different between ICH group and control group in a dominant model after adjusting for confounding factors. The subgroup analysis conducted for rs1194182 showed that the allele G frequencies were significantly different between ICH patients and controls in hypertension group via a dominant model. We then analyzed the rs1194182 genotype distributions among different groups of the serum lipid groups, including BMI, TC, TG, HDL, and LDL. However, no significant differences were found in the analysis of other subgroups. Taken together, these findings indicate that rs1194182 polymorphism in the CD36 gene was associated with ICH, and genotype GG could be an independent predictor. Qiu-Wen Gong, Mao-Fan Liao, Liang Liu, Xiao-Yi Xiong, Qin Zhang, Qi Zhong, Kai Zhou, Yuan-Rui Yang, Zhao-You Meng, Chang-Xiong Gong, Rui Xu, and Qing-Wu Yang Copyright © 2017 Qiu-Wen Gong et al. All rights reserved. Neurocardiology: Cardiovascular Changes and Specific Brain Region Infarcts Mon, 03 Jul 2017 00:00:00 +0000 There are complex and dynamic reflex control networks between the heart and the brain, including cardiac and intrathoracic ganglia, spinal cord, brainstem, and central nucleus. Recent literature based on animal model and clinical trials indicates a close link between cardiac function and nervous systems. It is noteworthy that the autonomic nervous-based therapeutics has shown great potential in the management of atrial fibrillation, ventricular arrhythmia, and myocardial remodeling. However, the potential mechanisms of postoperative brain injury and cardiovascular changes, particularly heart rate variability and the presence of arrhythmias, are not understood. In this chapter, we will describe mechanisms of brain damage undergoing cardiac surgery and focus on the interaction between cardiovascular changes and damage to specific brain regions. Rongjun Zou, Wanting Shi, Jun Tao, Hongmu Li, Xifeng Lin, Songran Yang, and Ping Hua Copyright © 2017 Rongjun Zou et al. All rights reserved. Body Posture, Postural Stability, and Metabolic Age in Patients with Parkinson’s Disease Tue, 27 Jun 2017 08:45:47 +0000 Background. The study aims to analyze the relationship between body posture and composition, as well as postural stability in Parkinson’s disease patients. Material and Methods. 32 people were evaluated. The study was conducted in the Laboratory of Posturology at Jan Kochanowski University in Kielce (Poland). Body posture was examined using the optoelectronic body posture Formetric Diers Method III 4D. Postural stability was evaluated using the Biodex Balance System platform. Body composition was assessed with the method of bioelectrical impedance analysis using the Tanita MC 780 MA analyzer. Results. 11 patients (34.37%) had hyperkyphosis, 10 (31.25%) hyperlordosis, and 3 (9.37%) hyperkyphosis-hyperlordosis posture. Scoliosis (>10°) was observed in 28 (87.5%) subjects, whereas 4 (12.5%) presented scoliotic body posture (1–9°). In the examined population, all parameters of postural stability were within normal limits. Conclusions. A significant positive correlation was observed between surface rotation (°), General Stability Index (, ), and Anteroposterior Stability Index (, ). There was also a significant positive correlation between surface rotation (+max) (°), General Stability Index (, ), and Anteroposterior Stability Index (, ). Metabolic age also presented a significant positive correlation between metabolic age and General Stability Index (, ), as well as Anteroposterior Stability Index (, ). Jacek Wilczyński, Agnieszka Pedrycz, Dariusz Mucha, Tadeusz Ambroży, and Dawid Mucha Copyright © 2017 Jacek Wilczyński et al. All rights reserved. Genetic Variant of Kalirin Gene Is Associated with Ischemic Stroke in a Chinese Han Population Mon, 19 Jun 2017 00:00:00 +0000 Introduction. Ischemic stroke is a complex disorder resulting from the interplay of genetic and environmental factors. Previous studies showed that kalirin gene variations were associated with cardiovascular disease. However, the association between this gene and ischemic stroke was unknown. We performed this study to confirm if kalirin gene variation was associated with ischemic stroke. Methods. We enrolled 385 ischemic stroke patients and 362 controls from China. Three SNPs of kalirin gene were genotyped by means of ligase detection reaction-PCR method. Data was processed with SPSS and SHEsis platform. Results. SNP rs7620580 (dominant model: OR = 1.590, p = 0.002 and adjusted OR = 1.662, p = 0.014; additive model: OR = 1.490, p = 0.002 and adjusted OR = 1.636, p = 0.005; recessive model: OR = 2.686, p = 0.039) and SNP rs1708303 (dominant model: OR = 1.523, p = 0.007 and adjusted OR = 1.604, p = 0.028; additive model: OR = 1.438, p = 0.01 and adjusted OR = 1.476, p = 0.039) were associated with ischemic stroke. The GG genotype and G allele of SNP rs7620580 were associated with a risk for ischemic stroke with an adjusted OR of 3.195 and an OR of 1.446, respectively. Haplotype analysis revealed that A–T–G,G-T-A, and A-T-A haplotypes were associated with ischemic stroke. Conclusions. Our results provide evidence that kalirin gene variations were associated with ischemic stroke in the Chinese Han population. Hong Li, Shasha Yu, Rui Wang, Zhaoqing Sun, Xinghu Zhou, Liqiang Zheng, Zhihua Yin, Xingang Zhang, and Yingxian Sun Copyright © 2017 Hong Li et al. All rights reserved. Current Status and Future Perspective of Stenting for Symptomatic Intracranial Atherosclerotic Disease: A Meta-Analysis Sun, 18 Jun 2017 00:00:00 +0000 The aim of this study was to evaluate the safety and effectiveness of percutaneous transluminal angioplasty and stenting (PTAS) for intracranial atherosclerotic disease (ICAD) by conducting a meta-analysis. Two independent observers searched PubMed, EMBASE, and Cochrane Library for relevant studies up to 31 December 2016. A meta-analysis was conducted using Review Manager 5.3. Three studies involving 581 cases were included. The meta-analysis indicated that any stroke (RR = 3.13; 95% CI: 1.80–5.42), ischemic stroke (RR = 2.15; 95% CI: 1.19–3.89), and intracranial hemorrhage (RR = 14.71; 95% CI: 1.96–110.48) within 30 days in medical therapy alone were lower compared with PTAS plus medical therapy, but there were no significant differences in any stroke and ischemic stroke beyond 30 days between the two groups. There were also no significant differences in any death and myocardial infarction between the two groups. This meta-analysis demonstrated that, compared with medical therapy alone, PTAS for ICAD had a high risk of complication, but most complications in PTAS group occurred within 30 days after the operation, and beyond 30 days the PTAS was not inferior compared with medical therapy alone. Further studies are needed to reduce the periprocedural complications and reappraise the PTAS. Zhong-Hao Li, Zhen-Hua Zhou, Xian-Jin Zhu, Wei Liu, Ya-Wen Chen, Zi-Yao Chen, and Zun-Jing Liu Copyright © 2017 Zhong-Hao Li et al. All rights reserved. Preclinical Studies and Translational Applications of Intracerebral Hemorrhage Sun, 18 Jun 2017 00:00:00 +0000 Intracerebral hemorrhage (ICH) which refers to bleeding in the brain is a very deleterious condition with high mortality and disability rate. Surgery or conservative therapy remains the treatment option. Various studies have divided the disease process of ICH into primary and secondary injury, for which knowledge into these processes has yielded many preclinical and clinical treatment options. The aim of this review is to highlight some of the new experimental drugs as well as other treatment options like stem cell therapy, rehabilitation, and nanomedicine and mention some translational clinical applications that have been done with these treatment options. Felix Siaw-Debrah, Mark Nyanzu, Haoqi Ni, Xiao Lin, Zhu Xu, Linhui Ruan, Qichuan Zhuge, and Lijie Huang Copyright © 2017 Felix Siaw-Debrah et al. All rights reserved. White Matter Injury and Recovery after Hypertensive Intracerebral Hemorrhage Wed, 07 Jun 2017 00:00:00 +0000 Hypertensive intracerebral hemorrhage (ICH) could very probably trigger white matter injury in patients. Through the continuous study of white matter injury after hypertensive ICH, we achieve a more profound understanding of the pathophysiological mechanism of its occurrence and development. At the same time, we found a series of drugs and treatment methods for the white matter repair. In the current reality, the research paradigm of white matter injury after hypertensive ICH is relatively obsolete or incomplete, and there are still lots of deficiencies in the research. In the face of the profound changes of stroke research perspective, we believe that the combination of the lenticulostriate artery, nerve nuclei of the hypothalamus-thalamus-basal ganglia, and the white matter fibers located within the capsula interna will be beneficial to the research of white matter injury and repair. This paper has classified and analyzed the study of white matter injury and repair after hypertensive ICH and also rethought the shortcomings of the current research. We hope that it could help researchers further explore and study white matter injury and repair after hypertensive ICH. Shilun Zuo, Pengyu Pan, Qiang Li, Yujie Chen, and Hua Feng Copyright © 2017 Shilun Zuo et al. All rights reserved. Intravenous Thrombolysis in Acute Ischemic Stroke with Active Cancer Sun, 04 Jun 2017 00:00:00 +0000 Ischemic stroke patients with active cancer are known to have poor clinical outcomes. However, the efficacy and safety of intravenous alteplase (IV t-PA) in this group are still unclear. In this study, we aimed to evaluate whether stroke patients with cancer had poor clinical outcomes after use of IV t-PA. We reviewed ischemic stroke patients with active cancer treated with isolated IV t-PA between April 2010 and March 2015 at three national university hospitals from the registry for ischemic stroke in Korea. The clinical outcomes of early neurological deterioration (END), hemorrhagic transformation, in-hospital mortality, 3-month modified Rankin scale (mRS), the National Institutes of Health Stroke Scale (NIHSS) discharge score, and duration of hospitalization were compared. We enrolled a total of 12 patients, and the cohort showed poor outcomes including 4 (33%) END events, 7 (58%) hemorrhagic transformations, 3 (25%) in-hospital mortality cases, and 7 (58%) poor mRS (3–6) scores. Additionally, the cryptogenic stroke group ( = 6) more frequently had high mRS scores (P = 0.043) as well as tendencies for frequent END events, hemorrhagic transformations, in-hospital mortality cases, and higher discharge NIHSS scores without statistical significance. In conclusion, ischemic stroke patients with active cancer, especially those with a cryptogenic mechanism, showed poor clinical outcomes after use of IV t-PA. Ki-Woong Nam, Chi Kyung Kim, Tae Jung Kim, Sang Joon An, Kyungmi Oh, Sang-Bae Ko, and Byung-Woo Yoon Copyright © 2017 Ki-Woong Nam et al. All rights reserved. Increase of Soluble RAGE in Cerebrospinal Fluid following Subarachnoid Haemorrhage Mon, 29 May 2017 06:23:27 +0000 Receptors for advanced glycation end-products (RAGE) mediate the inflammatory reaction that follows aneurysmal subarachnoid haemorrhage. Soluble RAGE (sRAGE) may function as a decoy receptor. The significance of this endogenous anti-inflammatory mechanism in subarachnoid haemorrhage (SAH) remains unknown. The present study aims to analyse sRAGE levels in the cerebrospinal fluid (CSF) of SAH patients. sRAGE levels were assayed by ELISA kit in 47 CSF samples collected on post-SAH days 0–3, 5–7, and 10–14 from 27 SAH patients with acute hydrocephalus. CSF levels of sRAGE were compared with a control group and correlated with other monitored parameters. In the control group, the CSF contained only a trace amount of sRAGE. By contrast, the CSF of 20 SAH patients collected on post-SAH days 0–3 was found to contain statistically significant higher levels of sRAGE (mean concentration 3.91 pg/mL, ). The most pronounced difference in CSF sRAGE levels between good and poor outcome patients was found on days 0–3 post-SAH but did not reach the significance threshold (). CSF sRAGE levels did not change significantly during hospitalisation () and correlated poorly with treatment outcome, systemic inflammatory markers, and other monitored parameters. Our study revealed an early and constant increase of sRAGE level in the CSF of SAH patients. Bartosz Sokół, Norbert Wąsik, Roman Jankowski, Marcin Hołysz, Witold Mańko, Robert Juszkat, Tomasz Małkiewicz, and Paweł P. Jagodziński Copyright © 2017 Bartosz Sokół et al. All rights reserved. Treatment of Cervical Artery Dissection: Antithrombotics, Thrombolysis, and Endovascular Therapy Sun, 21 May 2017 09:04:20 +0000 Cervical artery dissection (CAD) is an important cause of stroke for young patients, accounting for 5–22% of strokes in patients <45 years of age, which presents not only a great burden to the stroke victims but also a financial burden to the family and society. Because CAD can lead to different clinical lesions, including neuropathy, acute ischemic stroke, and subarachnoid hemorrhage, and is an arterial dissection with a self-healing tendency, the treatment options depend on the clinical manifestations. The main purpose of the treatment is to control CAD-induced neuronal damage and to restore blood flow. The treatment programs include drug treatment and endovascular treatment. However, antithrombotic treatment is crucial. Both antiplatelet drugs and anticoagulant drugs are used to reduce the risk of stroke, but whether one treatment strategy is more effective than the other is unknown. The efficacy and timing of the endovascular treatment of CAD remain controversial. Jing Peng, Zunjing Liu, Chunxia Luo, Lin Chen, Xianhua Hou, Li Xiao, and Zhenhua Zhou Copyright © 2017 Jing Peng et al. All rights reserved. Comment on “Controversies about Interspinous Process Devices in the Treatment of Degenerative Lumbar Spine Diseases: Past, Present, and Future” Thu, 11 May 2017 00:00:00 +0000 Alessandro Landi, Fabrizio Gregori, Giovanni Grasso, Cristina Mancarella, and Roberto Delfini Copyright © 2017 Alessandro Landi et al. All rights reserved. Management of Spontaneous Subarachnoid Hemorrhage Patients with Negative Initial Digital Subtraction Angiogram Findings: Conservative or Aggressive? Tue, 02 May 2017 00:00:00 +0000 Background. The ideal management of SAH patients with negative initial DSA findings remains unresolved. Objective. (i) To present risk factors, clinical courses, and outcomes in different types of SAH patients with negative DSA findings; (ii) to explore the differences of basal vein between aSAH patients and NASAH patients; and (iii) to evaluate the value of repeated DSA for these patients. Methods. All SAH patients with negative initial DSA findings between 2013 and 2015 in our hospital were enrolled and were further categorized as perimesencephalic SAH (PMN-SAH) or nonperimesencephalic SAH (nPMN-SAH). Risk factors, clinical courses, outcomes, and the basal vein drainage patterns were compared. Results. A total of 137 patients were enrolled in the present study. The PMN-SAH group had better GOS and mRS values at 1-year follow-up. Moreover, the nPMN-SAH group had a higher rate of complications. The basal vein drainage pattern showed significant difference when comparing each of the NASAH subtypes with aSAH groups. There was a significant higher rate of a responsible aneurysm in nPMN-SAH group upon repeated DSA. Conclusions. SAH patients with negative initial DSA findings had benign clinical courses and outcomes. Repeated DSA studies are strongly advised for patients with the nPMN-SAH pattern. Liang Xu, Yuanjian Fang, Xudan Shi, Xianyi Chen, Jun Yu, Zeyu Sun, Jianmin Zhang, and Jing Xu Copyright © 2017 Liang Xu et al. All rights reserved. α7 Nicotinic Acetylcholine Receptor Stimulation Attenuates Neuroinflammation through JAK2-STAT3 Activation in Murine Models of Intracerebral Hemorrhage Wed, 26 Apr 2017 08:21:24 +0000 Accounting for high mortality and morbidity rates, intracerebral hemorrhage (ICH) remains one of the most detrimental stroke subtypes lacking a specific therapy. Neuroinflammation contributes to ICH-induced brain injury and is associated with unfavorable outcomes. This study aimed to evaluate whether α7 nicotinic acetylcholine receptor (α7nAChR) stimulation ameliorates neuroinflammation after ICH. Male CD-1 mice and Sprague-Dawley were subjected to intracerebral injection of autologous blood or bacterial collagenase. ICH animals received either α7nAChR agonist PHA-543613 alone or combined with α7nAChR antagonist methyllycaconitine (MLA) or Janus kinase 2 (JAK2) antagonist AG490. Neurobehavioral deficits were evaluated at 24 hours, 72 hours, and 10 weeks after ICH induction. Perihematomal expressions of JAK2, signal transducer and activator of transcription 3 (STAT3), tumor necrosis factor-α (TNF-α), and myeloperoxidase (MPO) were quantified via Western blot. Histologic volumetric analysis of brain tissues was conducted after 10 weeks following ICH induction. PHA-543613 improved short-term neurobehavioral (sensorimotor) deficits and increased activated perihematomal JAK2 and STAT3 expressions while decreasing TNF-α and MPO expressions after ICH. MLA reversed these treatment effects. PHA-543613 also improved long-term neurobehavioral (sensorimotor, learning, and memory) deficits and ameliorated brain atrophy after ICH. These treatment effects were reduced by AG490. α7nAChR stimulation reduced neuroinflammation via activation of the JAK2-STAT3 pathway, thereby ameliorating the short- and long-term sequelae after ICH. Paul R. Krafft, Devin McBride, William B. Rolland, Tim Lekic, Jerry J. Flores, and John H. Zhang Copyright © 2017 Paul R. Krafft et al. All rights reserved. Therapeutic Effects of Phytochemicals and Medicinal Herbs on Depression Wed, 19 Apr 2017 08:18:32 +0000 Background. Depression is a recurrent, common, and potentially life-threatening psychiatric disease related to multiple assignable causes. Although conventional antidepressant therapy can help relieve symptoms of depression and prevent relapse of the illness, complementary therapies are required due to disadvantage of the current therapy such as adverse effects. Moreover, a number of studies have researched adjunctive therapeutic approaches to improve outcomes for depression patients. Purpose. One potential complementary method with conventional antidepressants involves the use of medicinal herbs and phytochemicals that provide therapeutic benefits. Studies have revealed beneficial effects of medical herbs and phytochemicals on depression and their central nervous system mechanism. Here, we summarize the current knowledge of the therapeutic benefits of phytochemicals and medicinal herbs against depression and describe their detailed mechanisms. Sections. There are two sections, phytochemicals against depression and medical herbs against depression, in this review. Conclusion. Use of phytomedicine may be an alternative option for the treatment of depression in case conventional drugs are not applicable due to their side effects, low effectiveness, or inaccessibility. However, the efficacy and safety of these phytomedicine treatments for depression have to be supported by clinical studies. Gihyun Lee and Hyunsu Bae Copyright © 2017 Gihyun Lee and Hyunsu Bae. All rights reserved. Overview of Experimental and Clinical Findings regarding the Neuroprotective Effects of Cerebral Ischemic Postconditioning Tue, 04 Apr 2017 08:10:41 +0000 Research on attenuating the structural and functional deficits observed following ischemia-reperfusion has become increasingly focused on the therapeutic potential of ischemic postconditioning. In recent years, various methods and animal models of ischemic postconditioning have been utilized. The results of these numerous studies have indicated that the mechanisms underlying the neuroprotective effects of ischemic postconditioning may involve reductions in the generation of free radicals and inhibition of calcium overload, as well as the release of endogenous active substances, alterations in membrane channel function, and activation of protein kinases. Here we review the novel discovery, mechanism, key factors, and clinical application of ischemic postconditioning and discuss its implications for future research and problem of clinical practice. Di Ma, Liangshu Feng, Fang Deng, and Jia-Chun Feng Copyright © 2017 Di Ma et al. All rights reserved. Microglia-Synapse Pathways: Promising Therapeutic Strategy for Alzheimer’s Disease Mon, 03 Apr 2017 10:39:16 +0000 The main hallmarks of Alzheimer’s disease (AD) are extracellular deposits of amyloid plaques and intracellular accumulation of hyperphosphorylated neurofibrillary tangles (tau). However, the mechanisms underlying these neuropathological changes remain largely unclear. To date, plenty of studies have shown that microglia-mediated neuroinflammation contributes to the pathogenesis of AD, and the microglia-synapse pathways have been repeatedly identified as the crucial factor in the disease process. In this review, evidences from microglia and synapse studies are presented, and the role of microglia in the pathogenesis of AD, the contributing factors to synapse dysfunction, and the role and mechanisms of microglia-synapse pathways will be discussed. Jingdun Xie, Haitao Wang, Ting Lin, and Bingtian Bi Copyright © 2017 Jingdun Xie et al. All rights reserved. Optimization of Catheter Based rtPA Thrombolysis in a Novel In Vitro Clot Model for Intracerebral Hemorrhage Sun, 26 Mar 2017 08:02:49 +0000 Hematoma lysis with recombinant tissue plasminogen activator (rtPA) has emerged as an alternative therapy for spontaneous intracerebral hemorrhage (ICH). Optimal dose and schedule are still unclear. The aim of this study was to create a reliable in vitro blood clot model for investigation of optimal drug dose and timing. An in vitro clot model was established, using 25 mL and 50 mL of human blood. Catheters were placed into the clots and three groups, using intraclot application of rtPA, placebo, and catheter alone, were analyzed. Dose-response relationship, repetition, and duration of rtPA treatment and its effectiveness in aged clots were investigated. A significant relative end weight difference was found in rtPA treated clots compared to catheter alone () and placebo treated clots (). Dose-response analysis revealed 95% effective dose around 1 mg rtPA in 25 and 50 mL clots. Approximately 80% of relative clot lysis could be achieved after 15 min incubation. Lysis of aged clots was less effective. A new clot model for in vitro investigation was established. Our data suggest that current protocols for rtPA based ICH therapy may be optimized by using less rtPA at shorter incubation times. Naureen Keric, Julia Masomi-Bornwasser, Hendrik Müller-Werkmeister, Sven Rainer Kantelhardt, Jochem König, Oliver Kempski, and Alf Giese Copyright © 2017 Naureen Keric et al. All rights reserved. The Impact of Homocysteine, Vitamin B12, and Vitamin D Levels on Functional Outcome after First-Ever Ischaemic Stroke Thu, 23 Mar 2017 10:03:45 +0000 We explored the relationship between acute ischaemic stroke (IS) early functional outcome and serum levels of homocysteine, vitamin B12, and D in a noninterventional prospective clinical study. We enrolled 50 patients with first-ever IS and performed laboratory tests and functional assessment at three time points: on admission and three and six months after stroke. Modified Rankin Scale (mRS), NIHSS scale, and Barthel index (BI) scores were assessed in all participants by trained examiner blinded to laboratory data. Patients did not receive treatment that might alter laboratory data. Admission NIHSS correlated with homocysteine levels (, ), B12 level (, ), and vitamin D levels (, ). Functional outcome measures (BI and mRS) did not significantly correlate with homocysteine and vitamin D3 levels at 3 and 6 months. However, a positive correlation with vitamin B12 levels was detected for BI both at 3 and 6 months and mRS at 6 months. Higher serum vitamin B12 levels were associated with better functional outcome at follow-up. Merdin Markišić, Aleksandra M. Pavlović, and Dragan M. Pavlović Copyright © 2017 Merdin Markišić et al. All rights reserved. Optic Nerve Sheath Diameter Ultrasound Evaluation in Intensive Care Unit: Possible Role and Clinical Aspects in Neurological Critical Patients’ Daily Monitoring Tue, 21 Mar 2017 00:00:00 +0000 Background. The increase of the optic nerve sheath diameter (ONSD) is a reliable, noninvasive sonographic marker of intracranial hypertension. Aim of the study was to demonstrate the efficacy of ONSD evaluation, when monitoring neurocritical patients, to early identify malignant intracranial hypertension in patients with brain death (BD). Methods. Data from ultrasound ONSD evaluation have been retrospectively analyzed in 21 sedated critical patients with neurological diseases who, during their clinical course, developed BD. 31 nonneurological controls were used for standard ONSD reference. Results. Patients with neurological diseases, before BD, showed higher ONSD values than control group (CTRL: RT  cm; LT  cm; pre-BD: RT  cm; LT  cm; ) even without intracranial hypertension, evaluated with invasive monitoring. ONSD was further significantly markedly increased in respect to the pre-BD evaluation in neurocritical patients after BD, with mean values above 0.7 cm (RT  cm; LT  cm; ), with a corresponding dramatic raise in intracranial pressure. Logistic regression analysis showed a strong correlation between ONSD and ICP ( 0,895, ). Conclusions. ONSD is a reliable marker of intracranial hypertension, easy to be performed with a minimal training. Routine ONSD daily monitoring could be of help in Intensive Care Units when invasive intracranial pressure monitoring is not available, to early recognize intracranial hypertension and to suspect BD in neurocritical patients. M. Toscano, G. Spadetta, P. Pulitano, M. Rocco, V. Di Piero, O. Mecarelli, and E. Vicenzini Copyright © 2017 M. Toscano et al. All rights reserved. White Matter Integrity in Genetic High-Risk Individuals and First-Episode Schizophrenia Patients: Similarities and Disassociations Sun, 19 Mar 2017 00:00:00 +0000 White matter (WM) neuroimaging studies have shown varied findings at different stages of schizophrenia (SZ). Understanding these variations may elucidate distinct markers of genetic vulnerability and conversion to psychosis. To examine the similarities and differences in WM connectivity between those at-risk for and in early stages of SZ, a cross-sectional diffusion tensor imaging study of 48 individuals diagnosed with first-episode SZ (FE-SZ), 37 nonpsychotic individuals at a high genetic risk of SZ (GHR-SZ), and 67 healthy controls (HC) was conducted. Decreased fractional anisotropy (FA) in the corpus callosum (CC), anterior cingulum (AC), and uncinate fasciculus (UF) was observed in both the GHR-SZ and FE-SZ groups, while decreased FAs in the superior longitudinal fasciculus (SLF) and the fornix were only seen in the FE-SZ participants. Additionally, both GHR-SZ and FE-SZ showed worse executive performance than HC. The left SLF III FA was significantly positively correlated with hallucinations, and right SLF II was positively correlated with thought disorder. The presence of shared WM deficits in both FE-SZ and GHR-SZ individuals may reflect the genetic liability to SZ, while the disparate FA changes in the FE-SZ group may represent symptom-generating circuitry that mediates perceptual and cognitive disturbances of SZ and ultimately culminates in the onset of psychotic episodes. Yifang Zhou, Jie Liu, Naomi Driesen, Fay Womer, Kaiyuan Chen, Ye Wang, Xiaowei Jiang, Qian Zhou, Chuan Bai, Dahai Wang, Yanqing Tang, and Fei Wang Copyright © 2017 Yifang Zhou et al. All rights reserved. Tyrosine Phosphorylation of NR2B Contributes to Chronic Migraines via Increased Expression of CGRP in Rats Tue, 14 Mar 2017 00:00:00 +0000 Tyrosine phosphorylation of NR2B (NR2B-pTyr), a subunit of the N-methyl-D-aspartate (NMDA) receptor, has been reported to develop central sensitization and persistent pain in the spine, but its effect in chronic migraines has not been examined. We hypothesized that tyrosine phosphorylation of NR2B contributes to chronic migraines (CM) through calcitonin gene-related peptide (CGRP) in rats. Ninety-four male Sprague-Dawley rats were subjected to seven inflammatory soup (IS) injections. In a subset of animals, the time course and location of NR2B tyrosine phosphorylation were detected by western blot and immunofluorescence double staining. Another set of animals were given either genistein, vehicle, or genistein and recombinant CGRP. The mechanical threshold was measured, the expressions of NR2B-pTyr, NR2B, and CGRP were quantified using western blot, and nitric oxide (NO) was measured with the nitric acid reductase method. NR2B-pTyr expression, in neurons, peaked at 24 hours after CM. Genistein improved the mechanical threshold and reduced migraine attacks 24 and 72 hours after CM. Tyrosine phosphorylation of NR2B decreased the mechanical threshold and increased migraine attacks via upregulated CGRP expression in the rat model of CM. Thus, tyrosine phosphorylation of NR2B may be a potential therapeutic target for treatment of CM. Xiping Liang, Sha Wang, Guangcheng Qin, Jingmei Xie, Ge Tan, Jiying Zhou, Devin W. McBride, and Lixue Chen Copyright © 2017 Xiping Liang et al. All rights reserved. Hydrocephalus after Subarachnoid Hemorrhage: Pathophysiology, Diagnosis, and Treatment Wed, 08 Mar 2017 00:00:00 +0000 Hydrocephalus (HCP) is a common complication in patients with subarachnoid hemorrhage. In this review, we summarize the advanced research on HCP and discuss the understanding of the molecular originators of HCP and the development of diagnoses and remedies of HCP after SAH. It has been reported that inflammation, apoptosis, autophagy, and oxidative stress are the important causes of HCP, and well-known molecules including transforming growth factor, matrix metalloproteinases, and iron terminally lead to fibrosis and blockage of HCP. Potential medicines for HCP are still in preclinical status, and surgery is the most prevalent and efficient therapy, despite respective risks of different surgical methods, including lamina terminalis fenestration, ventricle-peritoneal shunting, and lumbar-peritoneal shunting. HCP remains an ailment that cannot be ignored and even with various solutions the medical community is still trying to understand and settle why and how it develops and accordingly improve the prognosis of these patients with HCP. Sheng Chen, Jinqi Luo, Cesar Reis, Anatol Manaenko, and Jianmin Zhang Copyright © 2017 Sheng Chen et al. All rights reserved. Medical and Interventional Therapy for Spontaneous Vertebral Artery Dissection in the Craniocervical Segment Wed, 22 Feb 2017 00:00:00 +0000 Background and Purpose. Spontaneous vertebral artery dissection (SVAD) is an important reason for posterior-circulation-ischemic stroke in the young and middle-aged population. Although some previous reports reveal a favorable outcome with conservative therapy, it is still controversial in the treatment of SVAD in some specific patients. Herein, we present our 10 years of clinical experience for SVAD at this location. Material and Methods. 20 patients with 20 SVADs in V2 and V3 segments were retrospectively studied. Clinical manifestations and imageology materials were collected and analyzed. All the patients underwent anticoagulation except for one patient because of contraindication. 14 patients underwent Wingspan stents implantation with general anesthesia. Results. In our sample, ischemia (infarction or transient ischemic attack, TIA) was found in all the patients. Angiographic stenosis and dissection aneurysm were the most common findings in the segments mentioned above. 19 of the patients (95%) got the excellent imageological and clinical outcomes. Conclusions. According to our experience in this group, although anticoagulation is effective in vertebral artery dissection, interventional therapy for SVADs in V2 and/or V3 segments is preferred in some specific patients. Stent with higher radial supporting and flexibility, such as Wingspan stent, is suggested. Guiyun Zhang and Zuoquan Chen Copyright © 2017 Guiyun Zhang and Zuoquan Chen. All rights reserved. Erythropoietin Modification Enhances the Protection of Mesenchymal Stem Cells on Diabetic Rat-Derived Schwann Cells: Implications for Diabetic Neuropathy Sun, 19 Feb 2017 00:00:00 +0000 Diabetes-triggered apoptosis of Schwann cells (SC) contributes to the degradation of diabetic peripheral neuropathy (DNP). In recent years, mesenchymal stem cells (MSC) were applied to DPN repair and it was demonstrated that paracrine secretion played a key role in neuroprotection exerted by MSC. Erythropoietin (EPO) is a potent cytokine capable of reducing apoptosis of SC. However, the expression of EPO in MSC is limited. In this study, we hypothesized that overexpression of EPO in MSC (EPO-MSC) may significantly improve their neuroprotective potentials. The EPO overexpression in MSC was achieved by lentivirus transduction. SC derived from the periphery nerve of diabetic rats were cocultured with MSC or EPO-MSC in normal or high glucose culture condition, respectively. In normal glucose culture condition, the overexpression of EPO in MSC promoted the MSC-induced restoration of SC from diabetic rats, including increases in GSH level and cell viability, decrease in TUNEL apoptosis, upregulation of antiapoptotic proteins, p-Akt, and Bcl-2, and downregulation of proapoptotic proteins, cleaved caspase-3, and Bax. The subsequent results in high glucose culture condition showed similar promotions achieved by EPO-MSC. Thus, it could be concluded that EPO-MSC possessed a potent potential in hampering apoptosis of SC, and the suppression was probably attributed to attenuating oxidative stress and regulating apoptosis related protein factors. Shuyun Zhang and Baolin Shi Copyright © 2017 Shuyun Zhang and Baolin Shi. All rights reserved. Evidence for Startle Effects due to Externally Induced Lower Limb Movements: Implications in Neurorehabilitation Thu, 16 Feb 2017 08:22:20 +0000 Passive limb displacement is routinely used to assess muscle tone. If we attempt to quantify muscle stiffness using mechanical devices, it is important to know whether kinematic stimuli are able to trigger startle reactions. Whether kinematic stimuli are able to elicit a startle reflex and to accelerate prepared voluntary movements (StartReact effect) has not been studied extensively to date. Eleven healthy subjects were suspended in an exoskeleton and were exposed to passive left knee flexion (KF) at three intensities, occasionally replaced by fast right KF. Upon perceiving the movement subjects were asked to perform right wrist extension (WE), assessed by extensor carpi radialis (ECR) electromyographic activity. ECR latencies were shortest in fast trials. Startle responses were present in most fast trials, yet being significantly accelerated and larger with right versus left KF, since the former occurred less frequently and thus less expectedly. Startle responses were associated with earlier and larger ECR responses (StartReact effect), with the largest effect again upon right KF. The results provide evidence that kinematic stimuli are able to elicit both startle reflexes and a StartReact effect, which depend on stimulus intensity and anticipation, as well as on the subjects’ preparedness to respond. Juan M. Castellote, Markus Kofler, Andreas Mayr, and Leopold Saltuari Copyright © 2017 Juan M. Castellote et al. All rights reserved. Phase I and Phase II Therapies for Acute Ischemic Stroke: An Update on Currently Studied Drugs in Clinical Research Tue, 14 Feb 2017 00:00:00 +0000 Acute ischemic stroke is a devastating cause of death and disability, consequences of which depend on the time from ischemia onset to treatment, the affected brain region, and its size. The main targets of ischemic stroke therapy aim to restore tissue perfusion in the ischemic penumbra in order to decrease the total infarct area by maintaining blood flow. Advances in research of pathological process and pathways during acute ischemia have resulted in improvement of new treatment strategies apart from restoring perfusion. Additionally, limiting the injury severity by manipulating the molecular mechanisms during ischemia has become a promising approach, especially in animal research. The purpose of this article is to review completed and ongoing phases I and II trials for the treatment of acute ischemic stroke, reviewing studies on antithrombotic, thrombolytic, neuroprotective, and antineuroinflammatory drugs that may translate into more effective treatments. Cesar Reis, Onat Akyol, Wing Mann Ho, Camila Araujo, Lei Huang, Richard Applegate II, and John H. Zhang Copyright © 2017 Cesar Reis et al. All rights reserved. Characteristics of Hemorrhagic Stroke following Spine and Joint Surgeries Tue, 10 Jan 2017 00:00:00 +0000 Hemorrhagic stroke can occur after spine and joint surgeries such as laminectomy, lumbar spinal fusion, tumor resection, and total joint arthroplasty. Although this kind of stroke rarely happens, it may cause severe consequences and high mortality rates. Typical clinical symptoms of hemorrhagic stroke after spine and joint surgeries include headache, vomiting, consciousness disturbance, and mental disorders. It can happen several hours after surgeries. Most bleeding sites are located in cerebellar hemisphere and temporal lobe. A cerebrospinal fluid (CSF) leakage caused by surgeries may be the key to intracranial hemorrhages happening. Early diagnosis and treatments are very important for patients to prevent the further progression of intracranial hemorrhages. Several patients need a hematoma evacuation and their prognosis is not optimistic. Fei Yang, Jianning Zhao, and Haidong Xu Copyright © 2017 Fei Yang et al. All rights reserved. Synaptic Reorganization of the Perisomatic Inhibitory Network in Hippocampi of Temporal Lobe Epileptic Patients Mon, 02 Jan 2017 12:20:30 +0000 GABAergic inhibition and particularly perisomatic inhibition play a crucial role in controlling the firing properties of large principal cell populations. Furthermore, GABAergic network is a key element in the therapy attempting to reduce epileptic activity. Here, we present a review showing the synaptic changes of perisomatic inhibitory neuronal subtypes in the hippocampus of temporal lobe epileptic patients, including parvalbumin- (PV-) containing and cannabinoid Type 1 (CB1) receptor-expressing (and mainly cholecystokinin-positive) perisomatic inhibitory cells, known to control hippocampal synchronies. We have examined the synaptic input of principal cells in the dentate gyrus and Cornu Ammonis region in human control and epileptic hippocampi. Perisomatic inhibitory terminals establishing symmetric synapses were found to be sprouted in the dentate gyrus. Preservation of perisomatic input was found in the Cornu Ammonis 1 and Cornu Ammonis 2 regions, as long as pyramidal cells are present. Higher density of CB1-immunostained terminals was found in the epileptic hippocampus of sclerotic patients, especially in the dentate gyrus. We concluded that both types of (PV- and GABAergic CB1-containing) perisomatic inhibitory cells are mainly preserved or showed sprouting in epileptic samples. The enhanced perisomatic inhibitory signaling may increase principal cell synchronization and contribute to generation of epileptic seizures and interictal spikes. Lucia Wittner and Zsófia Maglóczky Copyright © 2017 Lucia Wittner and Zsófia Maglóczky. All rights reserved. The Potential Therapeutic Effects of Artesunate on Stroke and Other Central Nervous System Diseases Tue, 27 Dec 2016 09:19:13 +0000 Artesunate is an important agent for cerebral malaria and all kinds of other severe malaria because it is highly efficient, lowly toxic, and well-tolerated. Loads of research pointed out that it had widespread pharmacological activities such as antiparasites, antitumor, anti-inflammation, antimicrobes activities. As we know, the occurrence and development of neurological disorders usually refer to intricate pathophysiologic mechanisms and multiple etiopathogenesis. Recent progress has also demonstrated that drugs with single mechanism and serious side-effects are not likely the candidates for treatment of the neurological disorders. Therefore, the pluripotent action of artesunate may result in it playing an important role in the prevention and treatment of these neurological disorders. This review provides an overview of primary pharmacological mechanism of artesunate and its potential therapeutic effects on neurological disorders. Meanwhile, we also briefly summarize the primary mechanisms of artemisinin and its derivatives. We hope that, with the evidence presented in this review, the effect of artesunate in prevention and curing for neurological disorders can be further explored and studied in the foreseeable future. Shilun Zuo, Qiang Li, Xin Liu, Hua Feng, and Yujie Chen Copyright © 2016 Shilun Zuo et al. All rights reserved. Alice in Wonderland Syndrome: A Clinical and Pathophysiological Review Tue, 27 Dec 2016 08:26:56 +0000 Alice in Wonderland Syndrome (AIWS) is a perceptual disorder, principally involving visual and somesthetic integration, firstly reported by Todd, on the literary suggestion of the strange experiences described by Lewis Carroll in Alice in Wonderland books. Symptoms may comprise among others aschematia and dysmetropsia. This syndrome has many different etiologies; however EBV infection is the most common cause in children, while migraine affects more commonly adults. Many data support a strict relationship between migraine and AIWS, which could be considered in many patients as an aura or a migraine equivalent, particularly in children. Nevertheless, AIWS seems to have anatomical correlates. According to neuroimaging, temporoparietal-occipital carrefour (TPO-C) is a key region for developing many of AIWS symptoms. The final part of this review aims to find the relationship between AIWS symptoms, presenting a pathophysiological model. In brief, AIWS symptoms depend on an alteration of TPO-C where visual-spatial and somatosensory information are integrated. Alterations in these brain regions may cause the cooccurrence of dysmetropsia and disorders of body schema. In our opinion, the association of other symptoms reported in literature could vary depending on different etiologies and the lack of clear diagnostic criteria. Giulio Mastria, Valentina Mancini, Alessandro Viganò, and Vittorio Di Piero Copyright © 2016 Giulio Mastria et al. All rights reserved. Assessment of Serum Nitrogen Species and Inflammatory Parameters in Relapsing-Remitting Multiple Sclerosis Patients Treated with Different Therapeutic Approaches Mon, 19 Dec 2016 07:07:23 +0000 The role of nitric oxide and its reactive derivatives () is well known in the pathogenesis of multiple sclerosis, which is an inflammatory disease while seems to be important in coordinating inflammatory response. The purpose of the present study was to assess serum as one of the nitrogen species and inflammatory parameters in relapsing-remitting multiple sclerosis patients and to compare the effectiveness of various types of disease-modifying therapies that reduce nitric oxide and inflammatory biomarkers. Elevated level was observed in patients who received the first-line disease-modifying therapy (interferons beta-1a and beta-1b) in comparison with the subjects treated with the second-line disease-modifying therapy (natalizumab; fingolimod) and healthy controls without significant differences in C-reactive protein and interleukin-1 beta. A negative correlation was observed between serum level and the duration of multiple sclerosis confirmed in the whole study population and in subjects treated with the first-line agents. Only serum , concentration could reveal a potential efficacy of disease-modifying therapy with a better reduction in level due to the second-line agents of disease-modifying therapy. Natalia Niedziela, Monika Adamczyk-Sowa, Jacek T. Niedziela, Bogdan Mazur, Ewa Kluczewska, Paweł Sowa, and Mariusz Gąsior Copyright © 2016 Natalia Niedziela et al. All rights reserved. A Review of Recent Advances in Neuroprotective Potential of 3-N-Butylphthalide and Its Derivatives Thu, 08 Dec 2016 13:41:19 +0000 The research of alternative treatment for ischemic stroke and degenerative diseases has always been a priority in neurology. 3-N-Butylphthalide (NBP), a family of compounds initially isolated from the seeds of Apium graveolens Linn., has shown significant neuroprotective effects. Previous extensive studies have demonstrated that NBP promotes a better poststroke outcome and exerts a multitargeted action on several mechanisms, from oxidative stress to mitochondrial dysfunction to apoptosis to inflammation. Additionally, recent findings on several neurological disorders have shown that NBP’s beneficial effects extend beyond the management of stroke. However, despite the increasing number of studies toward a better understanding and the rapid advances made in therapeutic options, to date, dl-3-N-butylphthalide, a synthetic variation of l-3-N-butylphthalide, remains the only clinically approved anti-ischemic agent in China, stressing the difficulties for a viable and effective transition from experimental to clinical practice. Events indicate that NBP, due to its multitargeted effect and the adaptability of its basic structure, can be an important game changer and a precursor to a whole new therapeutic approach to several neurological conditions. The present review discusses recent advances pertaining to the neuroprotective mechanisms of NBP-derived compounds and the possibility of their clinical implementation in the management of various neurological conditions. Idriss Ali Abdoulaye and Yi Jing Guo Copyright © 2016 Idriss Ali Abdoulaye and Yi Jing Guo. All rights reserved. Lamotrigine Reduces Inflammatory Response and Ameliorates Executive Function Deterioration in an Alzheimer’s-Like Mouse Model Wed, 30 Nov 2016 13:36:14 +0000 Alzheimer’s disease (AD) has been described in the literature, to be associated with impairment of executive function which develops early in the course of disease, and an effective treatment for this clinical feature remains elusive. Preclinical studies have implied that lamotrigine, an antiepileptic agent, could be a potential treatment for executive dysfunction in AD patients. Although there have been promising results in previous studies with lamotrigine, executive function has never been measured using animal models. The aim of the present study was to evaluate the effects of lamotrigine on executive function and determine whether lamotrigine can attenuate inflammatory response in an AD mouse model. Nontransgenic and transgenic mice were treated with lamotrigine (0 or 30 mg/kg/day) in a standard laboratory chow diet starting at 3 months of age. After 6 months of continuous lamotrigine administration, there was a marked improvement in executive function and a significant attenuation in the expression of proinflammatory cytokines. These results suggest that lamotrigine could ameliorate executive dysfunction and brain inflammatory response in the mouse model of AD and early lamotrigine intervention may be a promising therapeutic strategy for AD. Kexin Wang, Alejandro Fernandez-Escobar, Shuhong Han, Ping Zhu, Jun-Hui Wang, and Yu Sun Copyright © 2016 Kexin Wang et al. All rights reserved. Clinical Comparison of Outcomes of Early versus Delayed Carotid Artery Stenting for Symptomatic Cerebral Watershed Infarction due to Stenosis of the Proximal Internal Carotid Artery Mon, 28 Nov 2016 12:20:50 +0000 The aim of this study was to compare the clinical outcomes of early versus delayed carotid artery stenting (CAS) for symptomatic cerebral watershed infarction (sCWI) patients due to stenosis of the proximal internal carotid artery. We retrospectively collected clinical data of those who underwent early or delayed CAS from March 2011 to April 2014. The time of early CAS and delayed CAS was within a week of symptom onset and after four weeks from symptom onset. Clinical data such as second stroke, the National Institutes of Health Stroke Scale (NHISS) score, and modified Rankin Scale (mRS) score and periprocedural complications were collected. The rate of second stroke in early CAS group is lower when compared to that of delayed CAS group. There was no significant difference regarding periprocedural complications in both groups. There was a significant difference regarding mean NHISS score 90 days after CAS in two groups. Early CAS group had a significant better good outcome (mRS score ≤ 2) than delayed CAS group. We suggest early CAS for sCWI due to severe proximal internal carotid artery stenosis as it provides lower rate of second stroke, comparable periprocedural complications, and better functional outcomes compared to that of delayed CAS. Huakun Liu, Jianfeng Chu, Lei Zhang, Chaolai Liu, Zhongrui Yan, and Shengnian Zhou Copyright © 2016 Huakun Liu et al. All rights reserved. Left Atrial Enlargement on Transthoracic Echocardiography Predicts Left Atrial Thrombus on Transesophageal Echocardiography in Ischemic Stroke Patients Sun, 16 Oct 2016 13:47:58 +0000 Background. Transesophageal echocardiogram (TEE) is superior to transthoracic echocardiogram (TTE) in detecting left atrial thrombus (LAT), a risk factor for stroke, but is costly and invasive, carrying a higher risk for complications. Aims. To determine the utility of using left atrial enlargement (LAE) on TTE to predict LAT on TEE. Methods. AIS patients who presented in and underwent both TTE and TEE were identified from our prospective stroke registry. Analysis consisted of multivariate logistic regression with propensity score adjustment and receiver operating characteristic (ROC) area under the curve (AUC) analyses. Results. 219 AIS patients underwent both TTE and TEE. LAE on TTE was detected in 113 (51.6%) of AIS patients. Patients with LAE on TTE had higher proportion of LAT on TEE (8.4% versus 1.0%, ). LAE on TTE predicted increased odds of LAT on TEE (, 95% CI 1.04–74.83, ). The sensitivity and specificity for LAT on TEE by LAE on TEE were 88.89% and 52.20%, respectively (, 95% CI 0.5906–0.8202). Conclusions. LAE on TTE can predict LAT detected on TEE in nearly 90% of patients. This demonstrates the utility of LAE on TTE as a potential screening tool for LAT, potentially limiting unneeded costs and complications associated with TEE. James Anaissie, Dominique Monlezun, A. Seelochan, James E. Siegler, Maria Chavez-Keatts, Jonathan Tiu, Denise Pineda, Alexander George, Amir Shaban, Nidal Abi Rafeh, Laurie Schluter, Sheryl Martin-Schild, and Ramy El Khoury Copyright © 2016 James Anaissie et al. All rights reserved. Obstructive Sleep Apnea in Women: Specific Issues and Interventions Tue, 06 Sep 2016 14:17:53 +0000 Obstructive sleep apnea (OSA) has traditionally been seen as a male disease. However, the importance of OSA in women is increasingly being recognized, along with a number of significant gender-related differences in the symptoms, diagnosis, consequences, and treatment of OSA. Women tend to have less severe OSA than males, with a lower apnea-hypopnea index (AHI) and shorter apneas and hypopneas. Episodes of upper airway resistance that do not meet the criteria for apneas are more common in women. Prevalence rates are lower in women, and proportionally fewer women receive a correct diagnosis. Research has also documented sex differences in the upper airway, fat distribution, and respiratory stability in OSA. Hormones are implicated in some gender-related variations, with differences between men and women in the prevalence of OSA decreasing as age increases. The limited data available suggest that although the prevalence and severity of OSA may be lower in women than in men, the consequences of the disease are at least the same, if not worse for comparable degrees of severity. Few studies have investigated gender differences in the effects of OSA treatment. However, given the differences in physiology and presentation, it is possible that personalized therapy may provide more optimal care. Alison Wimms, Holger Woehrle, Sahisha Ketheeswaran, Dinesh Ramanan, and Jeffery Armitstead Copyright © 2016 Alison Wimms et al. All rights reserved. Corrigendum to “Plasma Albumin Induces Cytosolic Calcium Oscilations and DNA Synthesis in Human Cultured Astrocytes” Wed, 27 Jul 2016 07:22:09 +0000 Lorena Vega-Zelaya, Ivan Herrera-Peco, Guillermo J. Ortega, Rafael G. Sola, and Jesús Pastor Copyright © 2016 Lorena Vega-Zelaya et al. All rights reserved. Relation between Resting State Front-Parietal EEG Coherence and Executive Function in Parkinson’s Disease Tue, 28 Jun 2016 15:05:15 +0000 Objective. To assess the relation between executive dysfunction (ED) in Parkinson’s disease (PD) and resting state functional connectivity evaluated using electroencephalography (EEG) coherence. Methods. Sixty-eight nondemented sporadic PD patients were assessed using the Behavioural Assessment of the Dysexecutive Syndrome (BADS) to evaluate executive function. EEG coherence in the left frontoparietal electrode pair (F3-P3) and the right frontoparietal electrode pair (F4-P4) was analyzed in the alpha and theta range. The BADS scores were compared across the coherence groups, and the multiple logistic regression analysis was performed to assess the contribution of confounders. Results. The standardized BADS score was significantly lower in the low F3-P3 coherence group in the alpha range (Mann-Whitney test, ), though there was no difference between F4-P4 coherence group in the alpha range, F3-P3, and F4-P4 coherence groups in the theta range and the standardized BADS score. The multiple logistic regression analysis revealed the significant relation between the F3-P3 coherence group in alpha range and age-controlled standardized BADS score (, 95% CI = 1.002–1.062). Conclusion. The decrease in resting state functional connectivity between the frontal and parietal cortices especially in the left side is related to ED in PD. Hiroko Teramoto, Akihiko Morita, Satoko Ninomiya, Takayoshi Akimoto, Hiroshi Shiota, and Satoshi Kamei Copyright © 2016 Hiroko Teramoto et al. All rights reserved. Effects of Shaoyao-Gancao Decoction on Infarcted Cerebral Cortical Neurons: Suppression of the Inflammatory Response following Cerebral Ischemia-Reperfusion in a Rat Model Mon, 20 Jun 2016 09:17:20 +0000 The mechanisms by which Shaoyao-Gancao decoction (SGD) inhibits the production of inflammatory cytokines in serum and brain tissue after cerebral ischemia-reperfusion (CI-RP) in rats were investigated. A right middle cerebral artery occlusion was used to induce CI-RP after which the rats were divided into model (), SGD (), clopidogrel () and sham operated () groups. The Bederson scale was used to evaluate changes in behavioral indices. The levels of IL-1β, TNF-α, MCP-1, IL-10, RANTES, VEGF, and TGF-β1 in the serum and infarcted brain tissues were measured. Nissl body and immunohistochemical staining methods were used to detect biochemical changes in neurons, microglial cells, and astrocytes. Serum levels of VEGF, TNF-α, MCP-1, IL-1β, and IL-10 increased significantly 24 h after CI-RP. In brain tissue, levels of TNF-α and IL-1β significantly increased 24 h after CI-RP, whereas levels of TGF-β1 and MCP-1 were significantly higher 96 h after CI-RP (). SGD or clopidogrel after CI-RP reduced TNF-α and IL-1β levels in brain tissue and serum levels of MCP-1, IL-1β, and IL-10. SGD increased the number of NeuN-positive cells in infarcted brain tissue and reduced the number of IBA1-positive and GFAP-positive cells. The efficacy of SGD was significantly higher than that of clopidogrel. Ying Zhang, Xinling Jia, Jian Yang, Qing Li, Guofeng Yan, Zhongju Xu, and Jingye Wang Copyright © 2016 Ying Zhang et al. All rights reserved. Information in a Network of Neuronal Cells: Effect of Cell Density and Short-Term Depression Tue, 14 Jun 2016 11:39:38 +0000 Neurons are specialized, electrically excitable cells which use electrical to chemical signals to transmit and elaborate information. Understanding how the cooperation of a great many of neurons in a grid may modify and perhaps improve the information quality, in contrast to few neurons in isolation, is critical for the rational design of cell-materials interfaces for applications in regenerative medicine, tissue engineering, and personalized lab-on-a-chips. In the present paper, we couple an integrate-and-fire model with information theory variables to analyse the extent of information in a network of nerve cells. We provide an estimate of the information in the network in bits as a function of cell density and short-term depression time. In the model, neurons are connected through a Delaunay triangulation of not-intersecting edges; in doing so, the number of connecting synapses per neuron is approximately constant to reproduce the early time of network development in planar neural cell cultures. In simulations where the number of nodes is varied, we observe an optimal value of cell density for which information in the grid is maximized. In simulations in which the posttransmission latency time is varied, we observe that information increases as the latency time decreases and, for specific configurations of the grid, it is largely enhanced in a resonance effect. Valentina Onesto, Carlo Cosentino, Enzo Di Fabrizio, Mario Cesarelli, Francesco Amato, and Francesco Gentile Copyright © 2016 Valentina Onesto et al. All rights reserved. Effect of TRPV4-p38 MAPK Pathway on Neuropathic Pain in Rats with Chronic Compression of the Dorsal Root Ganglion Sun, 05 Jun 2016 12:37:57 +0000 The aim of this study was to investigate the relationships among TRPV4, p38, and neuropathic pain in a rat model of chronic compression of the dorsal root ganglion. Mechanical allodynia appeared after CCD surgery, enhanced via the intrathecal injection of 4α-phorbol 12,13-didecanoate (4α-PDD, an agonist of TRPV4) and anisomycin (an agonist of p38), but was suppressed by Ruthenium Red (RR, an inhibitor of TRPV4) and SB203580 (an inhibitor of p38). The protein expressions of p38 and P-p38 were upregulated by 4α-PDD and anisomycin injection but reduced by RR and SB203580. Moreover, TRPV4 was upregulated by 4α-PDD and SB203580 and downregulated by RR and anisomycin. In DRG tissues, the numbers of TRPV4- or p38-positive small neurons were significantly changed in CCD rats, increased by the agonists, and decreased by the inhibitors. The amplitudes of ectopic discharges were increased by 4α-PDD and anisomycin but decreased by RR and SB203580. Collectively, these results support the link between TRPV4 and p38 and their intermediary role for neuropathic pain in rats with chronic compression of the dorsal root ganglion. Yu-Juan Qu, Xiao Zhang, Zhen-Zhen Fan, Juan Huai, Yong-Bo Teng, Yang Zhang, and Shou-Wei Yue Copyright © 2016 Yu-Juan Qu et al. All rights reserved. The Vulnerability of Vessels Involved in the Role of Embolism and Hypoperfusion in the Mechanisms of Ischemic Cerebrovascular Diseases Sun, 29 May 2016 12:57:27 +0000 Accurate definition and better understanding of the mechanisms of stroke are crucial as this will guide the effective care and therapy. In this paper, we review the previous basic and clinical researches on the causes or mechanisms of ischemic cerebrovascular diseases (ICVD) and interpret the correlation between embolism and hypoperfusion based on vascular stenosis and arterial intimal lesions. It was suggested that if there is no embolus (dynamic or in situ emboli), there might be no cerebral infarction. Three kinds of different clinical outcomes of TIA were theoretically interpreted based on its mechanisms. We suppose that there is a correlation between embolism and hypoperfusion, and which mechanisms (hypoperfusion or hypoperfusion induced microemboli) playing the dominant role in each type of ICVD depends on the unique background of arterial intimal lesions (the vulnerability of vessels). That is to say, the vulnerability of vessels is involved in the role of embolism and hypoperfusion in the mechanisms of ischemic cerebrovascular diseases. This inference might enrich and provide better understandings for the underlying etiologies of ischemic cerebrovascular events. Yong Peng Yu and Lan Tan Copyright © 2016 Yong Peng Yu and Lan Tan. All rights reserved. Cognitive Changes following Bilateral Deep Brain Stimulation of Subthalamic Nucleus in Parkinson’s Disease: A Meta-Analysis Mon, 23 May 2016 06:36:51 +0000 Background. Nowadays, it has been largely acknowledged that deep brain stimulation of subthalamic nucleus (STN DBS) can alleviate motor symptoms of Parkinson’s disease, but its effects on cognitive function remain unclear, which are not given enough attention by many clinical doctors and researchers. To date, 3 existing meta-analyses focusing on this issue included self-control studies and have not drawn consistent conclusions. The present study is the first to compare effect sizes of primary studies that include control groups, hoping to reveal the net cognitive outcomes after STN DBS and the clinical significance. Methods. A structured literature search was conducted using strict criteria. Only studies with control group could be included. Data on age, duration of disease, levodopa equivalent dosage (LED), and multiple cognitive scales were collected and pooled. Results. Of 172 articles identified, 10 studies (including 3 randomized controlled trials and 7 nonrandomized controlled studies) were eligible for inclusion. The results suggest that STN DBS results in decreased global cognition, memory, verbal fluency, and executive function compared with control group. No significant difference is found in other cognitive domains. Conclusions. STN DBS seems relatively safe with respect to cognitive function, and further studies should focus on the exact mechanisms of possible verbal deterioration after surgery in the future. Yi Xie, Xiangyu Meng, Jinsong Xiao, Jie Zhang, and Junjian Zhang Copyright © 2016 Yi Xie et al. All rights reserved. Deposition of BACE-1 Protein in the Brains of APP/PS1 Double Transgenic Mice Wed, 18 May 2016 06:33:53 +0000 The main causes of Alzheimer’s disease remain elusive. Previous data have implicated the BACE-1 protein as a central player in the pathogenesis of Alzheimer’s disease. However, many inhibitors of BACE-1 have failed during preclinical and clinical trials for AD treatment. Therefore, uncovering the exact role of BACE-1 in AD may have significant impact on the future development of therapeutic agents. Three- and six-month-old female APP/PS1 double transgenic mice were used to study abnormal accumulation of BACE-1 protein in brains of mice here. Immunofluorescence, immunohistochemistry, and western blot were performed to measure the distributing pattern and expression level of BACE-1. We found obvious BACE-1 protein accumulation in 3-month-old APP/PS1 mice, which had increased by the time of 6 months. Coimmunostaining results showed BACE-1 surrounded amyloid plaques in brain sections. The abnormal protein expression might not be attributable to the upregulation of BACE-1 protein, as no significant difference of protein expression was observed between wild-type and APP/PS1 mice. With antibodies against BACE-1 and CD31, we found a high immunoreactive density of BACE-1 protein on the outer layer of brain blood vessels. The aberrant distribution of BACE-1 in APP/PS1 mice suggests BACE-1 may be involved in the microvascular abnormality of AD. Gang Luo, Hongxia Xu, Yinuo Huang, Dapeng Mo, Ligang Song, Baixue Jia, Bo Wang, Zhanqiang Jin, and Zhongrong Miao Copyright © 2016 Gang Luo et al. All rights reserved. Corrigendum to “Magnesium Lithospermate B, an Active Extract of Salvia miltiorrhiza, Mediates sGC/cGMP/PKG Translocation in Experimental Vasospasm” Tue, 10 May 2016 08:14:10 +0000 Chih-Zen Chang, Shu-Chuan Wu, and Aij-Lie Kwan Copyright © 2016 Chih-Zen Chang et al. All rights reserved. Reducing the Cost of the Diagnostic Odyssey in Early Onset Epileptic Encephalopathies Sun, 08 May 2016 14:24:29 +0000 Whole exome sequencing (WES) has revolutionized the way we think about and diagnose epileptic encephalopathies. Multiple recent review articles discuss the benefits of WES and suggest various algorithms to follow for determining the etiology of epileptic encephalopathies. Incorporation of WES in these algorithms is leading to the discovery of new genetic diagnoses of early onset epileptic encephalopathies (EOEEs) at a rapid rate; however, WES is not yet a universally utilized diagnostic tool. Clinical WES may be underutilized due to provider discomfort in ordering the test or perceived costliness. At our hospital WES is not routinely performed for patients with EOEE due to limited insurance reimbursement. In fact for any patient with noncommercial insurance (Medicaid) the institution does not allow sending out WES as this is not “established”/“proven to be highly useful and cost effective”/“approved test” in patients with epilepsy. Recently, we performed WES on four patients from three families and identified novel mutations in known epilepsy genes in all four cases. These patients had State Medicaid as their insurance carrier and were followed up for several years for EOEE while being worked up using the traditional/approved testing methods. Following a recently proposed diagnostic pathway, we analyzed the cost savings (US dollars) that could be accrued if WES was performed earlier in the diagnostic odyssey. This is the first publication that addresses the dollar cost of traditional testing in EOEE as performed in these four cases versus WES and the potential cost savings. Charuta Joshi, Diana L. Kolbe, M. Adela Mansilla, Sara O. Mason, Richard J. H. Smith, and Colleen A. Campbell Copyright © 2016 Charuta Joshi et al. All rights reserved. Conditional Granger Causality Analysis of Effective Connectivity during Motor Imagery and Motor Execution in Stroke Patients Wed, 20 Apr 2016 06:26:22 +0000 Aims. Motor imagery has emerged as a promising technique for the improvement of motor function following stroke, but the mechanism of functional network reorganization in patients during this process remains unclear. The aim of this study is to evaluate the cortical motor network patterns of effective connectivity in stroke patients. Methods. Ten stroke patients with right hand hemiplegia and ten normal control subjects were recruited. We applied conditional Granger causality analysis (CGCA) to explore and compare the functional connectivity between motor execution and motor imagery. Results. Compared with the normal controls, the patient group showed lower effective connectivity to the primary motor cortex (M1), the premotor cortex (PMC), and the supplementary motor area (SMA) in the damaged hemisphere but stronger effective connectivity to the ipsilesional PMC and M1 in the intact hemisphere during motor execution. There were tighter connections in the cortical motor network in the patients than in the controls during motor imagery, and the patients showed more effective connectivity in the intact hemisphere. Conclusions. The increase in effective connectivity suggests that motor imagery enhances core corticocortical interactions, promotes internal interaction in damaged hemispheres in stroke patients, and may facilitate recovery of motor function. Li Wang, Jingna Zhang, Ye Zhang, Rubing Yan, Hongliang Liu, and Mingguo Qiu Copyright © 2016 Li Wang et al. All rights reserved. Skeletal Muscle Remodelling as a Function of Disease Progression in Amyotrophic Lateral Sclerosis Mon, 18 Apr 2016 08:17:09 +0000 Muscle weakness is considered the pivotal sign of amyotrophic lateral sclerosis (ALS). Knowledge about the skeletal muscle degeneration/regeneration process and the myogenic potential is limited in ALS patients. Therefore, we investigate these processes in a time course perspective by analysing skeletal muscle biopsies from ALS patients collected before and after a 12-week period of normal daily activities and compare these with healthy age-matched control tissue. We do this by evaluating mRNA and protein (immunohistochemical) markers of regeneration, neurodegeneration, myogenesis, cell cycle regulation, and inflammation. Our results show morphological changes indicative of active denervation and reinnervation and an increase in small atrophic fibres. We demonstrate differences between ALS and controls in pathways controlling skeletal muscle homeostasis, cytoskeletal and regenerative markers, neurodegenerative factors, myogenic factors, cell cycle determinants, and inflammatory markers. Our results on Pax7 and MyoD protein expression suggest that proliferation and differentiation of skeletal muscle stem cells are affected in ALS patients, and the myogenic processes cannot overcome the denervation-induced wasting. L. Jensen, L. H. Jørgensen, R. D. Bech, U. Frandsen, and H. D. Schrøder Copyright © 2016 L. Jensen et al. All rights reserved. Hemispheric Coherence in ASD with and without Comorbid ADHD and Anxiety Mon, 04 Apr 2016 13:17:17 +0000 There is a growing body of evidence suggesting that altered brain connectivity may be a defining feature of disorders such as autism spectrum disorder (ASD), anxiety, and ADHD. This study investigated whether resting state functional connectivity, measured by 128-channel EEG oscillation coherence, differs between developmental disorders. Analyses were conducted separately on groups with and without comorbid conditions. Analyses revealed increased coherence across central electrodes over the primary motor cortex and decreased coherence in the frontal lobe networks in those with ASD compared to neurotypical controls. There was increased coherence in occipital lobe networks in the ADHD group compared to other groups. Symptoms of generalised anxiety were positively correlated with both frontal-occipital intrahemispheric (alpha only) coherence and occipital interhemispheric coherence (alpha, approaching theta band). The patterns of coherence in the ASD pure group were different when comorbid conditions were included in the analyses, suggesting that aberrant coherence in the frontal and central areas of the brain is specifically associated with ASD. Our findings support the idea that comorbid conditions are additive, rather than being symptoms of the same disorder. A. Saunders, I. J. Kirk, and K. E. Waldie Copyright © 2016 A. Saunders et al. All rights reserved. Defining Prolonged Length of Acute Care Stay for Surgically and Conservatively Treated Patients with Spontaneous Intracerebral Hemorrhage: A Population-Based Analysis Sun, 27 Mar 2016 07:27:17 +0000 Background. The definition of prolonged length of stay (LOS) during acute care remains unclear among surgically and conservatively treated patients with intracerebral hemorrhage (ICH). Methods. Using a population-based quality assessment registry, we calculated change points in LOS for surgically and conservatively treated patients with ICH. The influence of comorbidities, baseline characteristics at admission, and in-hospital complications on prolonged LOS was evaluated in a multivariate model. Results. Overall, 13272 patients with ICH were included in the analysis. Surgical therapy of the hematoma was documented in 1405 (10.6%) patients. Change points for LOS were 22 days (CI: 8, 22; CL 98%) for surgically treated patients and 16 days (CI: 16, 16; CL: 99%) for conservatively treated patients. Ventilation therapy was related to prolonged LOS in surgically (OR: 2.2, 95% CI: 1.5–3.1; ) and conservatively treated patients (OR: 2.5, 95% CI: 2.2–2.9; ). Two or more in-hospital complications in surgical patients (OR: 2.7, 95% CI: 2.1–3.5) and ≥1 in conservative patients (OR: 3.0, 95% CI: 2.7–3.3) were predictors of prolonged LOS. Conclusion. The definition of prolonged LOS after ICH could be useful for several aspects of quality management and research. Preventing in-hospital complications could decrease the number of patients with prolonged LOS. Marco Stein, Björn Misselwitz, Gerhard F. Hamann, Malgorzata A. Kolodziej, Marcus H. T. Reinges, and Eberhard Uhl Copyright © 2016 Marco Stein et al. All rights reserved. Longitudinal Assessment of Motor Recovery of Contralateral Hand after Basal Ganglia Infarction Using Functional Magnetic Resonance Imaging Wed, 16 Mar 2016 09:56:55 +0000 We used functional fMRI to study the brain activation during active finger movements at different time points during the recovery phase following basal ganglia infarction. Four hemiplegic patients with basal ganglia infarction were serially evaluated at different time points spanning the acute and chronic phase using fMRI. To evaluate motor recovery, the patients were asked to perform functional tasks arranged in a block design manner with their hand. On follow-up (chronic phase), three patients achieved significant recovery of motor function of affected limbs. Activation of bilateral sensorimotor cortex (SMC) was observed in two of these patients, while activation of cerebellum was observed in all patients. No remarkable recovery of motor function was noted in one patient with left basal ganglia infarction. In this patient, the activation domain was located in SMC of both sides in acute phase and in ipsilateral SMC in chronic phase. Contralateral SMC appears to be involved in the functional rehabilitation following basal ganglia infarction. The cerebellum may act as an intermediary during functional recovery following basal ganglia infarction. The activation domain associated with active finger movement may be bilateral in acute phase; one patient was ipsilateral in the chronic stage. Yue Fu, Quan Zhang, Chunshui Yu, Jing Zhang, Ning Wang, Shanhuai Zuo, and Ningnannan Zhang Copyright © 2016 Yue Fu et al. All rights reserved. Altered Resting-State Amygdala Functional Connectivity after Real-Time fMRI Emotion Self-Regulation Training Sun, 21 Feb 2016 11:41:18 +0000 Real-time fMRI neurofeedback (rtfMRI-nf) is a promising tool for enhancing emotion regulation capability of subjects and for the potential alleviation of neuropsychiatric disorders. The amygdala is composed of structurally and functionally distinct nuclei, such as the basolateral amygdala (BLA) and centromedial amygdala (CMA), both of which are involved in emotion processing, generation, and regulation. However, the effect of rtfMRI-nf on the resting-state functional connectivity (rsFC) of BLA and CMA remains to be elucidated. In our study, participants were provided with ongoing information on their emotion states by using real-time multivariate voxel pattern analysis. Results showed that participants presented significantly increased rsFC of BLA and CMA with prefrontal cortex, rostral anterior cingulate cortex, and some others related to emotion after rtfMRI-nf training. The findings provide important evidence for the emotion regulation effectiveness of rtfMRI-nf training and indicate its usefulness as a tool for the self-regulation of emotion. Zhonglin Li, Li Tong, Min Guan, Wenjie He, Linyuan Wang, Haibin Bu, Dapeng Shi, and Bin Yan Copyright © 2016 Zhonglin Li et al. All rights reserved. Neurovascular Disorders: Novel Perspectives on Pathogenesis, Diagnosis, and Treatment Mon, 18 Jan 2016 13:05:08 +0000 David Hasan, Nohra Chalouhi, Aaron S. Dumont, Robert M. Starke, and Pascal Jabbour Copyright © 2016 David Hasan et al. All rights reserved. Electrocardiography as the First Step for the Further Examination of Cardiac Involvement in Myasthenia Gravis Sun, 17 Jan 2016 16:31:58 +0000 Introduction. Cardiac involvement of myasthenia gravis (MG) accompanies a poor prognosis. In the present study, we aimed to investigate the relationship between ECG abnormality and cardiac involvement. Methods. Of 178 patients diagnosed with MG between 2001 and 2013 at our hospital, we retrospectively analyzed consecutive 58 patients who underwent both ECG and echocardiography and without underlying cardiovascular disease. ECG abnormalities were defined by computer-assigned Minnesota-codes. Cardiac damage was defined as either (1) ejection fraction (EF) <55% on echocardiography or (2) elevated , the ratio of mitral velocity to early diastolic velocity of the mitral annulus >8 on echocardiography. Results. Thirty-three patients (56.8%) had ECG abnormality. An elevated was observed in patients with ECG abnormality compared to those without ECG abnormality (, , resp., ). Among patients with ECG abnormality, 14 of 15 patients showed cardiac damage. Among patients without ECG abnormality, 6 of 33 patients showed cardiac damage (). Reduced EF was observed in five patients (8.6%) with ECG abnormality and none in patients without ECG abnormality. Conclusions. ECG may aid as the first step for the further examination of cardiac damage in patients with MG. Takao Kato, Sayako Hirose, Shogo Kumagai, Akihiko Ozaki, Sadayuki Matsumoto, and Moriaki Inoko Copyright © 2016 Takao Kato et al. All rights reserved. Encoding and Recognition Processing of Chinese Characters: A Functional Magnetic Resonance Imaging Study Mon, 11 Jan 2016 09:21:25 +0000 This study aimed to investigate the conceptual memory processes that underlie encoding and recognition processing of Chinese characters. Healthy participants () performed a semantic-relatedness paradigm using categorically related logogram pairs from four different categories (fruit, animal, tool, and clothing). During intentional encoding, subjects were instructed to make semantic judgments and select category-correlated features to bind and memorize logogram pairs. During recognition, subjects were asked to recognize the memorized items. The MATLAB software and spatial clustering analysis were used for image data processing. Compared with baseline, encoding mainly activated BA13, with significant effects in BA6/8/9/46/45/47, BA24, BA7/39/40, BA37/20, and BA18/19; meanwhile, recognition mainly activated BA6/8/9/10/13/45/46/47, BA31, BA7/40, and BA18/19. Compared with recognition, encoding activated BA18/19/37/20/36 with a peak activation area in BA18. Compared with encoding, recognition significantly activated BA7, BA31/32, and BA10. In conclusion, distributed networks of discrete cortical regions with distinct roles are active during semantic processing of logograms. The ventral occipitotemporal and inferior frontal regions display increased levels of encoding-related activity. The dorsal medial brain regions, including the superior frontal gyrus and occipitoparietal regions, are associated with recognition-related activity. Jinlong Zheng, Siyun Shu, Bin Wang, Xiangyang Tian, Xinmin Bao, Yongming Wu, Zengqiang Zhang, Xiangyang Cao, and Lin Ma Copyright © 2016 Jinlong Zheng et al. All rights reserved. Erratum to “Need for Scientific Rigor in the Evaluation of Minimally Invasive Alternative Procedures” Sun, 03 Jan 2016 10:51:44 +0000 Johnny Padulo and Luca Paolo Ardigò Copyright © 2016 Johnny Padulo and Luca Paolo Ardigò. All rights reserved. New Trends in Instrumentation and Complex Techniques in Spine Surgery Wed, 30 Dec 2015 12:22:21 +0000 Alessandro Landi, Roberto Delfini, Alessandro Ricci, Andrea Barbanera, Giulio Anichini, and Christian Brogna Copyright © 2015 Alessandro Landi et al. All rights reserved. Somatosensory and Brainstem Auditory Evoked Potentials Assessed between 4 and 7 Days after Severe Stroke Onset Predict Unfavorable Outcome Mon, 21 Dec 2015 05:30:22 +0000 Our objective was to explore the best predictive timing of short-latency somatosensory evoked potentials (SLSEP) and brainstem auditory evoked potentials (BAEP) for unfavorable outcomes in patients with early stage severe stroke. One hundred fifty-six patients with acute severe supratentorial stroke were monitored according to SLSEP, BAEP, and the Glasgow Coma Scale (GCS) at 1–3 days and 4–7 days after the onset of stroke. All patients were followed up for outcomes at 6 months after onset using the modified Rankin Scale (mRS), with a score of 5-6 considered unfavorable. The predictive values of SLSEP, BAEP, and the GCS at 1–3 days were compared with 4–7 days after onset. Our results show that, according to the analysis of prognostic authenticity, the predictive values of SLSEP and BAEP at 4–7 days after stroke onset improved when compared with the values at 1–3 days for unfavorable outcomes. Most of the patients with change of worsening evoked potentials from 1–3 days to 4–7 days after onset had unfavorable outcomes. In conclusion, SLSEP and BAEP assessed at 4–7 days after onset predicted unfavorable outcomes for acute severe stroke patients. The worsening values of SLSEP and BAEP between 1–3 days and 4–7 days also present a prognostic value. Yan Zhang, Ying Ying Su, Shu Ying Xiao, and Yi Fei Liu Copyright © 2015 Yan Zhang et al. All rights reserved. Iron Deposition Is Positively Related to Cognitive Impairment in Patients with Chronic Mild Traumatic Brain Injury: Assessment with Susceptibility Weighted Imaging Sun, 20 Dec 2015 16:06:43 +0000 Background. This study aimed to evaluate the usability of SWI in assessment of brain iron to detect cognitive dysfunction in patients with chronic mild traumatic brain injury (mTBI). Methods. 39 patients with mTBI and 37 normal controls were given the Mini-Mental State Examination (MMSE) and underwent SWI scanning at least 6 months after injury. Angle radian values were calculated with phase images. The angle radian values were compared between groups using analysis of covariance, and their association with MMSE scores was analyzed using Spearman correlations. Results. Significantly higher angle radian values () were found in the head of the caudate nucleus, the lenticular nucleus, the hippocampus, the thalamus, the right substantia nigra, the red nucleus, and the splenium of the corpus callosum (SCC) in the mTBI group, compared to the control group. MMSE scores were negatively correlated with angle radian values in the right substantia nigra (, ). Conclusions. Patients with chronic mTBI might have abnormally high accumulations of iron, and their MMSE scores are negatively associated with angle radian values in the right substantia nigra, suggesting a role of SWI in the assessment of cognitive impairments of these patients. Liyan Lu, Heli Cao, Xiaoer Wei, Yuehua Li, and Wenbin Li Copyright © 2015 Liyan Lu et al. All rights reserved. Effect of Atlas Vertebrae Realignment in Subjects with Migraine: An Observational Pilot Study Thu, 10 Dec 2015 07:12:19 +0000 Introduction. In a migraine case study, headache symptoms significantly decreased with an accompanying increase in intracranial compliance index following atlas vertebrae realignment. This observational pilot study followed eleven neurologist diagnosed migraine subjects to determine if the case findings were repeatable at baseline, week four, and week eight, following a National Upper Cervical Chiropractic Association intervention. Secondary outcomes consisted of migraine-specific quality of life measures. Methods. After examination by a neurologist, volunteers signed consent forms and completed baseline migraine-specific outcomes. Presence of atlas misalignment allowed study inclusion, permitting baseline MRI data collection. Chiropractic care continued for eight weeks. Postintervention reimaging occurred at week four and week eight concomitant with migraine-specific outcomes measurement. Results. Five of eleven subjects exhibited an increase in the primary outcome, intracranial compliance; however, mean overall change showed no statistical significance. End of study mean changes in migraine-specific outcome assessments, the secondary outcome, revealed clinically significant improvement in symptoms with a decrease in headache days. Discussion. The lack of robust increase in compliance may be understood by the logarithmic and dynamic nature of intracranial hemodynamic and hydrodynamic flow, allowing individual components comprising compliance to change while overall it did not. Study results suggest that the atlas realignment intervention may be associated with a reduction in migraine frequency and marked improvement in quality of life yielding significant reduction in headache-related disability as observed in this cohort. Future study with controls is necessary, however, to confirm these findings. registration number is NCT01980927. H. Charles Woodfield III, D. Gordon Hasick, Werner J. Becker, Marianne S. Rose, and James N. Scott Copyright © 2015 H. Charles Woodfield III et al. All rights reserved. Temporal Changes in the Quality of Acute Stroke Care in Five National Audits across Europe Wed, 09 Dec 2015 08:46:53 +0000 Background. Data on potential variations in delivery of appropriate stroke care over time are scarce. We investigated temporal changes in the quality of acute hospital stroke care across five national audits in Europe over a period of six years. Methods. Data were derived from national stroke audits in Germany, Poland, Scotland, Sweden, and England/Wales/Northern Ireland participating within the European Implementation Score (EIS) collaboration. Temporal changes in predefined quality indicators with comparable information between the audits were investigated. Multivariable logistic regression analyses were performed to estimate adherence to quality indicators over time. Results. Between 2004 and 2009, individual data from 542,112 patients treated in 538 centers participating continuously over the study period were included. In most audits, the proportions of patients who were treated on a SU, were screened for dysphagia, and received thrombolytic treatment increased over time and ranged from 2-fold to almost 4-fold increase in patients receiving thrombolytic therapy in 2009 compared to 2004. Conclusions. A general trend towards a better quality of stroke care defined by standardized quality indicators was observed over time. The association between introducing a specific measure and higher adherence over time might indicate that monitoring of stroke care performance contributes to improving quality of care. Steffi Hillmann, Silke Wiedmann, Alec Fraser, Juan Baeza, Anthony Rudd, Bo Norrving, Kjell Asplund, Maciej Niewada, Martin Dennis, Peter Hermanek, Charles D. A. Wolfe, and Peter U. Heuschmann Copyright © 2015 Steffi Hillmann et al. All rights reserved. Computer Simulation and Analysis on Flow Characteristics and Distribution Patterns of Polymethylmethacrylate in Lumbar Vertebral Body and Vertebral Pedicle Mon, 07 Dec 2015 11:16:10 +0000 This study was designed to analyze the flow and distribution of polymethylmethacrylate (PMMA) in vertebral body through computer simulation. Cadaveric lumbar vertebrae were scanned through electron beam tomography (EBT). The data was imported into Mimics software to build computational model. Vertebral body center and junction of pedicle and vertebral body were chosen as injection points. Silicone oil with viscosity of 100,000 cSt matching with PMMA bone cement was chosen for injection. The flow and distribution of silicone oil were analyzed using Fluent software. In vertebral body, silicone oil formed a circle-like shape centered by injection point on transverse and longitudinal sections, finally forming a sphere-like shape as a whole. Silicone oil diffused along lateral and posterior walls forming a circle-like shape on transverse section centered by injection point in pedicle, eventually forming a sphere-like shape as a whole. This study demonstrated that silicone oil flowed and diffused into a circle-like shape centered by injection point and finally formed a sphere-like shape as a whole in both vertebral body and pedicle. The flow and distribution of silicon oil in computational model could simulate PMMA distribution in vertebral body. It may provide theoretical evidence to reduce PMMA leakage risk during percutaneous vertebroplasty. Da Liu, Xu-li Liu, Bo Zhang, Dong-fa Liao, Zhi-qiang Li, Jiang-jun Zhou, Xia Kang, Wei Zheng, and Wei Lei Copyright © 2015 Da Liu et al. All rights reserved. Histamine Induces Alzheimer’s Disease-Like Blood Brain Barrier Breach and Local Cellular Responses in Mouse Brain Organotypic Cultures Mon, 30 Nov 2015 11:46:39 +0000 Among the top ten causes of death in the United States, Alzheimer’s disease (AD) is the only one that cannot be cured, prevented, or even slowed down at present. Significant efforts have been exerted in generating model systems to delineate the mechanism as well as establishing platforms for drug screening. In this study, a promising candidate model utilizing primary mouse brain organotypic (MBO) cultures is reported. For the first time, we have demonstrated that the MBO cultures exhibit increased blood brain barrier (BBB) permeability as shown by IgG leakage into the brain parenchyma, astrocyte activation as evidenced by increased expression of glial fibrillary acidic protein (GFAP), and neuronal damage-response as suggested by increased vimentin-positive neurons occur upon histamine treatment. Identical responses—a breakdown of the BBB, astrocyte activation, and neuronal expression of vimentin—were then demonstrated in brains from AD patients compared to age-matched controls, consistent with other reports. Thus, the histamine-treated MBO culture system may provide a valuable tool in combating AD. Jonathan C. Sedeyn, Hao Wu, Reilly D. Hobbs, Eli C. Levin, Robert G. Nagele, and Venkat Venkataraman Copyright © 2015 Jonathan C. Sedeyn et al. All rights reserved. Effects of Bee Venom Injections at Acupoints on Neurologic Dysfunction Induced by Thoracolumbar Intervertebral Disc Disorders in Canines: A Randomized, Controlled Prospective Study Sun, 29 Nov 2015 11:30:58 +0000 Intervertebral disk disease (IVDD) is a major spine disorder in canines that causes neurological dysfunction, particularly in the thoracolumbar area. Analgesic and anti-inflammatory drugs are typically used to reduce nociceptive signals to decrease canine suffering. Bee venom (BV) has been reported to exert anti-inflammatory and analgesic effects. Injection of BV at acupoints has been widely used to treat clinical disorders including inflammation, pain, and arthritis. The current study was intended to determine whether BV injections at acupoints can enhance treatment of canine neurological dysfunction caused by IVDD. A single-blind controlled trial involving 40 adult canines with neurological dysfunction induced by IVDD subdivided into 2 groups was designed, and 36 canines finished the study. The myelopathy scoring system (MSS) grade and functional numeric scale (FNS) scores improved further after BV treatment than after control treatment. BV injection exerted a particularly strong effect on canines with moderate to severe IVDD and dramatically reduced clinical rehabilitation time. The results indicate that BV injections at acupoints are more effective at protecting canines from IVDD-induced neurological dysfunction and pain than is treatment alone. Li-Chuan Tsai, Yi-Wen Lin, and Ching-Liang Hsieh Copyright © 2015 Li-Chuan Tsai et al. All rights reserved. Lumbar Endoscopic Microdiscectomy: Where Are We Now? An Updated Literature Review Focused on Clinical Outcome, Complications, and Rate of Recurrence Tue, 24 Nov 2015 11:33:18 +0000 Endoscopic disc surgery (EDS) for lumbar spine disc herniation is a well-known but developing field, which is increasingly spreading in the last few years. Rate of recurrence/residual, complications, and outcomes, in comparison with standard microdiscectomy (MD), is still debated and need further data. We performed an extensive review based on the last 6 years of surgical series, systematic reviews, and meta-analyses reported in international, English-written literature. Articles regarding patients treated through endoscopic transforaminal or interlaminar approaches for microdiscectomy (MD) were included in the present review. Papers focused on endoscopic surgery for other spinal diseases were not included. From July 2009 to July 2015, we identified 51 surgical series, 5 systematic reviews, and one meta-analysis reported. In lumbar EDS, rate of complications, length of hospital staying, return to daily activities, and overall patients’ satisfaction seem comparable to standard MD. Rate of recurrence/residual seems higher in EDS, although data are nonhomogeneous among different series. Surgical indication and experience of the performing surgeon are crucial factors affecting the outcome. There is growing but still weak evidence that lumbar EDS is a valid and safe alternative to standard open microdiscectomy. Statistically reliable data obtained from randomized controlled trials (better if multicentric) are desirable to further confirm these results. Giulio Anichini, Alessandro Landi, Federico Caporlingua, André Beer-Furlan, Christian Brogna, Roberto Delfini, and Emiliano Passacantilli Copyright © 2015 Giulio Anichini et al. All rights reserved. Molecular Targets in Alzheimer’s Disease: From Pathogenesis to Therapeutics Thu, 19 Nov 2015 13:03:44 +0000 Alzheimer’s disease (AD) is characterized by progressive cognitive decline usually beginning with impairment in the ability to form recent memories. Nonavailability of definitive therapeutic strategy urges developing pharmacological targets based on cell signaling pathways. A great revival of interest in nutraceuticals and adjuvant therapy has been put forward. Tea polyphenols for their multiple health benefits have also attracted the attention of researchers. Tea catechins showed enough potentiality to be used in future as therapeutic targets to provide neuroprotection against AD. This review attempts to present a concise map of different receptor signaling pathways associated with AD with an insight into drug designing based on the proposed signaling pathways, molecular mechanistic details of AD pathogenesis, and a scientific rationale for using tea polyphenols as proposed therapeutic agents in AD. Xuan Cheng, Lu Zhang, and Ya-Jun Lian Copyright © 2015 Xuan Cheng et al. All rights reserved. Effects of Etanercept against Transient Cerebral Ischemia in Diabetic Rats Thu, 19 Nov 2015 11:49:54 +0000 Diabetes mellitus is known to exacerbate acute cerebral ischemic injury. Previous studies have demonstrated that infarction volumes caused by transient cerebral ischemia were greater in diabetic rats than in nondiabetic rats. Tumor necrosis factor-α (TNF-α) is a proinflammatory protein produced in the brain in response to cerebral ischemia that promotes apoptosis. Etanercept (ETN), a recombinant TNF receptor (p75)-Fc fusion protein, competitively inhibits TNF-α. Therefore, we evaluated the neuroprotective effects of chronic or acute treatment with ETN on cerebral injury caused by middle cerebral artery occlusion/reperfusion (MCAO/Re) in rats with streptozotocin-induced diabetes. Furthermore, we evaluated the effects of ETN against the apoptosis and myeloperoxidase activity. Single administration of ETN before MCAO significantly suppressed exacerbation of cerebral damage in nondiabetic rats, as assessed by infarct volume. In contrast, the diabetic state markedly aggravated MCAO/Re-induced cerebral damage despite ETN treatment within 24 h before MCAO. However, the damage was improved by repeated administration of ETN at 900 μg/kg/daily in rats in an induced diabetic state. These results suggested that repeated administration of ETN can prevent exacerbation of cerebral ischemic injury in the diabetic state and is mainly attributed to anti-inflammatory effects. Naohiro Iwata, Hiroko Takayama, Meiyan Xuan, Shinya Kamiuchi, Hirokazu Matsuzaki, Mari Okazaki, and Yasuhide Hibino Copyright © 2015 Naohiro Iwata et al. All rights reserved. Minimal Invasive Circumferential Management of Thoracolumbar Spine Fractures Mon, 16 Nov 2015 16:24:17 +0000 Introduction. While thoracolumbar fractures are common lesions, no strong consensus is available at the moment. Objectives. The aim of this study was to evaluate the results of a minimal invasive strategy using percutaneous instrumentation and anterior approach in the management of thoracolumbar unstable fractures. Methods. 39 patients were included in this retrospective study. Radiologic evaluation was based on vertebral and regional kyphosis, vertebral body height restoration, and fusion rate. Clinical evaluation was based on Visual Analogic Score (VAS). All evaluations were done preoperatively and at 1-year follow-up. Results. Both vertebral and regional kyphoses were significantly improved on postoperative evaluation (13° and 7° versus −1° and −9°  , resp.) as well as vertebral body height (0.92 versus 1.16, ). At 1-year follow-up, mean loss of correction was 1°. A solid fusion was visible in all the cases, and mean VAS was significantly reduced form 8/10 preoperatively to 1/10 at the last follow-up. Conclusion. Management of thoracolumbar fractures using percutaneous osteosynthesis and minimal invasive anterior approach (telescopic vertebral body prosthesis) is a valuable strategy. Results of this strategy offer satisfactory and stable results in time. S. Pesenti, T. Graillon, N. Mansouri, P. Rakotozanani, B. Blondel, and S. Fuentes Copyright © 2015 S. Pesenti et al. All rights reserved. The Effect of Body Weight Support Treadmill Training on Gait Recovery, Proximal Lower Limb Motor Pattern, and Balance in Patients with Subacute Stroke Mon, 16 Nov 2015 12:47:18 +0000 Objective. Gait performance is an indicator of mobility impairment after stroke. This study evaluated changes in balance, lower extremity motor function, and spatiotemporal gait parameters after receiving body weight supported treadmill training (BWSTT) and conventional overground walking training (CT) in patients with subacute stroke using 3D motion analysis. Setting. Inpatient department of rehabilitation medicine at a university-affiliated hospital. Participants. 24 subjects with unilateral hemiplegia in the subacute stage were randomized to the BWSTT and CT groups. Parameters were compared between the two groups. Data from twelve age matched healthy subjects were recorded as reference. Interventions. Patients received gait training with BWSTT or CT for an average of 30 minutes/day, 5 days/week, for 3 weeks. Main Outcome Measures. Balance was measured by the Brunel balance assessment. Lower extremity motor function was evaluated by the Fugl-Meyer assessment scale. Kinematic data were collected and analyzed using a gait capture system before and after the interventions. Results. Both groups improved on balance and lower extremity motor function measures , with no significant difference between the two groups after intervention. However, kinematic data were significantly improved after BWSTT but not after CT. Maximum hip extension and flexion angles were significantly improved for the BWSTT group during the stance and swing phases compared to baseline. Conclusion. In subacute patients with stroke, BWSTT can lead to improved gait quality when compared with conventional gait training. Both methods can improve balance and motor function. Yu-Rong Mao, Wai Leung Lo, Qiang Lin, Le Li, Xiang Xiao, Preeti Raghavan, and Dong-Feng Huang Copyright © 2015 Yu-Rong Mao et al. All rights reserved. Minimally Invasive Scoliosis Surgery: A Novel Technique in Patients with Neuromuscular Scoliosis Mon, 16 Nov 2015 11:45:50 +0000 Minimally invasive surgery (MIS) has been described in the treatment of adolescent idiopathic scoliosis (AIS) and adult scoliosis. The advantages of this approach include less blood loss, shorter hospital stay, earlier mobilization, less tissue disruption, and relatively less pain. However, despite these significant benefits, MIS approach has not been reported in neuromuscular scoliosis patients. This is possibly due to concerns with longer surgery time, which is further increased due to more levels fused and instrumented, challenges of pelvic fixation, size and number of incisions, and prolonged anesthesia. We modified the MIS approach utilized in our AIS patients to be implemented in our neuromuscular patients. Our technique allows easy passage of contoured rods, placement of pedicle screws without image guidance, partial/complete facet resection, and all standard reduction maneuvers. Operative time needed to complete this surgery is comparable to the standard procedure and the majority of our patients have been extubated at the end of procedure, spending 1 day in the PICU and 5-6 days in the hospital. We feel that MIS is not only a feasible but also a superior option in patients with neuromuscular scoliosis. Long-term results are unavailable; however, short-term results have shown multiple benefits of this approach and fewer limitations. Vishal Sarwahi, Terry Amaral, Stephen Wendolowski, Rachel Gecelter, Melanie Gambassi, Christos Plakas, Benita Liao, Sarika Kalantre, and Chhavi Katyal Copyright © 2015 Vishal Sarwahi et al. All rights reserved. Animal Models in Studying Cerebral Arteriovenous Malformation Mon, 16 Nov 2015 08:53:32 +0000 Brain arteriovenous malformation (AVM) is an important cause of hemorrhagic stroke. The etiology is largely unknown and the therapeutics are controversial. A review of AVM-associated animal models may be helpful in order to understand the up-to-date knowledge and promote further research about the disease. We searched PubMed till December 31, 2014, with the term “arteriovenous malformation,” limiting results to animals and English language. Publications that described creations of AVM animal models or investigated AVM-related mechanisms and treatments using these models were reviewed. More than 100 articles fulfilling our inclusion criteria were identified, and from them eight different types of the original models were summarized. The backgrounds and procedures of these models, their applications, and research findings were demonstrated. Animal models are useful in studying the pathogenesis of AVM formation, growth, and rupture, as well as in developing and testing new treatments. Creations of preferable models are expected. Ming Xu, Hongzhi Xu, and Zhiyong Qin Copyright © 2015 Ming Xu et al. All rights reserved. Simultaneous Lateral Interbody Fusion and Posterior Percutaneous Instrumentation: Early Experience and Technical Considerations Mon, 16 Nov 2015 08:27:46 +0000 Lumbar fusion surgery involving lateral lumbar interbody graft insertion with posterior instrumentation is traditionally performed in two stages requiring repositioning. We describe a novel technique to complete the circumferential procedure simultaneously without patient repositioning. Twenty patients diagnosed with worsening back pain with/without radiculopathy who failed exhaustive conservative management were retrospectively reviewed. Ten patients with both procedures simultaneously from a single lateral approach and 10 control patients with lateral lumbar interbody fusion followed by repositioning and posterior percutaneous instrumentation were analyzed. Pars fractures, mobile grade 2 spondylolisthesis, and severe one-level degenerative disk disease were matched between the two groups. In the simultaneous group, avoiding repositioning leads to lower mean operative times: 130 minutes (versus control 190 minutes; ) and lower intraoperative blood loss: 108 mL (versus 93 mL; NS). Nonrepositioned patients were hospitalized for an average of 4.1 days (versus 3.8 days; NS). There was one complication in the control group requiring screw revision. Lateral interbody fusion and percutaneous posterior instrumentation are both readily accomplished in a single lateral decubitus position. In select patients with adequately sized pedicles, performing simultaneous procedures decreases operative time over sequential repositioning. Patient outcomes were excellent in the simultaneous group and comparable to procedures done sequentially. Doniel Drazin, Terrence T. Kim, and J. Patrick Johnson Copyright © 2015 Doniel Drazin et al. All rights reserved. Association of the NOTCH4 Gene Polymorphism rs204993 with Schizophrenia in the Chinese Han Population Wed, 28 Oct 2015 08:20:21 +0000 NOTCH4 regulates signaling pathways associated with neuronal maturation, a process involved in the development and patterning of the central nervous system. The NOTCH4 gene has also been identified as a possible susceptibility gene for schizophrenia (SCZ). The objective of this study was to examine the relationship between NOTCH4 polymorphisms and SCZ in the Chinese Han population. The rs2071287 and rs204993 polymorphisms of the NOTCH4 gene were analyzed in 443 patients with SCZ and 628 controls of Han Chinese descent. Single SNP allele-, genotype-, and gender-specific associations were analyzed using different models (i.e., additive, dominant, and recessive models). This association study revealed that the rs204993 polymorphism is significantly associated with susceptibility for SCZ and that the AA genotype of rs204993 is associated with a higher risk for SCZ (; OR = 1.460; 95% CI, 1.043–2.054). Our data are consistent with those obtained in previous studies that suggested that rs204993 is associated with SCZ and that the AA genotype of rs204993 demonstrates a higher risk. Further large-scale association analyses in Han Chinese populations are warranted. Bao Zhang, Qian Rui Fan, Wen Hao Li, Ning Lu, Dong Ke Fu, Yan Jie Kang, Na Wang, Teng Li, Xiao Peng Wen, and Da Xu Li Copyright © 2015 Bao Zhang et al. All rights reserved. The Clinical Characteristics and Treatment of Cerebral Microarteriovenous Malformation Presenting with Intracerebral Hemorrhage: A Series of 13 Cases Mon, 19 Oct 2015 12:46:34 +0000 Object. The aim of this report was to explore the clinical presentation, radiological features, treatment methods, and outcome of micro-AVMs presenting with intracerebral hemorrhage. Methods. The clinical data, radiological features, treatment, and follow-up results for a consecutive series of 13 cases with micro-AVMs were retrospectively analyzed. Results. All 13 patients presented with intracerebral hemorrhage. Ten cases were confirmed by enhanced thin layer CT scanning and CTA, and the other 3 cases were confirmed by DSA. Treatment consisted of surgical removal in 10 cases, endovascular embolization in 1, and radiosurgery in 2. The modified GOS score was achieved in the third month after discharge: 10 cases were rated with 5 points (good recovery), 1 case was rated with 4 points (mild disability), and 2 cases were rated with 3 points (severe disability). During follow-up, No case of rebleeding was reported. Conclusions. Intracerebral hemorrhage is the main clinical manifestation of micro-AVMs. It is beneficial to find a tiny nidus of dense vessels located on hematoma wall on enhanced thin layer CT scanning for a clear diagnosis and to detect any abnormal feeding artery or venous drainage for an indirect diagnostic evidence. Resection is the main method of treatment for micro-AVMs. Jing-Fang Hong, Ying-Fang Song, Hai-Bing Liu, Zheng Liu, and Shou-Sen Wang Copyright © 2015 Jing-Fang Hong et al. All rights reserved. Electrical Bioimpedance Spectroscopy on Acute Unilateral Stroke Patients: Initial Observations regarding Differences between Sides Sun, 18 Oct 2015 11:58:28 +0000 Purpose. Electrical Bioimpedance Cerebral Monitoring is assessment in real time of health of brain tissue through study of passive dielectric properties of brain. During the last two decades theory and technology have been developed in parallel with animal experiments aiming to confirm feasibility of using bioimpedance-based technology for prompt detection of brain damage. Here, for the first time, we show that electrical bioimpedance measurements for left and right hemispheres are significantly different in acute cases of unilateral stroke within 24 hours from onset. Methods. Electrical BIS measurements have been taken in healthy volunteers and patients suffering from acute stroke within 24 hours of onset. BIS measurements have been obtained using SFB7 bioimpedance spectrometer manufactured by Impedimed ltd. and 4-electrode method. Measurement electrodes, current, and voltage have been placed according to 10–20 EEG system obtaining mutual BIS measurements from 4 different channels situated in pairs symmetrically from the midsagittal line. Obtained BIS data has been analyzed, assessing for symmetries and differences regarding healthy control data. Results. 7 out of 10 patients for Side-2-Side comparisons and 8 out 10 for central/lateral comparison presented values outside the range defined by healthy control group. When combined only 1 of 10 patients exhibited values within the healthy range. Conclusions. If these initial observations are confirmed with more patients, we can foresee emerging of noninvasive monitoring technology for brain damage with the potential to lead to paradigm shift in treatment of brain stroke and traumatic brain damage. Fernando Seoane, Seyed Reza Atefi, Jens Tomner, Konstantinos Kostulas, and Kaj Lindecrantz Copyright © 2015 Fernando Seoane et al. All rights reserved. The Level of Circulating Endothelial Progenitor Cell Is Associated with Cerebral Vasoreactivity: A Pilot Study Thu, 15 Oct 2015 06:42:14 +0000 Endothelial progenitor cell is known to be able to repair injured vessels. We assessed the hypothesis that endothelial progenitor cell also modulates cerebral endothelial function in healthy status. We used transcranial color-coded sonography to measure middle cerebral arterial vasoreactivity to CO2 (breath-holding index) in healthy subjects and observed its relationship with the number of circulating CD34CD133+ cells. To detect significant correlations between each characteristic and breath-holding index of middle cerebral artery, we used univariate and multivariate regression analyses. 22 young healthy subjects were included in the present study (6 men, 16 women; mean age: 28.45 ± 3.98 years, range: 22–34 years). The mean breath-holding index and CDCD34+CD133+ cells number were 0.95 ± 0.48% and 0.52 ± 0.26, respectively. The level of CD34CD133+ cells was independently associated with middle cerebral artery’s vasoreactivity . Our results suggest that endothelial progenitor cell also modulates healthy cerebral vessels’ endothelial function. This ability of endothelial progenitor cell could be potentially applied therapeutically and for prevention in conditions with cerebral endothelial dysfunction and cerebral ischemia. Chih-Ping Chung, Po-Hsun Huang, Jia-Shiong Chen, Jaw-Wen Chen, and Kuang-Yao Yang Copyright © 2015 Chih-Ping Chung et al. All rights reserved. Acute Cardioembolic and Thrombotic Middle Cerebral Artery Occlusions Have Different Morphological Susceptibility Signs on T2-Weighted Magnetic Resonance Images Mon, 12 Oct 2015 07:24:09 +0000 Presence of susceptibility sign on middle cerebral artery (MCA) in -weighted magnetic resonance (MR) images has been reported to detect acute MCA thromboembolic occlusion. However, the pathophysiologic course of thrombotic MCA occlusion differs from embolic occlusion, which might induce different imaging characters. Our study found that the occurrence rate of the MCA susceptibility sign in cardioembolism (CE) patients was significantly higher than in large artery atherosclerosis (LAA) patients, and the diameter of the MCA susceptibility sign for CE was greater than for LAA. Moreover, the patients with hemorrhagic transformation had MCA susceptibility signs with a significant larger mean diameter than patients without hemorrhagic transformation. Therefore, we hypothesized that the morphology of susceptibility signs could be used to differentiate acute cardioembolic and thrombotic MCA occlusions, which helped to select appropriate treatment strategies for different patients. Mei Zheng and Dong-sheng Fan Copyright © 2015 Mei Zheng and Dong-sheng Fan. All rights reserved. Implantation of 3D-Printed Patient-Specific Aneurysm Models into Cadaveric Specimens: A New Training Paradigm to Allow for Improvements in Cerebrovascular Surgery and Research Sun, 11 Oct 2015 10:29:44 +0000 Aim. To evaluate the feasibility of implanting 3D-printed brain aneurysm model in human cadavers and to assess their utility in neurosurgical research, complex case management/planning, and operative training. Methods. Two 3D-printed aneurysm models, basilar apex and middle cerebral artery, were generated and implanted in four cadaveric specimens. The aneurysms were implanted at the same anatomical region as the modeled patient. Pterional and orbitozygomatic approaches were done on each specimen. The aneurysm implant, manipulation capabilities, and surgical clipping were evaluated. Results. The 3D aneurysm models were successfully implanted to the cadaveric specimens’ arterial circulation in all cases. The features of the neck in terms of flexibility and its relationship with other arterial branches allowed for the practice of surgical maneuvering characteristic to aneurysm clipping. Furthermore, the relationship of the aneurysm dome with the surrounding structures allowed for better understanding of the aneurysmal local mass effect. Noticeably, all of these observations were done in a realistic environment provided by our customized embalming model for neurosurgical simulation. Conclusion. 3D aneurysms models implanted in cadaveric specimens may represent an untapped training method for replicating clip technique; for practicing certain approaches to aneurysms specific to a particular patient; and for improving neurosurgical research. Arnau Benet, Julio Plata-Bello, Adib A. Abla, Gabriel Acevedo-Bolton, David Saloner, and Michael T. Lawton Copyright © 2015 Arnau Benet et al. All rights reserved. Arctigenin, a Potent Ingredient of Arctium lappa L., Induces Endothelial Nitric Oxide Synthase and Attenuates Subarachnoid Hemorrhage-Induced Vasospasm through PI3K/Akt Pathway in a Rat Model Sun, 11 Oct 2015 09:53:46 +0000 Upregulation of protein kinase B (PKB, also known as Akt) is observed within the cerebral arteries of subarachnoid hemorrhage (SAH) animals. This study is of interest to examine Arctigenin, a potent antioxidant, on endothelial nitric oxide synthase (eNOS) and Akt pathways in a SAH in vitro study. Basilar arteries (BAs) were obtained to examine phosphatidylinositol-3-kinase (PI3K), phospho-PI3K, Akt, phospho-Akt (Western blot) and morphological examination. Endothelins (ETs) and eNOS evaluation (Western blot and immunostaining) were also determined. Arctigenin treatment significantly alleviates disrupted endothelial cells and tortured internal elastic layer observed in the SAH groups (). The reduced eNOS protein and phospho-Akt expression in the SAH groups were relieved by the treatment of Arctigenin (). This result confirmed that Arctigenin might exert dural effects in preventing SAH-induced vasospasm through upregulating eNOS expression via the PI3K/Akt signaling pathway and attenuate endothelins after SAH. Arctigenin shows therapeutic promise in the treatment of cerebral vasospasm following SAH. Chih-Zen Chang, Shu-Chuan Wu, Chia-Mao Chang, Chih-Lung Lin, and Aij-Lie Kwan Copyright © 2015 Chih-Zen Chang et al. All rights reserved. Middle Cerebral Artery Atherosclerotic Plaques in Recent Small Subcortical Infarction: A Three-Dimensional High-resolution MR Study Sun, 11 Oct 2015 09:26:21 +0000 Purpose. Conventional two-dimensional vessel wall imaging has been used to depict the middle cerebral artery (MCA) wall in patients with recent small subcortical infarctions (RSSIs). However, its clinical use has been limited by restricted spatial coverage, low signal-to-noise ratio (SNR), and long scan time. We used a novel three-dimensional high-resolution MR imaging (3D HR-MRI) technique to investigate the presence, locations, and contrast-enhanced patterns of MCA plaques and their relationship with RSSI. Methods. Nineteen consecutive patients with RSSI but no luminal stenosis on MR angiography were prospectively enrolled. 3D HR-MRI was performed using a T1w-SPACE sequence at 3.0 T. The presence, locations, and contrast-enhanced patterns of the MCA plaques on the ipsilateral and contralateral sides to the RSSI were analyzed. Results. Eighteen patients successfully completed the study. MCA atherosclerotic plaques occurred more frequently on the ipsilateral than the contralateral side to the RSSI (72.2% versus 33.3%, ). The occurrence of superiorly located plaques was significantly higher on the ipsilateral than the contralateral side of the MCA (66.7% versus 27.8%; ). Conclusions. Superiorly located plaques are closely associated with RSSI. 3D high-resolution vessel wall imaging may be a potential tool for etiologic assessment of ischemic stroke. Xiao-Dong Zou, Yiu-Cho Chung, Lei Zhang, Ying Han, Qi Yang, and Jianping Jia Copyright © 2015 Xiao-Dong Zou et al. All rights reserved. SAMHD1 Gene Mutations Are Associated with Cerebral Large-Artery Atherosclerosis Sun, 04 Oct 2015 14:26:48 +0000 Background. To investigate whether one or more SAMHD1 gene mutations are associated with cerebrovascular disease in the general population using a Chinese stroke cohort. Methods. Patients with a Chinese Han background () diagnosed with either cerebral large-artery atherosclerosis (LAA, ), cerebral small vessel disease (SVD, ), or other stroke-free neurological disorders (control, ) were recruited. Genomic DNA from the whole blood of each patient was isolated, and direct sequencing of the SAMHD1 gene was performed. Both wild type and mutant SAMHD1 proteins identified from the patients were expressed in E. coli and purified; then their dNTPase activities and ability to form stable tetramers were analysed in vitro. Results. Three heterozygous mutations, including two missense mutations c.64C>T (P22S) and c.841G>A (p.E281K) and one splice site mutation c.696+2T>A, were identified in the LAA group with a prevalence of 3%. No mutations were found in the patients with SVD or the controls (). The mutant SAMHD1 proteins were functionally impaired in terms of their catalytic activity as a dNTPase and ability to assemble stable tetramers. Conclusions. Heterozygous SAMHD1 gene mutations might cause genetic predispositions that interact with other risk factors, resulting in increased vulnerability to stroke. Wei Li, Baozhong Xin, Junpeng Yan, Ying Wu, Bo Hu, Liping Liu, Yilong Wang, Jinwoo Ahn, Jacek Skowronski, Zaiqiang Zhang, Yongjun Wang, and Heng Wang Copyright © 2015 Wei Li et al. All rights reserved. Neurorestoratologic Strategies and Mechanisms in the Nervous System Tue, 29 Sep 2015 08:09:55 +0000 Lin Chen, Qiang Ao, Hari Shanker Sharma, Aijun Wang, and Shiqing Feng Copyright © 2015 Lin Chen et al. All rights reserved. Effects of Acute Lithium Treatment on Brain Levels of Inflammatory Mediators in Poststroke Rats Sun, 27 Sep 2015 13:21:26 +0000 Stroke is a leading cause of mortality and morbidity worldwide. Few therapeutic options with proven efficacy are available for the treatment of this disabling disease. Lithium is the gold standard treatment for bipolar disorder. Moreover, lithium has been shown to exhibit neuroprotective effects and therapeutic efficacy as a treatment of other neurological disorders. This study was undertaken to examine the effects of lithium on brain inflammatory mediators levels, fever, and mortality in postischemic stroke rats. Ischemic stroke was induced by occlusion of the mid cerebral artery (MCAO). Pretreatment with a single dose of lithium at 2 hours before MCAO induction significantly reduced the elevation in interleukin- (IL-) 6 and prostaglandin E2 levels in brain of post-MCAO rats, as compared to vehicle-treated animals. On the other hand, lithium did not affect the elevation in IL-1α, IL-10, IL-12, and tumor necrosis factor-α levels in brain of post-MCAO rats. Moreover, pretreatment with lithium did not alter post-MCAO fever and mortality. These results suggest that acute pretreatment with a single dose of lithium did not markedly affect post-MCAO morbidity and mortality in rats. Matthew Boyko, Ahmad Nassar, Jacob Kaplanski, Alexander Zlotnik, Yael Sharon-Granit, and Abed N. Azab Copyright © 2015 Matthew Boyko et al. All rights reserved. Research Progress on the Role of ABC Transporters in the Drug Resistance Mechanism of Intractable Epilepsy Sun, 27 Sep 2015 12:45:12 +0000 The pathogenesis of intractable epilepsy is not fully clear. In recent years, both animal and clinical trials have shown that the expression of ATP-binding cassette (ABC) transporters is increased in patients with intractable epilepsy; additionally, epileptic seizures can lead to an increase in the number of sites that express ABC transporters. These findings suggest that ABC transporters play an important role in the drug resistance mechanism of epilepsy. ABC transporters can perform the funcions of a drug efflux pump, which can reduce the effective drug concentration at epilepsy lesions by reducing the permeability of the blood brain barrier to antiepileptic drugs, thus causing resistance to antiepileptic drugs. Given the important role of ABC transporters in refractory epilepsy drug resistance, antiepileptic drugs that are not substrates of ABC transporters were used to obtain ABC transporter inhibitors with strong specificity, high safety, and few side effects, making them suitable for long-term use; therefore, these drugs can be used for future clinical treatment of intractable epilepsy. Jie Xiong, Ding-an Mao, and Li-qun Liu Copyright © 2015 Jie Xiong et al. All rights reserved. Biomaterial Approaches to Enhancing Neurorestoration after Spinal Cord Injury: Strategies for Overcoming Inherent Biological Obstacles Sun, 27 Sep 2015 12:29:30 +0000 While advances in technology and medicine have improved both longevity and quality of life in patients living with a spinal cord injury, restoration of full motor function is not often achieved. This is due to the failure of repair and regeneration of neuronal connections in the spinal cord after injury. In this review, the complicated nature of spinal cord injury is described, noting the numerous cellular and molecular events that occur in the central nervous system following a traumatic lesion. In short, postinjury tissue changes create a complex and dynamic environment that is highly inhibitory to the process of neural regeneration. Strategies for repair are outlined with a particular focus on the important role of biomaterials in designing a therapeutic treatment that can overcome this inhibitory environment. The importance of considering the inherent biological response of the central nervous system to both injury and subsequent therapeutic interventions is highlighted as a key consideration for all attempts at improving functional recovery. Justin R. Siebert, Amber M. Eade, and Donna J. Osterhout Copyright © 2015 Justin R. Siebert et al. All rights reserved. Effects of Caloric Intake on Learning and Memory Function in Juvenile C57BL/6J Mice Sun, 27 Sep 2015 12:14:38 +0000 Dietary composition may influence neuronal function as well as processes underlying synaptic plasticity. In this study, we aimed to determine the effect of high and low caloric diets on a mouse model of learning and memory and to explore mechanisms underlying this process. Mice were divided into three different dietary groups: normal control , high-caloric (HC) diet , and low-caloric (LC) diet . After 6 months, mice were evaluated on the Morris water maze to assess spatial memory ability. We found that HC diet impaired learning and memory function relative to both control and LC diet. The levels of SIRT1 as well as its downstream effectors p53, p16, and peroxisome proliferator-activated receptor γ (PPARγ) were decreased in brain tissues obtained from HC mice. LC upregulated SIRT1 but downregulated p53, p16, and PPARγ. The expressions of PI3K and Akt were not altered after HC or LC diet treatment, but both LC and HC elevated the levels of phosphorylated-cAMP response element-binding protein (p-CREB) and IGF-1 in hippocampal CA1 region. Therefore, HC diet-induced dysfunction in learning and memory may be prevented by caloric restriction via regulation of the SIRT1-p53 or IGF-1 signaling pathways and phosphorylation of CREB. Bao-Lei Xu, Rong Wang, Li-Na Ma, Wen Dong, Zhi-Wei Zhao, Jing-Shuang Zhang, Yu-Lan Wang, and Xu Zhang Copyright © 2015 Bao-Lei Xu et al. All rights reserved. Oligodendrocyte Precursor Cells in Spinal Cord Injury: A Review and Update Sun, 27 Sep 2015 12:13:12 +0000 Spinal cord injury (SCI) is a devastating condition to individuals, families, and society. Oligodendrocyte loss and demyelination contribute as major pathological processes of secondary damages after injury. Oligodendrocyte precursor cells (OPCs), a subpopulation that accounts for 5 to 8% of cells within the central nervous system, are potential sources of oligodendrocyte replacement after SCI. OPCs react rapidly to injuries, proliferate at a high rate, and can differentiate into myelinating oligodendrocytes. However, posttraumatic endogenous remyelination is rarely complete, and a better understanding of OPCs’ characteristics and their manipulations is critical to the development of novel therapies. In this review, we summarize known characteristics of OPCs and relevant regulative factors in both health and demyelinating disorders including SCI. More importantly, we highlight current evidence on post-SCI OPCs transplantation as a potential treatment option as well as the impediments against regeneration. Our aim is to shed lights on important knowledge gaps and to provoke thoughts for further researches and the development of therapeutic strategies. Ning Li and Gilberto K. K. Leung Copyright © 2015 Ning Li and Gilberto K. K. Leung. All rights reserved. Determination of Serum Lost Goodwill Target Proteome in Patients with Severe Traumatic Brain Injury Sun, 27 Sep 2015 12:09:33 +0000 This study investigates the biokinetics of LGT proteome, a potential biomarker of severe TBI, in serum of severe TBI patients. The LGT proteome presents in the serum of severe TBI patients. The abundance diversity of LGT proteome is closely associated with pathologic condition of TBI patients. Serum LGT proteome may be used as a promising marker for evaluating severity of severe TBI. Hongming Ji, Changchen Hu, Gangli Zhang, Jinrui Ren, Yihu Tan, Wenxiao Sun, Junwen Wang, Jun Li, Hongchao Liu, Ruifan Xie, Zhipeng Hao, and Dongsheng Guo Copyright © 2015 Hongming Ji et al. All rights reserved. Bypassing P-Glycoprotein Drug Efflux Mechanisms: Possible Applications in Pharmacoresistant Schizophrenia Therapy Sun, 27 Sep 2015 12:05:22 +0000 The efficient noninvasive treatment of neurodegenerative disorders is often constrained by reduced permeation of therapeutic agents into the central nervous system (CNS). A vast majority of bioactive agents do not readily permeate into the brain tissue due to the existence of the blood-brain barrier (BBB) and the associated P-glycoprotein efflux transporter. The overexpression of the MDR1 P-glycoprotein has been related to the occurrence of multidrug resistance in CNS diseases. Various research outputs have focused on overcoming the P-glycoprotein drug efflux transporter, which mainly involve its inhibition or bypassing mechanisms. Studies into neurodegenerative disorders have shown that the P-glycoprotein efflux transporter plays a vital role in the progression of schizophrenia, with a noted increase in P-glycoprotein function among schizophrenic patients, thereby reducing therapeutic outcomes. In this review, we address the hypothesis that methods employed in overcoming P-glycoprotein in cancer and other disease states at the level of the BBB and intestine may be applied to schizophrenia drug delivery system design to improve clinical efficiency of drug therapies. In addition, the current review explores polymers and drug delivery systems capable of P-gp inhibition and modulation. Famida G. Hoosain, Yahya E. Choonara, Lomas K. Tomar, Pradeep Kumar, Charu Tyagi, Lisa C. du Toit, and Viness Pillay Copyright © 2015 Famida G. Hoosain et al. All rights reserved. Past, Present, and Future of Nerve Conduits in the Treatment of Peripheral Nerve Injury Sun, 27 Sep 2015 12:03:16 +0000 With significant advances in the research and application of nerve conduits, they have been used to repair peripheral nerve injury for several decades. Nerve conduits range from biological tubes to synthetic tubes, and from nondegradable tubes to biodegradable tubes. Researchers have explored hollow tubes, tubes filled with scaffolds containing neurotrophic factors, and those seeded with Schwann cells or stem cells. The therapeutic effect of nerve conduits is improving with increasing choice of conduit material, new construction of conduits, and the inclusion of neurotrophic factors and support cells in the conduits. Improvements in functional outcomes are expected when these are optimized for use in clinical practice. Aikeremujiang Muheremu and Qiang Ao Copyright © 2015 Aikeremujiang Muheremu and Qiang Ao. All rights reserved. Evaluation of APP695 Transgenic Mice Bone Marrow Mesenchymal Stem Cells Neural Differentiation for Transplantation Sun, 27 Sep 2015 11:57:29 +0000 Objective. Even though there is a therapeutic potential to treat Alzheimer’s disease (AD) with neural cell replenishment and replacement, immunological rejections of stem cell transplantation remain a challenging risk. Autologous stem cells from AD patients however may prove to be a promising candidate. Therefore, we studied the neuronal differentiation efficiency of bone marrow mesenchymal stem cells (MSCs) from APP695 transgenic mice, which share features of human AD. Method. Cultured MSCs from APP695 transgenic mice are used; neuronal differentiation was assessed by immunocytochemistry and Western blot. Correlation with Notch signaling was examined. Autophage flux was assessed by western blot analysis. Results. MSCs from APP695 mice have higher neuronal differentiation efficiency than MSCs from wild type mice (WT MSCs). The expression of Notch-1 signaling decreased during the differentiation process. However, autophagy flux, which is essential for neuronal cell survival and neuronal function, was impaired in the neuronally differentiated counterparts of APP695 MSCs (APP695 MSCs–n). Conclusion. These results suggested autologous MSCs of APP690 mice may not be a good candidate for cell transplantation. Qian Li, Yanjie Jia, John Zhang, and Jun Yang Copyright © 2015 Qian Li et al. All rights reserved. Effect of Long-Term Treatment with Fimasartan on Transient Focal Ischemia in Rat Brain Sun, 13 Sep 2015 13:22:48 +0000 Fimasartan is a newly developed angiotensin receptor blocker, which may have protective effects during myocardial infarction or atherosclerosis. In this context, we investigated the effects of long-term treatment with low-dose fimasartan on focal ischemia in rat brain. We induced focal ischemia in brain by transient intraluminal occlusion of middle cerebral artery (MCA) and administered low-dose (0.5 mg/kg) or regular doses (1 or 3 mg/kg) of fimasartan via intravenous routes. After the administration of low-dose (0.5 mg/kg) fimasartan, blood pressure did not decrease compared to the phosphate-buffered saline- (PBS-) control with MCA occlusion (MCAO) group. The infarct volume and ischemic cell death were reduced in the low-dose fimasartan-treated group (46 ± 41 mm3 for 0.5 mg/kg and 153 ± 47 mm3 for PBS-control with MCAO; ) but not in the regular-dose groups. Low-dose fimasartan treatment improved functional recovery after ischemia and significantly decreased mortality. In our study, fimasartan reduced the degradation of IκB and the formation of an inflammatory end-product, COX-2. As a result, the recruitment of inflammatory cells in the peri-infarct area decreased in fimasartan-treated group. We have demonstrated that long-term, low-dose fimasartan treatment improved outcomes after focal ischemia in the brain via a reduction of inflammation. Chi Kyung Kim, Xiu-Li Yang, Young-Ju Kim, In-Young Choi, Han-Gil Jeong, Hong-Kyun Park, Dohoung Kim, Tae Jung Kim, Hyunduk Jang, Sang-Bae Ko, and Byung-Woo Yoon Copyright © 2015 Chi Kyung Kim et al. All rights reserved. Association of Tag SNPs and Rare CNVs of the MIR155HG/miR-155 Gene with Epilepsy in the Chinese Han Population Sun, 06 Sep 2015 13:03:26 +0000 Background. miR-155 likely acts as an important modulator in the inflammatory mechanism of epilepsy, and this study investigated its association with epilepsy from the perspective of molecular genetics. Methods. This study enrolled 249 epileptic patients and 289 healthy individuals of the Chinese Han population; 4 tag single-nucleotide polymorphisms (SNPs: rs969885, rs12483428, rs987195, and rs4817027) of the MIR155HG/miR-155 gene were selected, and their association with epilepsy was investigated. Additionally, this study determined the copy numbers of the MIR155HG/miR-155 gene. Results. The TCA haplotype (rs12483428-rs987195-rs4817027) and the AA genotype at rs4817027 conferred higher vulnerability to epilepsy in males. Stratification by age of onset revealed that the CC haplotype (rs969885-rs987195) was a genetic susceptibility factor for early-onset epilepsy. Further stratification by drug-resistant status indicated the CC haplotype (rs969885-rs987195) and the AA genotype at rs4817027 were genetic susceptibility factors for drug-resistant epilepsy (DRE) but the CG haplotype (rs987195-rs969885) was a genetically protective factor against DRE. Besides, 3 epileptic patients with copy number variants of the MIR155HG/miR-155 gene were observed. Conclusions. This study first demonstrates the association of MIR155HG/miR-155 tag SNPs with epilepsy and shows that rare CNVs were found exclusively in epileptic patients, clarifying the genetic role of miR-155 in epilepsy. Hua Tao, Lili Cui, You Li, Xu Zhou, Guoda Ma, Lifen Yao, Jiawu Fu, Wen Li, Yujie Cai, Haihong Zhou, Wangtao Zhong, Shuyan Zhang, Zhien Xu, Keshen Li, and Bin Zhao Copyright © 2015 Hua Tao et al. All rights reserved. Right-to-Left Shunt Does Not Increase the Incidence of Silent Lacunar Infarcts in Patients with Migraine Tue, 21 Jul 2015 13:00:50 +0000 Right-to-left shunt (RLS) is associated with cryptogenic stroke and migraine. Herein we investigated the relationship between RLS and silent lacunar infarcts in patients with migraine. A total of 263 patients with migraine who met eligibility criteria were enrolled from January 2010 to December 2011, among which 127 subjects fell into RLS group. Baseline demographics were comparable between RLS and non-RLS groups (). The incidence of silent lacunar infarcts in RLS group was not significantly different from that of the non-RLS group (25.2% versus 21.3%, ). Furthermore, we found that the incidence of silent lacunar infarcts in permanent and latent RLS subgroups was comparable with non-shunt RLS subgroup (28.6% versus 24% versus 21.3%, ). Similarly, the incidence of silent lacunar infarcts in the non-RLS group, mild-shunt group, and large-shunt group was also comparable (21.3% versus 23.8% versus 29.3%, ). In addition, RLS did not increase the incidence of silent lacunar infarcts in migraine patients with elder age (<50 years age group: 15.8% versus 17.9%; ≥50 years age group: 53.1% versus 37.5%, both ). In conclusion, RLS does not increase the incidence of silent lacunar infarcts in patients with migraine. Further prospective studies are warranted to validate this finding. Wei Du, Xiujuan Wu, Yingqi Xing, Yunlong Geng, Jing Bai, and Xiaonan Song Copyright © 2015 Wei Du et al. All rights reserved. Therapeutic Efficacy of E-64-d, a Selective Calpain Inhibitor, in Experimental Acute Spinal Cord Injury Thu, 09 Jul 2015 07:04:54 +0000 This study aims to investigate the therapeutic effect of calpain inhibitor E-64-d on SCI and to find a new approach to treat SCI. When an SCI rat model was established, it was immediately administered with E-64-d. RT-PCR and Western blotting were used to determine the protein and mRNA levels of calpain 1 and 68-kD NFP. TUNEL staining and NeuN labeling were performed to analyze neuronal apoptosis in the lesion. Immunohistochemistry assay was carried out to observe the expressions of calpain 1 and GFAP. Cyclooxygenase-2 activity was measured to show the immune response status. Locomotor function was evaluated by inclined plane test and Basso, Beattie, and Bresnahan locomotor rating scale. The results showed that calpain 1 was activated after SCI occurred. Treatment with E-64-d decreased expressions of calpain 1 and GFAP, alleviated neuronal apoptosis, inhibited cyclooxygenase-2 activity, and resulted in the promoted locomotor function. Furthermore, combination of E-64-d and MP had better efficacy than did E-64-d or MP alone. E-64-d is expected to be applied to treat SCI, and its alliance with MP may provide a valid strategy for SCI therapy. Zifeng Zhang, Zheng Huang, Hao Dai, Licheng Wei, Songtao Sun, and Feng Gao Copyright © 2015 Zifeng Zhang et al. All rights reserved. The Role of Mifepristone in Meningiomas Management: A Systematic Review of the Literature Wed, 03 Jun 2015 07:00:42 +0000 Objectives. We performed a systematic literature review to analyze the clinical application and the safety of mifepristone, a prominent antiprogesterone agent, in meningioma patients. Materials and Methods. A systematic search was performed through Medline, Cochrane, and databases from 1960 to 2014. Study Selection. Studies were selected through a PICO approach. Population was meningioma patients, meningioma cells cultures, and animal models. Intervention was mifepristone administration. Control was placebo administration or any other drug tested. Outcomes were clinical and radiological responsiveness, safety profile, and cell growth inhibition. Results. A total of 7 preclinical and 6 clinical studies and one abstract were included. Encouraging results were found in preclinical studies. Concerning clinical studies, the response rate to mifepristone in terms of radiological regression and symptomatic improvement/stability in patients with inoperable meningioma was low. In meningiomatosis, favorable preliminary results were recorded. The safety profile was good. Limitations were as follows. The tumoral expression of progesterone receptors was not analyzed systematically in every study considered. Conclusions. No clear evidence exists to recommend mifepristone in inoperable meningiomas. Preliminary encouraging results were found in diffuse meningiomatosis. Mifepristone is a well-tolerated treatment. Patients’ selection and hormonal profile analysis in meningiomas are fundamental for a better understanding of its benefit. Multicenter placebo-controlled trials are required. Giulia Cossu, Marc Levivier, Roy Thomas Daniel, and Mahmoud Messerer Copyright © 2015 Giulia Cossu et al. All rights reserved. Outcome of Elderly Patients with Meningioma after Image-Guided Stereotactic Radiotherapy: A Study of 100 Cases Tue, 26 May 2015 07:33:31 +0000 Introduction. Incidence of meningioma increases with age. Surgery has been the mainstay treatment. Elderly patients, however, are at risk of severe morbidity. Therefore, we conducted this study to analyze long-term outcomes of linac-based fractionated stereotactic radiotherapy (FSRT) for older adults (aged ≥65 years) with meningioma and determine prognostic factors. Materials and Methods. Between October 1998 and March 2009, 100 patients (≥65, median age, 71 years) were treated with FSRT for meningioma. Two patients were lost to follow-up. Eight patients each had grade I and grade II meningiomas, and five patients had grade III meningiomas. The histology was unknown in 77 cases (grade 0). Results. The median follow-up was 37 months, and 3-year, 5-year, and 10-year progression-free survival (PFS) rates were 93.7%, 91.1%, and 82%. Patients with grade 0/I meningioma showed 3- and 5-year PFS rates of 98.4% and 95.6%. Patients with grade II or III meningiomas showed 3-year PFS rates of 36%. 93.8% of patients showed local tumor control. Multivariate analysis did not indicate any significant prognostic factors. Conclusion. FSRT may play an important role as a noninvasive and safe method in the clinical management of older patients with meningioma. David Kaul, Volker Budach, Lukas Graaf, Johannes Gollrad, and Harun Badakhshi Copyright © 2015 David Kaul et al. All rights reserved. Epigenetics of Meningiomas Mon, 25 May 2015 10:08:39 +0000 Meningiomas account for one-third of all adult central nervous system tumours and are divided into three WHO grades. In contrast to the relatively well characterized genetic alterations, our current understanding of epigenetic modifications involved in the meningioma-genesis and progression is rather incomplete. Contrary to genetic alterations, epigenetic changes do not alter the primary DNA sequence and their reversible nature serves as an excellent basis for prevention and development of novel personalised tumour therapies. Indeed, growing body of evidence suggests that disturbed epigenetic regulation plays a key role in the pathogenesis of meningiomas. Altered DNA methylation, microRNA expression, histone, and chromatin modifications are frequently noted in meningiomas bearing prognostic and therapeutic relevance. In this review we provide an overview on recently identified epigenetic alterations in meningiomas and discuss their role in tumour initiation, progression, and recurrence. Balázs Murnyák, László Bognár, Álmos Klekner, and Tibor Hortobágyi Copyright © 2015 Balázs Murnyák et al. All rights reserved. From Grey Scale B-Mode to Elastosonography: Multimodal Ultrasound Imaging in Meningioma Surgery—Pictorial Essay and Literature Review Mon, 25 May 2015 06:32:18 +0000 The main goal in meningioma surgery is to achieve complete tumor removal, when possible, while improving or preserving patient neurological functions. Intraoperative imaging guidance is one fundamental tool for such achievement. In this regard, intra-operative ultrasound (ioUS) is a reliable solution to obtain real-time information during surgery and it has been applied in many different aspect of neurosurgery. In the last years, different ioUS modalities have been described: B-mode, Fusion Imaging with pre-operative acquired MRI, Doppler, contrast enhanced ultrasound (CEUS), and elastosonography. In this paper, we present our US based multimodal approach in meningioma surgery. We describe all the most relevant ioUS modalities and their intraoperative application to obtain precise and specific information regarding the lesion for a tailored approach in meningioma surgery. For each modality, we perform a review of the literature accompanied by a pictorial essay based on our routinely use of ioUS for meningioma resection. Francesco Prada, Massimiliano Del Bene, Alessandro Moiraghi, Cecilia Casali, Federico Giuseppe Legnani, Andrea Saladino, Alessandro Perin, Ignazio Gaspare Vetrano, Luca Mattei, Carla Richetta, Marco Saini, and Francesco DiMeco Copyright © 2015 Francesco Prada et al. All rights reserved. Need for Scientific Rigor in the Evaluation of Minimally Invasive Alternative Procedures Tue, 28 Apr 2015 06:45:10 +0000 Johnny Padulo and Luca Paolo Ardigò Copyright © 2015 Johnny Padulo and Luca Paolo Ardigò. All rights reserved. Multiple Sclerosis in Older Adults: The Clinical Profile and Impact of Interferon Beta Treatment Wed, 01 Apr 2015 06:45:56 +0000 Background. We examined (1) patient characteristics and disease-modifying drug (DMD) exposure in late-onset (LOMS, ≥50 years at symptom onset) versus adult-onset (AOMS, 18–<50 years) MS and (2) the association between interferon-beta (IFNβ) and disability progression in older relapsing-onset MS adults (≥50 years). Methods. This retrospective study (1980–2004, British Columbia, Canada) included 358 LOMS and 5627 AOMS patients. IFNβ-treated relapsing-onset MS patients aged ≥50 (regardless of onset age, 90) were compared with 171 contemporary and 106 historical controls. Times to EDSS 6 from onset and from IFNβ eligibility were examined using survival analyses. Results. LOMS patients (6%) were more likely to be male, with motor onset and a primary-progressive course, and exhibit faster progression and were less likely to take DMDs. Nonetheless, 57% were relapsing-onset, of which 31% were prescribed DMDs, most commonly IFNβ. Among older relapsing-onset MS adults, no significant association between IFNβ exposure and disability progression was found when either the contemporary (hazard ratio [HR]: 0.46; 95% CI: 0.18–1.22) or historical controls (HR: 0.54; 95% CI: 0.20–1.42) were considered. Conclusion. LOMS differed clinically from AOMS. One-third of older relapsing-onset MS patients were prescribed a DMD. IFNβ exposure was not significantly associated with reduced disability in older MS patients. Afsaneh Shirani, Yinshan Zhao, John Petkau, Paul Gustafson, Mohammad Ehsanul Karim, Charity Evans, Elaine Kingwell, Mia L. van der Kop, Joel Oger, and Helen Tremlett Copyright © 2015 Afsaneh Shirani et al. All rights reserved. Embolic Signals during Routine Transcranial Doppler Ultrasonography in Aneurysmal Subarachnoid Hemorrhage Sun, 29 Mar 2015 08:24:05 +0000 Introduction. Cerebral emboli may occur in subarachnoid hemorrhage (SAH) and intracranial aneurysm surgery. Although embolic signs (ES) have been reported in SAH, their origin remains unclear. The aim of this study was to report the detection of ES during routine TCD monitoring in patients with aneurysmal SAH. Methods. A total of 105 patients with aneurysmal SAH were submitted to TCD evaluation. Patients were monitored almost daily (5 times per week). In each monitoring session, one experienced operator performed TCD to detect or assess vasospasm and ES in arteries of the Willis polygon. Results. Four patients out of a total of 105 patients with aneurysmal SAH were found to present spontaneous cerebral embolization during routine TCD monitoring. The average age of the 4 patients (mean ± standard deviation) was 59.5 ± 8.34 years (range 49–68 ys); female patients predominated representing 75% (3/4) of subjects. Conclusion. Although detection of ES was relatively rare in this study, rates of emboli occurrence may be higher under systematic monitoring. The detection of ES after SAH surgery reinforces the need to study the role of embolus in this condition and may be an indicator for prophylactic antithrombotic treatment. Fernando Mendes Paschoal Jr., Karla de Almeida Lins Ronconi, Marcelo de Lima Oliveira, Ricardo de Carvalho Nogueira, Eric Homero Albuquerque Paschoal, Manoel Jacobsen Teixeira, Eberval Gadelha Figueiredo, and Edson Bor-Seng-Shu Copyright © 2015 Fernando Mendes Paschoal Jr. et al. All rights reserved. Generation of Neurospheres from Human Adipose-Derived Stem Cells Thu, 26 Feb 2015 11:28:37 +0000 Transplantation of neural stem cells (NSCs) to treat neurodegenerative disease shows promise; however, the clinical application of NSCs is limited by the invasive procurement and ethical concerns. Adipose-derived stem cells (ADSCs) are a source of multipotent stem cells that can self-renew and differentiate into various kinds of cells; this study intends to generate neurospheres from human ADSCs by culturing ADSCs on uncoated culture flasks in serum-free neurobasal medium supplemented with B27, basic fibroblast growth factor (bFGF), and epidermal growth factor (EGF); the ADSCs-derived neurospheres were terminally differentiated after growth factor withdrawal. Expression of Nestin, NeuN, MAP2, and GFAP in ADSCs and terminally differentiated neurospheres was shown by quantitative reverse transcription-polymerase chain reaction (qRT-PCR), western blotting, and immunocytochemistry; cell proliferation in neurospheres was evaluated by cell cycle analyses, immunostaining, and flow cytometry. These data strongly support the conclusion that human ADSCs can successfully differentiate into neurospheres efficiently on uncoated culture flasks, which present similar molecular marker pattern and proliferative ability with NSCs derived from embryonic and adult brain tissues. Therefore, human ADSCs may be an ideal alternative source of stem cells for the treatment of neurodegenerative diseases. Erfang Yang, Na Liu, Yingxin Tang, Yang Hu, Ping Zhang, Chao Pan, Shasha Dong, Youping Zhang, and Zhouping Tang Copyright © 2015 Erfang Yang et al. All rights reserved. Results of Surgical Treatment of Schwannomas Arising from Extremities Sun, 22 Feb 2015 12:17:24 +0000 Schwannomas are benign neoplasms derived from Schwann cells. In this work, we present our experience in operative management of schwannomas and analyse results of treatment. Clinical material consisted of 34 patients, in whom 44 schwannomas located in extremities were excised between 1985 and 2013. Thirty-five tumours originated from major peripheral nerves and 9 from small nerve branches. Postoperatively, in the first group of tumours, pain resolved in 100%, paresthesias in 83.3%, and Hoffmann-Tinel sign in 91.6% of the patients. Improvement in motor function was noted in 28.5% of the cases, in sensory function: complete in 70%, and partial in 15%. The most frequently affected major peripheral nerves were the ulnar (11 tumours) and median (5 tumours) nerves. Schwannomas originating from small nerve branches were removed without identification of the site of origin. After their resection, definitive healing was achieved. Conclusions. (1) Schwannomas located in extremities arise predominantly from major peripheral nerves, most commonly the ulnar and median nerves. (2) Gradual tumour growth causes exacerbation of compression neuropathy, creating an indication for surgery. (3) In most cases, improvement in peripheral nerve function after excision of schwannoma is achieved. (4) The risk of new permanent postoperative neurological deficits is low. Jerzy Gosk, Olga Gutkowska, Maciej Urban, Witold Wnukiewicz, Paweł Reichert, and Piotr Ziółkowski Copyright © 2015 Jerzy Gosk et al. All rights reserved. Corrigendum to “Presymptomatic Treatment with Acetylcholinesterase Antisense Oligonucleotides Prolongs Survival in ALS (G93A-SOD1) Mice” Tue, 03 Feb 2015 09:02:41 +0000 Marc Gotkine, Leah Rozenstein, Ofira Einstein, Oded Abramsky, Zohar Argov, and Hanna Rosenmann Copyright © 2015 Marc Gotkine et al. All rights reserved. Anti-CCP Antibody Levels Are Not Associated with MS: Results from a Case-Control Study Mon, 02 Feb 2015 06:02:33 +0000 Citrullinated proteins have been suggested to play a critical role in the pathogenesis of multiple sclerosis (MS). Anticyclic citrullinated peptide (anti-CCP) antibody is used in the early diagnosis of rheumatoid arthritis (RA). The objective of this study was to investigate the presence of anti-CCP antibody in patients with MS compared to RA patients and healthy controls. Fifty patients with MS (38 females, 12 males; mean age 36.72 ± 8.82 years), 52 patients with RA (40 females, 12 males; mean age 40.87 ± 10.17 years), and 50 healthy controls (32 females, 18 males; mean age 38.22 ± 11.59 years) were included in this study. The levels of serum anti-CCP antibody were measured using an enzyme-linked immunosorbent assay (ELISA). The results of the study showed that anti-CCP antibody levels were significantly higher in RA patients versus MS or healthy controls . Moreover, anti-CCP antibody was positive in 43 (83%) patients with RA, while it was negative in all MS patients as well as in all healthy controls. Also, no significant correlation was found between the anti-CCP levels and EDSS scores . In conclusion, the results of this study did not support a positive association between serum anti-CCP antibody and MS. Mahmut Alpayci, Aysel Milanlioglu, Veysel Delen, Mehmet Nuri Aydin, Huseyin Guducuoglu, and Yasemin Bayram Copyright © 2015 Mahmut Alpayci et al. All rights reserved. Cholinergic Synaptic Transmissions Were Altered after Single Sevoflurane Exposure in Drosophila Pupa Sun, 01 Feb 2015 11:37:20 +0000 Purpose. Sevoflurane, one of the most used general anesthetics, is widely used in clinical practice all over the world. Previous studies indicated that sevoflurane could induce neuron apoptosis and neural deficit causing query in the safety of anesthesia using sevoflurane. The present study was designed to investigate the effects of sevoflurane on electrophysiology in Drosophila pupa whose excitatory neurotransmitter is acetylcholine early after sevoflurane exposure using whole brain recording technique. Methods. Wide types of Drosophila (canton-s flies) were allocated to control and sevoflurane groups randomly. Sevoflurane groups (1% sevoflurane; 2% sevoflurane; 3% sevoflurane) were exposed to sevoflurane and the exposure lasted 5 hours, respectively. All flies were subjected to electrophysiology experiment using patch clamp 24 hours after exposure. Results. The results showed that, 24 hours after sevoflurane exposure, frequency but not the amplitude of miniature excitatory postsynaptic currents (mEPSCs) was significantly reduced . Furthermore, we explored the underlying mechanism and found that calcium currents density, which partially regulated the frequency of mEPSCs, was significantly reduced after sevoflurane exposure . Conclusions. All these suggested that sevoflurane could alter the mEPSCs that are related to synaptic plasticity partially through modulating calcium channel early after sevoflurane exposure. Rongfa Chen, Tao Zhang, Liting Kuang, Zhen Chen, Dongzhi Ran, Yang Niu, Kangqing Xu, and Huaiyu Gu Copyright © 2015 Rongfa Chen et al. All rights reserved. Is There a Persistent Dysfunction of Neurovascular Coupling in Migraine? Sun, 01 Feb 2015 11:20:04 +0000 Changes in cerebral blood flow are one of the main features of migraine attack and have inspired the vascular theory of migraine. This traditional view has been reshaped with recent experimental data, which gave rise to the neural theory of migraine. In this review, we speculate that there might be an important link between the two theories, that is, the dysfunction of neurovascular coupling. Andrej Fabjan, Marjan Zaletel, and Bojana Žvan Copyright © 2015 Andrej Fabjan et al. All rights reserved. Risk Factors Associated with the Onset of Relapsing-Remitting and Primary Progressive Multiple Sclerosis: A Systematic Review Sat, 31 Jan 2015 07:36:27 +0000 Multiple sclerosis (MS) is a chronic central nervous system disease with a highly heterogeneous course. The aetiology of MS is not well understood but is likely a combination of both genetic and environmental factors. Approximately 85% of patients present with relapsing-remitting MS (RRMS), while 10–15% present with primary progressive MS (PPMS). PPMS is associated with an older onset age, a different sex ratio, and a considerably more rapid disease progression relative to RRMS. We systematically reviewed the literature to identify modifiable risk factors that may be associated with these different clinical courses. We performed a search of six databases and integrated twenty observational studies into a descriptive review. Exposure to Epstein-Barr virus (EBV) appeared to increase the risk of RRMS, but its association with PPMS was less clear. Other infections, such as human herpesvirus-6 and chlamydia pneumoniae, were not consistently associated with a specific disease course nor was cigarette smoking. Despite the vast literature examining risk factors for the development of MS, relatively few studies reported findings by disease course. This review exposes a gap in our understanding of the risk factors associated with the onset of PPMS, our current knowledge being predominated by relapsing-onset MS. Kyla A. McKay, Vivian Kwan, Thomas Duggan, and Helen Tremlett Copyright © 2015 Kyla A. McKay et al. All rights reserved. Early Aging in Chernobyl Clean-Up Workers: Long-Term Study Tue, 27 Jan 2015 11:47:41 +0000 This paper represents data of long-term open prospective study. 312 male clean-up workers, who participated in elimination of the Chernobyl disaster consequences in 1986-87, were observed and examined in Moscow Research Institute of Psychiatry. The average age of patients was 57,0 ± 6,8 years. All patients were diagnosed with psychoorganic syndrome, caused by combination of different factors, which led to early cerebrovascular pathology, which was confirmed by clinical, neuropsychological, and instrumental examination. Anamnesis and the level of social adaptation were also assayed. Clinical estimation was done with the use of specially developed Clinical Psychopathological Chart. All the symptoms were divided into 4 groups (asthenic, psychovegetative, dysthymic, and cognitive symptom-complexes). No pronounced signs of dementia were observed. The control group included 44 clean-up workers without mental disorders. Predomination of various exogenous factors before and after accident was noted. Therapy included different vasotropic remedies, as well as family therapy, art therapy, and cognitive training. The possibilities of the reverse development of symptoms were statistically proved. The results allow making a conclusion that these disorders could not be explained either by radiation effects or by PTSD but connected with cerebrovascular pathology. V. Krasnov, V. Kryukov, E. Samedova, I. Emelianova, and I. Ryzhova Copyright © 2015 V. Krasnov et al. All rights reserved. Melanoma Cells Homing to the Brain: An In Vitro Model Mon, 26 Jan 2015 06:46:50 +0000 We developed an in vitro contact through-feet blood brain barrier (BBB) model built using type IV collagen, rat astrocytes, and human umbilical vein endothelial cells (HUVECs) cocultured through Transwell porous polycarbonate membrane. The contact between astrocytes and HUVECs was demonstrated by electron microscopy: astrocytes endfeet pass through the 8.0 μm pores inducing HUVECs to assume a cerebral phenotype. Using this model we evaluated transmigration of melanoma cells from two different patients (M1 and M2) selected among seven melanoma primary cultures. M2 cells showed a statistically significant higher capability to pass across the in vitro BBB model, compared to M1. Expression of adhesion molecules was evaluated by flow cytometry: a statistically significant increased expression of MCAM, αvβ3, and CD49b was detected in M1. PCR array data showed that M2 had a higher expression of several matrix metalloproteinase proteins (MMPs) compared to M1. Specifically, data suggest that MMP2 and MMP9 could be directly involved in BBB permeability and that brain invasion by melanoma cells could be related to the overexpression of many MMPs. Future studies will be necessary to deepen the mechanisms of central nervous system invasion. A. Rizzo, C. Vasco, V. Girgenti, V. Fugnanesi, C. Calatozzolo, A. Canazza, A. Salmaggi, L. Rivoltini, M. Morbin, and E. Ciusani Copyright © 2015 A. Rizzo et al. All rights reserved. Meningeal Melanomatosis: A Challenge for Timely Diagnosis Wed, 14 Jan 2015 13:26:46 +0000 Neoplastic meningitis is a central nervous system complication that occurs in 3–5% of patients with cancer. Although most commonly seen in patients with disseminated disease, in a small percentage of patients, it may be the initial manifestation of cancer or even primitive in origin. In the absence of cancer history, the diagnosis of neoplastic meningitis may be challenging even for expert neurologists. Prognosis is poor, with a median overall survival of weeks from diagnosis. In the retrospective study herein, we described three cases of meningeal melanomatosis in patients without previous cancer history. The patients were diagnosed with significant delay (17 to 47 weeks from symptom onset) mainly due to the deferral in performing the appropriate testing. Even when the diagnosis was suspected, investigations by MRI, cerebrospinal fluid, or both proved at times unhelpful for confirmation. Prognosis was dismal, with a median survival of 4 weeks after diagnosis. Our observations are a cue to analyze the main pitfalls in the diagnosis of neoplastic meningitis in patients without cancer history and emphasize key elements that may facilitate early diagnosis. Giulia Berzero, Luca Diamanti, Anna Luisa Di Stefano, Paola Bini, Diego Franciotta, Ilaria Imarisio, Paolo Pedrazzoli, Lorenzo Magrassi, Patrizia Morbini, Lisa Maria Farina, Stefano Bastianello, Mauro Ceroni, and Enrico Marchioni Copyright © 2015 Giulia Berzero et al. All rights reserved. New Prognostic Score for the Prediction of 30-Day Outcome in Spontaneous Supratentorial Cerebral Haemorrhage Thu, 08 Jan 2015 12:22:56 +0000 Aims. The purpose of the present study was to evaluate predictors of outcome in primary supratentorial cerebral haemorrhage. Furthermore, we aimed to develop a prognostic model to predict 30-day fatality. Methods. We retrospectively analyzed a database of 156 patients with spontaneous supratentorial haemorrhage to explore the relationship between clinical and CT characteristics and fatal outcome within 30 days using multiple logistic regression analysis. The analyzed factors included volumetric data assessed by neuropathological and CT volumetry. A second CT scan in survivors or neuropathological ABC/2 volumetry in nonsurvivors was used along with the baseline CT to assess the growth index of haematoma. Results. Systolic blood pressure, serum potassium and glucose levels, platelet count, absolute and relative haematoma volumes, and presence and size of intraventricular haemorrhage statistically significantly predicted the fatal outcome within 30 days. Based on our results we formulated a six-factor scoring algorithm named SUSPEKT to predict outcome. Conclusions. After validation the SUSPEKT score may be applicable in general clinical practice for early patient selection to optimize individual management or for assessment of eligibility for treatment trials. Rita Szepesi, Ibolya Katalin Széll, Tibor Hortobágyi, László Kardos, Katalin Nagy, Levente István Lánczi, Ervin Berényi, Dániel Bereczki, and László Csiba Copyright © 2015 Rita Szepesi et al. All rights reserved. Quality of Life and Migraine Disability among Female Migraine Patients in a Tertiary Hospital in Malaysia Thu, 08 Jan 2015 07:20:53 +0000 Background. Disability caused by migraine may be one of the main causes of burden contributing to poor quality of life (QOL) among migraine patients. Thus, this study aimed to measure QOL among migraine sufferers in comparison with healthy controls. Methods. Female diagnosed migraine patients () and healthy controls () completed the Malay version of the World Health Organization QOL Brief (WHOQOL-BREF) questionnaire. Only migraine patients completed the Malay version of the Migraine Disability Assessment questionnaire. Results. Females with migraines had significantly lower total WHOQOL-BREF scores (84.3) than did healthy controls (91.9, ). Similarly, physical health (23.4 versus 27.7, ) and psychological health scores (21.7 versus 23.2, ) were significantly lower than those for healthy controls. Seventy-three percent of patients experienced severe disability, with significantly higher number of days with headaches (13.8 days/3 months, ) and pain scores (7.4, ). Furthermore, migraine patients with lower total QOL scores had 1.2 times higher odds of having disability than patients with higher total QOL scores. Conclusions. The present study showed that migraine sufferers experienced significantly lower QOL than the control group from a similar population. Disability was severe and frequent and was associated with lower QOL among the migraine patients. Munvar Miya Shaik, Norul Badriah Hassan, Huay Lin Tan, and Siew Hua Gan Copyright © 2015 Munvar Miya Shaik et al. All rights reserved. Current and Future Novel Treatments for Glioblastoma Multiforme Mon, 22 Dec 2014 07:00:30 +0000 Betty Tyler, Francesco DiMeco, Rachel Grossman, and Gustavo Pradilla Copyright © 2014 Betty Tyler et al. All rights reserved. Vinpocetine and Pyritinol: A New Model for Blood Rheological Modulation in Cerebrovascular Disorders—A Randomized Controlled Clinical Study Sun, 07 Dec 2014 14:15:04 +0000 Blood and plasma viscosity are the major factors affecting blood flow and normal circulation. Whole blood viscosity is mainly affected by plasma viscosity, red blood cell deformability/aggregation and hematocrit, and other physiological factors. Thirty patients (twenty males + ten females) with age range 50–65 years, normotensive with history of cerebrovascular disorders, were selected according to the American Heart Stroke Association. Blood viscosity and other rheological parameters were measured after two-day abstinence from any medications. Dual effects of vinpocetine and pyritinol exhibit significant effects on all hemorheological parameters (), especially on low shear whole blood viscosity (), but they produced insignificant effects on total serum protein and high shear whole blood viscosity (). Therefore, joint effects of vinpocetine and pyritinol improve blood and plasma viscosity in patients with cerebrovascular disorders. Hayder M. Alkuraishy, Ali I. Al-Gareeb, and Ali K. Albuhadilly Copyright © 2014 Hayder M. Alkuraishy et al. All rights reserved. Complex Network-Driven View of Genomic Mechanisms Underlying Parkinson’s Disease: Analyses in Dorsal Motor Vagal Nucleus, Locus Coeruleus, and Substantia Nigra Wed, 26 Nov 2014 07:51:54 +0000 Parkinson’s disease (PD)—classically characterized by severe loss of dopaminergic neurons in the substantia nigra pars compacta—has a caudal-rostral progression, beginning in the dorsal motor vagal nucleus and, in a less extent, in the olfactory system, progressing to the midbrain and eventually to the basal forebrain and the neocortex. About 90% of the cases are idiopathic. To study the molecular mechanisms involved in idiopathic PD we conducted a comparative study of transcriptional interaction networks in the dorsal motor vagal nucleus (VA), locus coeruleus (LC), and substantia nigra (SN) of idiopathic PD in Braak stages 4-5 (PD) and disease-free controls (CT) using postmortem samples. Gene coexpression networks (GCNs) for each brain region (patients and controls) were obtained to identify highly connected relevant genes (hubs) and densely interconnected gene sets (modules). GCN analyses showed differences in topology and module composition between CT and PD networks for each anatomic region. In CT networks, VA, LC, and SN hub modules are predominantly associated with neuroprotection and homeostasis in the ageing brain, whereas in the patient’s group, for the three brain regions, hub modules are mostly related to stress response and neuron survival/degeneration mechanisms. Beatriz Raposo Corradini, Priscila Iamashita, Edilaine Tampellini, José Marcelo Farfel, Lea Tenenholz Grinberg, and Carlos Alberto Moreira-Filho Copyright © 2014 Beatriz Raposo Corradini et al. All rights reserved. Increased DJ-1 in Urine Exosome of Korean Males with Parkinson’s Disease Thu, 13 Nov 2014 10:08:52 +0000 Parkinson’s disease (PD) is a difficult disease to diagnose although it is the second most common neurodegenerative disease. Recent studies show that exosome isolated from urine contains LRRK2 or DJ-1, proteins whose mutations cause PD. To investigate a potential use for urine exosomes as a tool for PD diagnosis, we compared levels of LRRK2, α-synuclein, and DJ-1 in urine exosomes isolated from Korean PD patients and non-PD controls. LRRK2 and DJ-1, but not α-synuclein, were detected in the urine exosome samples, as reported previously. We initially could not detect any significant difference in these protein levels between the patient and the control groups. However, when age, disease duration, L-dopa daily dose, and gender were considered as analytical parameters, LRRK2 and DJ-1 protein levels showed clear gender-dependent differences. In addition, DJ-1 level was significantly higher (1.7-fold) in male patients with PD than that in male non-PD controls and increased in an age-dependent manner in male patients with PD. Our observation might provide a clue to lead to a novel biomarker for PD diagnosis, at least in males. Dong Hwan Ho, Sanghak Yi, Hyemyung Seo, Ilhong Son, and Wongi Seol Copyright © 2014 Dong Hwan Ho et al. All rights reserved. Subunit Composition of Neurotransmitter Receptors in the Immature and in the Epileptic Brain Thu, 11 Sep 2014 06:23:54 +0000 Neuronal activity is critical for synaptogenesis and the development of neuronal networks. In the immature brain excitation predominates over inhibition facilitating the development of normal brain circuits, but also rendering it more susceptible to seizures. In this paper, we review the evolution of the subunit composition of neurotransmitter receptors during development, how it promotes excitation in the immature brain, and how this subunit composition of neurotransmission receptors may be also present in the epileptic brain. During normal brain development, excitatory glutamate receptors peak in function and gamma-aminobutiric acid (GABA) receptors are mainly excitatory rather than inhibitory. A growing body of evidence from animal models of epilepsy and status epilepticus has demonstrated that the brain exposed to repeated seizures presents a subunit composition of neurotransmitter receptors that mirrors that of the immature brain and promotes further seizures and epileptogenesis. Studies performed in samples from the epileptic human brain have also found a subunit composition pattern of neurotransmitter receptors similar to the one found in the immature brain. These findings provide a solid rationale for tailoring antiepileptic treatments to the specific subunit composition of neurotransmitter receptors and they provide potential targets for the development of antiepileptogenic treatments. Iván Sánchez Fernández and Tobias Loddenkemper Copyright © 2014 Iván Sánchez Fernández and Tobias Loddenkemper. All rights reserved. Cerebral Vasospasm after Aneurysmal Subarachnoid Hemorrhage: Mechanism and Therapies Mon, 08 Sep 2014 10:44:22 +0000 Chih-Lung Lin, Aaron S. Dumont, John H. Zhang, Mario Zuccarello, and Carl Muroi Copyright © 2014 Chih-Lung Lin et al. All rights reserved. Interleukin-13 Receptor Alpha 2-Targeted Glioblastoma Immunotherapy Wed, 27 Aug 2014 10:38:31 +0000 Glioblastoma (GBM) is the most lethal primary brain tumor, and despite several refinements in its multimodal management, generally has very poor prognosis. Targeted immunotherapy is an emerging field of research that shows great promise in the treatment of GBM. One of the most extensively studied targets is the interleukin-13 receptor alpha chain variant 2 (IL13Rα2). Its selective expression on GBM, discovered almost two decades ago, has been a target for therapy ever since. Immunotherapeutic strategies have been developed targeting IL13Rα2, including monoclonal antibodies as well as cell-based strategies such as IL13Rα2-pulsed dendritic cells and IL13Rα2-targeted chimeric antigen receptor-expressing T cells. Advanced therapeutic development has led to the completion of several clinical trials with promising outcomes. In this review, we will discuss the recent advances in the IL13Rα2-targeted immunotherapy and evaluate the most promising strategy for targeted GBM immunotherapy. Sadhak Sengupta, Bart Thaci, Andrew C. Crawford, and Prakash Sampath Copyright © 2014 Sadhak Sengupta et al. All rights reserved. Newcastle Disease Virus Interaction in Targeted Therapy against Proliferation and Invasion Pathways of Glioblastoma Multiforme Wed, 27 Aug 2014 00:00:00 +0000 Glioblastoma multiforme (GBM), or grade IV glioma, is one of the most lethal forms of human brain cancer. Current bioscience has begun to depict more clearly the signalling pathways that are responsible for high-grade glioma initiation, migration, and invasion, opening the door for molecular-based targeted therapy. As such, the application of viruses such as Newcastle disease virus (NDV) as a novel biological bullet to specifically target aberrant signalling in GBM has brought new hope. The abnormal proliferation and aggressive invasion behaviour of GBM is reported to be associated with aberrant Rac1 protein signalling. NDV interacts with Rac1 upon viral entry, syncytium induction, and actin reorganization of the infected cell as part of the replication process. Ultimately, intracellular stress leads the infected glioma cell to undergo cell death. In this review, we describe the characteristics of malignant glioma and the aberrant genetics that drive its aggressive phenotype, and we focus on the use of oncolytic NDV in GBM-targeted therapy and the interaction of NDV in GBM signalling that leads to inhibition of GBM proliferation and invasion, and subsequently, cell death. Jafri Malin Abdullah, Zulkifli Mustafa, and Aini Ideris Copyright © 2014 Jafri Malin Abdullah et al. All rights reserved. Morphometric Analysis of Connective Tissue Sheaths of Sural Nerve in Diabetic and Nondiabetic Patients Thu, 24 Jul 2014 00:00:00 +0000 One of the most common complications of diabetes mellitus is diabetic neuropathy. It may be provoked by metabolic and/or vascular factors, and depending on duration of disease, various layers of nerve may be affected. Our aim was to investigate influence of diabetes on the epineurial, perineurial, and endoneurial connective tissue sheaths. The study included 15 samples of sural nerve divided into three groups: diabetic group, peripheral vascular disease group, and control group. After morphological analysis, morphometric parameters were determined for each case using ImageJ software. Compared to the control group, the diabetic cases had significantly higher perineurial index () and endoneurial connective tissue percentage (). The diabetic group showed significantly higher epineurial area (), as well as percentage of endoneurial connective tissue (), in relation to the peripheral vascular disease group. It is obvious that hyperglycemia and ischemia present in diabetes lead to substantial changes in connective tissue sheaths of nerve, particularly in peri- and endoneurium. Perineurial thickening and significant endoneurial fibrosis may impair the balance of endoneurial homeostasis and regenerative ability of the nerve fibers. Future investigations should focus on studying the components of extracellular matrix of connective tissue sheaths in diabetic nerves. Braca Kundalić, Slađana Ugrenović, Ivan Jovanović, Natalija Stefanović, Vladimir Petrović, Jasen Kundalić, Vesna Stojanović, Vladimir Živković, and Vladimir Antić Copyright © 2014 Braca Kundalić et al. All rights reserved. Upregulation of Relaxin after Experimental Subarachnoid Hemorrhage in Rabbits Wed, 16 Jul 2014 10:00:47 +0000 Background. Although relaxin causes vasodilatation in systemic arteries, little is known about its role in cerebral arteries. We investigated the expression and role of relaxin in basilar arteries after subarachnoid hemorrhage (SAH) in rabbits. Methods. Microarray analysis with rabbit basilar artery RNA was performed. Messenger RNA expression of relaxin-1 and relaxin/insulin-like family peptide receptor 1 (RXFP1) was investigated with quantitative RT-PCR. RXFP1 expression in the basilar artery was investigated with immunohistochemistry. Relaxin concentrations in cerebrospinal fluid (CSF) and serum were investigated with an enzyme-linked immunosorbent assay. Using human brain vascular smooth muscle cells (HBVSMC) preincubated with relaxin, myosin light chain phosphorylation (MLC) was investigated with immunoblotting after endothelin-1 stimulation. Results. After SAH, RXFP1 mRNA and protein were significantly downregulated on day 3, whereas relaxin-1 mRNA was significantly upregulated on day 7. The relaxin concentration in CSF was significantly elevated on days 5 and 7. Pretreatment with relaxin reduced sustained MLC phosphorylation induced by endothelin-1 in HBVSMC. Conclusion. Upregulation of relaxin and downregulation of RXFP1 after SAH may participate in development of cerebral vasospasm. Downregulation of RXFP1 may induce a functional decrease in relaxin activity during vasospasm. Understanding the role of relaxin may provide further insight into the mechanisms of cerebral vasospasm. Yuichiro Kikkawa, Satoshi Matsuo, Ryota Kurogi, Akira Nakamizo, Masahiro Mizoguchi, and Tomio Sasaki Copyright © 2014 Yuichiro Kikkawa et al. All rights reserved. Patient Outcomes following Subarachnoid Hemorrhage between the Medical Center and Regional Hospital: Whether All Patients Should Be Transferred to Medical Centers Mon, 14 Jul 2014 08:58:57 +0000 Subarachnoid hemorrhage (SAH) is a critical illness that may result in patient mortality or morbidity. In this study, we investigated the outcomes of patients treated in medical center and nonmedical center hospitals and the relationship between such outcomes and hospital and surgeon volume. Patient data were abstracted from the National Health Insurance Research Database of Taiwan in the Longitudinal Health Insurance Database 2000, which contains all claims data of 1 million beneficiaries randomly selected in 2000. The International Classification of Diseases, Ninth Revision, subarachnoid hemorrhage (430) was used for the inclusion criteria. We identified 355 patients between 11 and 87 years of age who had subarachnoid hemorrhage. Among them, 32.4% (115/355) were men. The median Charlson comorbidity index (CCI) score was 1.3 (SD ± 0.6). Unadjusted logistic regression analysis demonstrated that low mortality was associated with high hospital volume (OR = 3.21; 95% CI: 1.18–8.77). In this study, we found no statistical significances of mortality, LOS, and total charges between medical centers and nonmedical center hospitals. Patient mortality was associated with hospital volume. Nonmedical center hospitals could achieve resource use and outcomes similar to those of medical centers with sufficient volume. Tsung-Ying Lin, Chieh Hsin Wu, Wei-Che Lee, Chao-Wen Chen, Liang-Chi Kuo, Shiuh-Lin Huang, Hsing-Lin Lin, and Chih-Lung Lin Copyright © 2014 Tsung-Ying Lin et al. All rights reserved. Usefulness of Anticoagulant Therapy in the Prevention of Embolic Complications in Patients with Acute Infective Endocarditis Thu, 10 Jul 2014 08:31:24 +0000 Background. The use of anticoagulant therapy (ACT) in patients with acute infective endocarditis (IE) remains a controversial issue. Our study attempts to estimate the impact of ACT on the occurrence of embolic complications and the usefulness of ACT in the prevention of embolism in IE patients. Methods. The present authors analyzed 150 patients with left-sided IE. Embolisms including cerebrovascular events (CVE) and the use of ACT were checked at the time of admission and during hospitalization. Results. 57 patients (38.0%) experienced an embolic event. There was no significant difference in the incidence of CVE and in-hospital mortality between patients with and without warfarin use at admission, although warfarin-naïve patients were significantly more likely to have large (>1 cm) and mobile vegetation. In addition, there was no significant difference in the incidence of postadmission embolism and in-hospital death between patients with and without in-hospital ACT. On multivariate logistic regression analysis, ACT at admission was not significantly associated with a lower risk of embolism in patients with IE. Conclusions. The role of ACT in the prevention of embolism was limited in IE patients undergoing antibiotic therapy, although it seems to reduce the embolic potential of septic vegetation before treatment. Seung-Jae Lee, Sam-Sae Oh, Dal-Soo Lim, Suk-Keun Hong, Rak-Kyeong Choi, and Jin-Sik Park Copyright © 2014 Seung-Jae Lee et al. All rights reserved. Biomechanics of Interspinous Devices Wed, 09 Jul 2014 14:10:25 +0000 A number of interspinous devices (ISD) have been introduced in the lumbar spine implant market. Unfortunately, the use of these devices often is not associated with real comprehension of their biomechanical role. The aim of this paper is to review the biomechanical studies about interspinous devices available in the literature to allow the reader a better comprehension of the effects of these devices on the treated segment and on the adjacent segments of the spine. For this reason, our analysis will be limited to the interspinous devices that have biomechanical studies published in the literature. Paolo D. Parchi, Gisberto Evangelisti, Antonella Vertuccio, Nicola Piolanti, Lorenzo Andreani, Valentina Cervi, Christian Giannetti, Giuseppe Calvosa, and Michele Lisanti Copyright © 2014 Paolo D. Parchi et al. All rights reserved. Validity and Reliability of the Bahasa Melayu Version of the Migraine Disability Assessment Questionnaire Wed, 09 Jul 2014 11:01:48 +0000 Background. The study was designed to determine the validity and reliability of the Bahasa Melayu version (MIDAS-M) of the Migraine Disability Assessment (MIDAS) questionnaire. Methods. Patients having migraine for more than six months attending the Neurology Clinic, Hospital Universiti Sains Malaysia, Kubang Kerian, Kelantan, Malaysia, were recruited. Standard forward and back translation procedures were used to translate and adapt the MIDAS questionnaire to produce the Bahasa Melayu version. The translated Malay version was tested for face and content validity. Validity and reliability testing were further conducted with 100 migraine patients (1st administration) followed by a retesting session 21 days later (2nd administration). Results. A total of 100 patients between 15 and 60 years of age were recruited. The majority of the patients were single (66%) and students (46%). Cronbach’s alpha values were 0.84 (1st administration) and 0.80 (2nd administration). The test-retest reliability for the total MIDAS score was 0.73, indicating that the MIDAS-M questionnaire is stable; for the five disability questions, the test-retest values ranged from 0.77 to 0.87. Conclusion. The MIDAS-M questionnaire is comparable with the original English version in terms of validity and reliability and may be used for the assessment of migraine in clinical settings. Munvar Miya Shaik, Norul Badriah Hassan, Huay Lin Tan, Shalini Bhaskar, and Siew Hua Gan Copyright © 2014 Munvar Miya Shaik et al. All rights reserved. The Harmful Effects of Subarachnoid Hemorrhage on Extracerebral Organs Mon, 07 Jul 2014 09:08:12 +0000 Subarachnoid hemorrhage (SAH) is a devastating neurological disorder. Patients with aneurysmal SAH develop secondary complications that are important causes of morbidity and mortality. Aside from secondary neurological injuries, SAH has been associated with nonneurologic medical complications, such as neurocardiogenic injury, neurogenic pulmonary edema, hyperglycemia, and electrolyte imbalance, of which cardiac and pulmonary complications are most common. The related mechanisms include activation of the sympathetic nervous system, release of catecholamines and other hormones, and inflammatory responses. Extracerebral complications are directly related to the severity of SAH-induced brain injury and indicate the clinical outcome in patients. This review provides an overview of the extracerebral complications after SAH. We also aim to describe the manifestations, underlying mechanisms, and the effects of those extracerebral complications on outcome following SAH. Sheng Chen, Qian Li, Haijian Wu, Paul R. Krafft, Zhen Wang, and John H. Zhang Copyright © 2014 Sheng Chen et al. All rights reserved. The Role of Microclot Formation in an Acute Subarachnoid Hemorrhage Model in the Rabbit Mon, 07 Jul 2014 08:52:31 +0000 Background. Microvascular dysfunction and microthrombi formation are believed to contribute to development of early brain injury (EBI) after aneurysmal subarachnoid hemorrhage (SAH). Objective. This study aimed to determine (i) extent of microthrombus formation and neuronal apoptosis in the brain parenchyma using a blood shunt SAH model in rabbits; (ii) correlation of structural changes in microvessels with EBI characteristics. Methods. Acute SAH was induced using a rabbit shunt cisterna magna model. Extent of microthrombosis was detected 24 h post-SAH () by fibrinogen immunostaining, compared to controls (). We assessed apoptosis by terminal deoxynucleotidyl transferase nick end labeling (TUNEL) in cortex and hippocampus. Results. Our results showed significantly more TUNEL-positive cells (SAH: 115 ± 13; controls: 58 ± 10; ) and fibrinogen-positive microthromboemboli (SAH: 9 ± 2; controls: 2 ± 1; ) in the hippocampus after aneurysmal SAH. Conclusions. We found clear evidence of early microclot formation in a rabbit model of acute SAH. The extent of microthrombosis did not correlate with early apoptosis or CPP depletion after SAH; however, the total number of TUNEL positive cells in the cortex and the hippocampus significantly correlated with mean CPP reduction during the phase of maximum depletion after SAH induction. Both microthrombosis and neuronal apoptosis may contribute to EBI and subsequent DCI. Lukas Andereggen, Volker Neuschmelting, Michael von Gunten, Hans Rudolf Widmer, Javier Fandino, and Serge Marbacher Copyright © 2014 Lukas Andereggen et al. All rights reserved. Inflammation, Vasospasm, and Brain Injury after Subarachnoid Hemorrhage Thu, 03 Jul 2014 07:37:39 +0000 Subarachnoid hemorrhage (SAH) can lead to devastating neurological outcomes, and there are few pharmacologic treatments available for treating this condition. Both animal and human studies provide evidence of inflammation being a driving force behind the pathology of SAH, leading to both direct brain injury and vasospasm, which in turn leads to ischemic brain injury. Several inflammatory mediators that are elevated after SAH have been studied in detail. While there is promising data indicating that blocking these factors might benefit patients after SAH, there has been little success in clinical trials. One of the key factors that complicates clinical trials of SAH is the variability of the initial injury and subsequent inflammatory response. It is likely that both genetic and environmental factors contribute to the variability of patients’ post-SAH inflammatory response and that this confounds trials of anti-inflammatory therapies. Additionally, systemic inflammation from other conditions that affect patients with SAH could contribute to brain injury and vasospasm after SAH. Continuing work on biomarkers of inflammation after SAH may lead to development of patient-specific anti-inflammatory therapies to improve outcome after SAH. Brandon A. Miller, Nefize Turan, Monica Chau, and Gustavo Pradilla Copyright © 2014 Brandon A. Miller et al. All rights reserved. Efficacy of Zonisamide in Migraineurs with Nonresponse to Topiramate Wed, 02 Jul 2014 12:06:22 +0000 This study investigated another type of carbonic anhydrase inhibitor and antiepileptic drug, zonisamide, in order to evaluate its potential effectiveness for migraine prophylaxis refractory to topiramate, and to assess intolerability to adverse events, paresthesia in particular. This is an open-labeled retrospective single center study. We included headache patients who met the requirement of migraine without aura and were refractory to topiramate. Patients were treated only with zonisamide 100 mg/day, directly switching from topiramate. Patients were monitored every month for three months. A positive response to treatment (responders) was defined as a 50% or greater reduction in headache days at three months after study commencement, compared with baseline. One hundred and twenty migraineurs who were refractory to topiramate were recruited. Compared with baseline, headache days with zonisamide showed a decrease, compared with baseline (). Two patients complained of adverse effects, such as paresthesia. These results suggest that zonisamide is effective for migraine prophylaxis refractory to topiramate, or intolerable patients due to topiramate-induced paresthesia. Jin-Young Chung, Min-Wook Kim, and Manho Kim Copyright © 2014 Jin-Young Chung et al. All rights reserved. Iron Metabolism Disturbance in a French Cohort of ALS Patients Wed, 02 Jul 2014 07:39:08 +0000 Objective. The aim of this study was to assess iron status in a cohort of amyotrophic lateral sclerosis (ALS) patients compared to controls in order to evaluate these parameters as a risk factor or a modifying factor of ALS. Methods. We collected serum iron, ferritin, transferrin, total iron-binding capacity, and transferrin saturation coefficient (TSC) from 104 ALS patients at the time of diagnosis and from 145 controls. We reported phenotypic characteristics and evolution parameters such as ALSFRS-R and forced vital capacity at diagnosis and after one year of follow-up. In a first step we compared iron status between ALS patients and controls, and then we evaluated the relation between iron status and disease evolution of ALS patients using univariate and multivariate analysis. Results. We observed increased concentrations of serum iron () and ferritin () and increased TSC () in ALS patients. We also showed an association between markers of iron status and high body weight loss in ALS patients. The multivariate analysis of survival highlighted a significant relation between ferritin level and disease duration (). Conclusion. This is the first study showing a higher concentration of serum iron in ALS patients, strengthening the involvement of a deregulation of iron metabolism in ALS. Charlotte Veyrat-Durebex, Philippe Corcia, Aleksandra Mucha, Simon Benzimra, Cindy Mallet, Chantal Gendrot, Caroline Moreau, David Devos, Eric Piver, Jean-Christophe Pagès, François Maillot, Christian R. Andres, Patrick Vourc’h, and Hélène Blasco Copyright © 2014 Charlotte Veyrat-Durebex et al. All rights reserved. Electroacupuncture at ST36-ST37 and at Ear Ameliorates Hippocampal Mossy Fiber Sprouting in Kainic Acid-Induced Epileptic Seizure Rats Sun, 22 Jun 2014 13:17:39 +0000 Our previous study showed that mossy fiber sprouting can occur in the hippocampus region in rats 6 wk after kainic acid-induced epileptic seizure, and this mossy fiber sprouting can facilitate epileptogenesis. Transcutaneous auricular vagal nerve stimulation (VNS), which is similar to cervical VNS, can reduce the occurrence of epileptic seizure in intractable epilepsy patients. Greater parasympathetic nerve activity can be caused by 2 Hz electroacupuncture (EA). Therefore, we investigated the effect of 2 Hz EA at ST-36-ST37 and at the ear on mossy fiber sprouting in kainic-treated Sprague-Dawley rats. The results indicated that applying 2 Hz EA at ST36-ST37 and at the ear for 3 d per week over 6 consecutive weeks can ameliorate mossy fiber sprouting in the hippocampus region of rats. These results indicated that applying 2 Hz EA at ST36-ST37 and at the ear might be beneficial for the treatment and prevention of epilepsy in humans. Chung-Hsiang Liu, Yi-Wen Lin, Hsin-Cheng Hsu, Hsu-Jan Liu, Wan-Jung Lin, and Ching-Liang Hsieh Copyright © 2014 Chung-Hsiang Liu et al. All rights reserved. Intraoperative Cerebral Glioma Characterization with Contrast Enhanced Ultrasound Thu, 12 Jun 2014 11:10:30 +0000 Background. Contrast enhanced ultrasound (CEUS) is a dynamic and continuous modality providing real-time view of vascularization and flow distribution patterns of different organs and tumors. Nevertheless its intraoperative use for brain tumors visualization has been performed few times, and a thorough characterization of cerebral glioma had never been performed before. Aim. To perform the first characterization of cerebral glioma using CEUS and to possibly achieve an intraoperative differentiation of different gliomas. Methods. We performed CEUS in an off-label setting in 69 patients undergoing surgery for cerebral glioma. An intraoperative qualitative analysis was performed comparing iCEUS with B-mode imaging. A postprocedural semiquantitative analysis was then performed for each case, according to EFSUMB criteria. Results were related to histopathology. Results. We observed different CE patterns: LGG show a mild, dotted CE with diffuse appearance and slower, delayed arterial and venous phase. HGG have a high CE with a more nodular, nonhomogeneous appearance and fast perfusion patterns. Conclusion. Our study characterizes for the first time human brain glioma with CEUS, providing further insight regarding these tumors’ biology. CEUS is a fast, safe, dynamic, real-time, and economic tool that might be helpful during surgery in differentiating malignant and benign gliomas and refining surgical strategy. Francesco Prada, Luca Mattei, Massimiliano Del Bene, Luca Aiani, Marco Saini, Cecilia Casali, Assunta Filippini, Federico Giuseppe Legnani, Alessandro Perin, Andrea Saladino, Ignazio Gaspare Vetrano, Luigi Solbiati, Alberto Martegani, and Francesco DiMeco Copyright © 2014 Francesco Prada et al. All rights reserved. Alteration of Basilar Artery Rho-Kinase and Soluble Guanylyl Cyclase Protein Expression in a Rat Model of Cerebral Vasospasm following Subarachnoid Hemorrhage Sun, 01 Jun 2014 00:00:00 +0000 Background and Purpose. The vasoconstrictor endothelin-1 (ET-1) has been implicated in the pathogenesis of cerebral vasospasm following subarachnoid hemorrhage (SAH). Previous results showed that CGS 26303, an endothelin converting enzyme (ECE) inhibitor, effectively prevented and reversed arterial narrowing in animal models of SAH. In the present study, we assessed the effect of CGS 26303 on neurological deficits in SAH rats. The involvement of vasoactive pathways downstream of ET-1 signaling in SAH was also investigated. Methods. Sprague-Dawley rats were divided into five groups (/group): (1) normal control, (2) SAH, (3) SAH+vehicle, (4) SAH+CGS 26303 (prevention), and (5) SAH+CGS 26303 (reversal). SAH was induced by injecting autologous blood into cisterna magna. CGS 26303 (10 mg/kg) was injected intravenously at 1 and 24 hr after the initiation of SAH in the prevention and reversal protocols, respectively. Behavioral changes were assessed at 48 hr after SAH. Protein expression was analyzed by Western blots. Results. Deficits in motor function were obvious in the SAH rats, and CGS 26303 significantly improved the rate of paraplegia. Expressions of rho-kinase-II and membrane-bound protein kinase C-δ and rhoA were significantly increased, while those of soluble guanylyl cyclase α1 and β1 as well as protein kinase G were significantly decreased in the basilar artery of SAH rats. Treatment with CGS 26303 nearly normalized these effects. Conclusions. These results demonstrate that the rhoA/rho-kinase and sGC/cGMP/PKG pathways play pivotal roles in cerebral vasospasm after SAH. It also shows that ECE inhibition is an effective strategy for the treatment of this disease. Chih-Jen Wang, Pei-Yu Lee, Bin-Nan Wu, Shu-Chuan Wu, Joon-Khim Loh, Hung-Pei Tsai, Chia-Li Chung, Neal F. Kassell, and Aij-Lie Kwan Copyright © 2014 Chih-Jen Wang et al. All rights reserved. Plasma Albumin Induces Cytosolic Calcium Oscilations and DNA Synthesis in Human Cultured Astrocytes Thu, 22 May 2014 15:49:12 +0000 So far, a little is known about transition from normal to focal epileptic brain, although disruption in blood-brain barrier and albumin had recently involved. The main objective of this work is to characterize the response of cultured human astrocytes to plasma albumin, including induction of DNA synthesis. Cortical tissue was obtained from 9 patients operated from temporal lobe epilepsy. Astrocytes were cultured for 3-4 weeks and cytosolic calcium concentration () was measured. Bovine and human plasma albumin were used. We observed that low albumin concentration decreases , while higher concentration, induces increase in . It was shown that increase in was mediated by inositol 1,4,5-trisphosphate and released from internal stores. Increase in was reduced to 19% by blocking the transforming growth factor-beta (TGF-βR) receptor. Albumin induces DNA synthesis in a dose-response manner. Finally, induction of DNA synthesis can be partially blocked by heparin and block of TGF-β; however, the combination of both incompletely inhibits DNA synthesis. Therefore, results suggest that mechanisms other than Ca2+ signals and TGF-β receptor activation might induce DNA synthesis in a lesser degree. These results may be important to further understand the mechanisms involved in the transition from normal to focal epileptic brain. Lorena Vega-Zelaya, Guillermo J. Ortega, Rafael G. Sola, and Jesús Pastor Copyright © 2014 Lorena Vega-Zelaya et al. All rights reserved. Body Pigmentation as a Risk Factor for the Formation of Intracranial Aneurysms Thu, 22 May 2014 11:38:45 +0000 Recent studies demonstrated pigmented cells both in the murine heart, in pulmonary veins, and in brain arteries. Moreover, a role for melanocytes in the downregulation of inflammatory processes was suggested. As there is increasing evidence that inflammation is contributing significantly to the pathogenesis of intracranial aneurysms, melanocyte-like cells may be relevant in preventing age-related impairment of vessels. As pigmentation of the heart reflects that of coat color, aspects of body pigmentation might be associated with the incidence of intracranial aneurysms. We performed a case-control study to evaluate associations between the pigmentation of hair and eyes and the formation of aneurysms. In addition to hair and eye color, constitutive and facultative skin pigmentation were assessed in a replication study as well as individual handedness which can be seen as a neurophysiological correlate of developmental pigmentation processes. Hair pigmentation was highly associated with intracranial aneurysms in both samples, whereas eye pigmentation was not. In the replication cohort, facultative but not constitutive skin pigmentation proved significant. The strongest association was observed for individual handedness. Results indicate a significant association of intracranial aneurysms with particular aspects of body pigmentation as well as handedness, and imply clinical usefulness for screening of aneurysms and possible interventions. Günter Schulter, Klaus Leber, Elke Kronawetter, Viktoria R. Rübenbauer, Peter Konstantiniuk, and Ilona Papousek Copyright © 2014 Günter Schulter et al. All rights reserved. Progesterone Induces the Growth and Infiltration of Human Astrocytoma Cells Implanted in the Cerebral Cortex of the Rat Thu, 22 May 2014 05:50:29 +0000 Progesterone (P4) promotes cell proliferation in several types of cancer, including brain tumors such as astrocytomas, the most common and aggressive primary intracerebral neoplasm in humans. In this work, we studied the effects of P4 and its intracellular receptor antagonist, RU486, on growth and infiltration of U373 cells derived from a human astrocytoma grade III, implanted in the motor cortex of adult male rats, using two treatment schemes. In the first one, fifteen days after cells implantation, rats were daily subcutaneously treated with vehicle (propylene glycol, 160 μL), P4 (1 mg), RU486 (5 mg), or P4 + RU486 (1 mg and 5 mg, resp.) for 21 days. In the second one, treatments started 8 weeks after cells implantation and lasted for 14 days. In both schemes we found that P4 significantly increased the tumor area as compared with the rest of the treatments, whereas RU486 blocked P4 effects. All rats treated with P4 showed tumor infiltration, while 28.6% and 42.9% of the animals treated with RU486 and P4 + RU486, respectively, presented it. Our data suggest that P4 promotes growth and migration of human astrocytoma cells implanted in the motor cortex of the rat through the interaction with its intracellular receptor. Liliana Germán-Castelán, Joaquín Manjarrez-Marmolejo, Aliesha González-Arenas, María Genoveva González-Morán, and Ignacio Camacho-Arroyo Copyright © 2014 Liliana Germán-Castelán et al. All rights reserved. Fluorescence-Guided Surgery and Biopsy in Gliomas with an Exoscope System Wed, 21 May 2014 08:51:57 +0000 Background. The introduction of fluorescence-guided resection allows a better identification of tumor tissue and its more radical resection. We describe our experience with a modified exoscope to detect 5 ALA-induced fluorescence in neuronavigation-guided brain surgery or biopsy of malignant brain tumors. Methods. Thirty-eight patients with a suspected preoperative diagnosis of high-grade astrocytoma were included. We used a neuronavigation device and a high-definition exoscope system with a built-in filter to detect 5-ALA fluorescence in all cases. Thirty patients underwent craniotomy with tumor resection and 8 underwent frameless stereotactic brain biopsy. Results. Histopathological diagnosis confirmed the presence of high-grade gliomas in 34 patients. Total resection was achieved in 23 cases and subtotal in 7. No relevant complications related to the administration of 5-ALA were detected. Conclusions. The use of the exoscope in 5-ALA fluorescence-guided tumor surgery has twofold implications: during brain tumor surgery it can be considered a valuable tool to achieve a more radical resection of the lesion, and when applied to a biopsy of a suspected brain high-grade glioma, it decreases the possibility of a negative biopsy. José Piquer, Jose L. Llácer, Vicente Rovira, Pedro Riesgo, Ruben Rodriguez, and Antonio Cremades Copyright © 2014 José Piquer et al. All rights reserved. To Look Beyond Vasospasm in Aneurysmal Subarachnoid Haemorrhage Mon, 19 May 2014 10:50:14 +0000 Delayed cerebral vasospasm has classically been considered the most important and treatable cause of mortality and morbidity in patients with aneurysmal subarachnoid hemorrhage (aSAH). Secondary ischemia (or delayed ischemic neurological deficit, DIND) has been shown to be the leading determinant of poor clinical outcome in patients with aSAH surviving the early phase and cerebral vasospasm has been attributed to being primarily responsible. Recently, various clinical trials aimed at treating vasospasm have produced disappointing results. DIND seems to have a multifactorial etiology and vasospasm may simply represent one contributing factor and not the major determinant. Increasing evidence shows that a series of early secondary cerebral insults may occur following aneurysm rupture (the so-called early brain injury). This further aggravates the initial insult and actually determines the functional outcome. A better understanding of these mechanisms and their prevention in the very early phase is needed to improve the prognosis. The aim of this review is to summarize the existing literature on this topic and so to illustrate how the presence of cerebral vasospasm may not necessarily be a prerequisite for DIND development. The various factors determining DIND that worsen functional outcome and prognosis are then discussed. Giulia Cossu, Mahmoud Messerer, Mauro Oddo, and Roy Thomas Daniel Copyright © 2014 Giulia Cossu et al. All rights reserved. Progesterone Attenuates Experimental Subarachnoid Hemorrhage-Induced Vasospasm by Upregulation of Endothelial Nitric Oxide Synthase via Akt Signaling Pathway Tue, 13 May 2014 08:12:41 +0000 Cerebral vasospasm is the leading cause of mortality and morbidity in patients after aneurysmal subarachnoid hemorrhage (SAH). However, the mechanism and adequate treatment of vasospasm are still elusive. In the present study, we evaluate the effect and possible mechanism of progesterone on SAH-induced vasospasm in a two-hemorrhage rodent model of SAH. Progesterone (8 mg/kg) was subcutaneously injected in ovariectomized female Sprague-Dawley rats one hour after SAH induction. The degree of vasospasm was determined by averaging the cross-sectional areas of basilar artery 7 days after first SAH. Expressions of endothelial nitric oxide synthase (eNOS) and phosphorylated Akt (phospho-Akt) in basilar arteries were evaluated. Prior to perfusion fixation, there were no significant differences among the control and treated groups in physiological parameters recorded. Progesterone treatment significantly attenuated SAH-induced vasospasm. The SAH-induced suppression of eNOS protein and phospho-Akt were relieved by progesterone treatment. This result further confirmed that progesterone is effective in preventing SAH-induced vasospasm. The beneficial effect of progesterone might be in part related to upregulation of expression of eNOS via Akt signaling pathway after SAH. Progesterone holds therapeutic promise in the treatment of cerebral vasospasm following SAH. Chia-Mao Chang, Yu-Feng Su, Chih-Zen Chang, Chia-Li Chung, Yee-Jean Tsai, Joon-Khim Loh, and Chih-Lung Lin Copyright © 2014 Chia-Mao Chang et al. All rights reserved. The Role of Arterioles and the Microcirculation in the Development of Vasospasm after Aneurysmal SAH Sun, 11 May 2014 13:41:30 +0000 Cerebral vasospasm of the major cerebral arteries, which is characterized by angiographic narrowing of those vessels, had been recognized as a main contributor to delayed cerebral ischemia (DCI) in subarachnoid hemorrhage (SAH) patients. However, the CONSCIOUS-1 trial revealed that clazosentan could not improve mortality or clinical outcome in spite of successful reduction of relative risk in angiographic vasospasm. This result indicates that the pathophysiology underlying DCI is multifactorial and that other pathophysiological factors, which are independent of angiographic vasospasm, can contribute to the outcome. Recent studies have focused on microcirculatory disturbance, such as microthrombosis and arteriolar constriction, as a factor affecting cerebral ischemia after SAH. Reports detecting microthrombosis and arteriolar constriction will be reviewed, and the role of the microcirculation on cerebral ischemia during vasospasm after SAH will be discussed. Masato Naraoka, Naoya Matsuda, Norihito Shimamura, Kenichiro Asano, and Hiroki Ohkuma Copyright © 2014 Masato Naraoka et al. All rights reserved. Through Diffusion Tensor Magnetic Resonance Imaging to Evaluate the Original Properties of Neural Pathways of Patients with Partial Seizures and Secondary Generalization by Individual Anatomic Reference Atlas Mon, 05 May 2014 11:31:57 +0000 To investigate white matter (WM) abnormalities in neocortical epilepsy, we extract supratentorial WM parameters from raw tensor magnetic resonance images (MRI) with automated region-of-interest (ROI) registrations. Sixteen patients having neocortical seizures with secondarily generalised convulsions and 16 age-matched normal subjects were imaged with high-resolution and diffusion tensor MRIs. Automated demarcation of supratentorial fibers was accomplished with personalized fiber-labeled atlases. From the individual atlases, we observed significant elevation of mean diffusivity (MD) in fornix (cres)/stria terminalis (FX/ST) and sagittal stratum (SS) and a significant difference in fractional anisotropy (FA) among FX/ST, SS, posterior limb of the internal capsule (PLIC), and posterior thalamic radiation (PTR). For patients with early-onset epilepsy, the diffusivities of the SS and the retrolenticular part of the internal capsule were significantly elevated, and the anisotropies of the FX/ST and SS were significantly decreased. In the drug-resistant subgroup, the MDs of SS and PTR and the FAs of SS and PLIC were significantly different. Onset age was positively correlated with increases in FAs of the genu of the corpus callosum. Patients with neocortical seizures and secondary generalisation had microstructural anomalies in WM. The changes in WM are relevant to early onset, progression, and severity of epilepsy. Syu-Jyun Peng, Tomor Harnod, Jang-Zern Tsai, Chien-Chun Huang, Ming-Dou Ker, Jun-Chern Chiou, Herming Chiueh, Chung-Yu Wu, and Yue-Loong Hsin Copyright © 2014 Syu-Jyun Peng et al. All rights reserved. Cerebral Endothelial Function Determined by Cerebrovascular Reactivity to L-Arginine Thu, 17 Apr 2014 12:41:27 +0000 Endothelium forms the inner cellular lining of blood vessels and plays an important role in many physiological functions including the control of vasomotor tone. Cerebral endothelium is probably one of the most specific types but until recently it was impossible to determine its function. In this review, the role of cerebrovascular reactivity to L-arginine (CVR-L-Arg) for assessment of cerebral endothelial function is discussed. L-Arginine induces vasodilatation through enhanced production of nitric oxide (NO) in the cerebral endothelium. Transcranial Doppler sonography is used for evaluation of cerebral blood flow changes. The method is noninvasive, inexpensive, and enables reproducible measurements. CVR-L-Arg has been compared to flow-mediated dilatation as a gold standard for systemic endothelial function and intima-media thickness as a marker for morphological changes. However, it seems to show specific cerebral endothelial function. So far CVR-L-Arg has been used to study cerebral endothelial function in many pathological conditions such as stroke, migraine, etc. In addition CVR-L-Arg has also proven its usefulness in order to show potential improvement after pharmacological interventions. In conclusion CVR-L-Arg is a promising noninvasive research method that could provide means for evaluation of cerebral endothelial function in physiological and pathological conditions. Janja Pretnar-Oblak Copyright © 2014 Janja Pretnar-Oblak. All rights reserved. Prophylactic Intra-Arterial Injection of Vasodilator for Asymptomatic Vasospasm Converts the Patient to Symptomatic Vasospasm due to Severe Microcirculatory Imbalance Wed, 16 Apr 2014 12:35:40 +0000 Object. The strategy to treat asymptomatic angiographic vasospasm following subarachnoid hemorrhage (SAH) is controversial. In this study we review our consecutive vasospasm series and discuss an adequate treatment strategy for asymptomatic vasospasm. Methods. From January 2007 to December 2012 we treated 281 aneurysmal SAH cases, with postoperative angiography performed 9 ± 2 days after the onset of SAH. Four asymptomatic cases received intra-arterial (IA) injection of vasodilator due to angiographic vasospasm. All cases improved vasospasm immediately following intervention. But all cases turned symptomatic within 48 hours. We retrospectively analyzed the time-density angiography curve and calculated the time to peak (TTP), mean transit time (MTT), and relative blood flow (rBF). Relative blood flow was calculated as follows. The integration of the value of the time-density curve for the artery was divided by the same value for the internal carotid artery multiplied by the MTT. Results. The decrease in TTP and MTT for the etiologic artery was similar to that of the nonetiologic artery. But the improvement in rBF for the etiologic artery and nonetiologic artery was 10% and 17%, respectively. Blood supply to the spastic artery decreased due to iatrogenic steal. Conclusion. Prophylactic IA injection of vasodilator in cases of asymptomatic vasospasm can produce symptomatic vasospasm. Norihito Shimamura, Masato Naraoka, Naoya Matsuda, Kiyohide Kakuta, and Hiroki Ohkuma Copyright © 2014 Norihito Shimamura et al. All rights reserved. One-Year Follow-Up of a Series of 100 Patients Treated for Lumbar Spinal Canal Stenosis by Means of HeliFix Interspinous Process Decompression Device Tue, 15 Apr 2014 14:01:32 +0000 Purpose. New interspinous process decompression devices (IPDs) provide an alternative to conservative treatment and decompressive surgery for patients with neurogenic intermittent claudication (NIC) due to degenerative lumbar spinal stenosis (DLSS). HeliFix is a minimally invasive IPD that can be implanted percutaneously. This is a preliminary evaluation of safety and effectiveness of this IPD up to 12 months after implantation. Methods. After percutaneous implantation in 100 patients with NIC due to DLSS, data on symptoms, quality of life, pain, and use of pain medication were obtained for up to 12 months. Results. Early symptoms and physical function improvements were maintained for up to 12 months. Leg, buttock/groin, and back pain were eased throughout, and the use and strength of related pain medication were reduced. Devices were removed from 2% of patients due to lack of effectiveness. Conclusions. Overall, in a period of up to 12-month follow-up, the safety and effectiveness of the HeliFix offered a minimally invasive option for the relief of NIC complaints in a high proportion of patients. Further studies are undertaken in order to provide insight on outcomes and effectiveness compared to other decompression methods and to develop guidance on optimal patient selection. Alberto Alexandre, Andrea Maria Alexandre, Mario De Pretto, Luca Corò, and Raul Saggini Copyright © 2014 Alberto Alexandre et al. All rights reserved. Stem Cell Niches in Glioblastoma: A Neuropathological View Tue, 15 Apr 2014 06:25:02 +0000 Glioblastoma (GBM) stem cells (GSCs), responsible for tumor growth, recurrence, and resistance to therapies, are considered the real therapeutic target, if they had no molecular mechanisms of resistance, in comparison with the mass of more differentiated cells which are insensitive to therapies just because of being differentiated and nonproliferating. GSCs occur in tumor niches where both stemness status and angiogenesis are conditioned by the microenvironment. In both perivascular and perinecrotic niches, hypoxia plays a fundamental role. Fifteen glioblastomas have been studied by immunohistochemistry and immunofluorescence for stemness and differentiation antigens. It has been found that circumscribed necroses develop inside hyperproliferating areas that are characterized by high expression of stemness antigens. Necrosis developed inside them because of the imbalance between the proliferation of tumor cells and endothelial cells; it reduces the number of GSCs to a thin ring around the former hyperproliferating area. The perinecrotic GSCs are nothing else that the survivors remnants of those populating hyperproliferating areas. In the tumor, GSCs coincide with malignant areas so that the need to detect where they are located is not so urgent. Davide Schiffer, Marta Mellai, Laura Annovazzi, Valentina Caldera, Angela Piazzi, Tetyana Denysenko, and Antonio Melcarne Copyright © 2014 Davide Schiffer et al. All rights reserved. Controversies about Interspinous Process Devices in the Treatment of Degenerative Lumbar Spine Diseases: Past, Present, and Future Sun, 13 Apr 2014 13:11:57 +0000 A large number of interspinous process devices (IPD) have been recently introduced to the lumbar spine market as an alternative to conventional decompressive surgery in managing symptomatic lumbar spinal pathology, especially in the older population. Despite the fact that they are composed of a wide range of different materials including titanium, polyetheretherketone, and elastomeric compounds, the aim of these devices is to unload spine, restoring foraminal height, and stabilize the spine by distracting the spinous processes. Although the initial reports represented the IPD as a safe, effective, and minimally invasive surgical alternative for relief of neurological symptoms in patients with low back degenerative diseases, recent studies have demonstrated less impressive clinical results and higher rate of failure than initially reported. The purpose of this paper is to provide a comprehensive overview on interspinous implants, their mechanisms of action, safety, cost, and effectiveness in the treatment of lumbar stenosis and degenerative disc diseases. Roberto Gazzeri, Marcelo Galarza, and Alex Alfieri Copyright © 2014 Roberto Gazzeri et al. All rights reserved. Impact of Clipping versus Coiling on Postoperative Hemodynamics and Pulmonary Edema after Subarachnoid Hemorrhage Wed, 09 Apr 2014 08:52:09 +0000 Volume management is critical for assessment of cerebral vasospasm after aneurysmal subarachnoid hemorrhage (SAH). This multicenter prospective cohort study compared the impact of surgical clipping versus endovascular coiling on postoperative hemodynamics and pulmonary edema in patients with SAH. Hemodynamic parameters were measured for 14 days using a transpulmonary thermodilution system. The study included 202 patients, including 160 who underwent clipping and 42 who underwent coiling. There were no differences in global ejection fraction (GEF), cardiac index, systemic vascular resistance index, or global end-diastolic volume index between the clipping and coiling groups in the early period. However, extravascular lung water index (EVLWI) and pulmonary vascular permeability index (PVPI) were significantly higher in the clipping group in the vasospasm period. Postoperative C-reactive protein (CRP) level was higher in the clipping group and was significantly correlated with postoperative brain natriuretic peptide level. Multivariate analysis found that PVPI and GEF were independently associated with high EVLWI in the early period, suggesting cardiogenic edema, and that CRP and PVPI, but not GEF, were independently associated with high EVLWI in the vasospasm period, suggesting noncardiogenic edema. In conclusion, clipping affects postoperative CRP level and may thereby increase noncardiogenic pulmonary edema in the vasospasm period. His trial is registered with University Hospital Medical Information Network UMIN000003794. Nobutaka Horie, Mitsutoshi Iwaasa, Eiji Isotani, Shunsuke Ishizaka, Tooru Inoue, and Izumi Nagata Copyright © 2014 Nobutaka Horie et al. All rights reserved. Magnesium Lithospermate B, an Active Extract of Salvia miltiorrhiza, Mediates sGC/cGMP/PKG Translocation in Experimental Vasospasm Wed, 02 Apr 2014 06:36:13 +0000 Background. Soluble guanylyl cyclases (sGCs) and Ras homolog gene family, member A (rhoA)/Ras homolog gene family kinase(rho-kinase) plays a role in vascular smooth muscle relaxation in subarachnoid hemorrhage (SAH). It is of interest to examine the effect of MLB on rhoA/ROCK and sGC/cGMP/PKG expression. Methods. A rodent SAH model was employed. Tissue samples were for sGCα1, sGCβ1, PKG, rhoA, ROCK (Western blot), and cGMP (ELISA) measurement. Results. MLB morphologically improved convolution of the internal elastic lamina, distortion of endothelial wall, and necrosis of the smooth muscle in the SAH rats. Expressed cGMP, sGCα1, sGCβ1, and PKG in the SAH groups were reduced (), and MLB precondition significantly induced cGMP, sGC1, sGC1, and PKG. L-NAME reversed the vasodilation effect of MLB, reduced the bioexpression of PKG and cGMP (), and tends to reduce sGC1 level and induce rhoA, ROCK level in MLB precondition + SAH groups. Conclusion. These results demonstrate that sGC/cGMP/PKG and NO/ET pathways play pivotal roles in SAH-induced vasospasm. Through activating sGC/cGMP/PKG pathway and partially by inactivating rho-kinase in a NO-dependent mechanism, MLB shows promise to be an effective strategy for the treatment of this disease entity. Chih-Zen Chang, Shu-Chuan Wu, and Aij-Lie Kwan Copyright © 2014 Chih-Zen Chang et al. All rights reserved. Postsurgical Pathologies Associated with Intradural Electrical Stimulation in the Central Nervous System: Design Implications for a New Clinical Device Tue, 01 Apr 2014 08:01:07 +0000 Spinal cord stimulation has been utilized for decades in the treatment of numerous conditions such as failed back surgery and phantom limb syndromes, arachnoiditis, cancer pain, and others. The placement of the stimulating electrode array was originally subdural but, to minimize surgical complexity and reduce the risk of certain postsurgical complications, it became exclusively epidural eventually. Here we review the relevant clinical and experimental pathologic findings, including spinal cord compression, infection, hematoma formation, cerebrospinal fluid leakage, chronic fibrosis, and stimulation-induced neurotoxicity, associated with the early approaches to subdural electrical stimulation of the central nervous system, and the spinal cord in particular. These findings may help optimize the safety and efficacy of a new approach to subdural spinal cord stimulation now under development. Katherine N. Gibson-Corley, Oliver Flouty, Hiroyuki Oya, George T. Gillies, and Matthew A. Howard Copyright © 2014 Katherine N. Gibson-Corley et al. All rights reserved. Incidence, National Trend, and Outcome of Nontraumatic Subarachnoid Haemorrhage in Taiwan: Initial Lower Mortality, Poor Long-Term Outcome Mon, 31 Mar 2014 16:11:38 +0000 To investigate the longitudinal trend of nontraumatic subarachnoid haemorrhage (SAH), we analyzed the annual population-based incidence and mortality rate of nontraumatic subarachnoid hemorrhage in Taiwan. Logistic regression was used to identify independent predictors of mortality. The average incidence rate (IR) of nontraumatic SAH was per 100,000 per year. The prevalence of female patients was higher than in the male population (54.5% versus 45.5%). The average age of these patients was and females were older than males ( versus , ). Of these patients, 97.6% (611/626) were treated with surgical intervention with clipping procedure and 2.9% (18/626) with coiling. Total mortality of these patients was 13.4% (84/626). In adjusted analysis, age (odds ratio [OR], 0.97; 95% confidence interval [CI], 0.98-0.98; ) and Charlson comorbidity index (OR, 0.709; 95% CI, 0.57–0.88; ) remained independent predictors of the mortality. Patients with nontraumatic SAH had a much higher prevalence in older age groups and in females than in the general population. Patients with old age and more comorbidity have higher mortality. Aggressive management of patients might reduce the initial mortality; however, patient outcome still remains poor. Hsing-Lin Lin, Kwan-Ming Soo, Chao-Wen Chen, Yen-Ko Lin, Tsung-Ying Lin, Liang-Chi Kuo, Wei-Che Lee, and Shiuh-Lin Huang Copyright © 2014 Hsing-Lin Lin et al. All rights reserved. Comment on “Vitamin D Status in Migraine Patients: A Case-Control Study” Mon, 31 Mar 2014 00:00:00 +0000 Fevzi Nuri Aydin, Ibrahim Aydin, and Mehmet Agilli Copyright © 2014 Fevzi Nuri Aydin et al. All rights reserved. Cerebral Vasospasm in Patients over 80 Years Treated by Coil Embolization for Ruptured Cerebral Aneurysms Mon, 24 Mar 2014 09:25:29 +0000 Object. The effect on clinical outcomes of symptomatic vasospasm after aneurysmal subarachnoid hemorrhage (SAH) in patients over 80 years who underwent coil embolization was evaluated. Methods. Forty-four cases were reviewed and divided into two groups according to patient age: Group A, 79 years or younger, and Group B, 80 or older. Patient characteristics, prevalence of symptomatic vasospasm, modified Rankin Scale (mRS) scores at discharge and frequency of symptomatic vasospasm in patients with mRS scores of 3–6 were analyzed. Results. Thirty-two (73%) of the 44 cases were categorized as Group A and 12 (27%) as Group B. Group B had a significantly higher prevalence of symptomatic vasospasm compared to Group A . mRS scores at discharge were significantly higher in Group B than in Group A . Among cases with mRS scores of 3–6, there was a significantly higher frequency of symptomatic vasospasm in Group B than in Group A . Conclusions. In our cohort of aneurysmal SAH patients treated by coil embolization, patients over 80 years of age were more likely to suffer symptomatic vasospasm, which significantly correlated with worse clinical outcomes, than those 79 years and under. Tomohito Hishikawa, Yuji Takasugi, Tomohisa Shimizu, Jun Haruma, Masafumi Hiramatsu, Koji Tokunaga, Kenji Sugiu, and Isao Date Copyright © 2014 Tomohito Hishikawa et al. All rights reserved. Computed Tomography Angiography for Detection of Middle Meningeal Artery Lesions Associated with Acute Epidural Hematomas Thu, 13 Mar 2014 00:00:00 +0000 Background. The natural history of traumatic aneurysms of the middle meningeal artery (MMA) is not well known, but patients with these lesions are more likely to have delayed bleeds. In this paper, we described a series of patients with epidural hematoma who underwent angiotomography (CTA) for MMA vascular lesion diagnosis. Methods. Eleven patients admitted to our emergency unit with small acute epidural hematoma were prospectively studied. All patients with temporal acute epidural hematomas underwent CTA and cerebral angiogram at our institution for diagnosis of posttraumatic lesions of middle meningeal artery. The findings of angiotomography and digital angiography were reviewed by radiologist and angiographers, respectively, to ensure that the lesions were readily diagnosed without knowing the results of angiotomography and to compare CTA findings with standard angiogram. Results. The causes of head injury were traffic accidents, falls, and aggression. Three of these patients presented traumatic MMA pseudoaneurysm. CT angiography was able to diagnose all of them, with dimensions ranging from 1.5 to 2.8 mm. Conventional angiography confirmed the findings of CT angiography, and the lesions presented with similar dimensions at both methods. Conclusions. We believe that angiotomography can be a useful technique for diagnosis of vascular lesion associated with small epidural hematoma. Wellingson Silva Paiva, Almir Ferreira Andrade, Robson Luis Oliveira De Amorim, Edson Bor-Seng-Shu, Gabriel Gattas, Iuri Santana Neville, Jose Guilherme Caldas, Eberval Gadelha Figueiredo, and Manoel Jacobsen Teixeira Copyright © 2014 Wellingson Silva Paiva et al. All rights reserved. Therapeutic Implications of Estrogen for Cerebral Vasospasm and Delayed Cerebral Ischemia Induced by Aneurysmal Subarachnoid Hemorrhage Sun, 02 Mar 2014 13:27:52 +0000 Cerebral vasospasm (CV) remains the leading cause of delayed morbidity and mortality following aneurysmal subarachnoid hemorrhage (SAH). However, increasing evidence supports etiologies of delayed cerebral ischemia (DCI) other than CV. Estrogen, specifically 17β-estradiol (E2), has potential therapeutic implications for ameliorating the delayed neurological deterioration which follows aneurysmal SAH. We review the causes of CV and DCI and examine the evidence for E2-mediated vasodilation and neuroprotection. E2 potentiates vasodilation by activating endothelial nitric oxide synthase (eNOS), preventing increased inducible NOS (iNOS) activity caused by SAH, and decreasing endothelin-1 production. E2 provides neuroprotection by increasing thioredoxin expression, decreasing c-Jun N-terminal kinase activity, increasing neuroglobin levels, preventing SAH-induced suppression of the Akt signaling pathway, and upregulating the expression of adenosine A2a receptor. The net effect of E2 modulation of these various effectors is the promotion of neuronal survival, inhibition of apoptosis, and decreased oxidative damage and inflammation. E2 is a potentially potent therapeutic tool for improving outcomes related to post-SAH CV and DCI. However, clinical evidence supporting its benefits remains lacking. Given the promising preclinical data available, further studies utilizing E2 for the treatment of patients with ruptured intracranial aneurysms appear warranted. Dale Ding, Robert M. Starke, Aaron S. Dumont, Gary K. Owens, David M. Hasan, Nohra Chalouhi, Ricky Medel, and Chih-Lung Lin Copyright © 2014 Dale Ding et al. All rights reserved. Microbleeds in Late-Life Depression: Comparison of Early- and Late-Onset Depression Wed, 26 Feb 2014 15:58:26 +0000 Late-life depression could be classified roughly as early-onset depression (EOD) and late-onset depression (LOD). LOD was proved to be associated with cerebral lesions including white matter hyperintensities (WMH) and silent brain infarctions (SBI), differently from EOD. However, it is unclear whether similar association is present between LOD and microbleeds which are also silent lesions. In this study, 195 patients of late-life depression were evaluated and divided into EOD, presenile-onset depression (POD), and LOD groups; 85 healthy elderly controls were enrolled as controls. Subjects were scanned by MRI including susceptibility weighted images to evaluate white matter hyperintensities (WMH), silent brain infarctions (SBI), and microbleeds. The severity of depression was evaluated with 15-item Geriatric Depression Scale. Psychosocial factors were investigated with Scale of Life Events and Lubben Social Network Scale. Logistic regression and linear regression were performed to identify the independent risk factors for depression. Results showed that LOD patients had higher prevalence of microbleeds than EOD, POD, and control patients. The prevalence of lobar microbleeds and microbleeds in the left hemisphere was the independent risk factor for the occurrence of LOD; a high number of microbleeds were associated with severe state of LOD, whereas life events and lack of social support were more important for EOD and POD. All these results indicated that Microbleeds especially lobar microbleeds and microbleeds in the left hemisphere were associated with LOD but not with EOD. Chao Feng, Min Fang, Yu Xu, Ting Hua, and Xue-Yuan Liu Copyright © 2014 Chao Feng et al. All rights reserved. Stem Cell-Based Therapies for Ischemic Stroke Wed, 26 Feb 2014 13:59:45 +0000 In recent years, stem cell-based approaches have attracted more attention from scientists and clinicians due to their possible therapeutical effect on stroke. Animal studies have demonstrated that the beneficial effects of stem cells including embryonic stem cells (ESCs), inducible pluripotent stem cells (iPSCs), neural stem cells (NSCs), and mesenchymal stem cell (MSCs) might be due to cell replacement, neuroprotection, endogenous neurogenesis, angiogenesis, and modulation on inflammation and immune response. Although several clinical studies have shown the high efficiency and safety of stem cell in stroke management, mainly MSCs, some issues regarding to cell homing, survival, tracking, safety, and optimal cell transplantation protocol, such as cell dose and time window, should be addressed. Undoubtably, stem cell-based gene therapy represents a novel potential therapeutic strategy for stroke in future. Lei Hao, Zhongmin Zou, Hong Tian, Yubo Zhang, Huchuan Zhou, and Lei Liu Copyright © 2014 Lei Hao et al. All rights reserved. Perspectives on Molecular Biomarkers of Oxidative Stress and Antioxidant Strategies in Traumatic Brain Injury Thu, 13 Feb 2014 13:38:43 +0000 Traumatic brain injury (TBI) is frequently associated with abnormal blood-brain barrier function, resulting in the release of factors that can be used as molecular biomarkers of TBI, among them GFAP, UCH-L1, S100B, and NSE. Although many experimental studies have been conducted, clinical consolidation of these biomarkers is still needed to increase the predictive power and reduce the poor outcome of TBI. Interestingly, several of these TBI biomarkers are oxidatively modified to carbonyl groups, indicating that markers of oxidative stress could be of predictive value for the selection of therapeutic strategies. Some drugs such as corticosteroids and progesterone have already been investigated in TBI neuroprotection but failed to demonstrate clinical applicability in advanced phases of the studies. Dietary antioxidants, such as curcumin, resveratrol, and sulforaphane, have been shown to attenuate TBI-induced damage in preclinical studies. These dietary antioxidants can increase antioxidant defenses via transcriptional activation of NRF2 and are also known as carbonyl scavengers, two potential mechanisms for neuroprotection. This paper reviews the relevance of redox biology in TBI, highlighting perspectives for future studies. André Mendes Arent, Luiz Felipe de Souza, Roger Walz, and Alcir Luiz Dafre Copyright © 2014 André Mendes Arent et al. All rights reserved. Neuroprotective Effects of Adipose-Derived Stem Cells Are Maintained for 3 Weeks against Ischemic Damage in the Rabbit Spinal Cord Wed, 29 Jan 2014 09:05:17 +0000 In the previous study, we demonstrated that adipose-derived stem cells (ASCs) have neuroprotective effects against ischemic damage in the ventral horn of levels at 3 days after ischemia/reperfusion. In the present study, we expanded our observations for 3 weeks after ischemia/reperfusion to rule out the possibility of delayed neuronal death in several days after ischemia/reperfusion. Transient spinal cord ischemia was induced by a 15 min aortic artery occlusion in the subrenal region and rabbit ASCs were administered intrathecally into recipient rabbits () immediately after reperfusion. Transplantation of ASCs improved the neurological motor functions of the hindlimb 3 weeks after ischemia/reperfusion. Similarly, the cresyl violet-positive neurons were significantly increased at 3 weeks after ischemia/reperfusion compared to that in the vehicle (artificial cerebrospinal fluid)-treated group. The transplantation of ASCs significantly reduced reactive microglia induced by ischemia at 3 weeks after ischemia/reperfusion. In addition, transplantation of ASCs maintained the brain-derived neurotrophic factor (BDNF) levels 3 weeks after ischemia/reperfusion. These results suggest that the neuroprotective effects of ASCs are maintained 3 weeks after ischemia/reperfusion by modulating microgliosis and BDNF levels in the spinal cord. Seung Myung Moon, Woosuk Kim, Jin Young Chung, Wooseok Im, Dae Young Yoo, Hyo Young Jung, Moo-Ho Won, Jung Hoon Choi, and In Koo Hwang Copyright © 2014 Seung Myung Moon et al. All rights reserved. Primary Headache Disorders at a Tertiary Health Facility in Lagos, Nigeria: Prevalence and Consultation Patterns Thu, 23 Jan 2014 06:23:12 +0000 Background. Primary headaches are underdiagnosed and undertreated, with a significant impact on social activities and work. Aim. To determine the last-year prevalence and health care utilization pattern of primary headaches at a tertiary centre. Methods. A cross-sectional study was carried out amongst staff of the Lagos State University Teaching Hospital in Lagos, Nigeria. 402 staff members were selected by simple random sampling and administered a detailed structured headache assessment questionnaire. Migraine and tension-type headache were diagnosed according to the criteria of the International Headache Society (2004). Results. The participants comprised 168 males and 234 females. The mean age was years. The overall headache prevalence was 39.3% with female predominance (). Tension-type headache was the most prevalent at 72.8% and migraine at 18.9%. Unclassifiable headache constituted 8.2%. Migraine headache showed female preponderance (). 80.4% of participants did not seek medical consultation compared with 19.6% who did (). Of the latter, 83.9% consulted the general practitioner (GP), whilst 16.1% consulted the neurologist. Conclusions. Primary headache prevalence is high in our population. It is not recognised as that requiring care by most of the staff of this tertiary health facility; thus education is required to increase health care utilization. Olajumoke Oshinaike, Oluwadamilola Ojo, Njideka Okubadejo, Olaitan Ojelabi, and Akinola Dada Copyright © 2014 Olajumoke Oshinaike et al. All rights reserved. Reliability and Validity of the Migraine Disability Assessment Scale among Migraine and Tension Type Headache in Iranian Patients Thu, 16 Jan 2014 10:23:08 +0000 Introduction. MIDAS is a valid and reliable short questionnaire for assessment of headache related disability. Linguistic validation of Persian MIDAS and assessment of psychometric properties between tension type headache (TTH) and migraine were the aims of this study. Methods. Patients with migraine or TTH were included. At the first visit, we administered a headache symptom questionnaire, MIDAS, and SF-36. Patients filled out MIDAS in second and third visit within three and eight weeks after base line visit. Internal consistency (Cronbach α) and test-retest reproducibility (Spearman correlation coefficient) were used to assess reliability. Convergent validity and MIDAS capability to differentiate between chronic and episodic headaches (migraine and TTH) were also assessed. Results. The 267 participants had episodic migraine (EM-64%), chronic migraine (CM-13.5%), episodic TTH (ETTH-13.5%), and chronic TTH (CTTH-9). Internal consistency reliability was 0.8 for the entire sample, 0.72 for TTH, and 0.82 for migraine. Test-retest reliability for all questions between visit 1 and visit 2 varied from 0.54 to 0.71. Convergent validity was assessed using SF-36 as an external referent. Patients with episodic headaches (EM and ETTH) had significantly lower MIDAS scores than chronic headaches (CM and CTTH). Conclusion. Persian MIDAS is a valid and reliable questionnaire for migraine and TTH that can differentiate between episodic headache and chronic headache. Alireza Zandifar, Fatemeh Asgari, Faraidoon Haghdoost, Samaneh Sadat Masjedi, Navid Manouchehri, Mahboobeh Banihashemi, Abbas Ghorbani, Mohammad Reza Najafi, Mohammad Saadatnia, and Richard B. Lipton Copyright © 2014 Alireza Zandifar et al. All rights reserved. Acute Supratentorial Ischemic Stroke: When Surgery Is Mandatory Tue, 14 Jan 2014 08:15:10 +0000 Acute occlusion of middle cerebral artery (MCA) leads to severe brain swelling and to a malignant, often fatal syndrome. The authors summarize the current knowledge about such a condition and review the main surgical issues involved. Decompressive hemicraniectomy keeps being a valid option in accurately selected patients. Gabriele Ronchetti, Pier Paolo Panciani, Roberto Stefini, Giannantonio Spena, and Marco Maria Fontanella Copyright © 2014 Gabriele Ronchetti et al. All rights reserved. Vitamin D Status in Migraine Patients: A Case-Control Study Thu, 02 Jan 2014 15:50:10 +0000 Background. There have been few studies on the relation between vitamin D and migraine. We investigated the prevalence of vitamin D deficiency in migraine patients and compared it with a control group. We also evaluated the relationship of vitamin D deficiency with severity of migraine. Methods. 105 newly diagnosed migraine patients and 110 controls, matched for age, sex, socioeconomic status, education, and sun exposure, were enrolled during the spring of 2011. 25-Hydroxy vitamin D [25(OH)D] plasma levels were measured by chemiluminescence immunoassay. Results. The mean ± SE concentration of 25(OH)D was  ng/mL in cases and  ng/mL in controls. There was no significant difference in 25(OH)D concentration between cases and controls. We found no relationship between severity of headache and 25(OH)D status. Conclusions. We did not find any association between migraine and vitamin D status; also, severity of headaches was not related to 25(OH)D level. Further studies with larger sample sizes are required to confirm our results. Alireza Zandifar, Samaneh sadat Masjedi, Mahboobeh Banihashemi, Fatemeh Asgari, Navid Manouchehri, Homa Ebrahimi, Faraidoon Haghdoost, and Mohammad Saadatnia Copyright © 2014 Alireza Zandifar et al. All rights reserved. Description of the Vasospasm Phenomena following Perimesencephalic Nonaneurysmal Subarachnoid Hemorrhage Sat, 28 Dec 2013 10:18:19 +0000 Background. Perimesencephalic nonaneurysmal subarachnoid hemorrhage (PM-NASAH) is characterized by a benign course compared with aneurysmal SAH. While vasospasm (VS) after aneurysmal SAH is considered responsible for serious complications, VS post-PM-NASAH is not well documented. Our purpose was to characterize the incidence and course of VS among 63 patients—one of the largest databases of PM-NASAH patients with documented blood flow velocities in the literature. Methods. Data from 63 patients that were admitted with PM-NASAH from 2000 to 2012 and underwent transcranial Doppler tests to assess cranial vessel flow velocity was analyzed. Results. On average, the maximal flow velocity was measured on the 7th day after hemorrhage. Higher risk for VS was associated with younger age, female sex, and higher Hunt and Hess scores, a lower risk for patients treated with statins (). Using velocity thresholds for diagnosis of VS, 49.2% showed evidence of VS. This is the first description of blood flow velocities in PM-NASAH. VS average onset was on the 4th day, average cessation on day 15 after hemorrhage. No patients showed clinical manifestation of VS. Conclusions. VS post-PM-NASAH is not as rare as previously believed. However, its lack of clinical significance raises questions regarding the need for diagnosis and may suggest a less intensive treatment protocol. Daphna Prat, Oded Goren, Bela Bruk, Mati Bakon, Moshe Hadani, and Sagi Harnof Copyright © 2013 Daphna Prat et al. All rights reserved. Protective Effects of p38 MAPK Inhibitor SB202190 against Hippocampal Apoptosis and Spatial Learning and Memory Deficits in a Rat Model of Vascular Dementia Wed, 25 Dec 2013 16:51:21 +0000 Vascular dementia (VaD) is a common age-related neurodegenerative disease resulting from chronic hypoxia. In the present study, we examined the protective effects of p38 MAPK inhibitor SB202190 against hippocampal apoptosis and spatial learning and memory deficits in a chronic hypoperfusion rat model of VaD established by permanent bilateral carotid occlusion (2-VO). Sixty rats were randomly divided into sham-operated, VaD model, and VaD plus SB202190 groups (/group). After sham/2-VO surgery, rats were administered 0.1% DMSO (sham-operated and VaD groups) or SB202190 by intracerebroventricular injection. One week after inhibitor/vehicle treatment, hippocampal p38 MAPK phosphorylation was higher in the model group than in the SB202190 group (). Compared to the model group, the SB202190 group exhibited significantly shorter escape latencies in the Morris water maze hidden platform trials () and longer times in the original platform quadrant during probe trials (). The SB202190 group also showed significantly reduced neuronal apoptosis in the hippocampus compared to VaD model rats () as well as higher (antiapoptotic) Bcl-2 expression and lower (proapoptotic) caspase-3 expression ( for both). In conclusion, blockade of the p38 MAPK signaling pathway by SB202190 following permanent 2-OV reduced apoptosis of hippocampal neurons and rescued spatial learning and memory deficits. Shen Yang, Guangan Zhou, Hong Liu, Bo Zhang, Juan Li, Ruiting Cui, and Yifeng Du Copyright © 2013 Shen Yang et al. All rights reserved. Presymptomatic Treatment with Acetylcholinesterase Antisense Oligonucleotides Prolongs Survival in ALS (G93A-SOD1) Mice Sun, 22 Dec 2013 18:04:30 +0000 Objective. Previous research suggests that acetylcholinesterase (AChE) may be involved in ALS pathogenesis. AChE enzyme inhibitors can upregulate AChE transcription which in certain contexts can have deleterious (noncatalytic) effects, making them theoretically harmful in ALS, whilst AChE antisense-oligonucleotides (mEN101), which downregulate AChE may be beneficial. Our aim was to investigate whether downregulation of AChE using mEN101 is beneficial in an ALS mouse model. Methods. ALS (G93A-SOD1) mice received saline, mEN101, inverse-EN101, or neostigmine. Treatments were administered from 5 weeks. Disease-onset and survival were recorded. Additional mice were sacrificed for pathological analysis at 15 weeks of age. In a follow-up experiment treatment was started at the symptomatic stage at a higher dose. Results. mEN101 given at the presymptomatic (but not symptomatic) stage prolonged survival and attenuated motor-neuron loss in ALS mice. In contrast, neostigmine exacerbated the clinical parameters. Conclusions. These results suggest that AChE may be involved in ALS pathogenesis. The accelerated disease course with neostigmine suggests that any beneficial effects of mEN101 occur through a non-catalytic rather than cholinergic mechanism. Gotkine Marc, Rozenstein Leah, Einstein Ofira, Abramsky Oded, Argov Zohar, and Rosenmann Hanna Copyright © 2013 Gotkine Marc et al. All rights reserved. Cardiovascular Autonomic Neuropathy in Context of Other Complications of Type 2 Diabetes Mellitus Wed, 18 Dec 2013 14:45:02 +0000 The aim of this study was to investigate the relationship between cardiac autonomic neuropathy (CAN) and other micro- and macrovascular complications and risk factors for type 2 diabetes. We included, in this study, 149 patients with type 2 diabetes. We evaluated their cardiovascular risk factors, demographic data, and any major micro- and macrovascular complications of their diabetes. Assessments of CAN were based upon Ewing’s battery. Results. CAN was present in 38.9% of patients. In the CAN group, the duration of diabetes, BMI, systolic blood pressure, lipid levels, and HBA1c were all significantly higher than those in the other group. A significant association was found between CAN and retinopathy, peripheral neuropathy, ABI, and IMT. Multivariate logistic regression demonstrated that, in type 2 diabetes, the odds of CAN (OR (95% confidence intervals)) increase with the age of the patients (1.68 (1,4129–2.0025)), the average diabetes duration (0.57 (0.47–0.67)), cholesterol (1.009 (1.00-1.01)), HbA1c levels (1.88 (1.31–2.72)), peripheral neuropathy (15.47 (5.16–46.38)), BMI (1.12 (1.05–1.21)), and smoking (2.21 (1.08–4.53)). Conclusions. This study shows that CAN in type 2 diabetes is significantly associated with other macro- and microvascular complications and that there are important modifiable risk factors for its development. Anca Moţăţăianu, Rodica Bălaşa, Septimiu Voidăzan, and Zoltán Bajkó Copyright © 2013 Anca Moţăţăianu et al. All rights reserved. Posttraumatic Refractory Intracranial Hypertension and Brain Herniation Syndrome: Cerebral Hemodynamic Assessment before Decompressive Craniectomy Wed, 27 Nov 2013 15:53:10 +0000 Background. The pathophysiology of traumatic brain swelling remains little understood. An improved understanding of intracranial circulatory process related to brain herniation may have treatment implications. Objective. To investigate the cerebral hemodynamic changes associated with brain herniation syndrome due to traumatic brain swelling. Methods. Nineteen head-injured patients with evidence of refractory intracranial hypertension and transtentorial herniation were prospectively studied. Cerebral hemodynamic assessment by transcranial Doppler (TCD) ultrasonography was performed prior to decompressive craniectomy. Patients and their cerebral hemispheres were classified according to TCD-hemodynamic patterns, and the data correlated with neurological status, midline shift on CT scan, and Glasgow outcome scale scores at 6 months after injury. Results. A wide variety of cerebral hemodynamic findings were observed. Ten patients (52.7%) presented with cerebral oligoemia, 3 patients (15.8%) with cerebral hyperemia, and 6 patients with nonspecific circulatory pattern. Circulatory disturbances were more frequently found in the side of maximal cerebral swelling than in the opposite side. Pulsatility index (PI) values suggested that ICP varied from acceptable to considerably high; patients with increased PI, indicating higher microvascular resistance. No correlation was found between cerebral hemodynamic findings and outcome. Conclusions. There is a marked heterogeneity of cerebral hemodynamic disturbances among patients with brain herniation syndrome. Edson Bor-Seng-Shu, Wellingson Silva Paiva, Eberval G. Figueiredo, Yasunori Fujimoto, Almir Ferreira de Andrade, Erich Talamoni Fonoff, and Manoel Jacobsen Teixeira Copyright © 2013 Edson Bor-Seng-Shu et al. All rights reserved. Abnormal Nerve Conduction Study Findings Indicating the Existence of Peripheral Neuropathy in Multiple Sclerosis and Neuromyelitis Optica Thu, 07 Nov 2013 10:11:24 +0000 Objective. Chronic inflammatory demyelinating polyneuropathy (CIDP) has been reported in patients with multiple sclerosis (MS). However, there have been limited reports of peripheral neuropathy as a complication of neuromyelitis optica (NMO). In this paper, we showed the characteristics and differences between peripheral neuropathy as a complication of MS and NMO. Method. We analyzed a series of 58 MS and 28 NMO patients and evaluated nerve conduction studies (NCS) in 21 MS and 5 NMO patients. Results. Six of the 58 MS and 3 of the 28 NMO patients revealed abnormal NCS findings. Three (5.2%) of the 58 MS patients fulfilled the criteria for CIDP. One (3.6%) of the 28 NMO patients showed peripheral neuropathy at the same time of NMO relapse, although CIDP was not seen in NMO. The other 5 (3 MS and 2 NMO) patients were complicated with neuropathy caused by concomitant diabetes mellitus and Sjögren’s syndrome. Conclusion. Frequency of abnormal NCS findings might exhibit no significant difference between MS and NMO, although the cause and pathophysiology of peripheral neuropathy were different in MS and in NMO. There might be a group of NMO who were affected simultaneously in the central and peripheral nervous tissues. Yoko Warabi, Mikihiro Yamazaki, Toshio Shimizu, and Masahiro Nagao Copyright © 2013 Yoko Warabi et al. All rights reserved. Monocyte Locomotion Inhibitory Factor Produced by E. histolytica Improves Motor Recovery and Develops Neuroprotection after Traumatic Injury to the Spinal Cord Sun, 03 Nov 2013 13:40:54 +0000 Monocyte locomotion inhibitory factor (MLIF) is a pentapeptide produced by Entamoeba histolytica that has a potent anti-inflammatory effect. Either MLIF or phosphate buffered saline (PBS) was administered directly onto the spinal cord (SC) immediately after injury. Motor recovery was evaluated. We also analyzed neuroprotection by quantifying the number of surviving ventral horn motor neurons and the persistence of rubrospinal tract neurons. To evaluate the mechanism through which MLIF improved the outcome of SC injury, we quantified the expression of inducible nitric oxide synthase (iNOS), interleukin-10 (IL-10), and transforming growth factor-β (TGF-β) genes at the site of injury. Finally, the levels of nitric oxide and of lipid peroxidation were also determined in peripheral blood. Results showed that MLIF improved the rate of motor recovery and this correlated with an increased survival of ventral horn and rubrospinal neurons. These beneficial effects were in turn associated with a reduction in iNOS gene products and a significant upregulation of IL-10 and TGF-β expression. In the same way, MLIF reduced the concentration of nitric oxide and the levels of lipid peroxidation in systemic circulation. The present results demonstrate for the first time the neuroprotective effects endowed by MLIF after SC injury. Gabriela Bermeo, Antonio Ibarra, Elisa García, Adrian Flores-Romero, Guadalupe Rico-Rosillo, Rubén Marroquín, Humberto Mestre, Carmina Flores, Francisco Blanco-Favela, and Raúl Silva-García Copyright © 2013 Gabriela Bermeo et al. All rights reserved. Analysis of Risk Factors for First Seizure after Stroke in Chinese Patients Sat, 02 Nov 2013 14:24:42 +0000 The aim of this study is to assess related risk factors and predict early- and late-onset seizure after first-ever stroke. A total of 2474 consecutive patients with initial stroke in China from 1997 to 2007 were retrospectively investigated, in which, 24 clinical and radiological indexes were used for evaluation. Odds ratio (OR) and 95% confidence interval (CI) were calculated by logistic regression. A total of 232 (11.1%) of patients developed seizures during a mean follow-up period of 18 months, with 123 experiencing early-onset and 109 late-onset seizure. The independent risk factors for early-onset seizure were large lesion (), subarachnoid hemorrhage (), initial hyponatremia (), and cortical involvement (). The independent risk factors for late-onset seizure were cortical involvement () and large lesion (). These results demonstrated that the risk factors for early seizure after stroke are large lesion, subarachnoid hemorrhage, and cortical involvement. Surprisingly, hyponatremia also predicts seizure in stroke patients. Cortical involvement is a major risk factor for late-onset seizure after stroke. Guoqing Wang, Haiyan Jia, Chunfu Chen, Senyang Lang, Xinfeng Liu, Cheng Xia, Yan Sun, and Jun Zhang Copyright © 2013 Guoqing Wang et al. All rights reserved. Psychomotor Retardation in Depression: A Systematic Review of Diagnostic, Pathophysiologic, and Therapeutic Implications Wed, 30 Oct 2013 17:42:46 +0000 Psychomotor retardation is a central feature of depression which includes motor and cognitive impairments. Effective management may be useful to improve the classification of depressive subtypes and treatment selection, as well as prediction of outcome in patients with depression. The aim of this paper was to review the current status of knowledge regarding psychomotor retardation in depression, in order to clarify its role in the diagnostic management of mood disorders. Retardation modifies all the actions of the individual, including motility, mental activity, and speech. Objective assessments can highlight the diagnostic importance of psychomotor retardation, especially in melancholic and bipolar depression. Psychomotor retardation is also related to depression severity and therapeutic change and could be considered a good criterion for the prediction of therapeutic effect. The neurobiological process underlying the inhibition of activity includes functional deficits in the prefrontal cortex and abnormalities in dopamine neurotransmission. Future investigations of psychomotor retardation should help improve the understanding of the pathophysiological mechanisms underlying mood disorders and contribute to improving their therapeutic management. Djamila Bennabi, Pierre Vandel, Charalambos Papaxanthis, Thierry Pozzo, and Emmanuel Haffen Copyright © 2013 Djamila Bennabi et al. All rights reserved. Immunization with a Neural-Derived Peptide Protects the Spinal Cord from Apoptosis after Traumatic Injury Wed, 23 Oct 2013 09:34:10 +0000 Apoptosis is one of the most destructive mechanisms that develop after spinal cord (SC) injury. Immunization with neural-derived peptides (INDPs) such as A91 has shown to reduce the deleterious proinflammatory response and the amount of harmful compounds produced after SC injury. With the notion that the aforementioned elements are apoptotic inducers, we hypothesized that INDPs would reduce apoptosis after SC injury. In order to test this assumption, adult rats were subjected to SC contusion and immunized either with A91 or phosphate buffered saline (PBS; control group). Seven days after injury, animals were euthanized to evaluate the number of apoptotic cells at the injury site. Apoptosis was evaluated using DAPI and TUNEL techniques; caspase-3 activity was also evaluated. To further elucidate the mechanisms through which A91 exerts this antiapoptotic effects we quantified tumor necrosis factor-alpha (TNF-α). To also demonstrate that the decrease in apoptotic cells correlated with a functional improvement, locomotor recovery was evaluated. Immunization with A91 significantly reduced the number of apoptotic cells and decreased caspase-3 activity and TNF-α concentration. Immunization with A91 also improved the functional recovery of injured rats. The present study shows the beneficial effect of INDPs on preventing apoptosis and provides more evidence on the neuroprotective mechanisms exerted by this strategy. Roxana Rodríguez-Barrera, Ana M. Fernández-Presas, Elisa García, Adrian Flores-Romero, Susana Martiñón, Viridiana Yazmín González-Puertos, Humberto Mestre, Carmina Flores-Dominguez, Verónica Rodriguez-Mata, Mina Königsberg, Sandra Solano, and Antonio Ibarra Copyright © 2013 Roxana Rodríguez-Barrera et al. All rights reserved. Elevated Expression of Fractalkine (CX3CL1) and Fractalkine Receptor (CX3CR1) in the Dorsal Root Ganglia and Spinal Cord in Experimental Autoimmune Encephalomyelitis: Implications in Multiple Sclerosis-Induced Neuropathic Pain Tue, 24 Sep 2013 09:38:35 +0000 Multiple sclerosis (MS) is a central nervous system (CNS) disease resulting from a targeted autoimmune-mediated attack on myelin proteins in the CNS. The release of Th1 inflammatory mediators in the CNS activates macrophages, antibodies, and microglia resulting in myelin damage and the induction of neuropathic pain (NPP). Molecular signaling through fractalkine (CX3CL1), a nociceptive chemokine, via its receptor (CX3CR1) is thought to be associated with MS-induced NPP. An experimental autoimmune encephalomyelitis (EAE) model of MS was utilized to assess time dependent gene and protein expression changes of CX3CL1 and CX3CR1. Results revealed significant increases in mRNA and the protein expression of CX3CL1 and CX3CR1 in the dorsal root ganglia (DRG) and spinal cord (SC) 12 days after EAE induction compared to controls. This increased expression correlated with behavioural thermal sensory abnormalities consistent with NPP. Furthermore, this increased expression correlated with the peak neurological disability caused by EAE induction. This is the first study to identify CX3CL1 signaling through CX3CR1 via the DRG /SC anatomical connection that represents a critical pathway involved in NPP induction in an EAE model of MS. Wenjun Zhu, Crystal Acosta, Brian MacNeil, Claudia Cortes, Howard Intrater, Yuewen Gong, and Mike Namaka Copyright © 2013 Wenjun Zhu et al. All rights reserved. Different Levels in Orexin Concentrations and Risk Factors Associated with Higher Orexin Levels: Comparison between Detoxified Opiate and Methamphetamine Addicts in 5 Chinese Cities Thu, 12 Sep 2013 11:57:24 +0000 This study sought to explore the degree of orexin levels in Chinese opiate and methamphetamine addicts and the differences between them. The cross-sectional study was conducted among detoxified drug addicts from Mandatory Detoxification Center (MDC) in five Chinese cities. Orexin levels were assayed with radioimmunoassay (RIA). Mann-Whitney test and Kruskal-Wallis test were used to detect differences across groups, and logistic regression was used to explore the association between orexin levels and characteristics of demographic and drug abuse. Between November 2009 and January 2011, 285 opiates addicts, 112 methamphetamine addicts, and 79 healthy controls were enrolled. At drug withdrawal period, both opiate and methamphetamine addicts had lower median orexin levels than controls, and median orexin levels in opiate addicts were higher than those in methamphetamine addicts (all above ). Adjusted odds of the above median concentration of orexin were higher for injection than “chasing the dragon” (AOR = 3.1, 95% CI = 1.2–7.9). No significant factors associated with orexin levels of methamphetamine addicts were found. Development of intervention method on orexin system by different administration routes especially for injected opiate addicts at detoxification phase may be significant and was welcome. Haoran Zhang, Zhi Lian, Shiyan Yan, Yanping Bao, and Zhimin Liu Copyright © 2013 Haoran Zhang et al. All rights reserved. Neuroprotective Effects of MicroRNA-210 on Hypoxic-Ischemic Encephalopathy Mon, 09 Sep 2013 17:59:21 +0000 Objectives. To reveal the effect of microRNA-210 on cell apoptosis caused by HIE. Methods. Postnatal day 7 rats after HI injury were intraventricularly injected with microRNA-210 mimic, microRNA-210 inhibitor, or physiological saline. 72 h after the injection, rats were sacrificed and the left hemispheres were collected. The expression level of microRNA-210 was identified by quantitative real-time PCR analysis. Apoptosis in brain sections was investigated by TUNEL assay. Apoptosis-related protein expressions were studied by Western blot analysis. Results. The results showed that microRNA-210, whose expression was downregulated in the brain 72 h after HI injury, suppressed neuronal apoptosis by inhibiting caspase activity and regulating the balance between bcl-2 and bax levels. Discussion. Recent study demonstrated that microRNA-210 has neuroprotective effects through inhibiting apoptosis in a murine model of HIE. It represents a potential novel therapeutic approach for the treatment of HIE. Jie Qiu, Xiao-yu Zhou, Xiao-guang Zhou, Rui Cheng, Hai-ying Liu, and Yong Li Copyright © 2013 Jie Qiu et al. All rights reserved. Immunocytochemical Characterization of Alzheimer Disease Hallmarks in APP/PS1 Transgenic Mice Treated with a New Anti-Amyloid-β Vaccine Mon, 09 Sep 2013 17:52:08 +0000 APP/PS1 double-transgenic mouse models of Alzheimer’s disease (AD), which overexpress mutated forms of the gene for human amyloid precursor protein (APP) and presenilin 1 (PS1), have provided robust neuropathological hallmarks of AD-like pattern at early ages. This study characterizes immunocytochemical patterns of AD mouse brain as a model for human AD treated with the EB101 vaccine. In this novel vaccine, a new approach has been taken to circumvent past failures by judiciously selecting an adjuvant consisting of a physiological matrix embedded in liposomes, composed of naturally occurring phospholipids (phosphatidylcholine, phosphatidylglycerol, and cholesterol). Our findings showed that administration of amyloid-β1−42 (Aβ) and sphingosine-1-phosphate emulsified in liposome complex (EB101) to APP/PS1 mice before onset of Aβ deposition (7 weeks of age) and/or at an older age (35 weeks of age) is effective in halting the progression and clearing the AD-like neuropathological hallmarks. Passive immunization with EB101 did not activate inflammatory responses from the immune system and astrocytes. Consistent with a decreased inflammatory background, the basal immunological interaction between the T cells and the affected areas (hippocampus) in the brain of treated mice was notably reduced. These results demonstrate that immunization with EB101 vaccine prevents and attenuates AD neuropathology in this type of double-transgenic mice. Iván Carrera, Ignacio Etcheverría, Yi Li, Lucía Fernández-Novoa, Valter Lombardi, Carmen Vigo, Hector H. Palacios, Valery V. Benberin, Ramón Cacabelos, and Gjumrakch Aliev Copyright © 2013 Iván Carrera et al. All rights reserved. Endostatin/Collagen XVIII Is Increased in Cerebrospinal Fluid after Severe Traumatic Brain Injury Sun, 08 Sep 2013 15:29:43 +0000 Recent studies have suggested that endogenous angiogenesis inhibitor endostatin/collagen XVIII might play an important role in the secondary brain injury following traumatic brain injury (TBI). In this study, we measured endostatin/collagen XVIII concentrations serially for 1 week after hospitalization by using the enzyme-linked immunosorbent assay method in the cerebrospinal fluid (CSF) of 30 patients with TBI and a Glasgow Coma Scale (GCS) score of 8 or less on admission. There was a significant trend toward increased CSF levels of endostatin after TBI versus control from 72 h after injury. In patients with GCS score of 3–5, CSF endostatin concentration was substantially higher at 72 h after injury than that in patients with GCS score of 6–8 () and peaked rapidly at day 5 after injury, but decreased thereafter. The CSF endostatin concentration in 12 patients with an unfavorable outcome was significantly higher than that in 18 patients with a favorable outcome at day 5 () and day 7 () after trauma. Receiver operating characteristic curve analysis suggested a reliable operating point for the 7-day CSF endostatin concentration predicting poor prognosis to be 67.29 pg/mL. Our preliminary findings provide new evidence that endostatin/collagen XVIII concentration in the CSF increases substantially in patients with sTBI. Its dynamic change may have some clinical significance on the judgment of brain injury severity and the assessment of prognosis. This trial is registered with the Identifier: NCT01846546. Hao Chen, Li-Xia Xue, He-Li Cao, Shi-Wen Chen, Yan Guo, Wen-Wei Gao, Shi-Ming Ju, and Heng-Li Tian Copyright © 2013 Hao Chen et al. All rights reserved. Schwannoma in the Upper Limbs Wed, 04 Sep 2013 10:50:25 +0000 Schwannomas are the commonest tumours of peripheral nerves. Despite the classical description that schwannomas are well encapsulated and can be completely enucleated during excision, a portion of them have fascicular involvement and could not be completely shelled out. A retrospective review for 8 patients was carried out over 10 years. 75% of schwannoma occurred over the distal region of upper limb (at elbow or distal to it). It occurs more in the mixed nerve instead of pure sensory or motor nerve. 50% of patients had mixed nerve involvement. Fascicular involvement was very common in schwannoma (75% of patients). Removal of the tumour with fascicles can cause functional deficit. At present, there is no method (including preoperative MRI) which can predict the occurrence of fascicular involvement; the authors therefore proposed a new system to stratify patients who may benefit from interfascicular nerve grafts. In this group of patients, the authors strongly recommend that the possibility and option of nerve graft should be discussed with patients prior to schwannoma excision, so that nerve grafting could be directly proceeded with patient consent in case there is fascicular involvement of tumour found intraoperatively. Chris Yuk Kwan Tang, Boris Fung, Margaret Fok, and Janet Zhu Copyright © 2013 Chris Yuk Kwan Tang et al. All rights reserved. Nosology of Juvenile Muscular Atrophy of Distal Upper Extremity: From Monomelic Amyotrophy to Hirayama Disease—Indian Perspective Mon, 26 Aug 2013 14:49:11 +0000 Since its original description by Keizo Hirayama in 1959, “juvenile muscular atrophy of the unilateral upper extremity” has been described under many nomenclatures from the east. Hirayama disease (HD), also interchangeably referred to as monomelic amyotrophy, has been more frequently recognised in the west only in the last two decades. HD presents in adolescence and young adulthood with insidious onset unilateral or bilateral asymmetric atrophy of hand and forearm with sparing of brachioradialis giving the characteristic appearance of oblique amyotrophy. Symmetrically bilateral disease has also been recognized. Believed to be a cervical flexion myelopathy, HD differs from motor neuron diseases because of its nonprogressive course and pathologic findings of chronic microcirculatory changes in the lower cervical cord. Electromyography shows features of acute and/or chronic denervation in C7, C8, and T1 myotomes in clinically affected limb and sometimes also in clinically unaffected contralateral limb. Dynamic forward displacement of dura in flexion causes asymmetric flattening of lower cervical cord. While dynamic contrast magnetic resonance imaging is diagnostic, routine study has high predictive value. There is a need to lump all the nomenclatures under the rubric of HD as prognosis in this condition is benign and prompt diagnosis is important to institute early collar therapy. Kaukab Maqbool Hassan and Hirdesh Sahni Copyright © 2013 Kaukab Maqbool Hassan and Hirdesh Sahni. All rights reserved. Sporadic Cerebral Cavernous Malformations: Report of Further Mutations of CCM Genes in 40 Italian Patients Thu, 22 Aug 2013 08:23:35 +0000 Cerebral cavernous malformations (CCMs) are vascular lesions characterized by abnormally enlarged capillary cavities, affecting the central nervous system. CCMs can occur sporadically or as a familial autosomal dominant condition with incomplete penetrance and variable clinical expression attributable to mutations in three different genes: CCM1 (K-Rev interaction trapped 1 (KRIT1)), CCM2 (MGC4607), and CCM3 (PDCD10). CCMs occur as a single or multiple malformations that can lead to seizures, focal neurological deficits, hemorrhagic stroke, and headache. However, patients are frequently asymptomatic. In our previous mutation screening, performed in a cohort of 95 Italian patients, both sporadic and familial, we have identified several mutations in CCM genes, three of which in three distinct sporadic patients. In this study, representing further molecular screening of the three CCM genes, in a south Italian cohort of CCM patients enrolled by us in the last three years, we report the identification of other four new mutations in 40 sporadic patients with either single or multiple CCM. Rosalia D’Angelo, Concetta Alafaci, Concetta Scimone, Alessia Ruggeri, Francesco Maria Salpietro, Placido Bramanti, Francesco Tomasello, and Antonina Sidoti Copyright © 2013 Rosalia D’Angelo et al. All rights reserved. Quality of Life in Parkinson's Disease Caregivers: The Contribution of Personality Traits Mon, 19 Aug 2013 08:16:16 +0000 Parkinson's disease imposes significant demands not only on patients but also on those people living and caring for them, who often have a reduction in their quality of life. The factors that may ameliorate these effects, such as an individual's personality, are not understood. Therefore, the aim of this study was to look at the relative contribution of caregiver personality on their quality of life, specifically attempting to identify those traits, which may be protective or harmful. Two hundred and seventy-four caregivers of patients with Parkinson's disease were included in this study. Caregivers were given questionnaires to complete, including the Big Five Inventory and the World Health Organisation Quality of Life BREF version. Univariate correlations demonstrated that depression and anxiety were the largest predictors of reduced quality of life amongst caregivers. However, after controlling for these potential confounds, conscientiousness was associated with enhanced psychological quality of life and openness positively predicted benefits in the environmental domain. Neuroticism was associated with reduced quality of life in the psychological domain. Thus, screening for neuroticism may help identify those caregivers who would benefit from intervention strategies, which could in the long term help reduce the need for nursing home placement of Parkinson's disease patients. Eloise H. Tew, Sharon L. Naismith, Marilia Pereira, and Simon J. G. Lewis Copyright © 2013 Eloise H. Tew et al. All rights reserved. The Influence of Hemocoagulation Disorders on the Development of Posttraumatic Cerebral Infarction and Outcome in Patients with Moderate or Severe Head Trauma Sun, 04 Aug 2013 10:42:10 +0000 Posttraumatic cerebral infarction (PTCI) is a severe secondary insult of head injury and often leads to a poor prognosis. Hemocoagulation disorder is recognized to have important effects on hemorrhagic or ischemic damages. We sought to assess if posttraumatic hemocoagulation disorders were associated with cerebral infarction, and evaluate their influence on outcome among patients with moderate or severe head trauma. In this study, PTCI was observed in 28 (10.57%) of the 265 patients within the first week after injury. In multivariate analysis, the thrombocytopenia (odds ratio (OR) 2.210, 95% confidence interval (CI) 1.065–4.674), abnormal prothrombin time (PT) (OR 3.241, 95% CI 1.090–7.648), D-dimer (>2 mg/L) (OR 7.260, 95% CI 1.822–28.076), or disseminated intravascular coagulation (DIC) scores (≥5) (OR 4.717, 95% CI 1.778–12.517) were each independently associated with an increased risk of PTCI. Admission Glasgow Coma Scale (GCS) score, abnormal activated partial thromboplastin time (APTT) and fibrinogen, and D-dimer (>2 mg/L) and DIC scores (≥5) showed an independent predictive effect on poor outcome. In conclusion, recognition of this important treatable cause of PTCI and the associated risk factors may help identify the group at risk and tailor management of patients with TBI. Hao Chen, Li-Xia Xue, Yan Guo, Shi-Wen Chen, Gan Wang, He-Li Cao, Jiong Chen, and Heng-Li Tian Copyright © 2013 Hao Chen et al. All rights reserved. Calcifications of Vertebrobasilar Arteries on CT: Detailed Distribution and Relation to Risk Factors in 245 Ischemic Stroke Patients Sun, 04 Aug 2013 10:34:30 +0000 Introduction. Intracranial atherosclerosis is responsible for a substantial proportion of strokes worldwide but its detailed morphology in the vertebrobasilar arteries (VBA) is unknown. Subject and Methods. Cases with ischemic strokes were retrospectively sought from the hospital database. Native CT scans were assessed for vessel area and intracranial artery calcifications (ICACs) in VBA. The calcifications were classified as focal (FCs), crescent, and circular. Results. 245 patients (mean age: years, 57.6% females) had visible ICACs. Calcifications were found in 75.9%, 63.3%, and 17.1% in the left vertebral artery (LVA), the right vertebral artery (RVA), and the basilar artery (BA), respectively. FCs were present in 91.0%, 90.3%, and 100.0%; crescents in 30.3%, 29.0%, and 7.1%, and circulars in 6.4%, 4.8%, and 0.0% of the RVA, LVA, and BA, respectively. FCs in dorsolateral quadrant were least prevalent in both vertebral arteries (VAs): 46 (29.8%) and 46 (27.4%) for RVA and LVA, respectively. Risk factors associated with vertical dispersion of ICACs were male gender (OR : 2.69, 1.38–5.28) and diabetes (OR : 2.28, 1.04–4.99). Conclusions. FCs in VAs are least prevalent in dorsolateral quadrants. The vertical dispersion of ICACs seems to be associated with the male gender and diabetes. Slaven Pikija, Jožef Magdič, and Tanja Hojs-Fabjan Copyright © 2013 Slaven Pikija et al. All rights reserved. CYP3A5*3 and C3435T MDR1 Polymorphisms in Prognostication of Drug-Resistant Epilepsy in Children and Adolescents Thu, 01 Aug 2013 08:42:31 +0000 Drug-resistant epilepsies still remain one of the most profound problems of contemporary epileptology. Several mechanisms of drug resistance are possible; among them, genetic factors have a prominent place. Much importance is attached to genes, which encode enzymes that metabolize antiepileptic drugs CYP 3A, which belong to the family of cytochromes P450 and the genome of multidrug resistance, such as multidrug resistance 1 (MDR1) that expresses P-glycoprotein (P-gp), a drug transporter protein. The aim of the study was to assess the relation between polymorphism of gene CYP3A5 and polymorphism C3435T of MDR1 gene with the occurrence of focal, drug-resistant epilepsy in children and youths up to 18 years of age. The study comprised 85 patients, and their age range was from 33 months to 18 years of age, suffering from epilepsy, partly responding well to treatment, partly drug resistant. The polymorphism of both genes has been analysed using the PCR-RFLP method. The study failed to corroborate association between polymorphism CYP3A5*3 and C3435T polymorphism in MDR1 gene and pharmacoresistant epilepsy. The results of our research do not confirm the prognostic value of the polymorphisms examined in the prognostication of drug resistance in epilepsies. Ewa Emich-Widera, Wirginia Likus, Beata Kazek, Paweł Niemiec, Anna Balcerzyk, Aleksander L. Sieroń, and Iwona Żak Copyright © 2013 Ewa Emich-Widera et al. All rights reserved. Rotenone Upregulates Alpha-Synuclein and Myocyte Enhancer Factor 2D Independently from Lysosomal Degradation Inhibition Tue, 30 Jul 2013 09:23:30 +0000 Dysfunctions of chaperone-mediated autophagy (CMA), the main catabolic pathway for alpha-synuclein, have been linked to the pathogenesis of Parkinson’s disease (PD). Since till now there is limited information on how PD-related toxins may affect CMA, in this study we explored the effect of mitochondrial complex I inhibitor rotenone on CMA substrates, alpha-synuclein and MEF2D, and effectors, lamp2A and hsc70, in a human dopaminergic neuroblastoma SH-SY5Y cell line. Rotenone induced an upregulation of alpha-synuclein and MEF2D protein levels through the stimulation of their de novo synthesis rather than through a reduction of their CMA-mediated degradation. Moreover, increased MEF2D transcription resulted in higher nuclear protein levels that exert a protective role against mitochondrial dysfunction and oxidative stress. These results were compared with those obtained after lysosome inhibition with ammonium chloride. As expected, this toxin induced the cytosolic accumulation of both alpha-synuclein and MEF2D proteins, as the result of the inhibition of their lysosome-mediated degradation, while, differently from rotenone, ammonium chloride decreased MEF2D nuclear levels through the downregulation of its transcription, thus reducing its protective function. These results highlight that rotenone affects alpha-synuclein and MEF2D protein levels through a mechanism independent from lysosomal degradation inhibition. Gessica Sala, Alessandro Arosio, Giovanni Stefanoni, Laura Melchionda, Chiara Riva, Daniele Marinig, Laura Brighina, and Carlo Ferrarese Copyright © 2013 Gessica Sala et al. All rights reserved.