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Qingqing Huang,1,2 Xiao Wu,1,3 Ni Lei,1 Xin Chen,4 Sixun Yu,4 Xuemei Dai,1 Qin Shi,1,3 Gu Gong,1,* Hai-Feng Shu2,4,* 1Department of Anesthesiology, The General Hospital of Western Theater Command, Chengdu, People’s Republic of China; 2College of Medicine, Southwest Jiaotong University, Chengdu, People’s Republic of China; 3Department of Anesthesiology, North Sichuan Medical College, Nanchong, People’s Republic of China; 4Department of Neurosurgery, The General Hospital of Western Theater Command, Chengdu, People’s Republic of China*These authors contributed equally to this workCorrespondence: Gu Gong, Department of Anesthesiology, The General Hospital of Western Theater Command, 270 Tianhui Road, Rongdu Avenue, Jinniu District, Chengdu, Sichuan, 610083, People’s Republic of China, Tel +8617360137572, Fax +86 028571770, Email gonggu68@163.comBackground: Postoperative delirium (POD) is a common neurological complication associated with valve replacement. Preoperative sleep disturbance is a risk factor for POD development, and nasal insulin modulates the sleep-wake cycle. This study investigated the beneficial effects of intranasal insulin pretreatment on preoperative sleep quality and reducing POD in patients undergoing valve replacement for rheumatic heart disease.Patients and Methods: This prospective, single-center, randomized controlled trial (RCT) included 76 adult patients aged 18– 65 years undergoing valve surgery with cardiopulmonary bypass who were randomly allocated to receive intranasal insulin or normal saline interventions two days before surgery. POD incidence was on postoperative days 1 (T3), 2 (T4), and 3 (T5). Before the first intervention (T0), 1 d before surgery (T1), and before anesthesia on the day of surgery (T2), sleep quality was assessed and serum cortisol concentrations were measured. At T1 and T2, sleep quality related indicators monitored by sleep monitoring watches from the previous night were recorded.Results: Compared with the normal saline group, 3 days after surgery, the insulin group showed a significantly reduced incidence of POD; significantly increased deep sleep, REM sleep, deep sleep continuity, and total sleep quality scores at T1 and T2; and significantly reduced serum cortisol concentration, PSQI scale, light sleep ratio, and wakefulness at T1 and T2.Conclusion: The administration of 20 U of intranasal insulin twice daily, from 2 days preoperatively until 10 minutes preanesthesia on the day of surgery, can improved preoperative sleep quality significantly and reduced POD incidence in patients with rheumatic heart disease undergoing valve replacement.Clinical Trial Registration: This study was registered with the Chinese Clinical Trial Registry (www.chictr.org.cn, with the unique identifier ChiCTR2100048515; July 9, 2021).Keywords: postoperative delirium, rheumatic heart disease, valve replacement, preoperative sleep quality, intranasal insulin

Background: Gliomas, especially high-grade gliomas, are highly malignant with a poor prognosis. Although existing treatments have improved the survival rate of patients with glioma, the recurrence and mortality rates are still not ideal. The molecular mechanisms involved in the occurrence and development of glioma are still poorly understood. We previously reported that thrombospondin-2 (TSP2) expression was increased in tumor specimens from rat models, promoting excitatory synapse formation. However, little is known about the effect of TSP2 on the biological characteristics of glioma., Methods: Glioma and cerebral cortex tissues were collected from 33 patients, and the expression of TSP2 in them was analyzed. Next, the proliferation and migration of TSP2 on glioma cells were analyzed in vitro. At last, a glioma transplantation model was constructed to explore the growth of TSP2 on glioma in vivo., Results: The expression of TSP2 in surgical glioma specimens was increased compared to that in the normal cortex. Interestingly, the TSP2 protein level was higher in high-grade glioma (HGG, World Health Organization (WHO) grades 3-4) than in low-grade glioma (LGG, WHO grades 1-2) tissues. Exogenous addition of the TSP2 protein at an appropriate concentration promoted the migration of glioma cells but did not significantly affect their proliferation. Surprisingly, overexpression of TSP2 promoted both the migration and proliferation of cultured glioma cells. Moreover, in vivo experimental data implied that overexpression of TSP2 in C6 cells promoted the malignant growth of gliomas, while knockout of TSP2 slowed glioma growth., Conclusions: TSP2 promotes the migration and proliferation of glioma cells, which may provide new ideas for blocking glioma progression., (© 2022. The Author(s).)

Nipah virus disease (NVD) is a newly emerged zoonosis with a case fatality rate of 40%-75%. NVD is a severe threat to human health and the development of livestock farming. NVD has become one of the emerging infectious diseases with great concern globally during more than 20 years. Nipah virus (NiV) is a pathogen for NVD, the natural host of which is Fruit bats of the Pteropodidae family. The clinical spectrum of NiV infection is broad, including asymptomatic infection, acute respiratory infection, fatal encephalitis, and even death. Since NiV was first identified in Malaysia in 1999, it has been prevalent mainly in Southeast Asia and South Asia. NiV is primarily transmitted to humans through bat-pig-human, contaminated food. Currently, there are no specific therapeutic drugs and vaccines for NVD. Although there are no cases of NVD reported in China, which has close personnel and trade exchanges with major NVD-endemic countries, and NiV antibody has also been detected in relevant bats. There is a potential risk of importing NVD and domestic outbreaks in the future in this country. This paper provides a systematic review of the research progress in the prevention and control of NVD etiology, epidemiology, clinical manifestations and laboratory diagnosis to help relevant staff to understand NVD more comprehensively and systematically.

Abnormal migration of subventricular zone (SVZ)-derived neural progenitor cells (SDNPs) is involved in the pathological and epileptic processes of focal cortical dysplasias (FCDs), but the underlying mechanisms are not clear. Recent studies indicated that high mobility group box 1 (HMGB1)/receptor for advanced glycation end products (RAGE) are widely expressed in epileptic specimens of FCDs, which suggests that the HMGB1-RAGE pathway is involved in the pathological and/or epileptic processes of FCDs. The present study used Nestin-GFP tg/+ transgenic mice, and we established a model of freezing lesion (FL), as described in our previous report. A "migrating stream" composed of GFP-Nestin + SDNPs was derived from the SVZ region and migrated to the cortical FL area. We found that translocated HMGB1 and RAGE were expressed in cortical lesion in a clustered distribution pattern, which was especially obvious in the early stage of FL compared to the sham group. Notably, the number of GFP-Nestin + SDNPs within the "migrating stream" was significantly decreased when the HMGB1-RAGE pathway was blocked by a RAGE antagonist or deletion of the RAGE gene. The absence of RAGE also decreased the activity of pentylenetetrazol-induced cortical epileptiform discharge. In summary, this study provided experimental evidence that the levels of extranuclear HMGB1 and its receptor RAGE were increased in cortical lesion in the early stage of the FL model. Activation of the HMGB1-RAGE pathway may contribute to the abnormal migration of SDNPs and the hyperexcitability of cortical lesion in the FL model., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Seizures are common in patients with glioma, especially low-grade glioma (LGG). However, the epileptogenic mechanisms are poorly understood. Recent evidence has indicated that abnormal excitatory synaptogenesis plays an important role in epileptogenesis. The thrombospondin (TSP) family is a key regulator of synaptogenesis. Thus, this study aimed to elucidate the role of TSP2 in epileptogenesis in glioma-related epilepsy. The expression of TSP2 was increased in tumor tissue specimens from LGG patients, and this increase may have contributed to an increase in the density of spines and excitatory synapses in the peritumoral area. A glioma cell-implanted rat model was established by stereotactic implantation of wild-type TSP2-expressing, TSP2-overexpressing or TSP2-knockout C6 cells into the neocortex. Similarly, an increase in the density of excitatory synapses was also observed in the peritumoral area of the implanted tumor. In addition, epileptiform discharges occurred in the peritumoral cortex and were positively correlated with the TSP2 level in glioma tissues. Moreover, α2δ1/Rac1 signaling was enhanced in the peritumoral region, and treatment with the α2δ1 antagonist gabapentin inhibited epileptiform discharges in the peritumoral cortex. In conclusion, glioma-derived TSP2 promotes excitatory synapse formation, probably via the α2δ1/Rac1 signaling pathway, resulting in hyperexcitability in the peritumoral cortical networks, which may provide new insight into the epileptogenic mechanisms underlying glioma-related epilepsy., (© 2020 American Association of Neuropathologists, Inc. All rights reserved.)

Focal cortical dysplasia (FCD) likely results from abnormal migration of neural progenitor cells originating from the subventricular zone. To elucidate the roles in molecules that are involved in neural migration pathway abnormalities in FCDs, we investigated the expression patterns of transient receptor potential canonical channel 6 (TRPC6) and brain-derived neurotrophic factor (BDNF) in cortical lesions from FCD patients and in samples of normal control cortex. TRPC6 and BDNF mRNA and protein levels were increased in FCD lesions. By immunohistochemistry, they were strongly expressed in microcolumns, heterotopic neurons, dysmorphic neurons, and balloon cells (BCs). Colocalization assays revealed that most of the misshapen TRPC6-positive or heterotopic cells had a neuronal lineage with the exception of TRPC6-positive FCDiib patient BCs, which had both neuronal and glial features. Most TRPC6-positive cells were glutamatergic neurons. There was also greater expression of calmodulin-dependent kinase IV (CaMKIV), the downstream factor of TRPC6, in FCD lesions, suggesting that TRPC6 expression promoted dendritic growth and the development of dendritic spines and excitatory synapses via the CaMKIV-CREB pathway in FCD. Thus, overexpression of BDNF and TRPC6 and activation of the TRPC6 signal transduction pathway in cortical lesions of FCD patients may contribute to FC pathogenesis and epileptogenesis., (© 2016 American Association of Neuropathologists, Inc. All rights reserved.)

Objective: Toll-like receptors (TLRs) that mediate inflammatory responses play an important role in epilepsy; however, whether TLR1 is also involved in epileptogenesis remains unclear. Thus, in this study, we investigated the extent and pattern of TLR1 expression in epileptic tissues., Methods: One-hundred and thirty-two mice were intra-cerebroventricularly injected with PBS or kainic acid (KA) and were examined at 1, 3, 8 and 24 h. The expression pattern and distribution of TLR1 were examined by reverse-transcriptase polymerase chain reaction (RT-PCR), western blot analysis and immunohistochemistry staining., Results: The mRNA and protein levels of TLR1 were significantly upregulated in the hippocampus and temporal cortex of epileptic mice compared with those of controls. TLR1 expression was increased as early as 1 h following KA treatment and peaked at 8 and 24 h. Immunohistochemistry staining demonstrated that TLR1 was distributed in the CA1-3, dentate gyrus and hilus regions of the hippocampus and different cortical regions. Immunofluorescent staining further revealed that TLR1 was primarily expressed in the neurons, microglia, and astrocytes of epileptogenic tissue., Significance: These results demonstrate that cortical and hippocampal sub-regional expression of TLR1 is altered during epileptogenesis in a time- and location-specific manner, suggesting a close association with the process of epilepsy.

Introduction: Parvovirus B19 virus commonly causes subclinical infection, but it can prove fatal to the fetus during pregnancy and cause severe anemia in an adult with hemolytic diseases. We present the case of a woman with autoimmune hemolytic anemia who was diagnosed with parvovirus B19-induced transient aplastic crisis during her second trimester of pregnancy and faced the high risk of both fetal and maternal complications related to this specific viral infection. To the best of our knowledge, the experience of successful intravenous immunoglobulin treatment for B19 virus infection during pregnancy, as in our case, is limited., Case Presentation: A 28-year-old and 20-week pregnant Chinese woman with genetically confirmed alpha-thalassemia trait was diagnosed with cold antibody autoimmune hemolytic anemia and suffered from transient aplastic crisis caused by B19 virus infection. She received intravenous immunoglobulin treatment to reduce the risk of hydrops fetalis. Her peripheral blood reticulocyte percentage recovered, but anemia persisted, so she underwent several courses of high dose intravenous dexamethasone for controlling her underlying hemolytic problem. Finally, her hemoglobin levels remained stable with no need of erythrocyte transfusion, and a healthy baby boy was naturally delivered., Conclusions: Parvovirus B19 virus infection should be considered when a sudden exacerbation of anemia occurs in a patient with hemolytic disease, and the possible fetal complications caused by maternal B19 virus infection during pregnancy should not be ignored. Close monitoring and adequate management can keep both mother and fetus safe.

Focal cortical dysplasias (FCDs) are frequently associated with the medical refractory epilepsy in both children and adults. Transient receptor potential canonical channel 5 (TRPC5), a receptor-operated cation channel, has been well recognized as a regulator in the central nervous system. Here, we examined the expression and cellular distribution of TRPC5 in the specimens from patients with FCDIa (n = 14), FCDIIa (n = 12), and FCDIIb (n = 12) compared with the age-matched control cortex (CTX). TRPC5 mRNA and protein levels were significantly higher in FCDs compared with CTX. Immunohistochemical data showed that TRPC5 was strongly expressed in the misshapen cells, particularly in neuronal microcolumns, dysmorphic neurons, and balloon cells. Moreover, the double-label immunofluorescence analyses demonstrated that TRPC5 localized on NeuN-positive neurons. In addition, its co-localization with glutamate and gamma-aminobutyric acid (GABA) indicated that TRPC5 was distributed on both glutamatergic and GABAergic neurons. Taken together, these results suggested that increased expression of TRPC5 in FCDs and the cell-specific distribution patterns of TRPC5 in the misshapen neurons in FCDs could potentially contribute to the epileptogenesis of FCDs.

Stroke, either ischemic or hemorrhagic, is the leading cause of death and morbidity worldwide. Identifying the risk factors is a prerequisite step for stroke prevention and treatment. It is believed that a major portion of the currently unidentified risk factors is of genetic origin. Consistent with this idea, numerous potential risk alleles for stroke have been reported, however, the genetic evidence so far is not conclusive. The major goal of this review is to update the current knowledge about the genetic predisposition to the common multifactorial stroke, and to provide a bird's-eye view of this fast moving field. We selectively review and meta-analyze the related English literatures in public domain (PubMed) from 2000 onward, including the original reports and meta-analyses, to evaluate the genetic risk factors of common multifactorial stroke. The results indicated that we reviewed and meta-analyzed original reports and existing meta-analyses that studied the genetic predisposition to the common multifactorial stroke. Some original reports and meta-analyses were specific for ischemic stroke and others were for hemorrhagic stroke only. We also evaluated the major evolving issues in this field and discussed the future directions. In conclusion, strong evidences suggest that genetic risk factors contribute to common multifactorial stroke, and many genetic risk genes have been implicated in the literatures. However, not a single risk allele has been conclusively approved.

Experimental studies have demonstrated significant secondary damage (including cell apoptosis, blood-brain barrier disruption, inflammatory responses, excitotoxic damage, and free radical production) after traumatic brain injury (TBI). Quercetin is a natural flavonoid found in high quantities in fruits and vegetables, and may be a potential antioxidant and free radical scavenger. The purpose of this study was to determine the effects of quercetin on TBI-induced upregulation of oxidative stress, inflammation, and apoptosis in adult Sprague-Dawley rats. Animals were subjected to Feeney's weight-drop injury, thus inducing the parietal contusion brain injury model. Quercetin was administered (30 mg/kg intraperitoneal injection) 0, 24, 48, and 72 h after TBI. Quercetin reduced cognitive deficits, the number of TUNEL- and ED-1-positive cells, the protein expressions of Bax and cleaved-caspase-3 proteins, and the levels of TBARS and proinflammatory cytokines, and increased the activity of antioxidant enzymes (GSH-Px, SOD, and CAT) at 1 week after TBI. Our results suggest that in TBI rats, quercetin improves cognitive function owing to its neuroprotective action via the inhibition of oxidative stress, leading to a reduced inflammatory response, thereby reducing neuronal death.

Background: Although some trials assessed the effectiveness of aerobic exercise for Parkinson's disease (PD), the role of aerobic exercise in the management of PD remained controversial., Objective: The purpose of this systematic review is to evaluate the evidence about whether aerobic exercise is effective for PD., Methods: Seven electronic databases, up to December 2013, were searched to identify relevant studies. Two reviewers independently extracted data and assessed methodological quality based on PEDro scale. Standardised mean difference (SMD) and 95% confidence intervals (CI) of random-effects model were calculated. And heterogeneity was assessed based on the I2 statistic., Results: 18 randomized controlled trials (RCTs) with 901 patients were eligible. The aggregated results suggested that aerobic exercise should show superior effects in improving motor actions (SMD, -0.57; 95% CI -0.94 to -0.19; p = 0.003), balance (SMD, 2.02; 95% CI 0.45 to 3.59; p = 0.01), and gait (SMD, 0.33; 95% CI 0.17 to 0.49; p<0.0001) in patients with PD, but not in quality of life (SMD, 0.11; 95% CI -0.23 to 0.46; p = 0.52). And there was no valid evidence on follow-up effects of aerobic exercise for PD., Conclusion: Aerobic exercise showed immediate beneficial effects in improving motor action, balance, and gait in patients with PD. However, given no evidence on follow-up effects, large-scale RCTs with long follow-up are warrant to confirm the current findings.

Microgyria is associated with epilepsy and due to developmental disruption of neuronal migration. However, the role of endogenous subventricular zone-derived neural progenitors (SDNPs) in formation and hyperexcitability has not been fully elucidated. Here, we establish a neonatal cortex freeze-lesion (FL) model, which was considered as a model for focal microgyria, and simultaneously label SDNPs by CM-DiI. Morphological investigation showed that SDNPs migrated into FL and differentiated into neuronal and glia cell types, suggesting the involvement of endogenous SDNPs in the formation of FL-induced microgyria. Patch-clamp recordings in CM-DiI positive (CM-DiI(+)) pyramidal neurons within FL indicated an increase in frequency of spontaneous action potentials, while the resting membrane potential did not differ from the controls. We also found that spontaneous excitatory postsynaptic currents (EPSCs) increased in frequency but not in amplitude compared with controls. The evoked EPSCs showed a significant increase of 10-90% in rise time and decay time in the CM-DiI(+) neurons. Moreover, paired-pulse facilitation was dramatically larger in CM-DiI(+) pyramidal neurons. Western blotting data showed that AMPA and NMDA receptors were increased to some extent in the FL cortex compared with controls, and the NMDA/AMPA ratio of eEPSCs at CM-DiI(+) pyramidal neurons was significantly increased. Taken together, our findings provide novel evidence for the contribution of endogenous SDNPs in the formation and epileptogenicity of FL-induced focal microgyria.

Objective: To perform a meta-analysis to compare the safety and efficacy of propofol with midazolam for sedation of patients with severe traumatic brain injury., Materials and Methods: Studies were included in the meta-analysis if they met the following criteria: randomized controlled trial of sedative-hypnotic agents including propofol and midazolam; patients had severe traumatic brain injury; the primary outcome was the Glasgow Outcome Scale score; secondary outcomes included mortality, therapeutic failure, intracranial pressure, and cerebral perfusion pressure. The data were analyzed using software for meta-analysis., Results: Seven relevant studies were identified. Three of these studies were excluded: one was a single-arm study, one compared morphine and propofol, and for one the full text article could not be obtained. The remaining 4 studies were included in the meta-analysis. The results of the meta-analysis showed that propofol and midazolam have similar effects on the Glasgow Outcome Scale score, mortality, intracranial pressure, and cerebral perfusion pressure., Conclusion: Our meta-analysis of 4 studies showed that there are no important differences between propofol and midazolam when administered to provide sedation for patients with severe traumatic brain injury. Further randomized, controlled trials comparing propofol with midazolam for sedation of such patients are needed., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Metastasis associated in colon cancer 1 (MACC1) has been regarded as a novel potential therapeutic target for multiple cancers. However, the impact of MACC1 in glioma remains unclear. The aim of this study was to analyze the correlation of MACC1 expression with the clinicopathological features of glioma. MACC1 mRNA and protein expression levels in human glioma tissues were detected by quantitative real-time polymerase chain reaction and immunohistochemistry assays, respectively. MACC1 mRNA and protein expression were both significantly higher in glioma tissues than in corresponding noncancerous brain tissues (both P < 0.001). In addition, statistical analysis suggested that high MACC1 expression was significantly correlated with advanced pathological grade (P = 0.004) and that patients with high expression of MACC1 protein exhibited a poorer prognosis than those with low MACC1 expression. Furthermore, Cox multivariate analysis showed that MACC1 overexpression was an independent prognostic factor for predicting the overall survival of glioma patients. In conclusion, expression of MACC1 in glioma could be adopted as a candidate biomarker for the diagnosis of clinical stage and for assessing prognosis, indicating for the first time that MACC1 may play an important role in the tumor development and progression in glioma. MACC1 might be considered as a novel therapeutic target against this cancer.

The role of interleukin 17 (IL-17) to epilepsy-associated cortical tubers of tuberous sclerosis complex (TSC) is unknown. We investigated the expression patterns of the IL-17 and IL-17 receptor (IL-17R) in cortical tubers of TSC compared with normal control cortex (CTX). We found that IL-17 and IL-17R were clearly upregulated in cortical tubers at the protein levels. Immunostaining indicated that IL-17 was specifically distributed in the innate immunity cells (DNs, GCs, astrocytes, and microglia) and adaptive immunity cells (T-lymphocytes) as well as the endothelial cells of blood vessels. The overexpression and distribution patterns of IL-17 may be involved in the epileptogenicity of cortical tubers in TSC., (Copyright © 2013 The Authors. Published by Elsevier B.V. All rights reserved.)

Focal cortical dysplasia type IIb (FCD IIb) and tuberous sclerosis complex (TSC) are malformations of cortical development (MCDs) and are frequently associated with medically intractable epilepsy. Previous studies have indicated that developmental abnormalities during the early stages of cortical development contribute to the onset of these diseases. Bone morphogenetic protein-4 (BMP-4) is a well-documented key regulator of cortical development. To understand the potential roles of BMP-4 in the cortical lesions associated with MCDs, we investigated the expression pattern of BMP-4 in surgical specimens from patients with FCD IIb (n = 8) and TSC (cortical tubers; n = 12), and age-matched normal cortices (CTX) (n = 8) from autopsy samples were used as controls. The immunohistochemical results demonstrated that the overall immunoreactivity of the BMP-4 staining was diminished in the dysplastic cortices of the FCD IIb and TSC samples compared to the CTX samples. Moderate to strong BMP-4 immunoreactivity, however, was observed in malformed neurons, including dysmorphic neurons, giant neurons, balloon cells, giant cells, and reactive astrocytes. The confocal analysis demonstrated that most malformed neurons expressing BMP-4 were co-labeled with neuronal rather than astrocytic markers, indicating a neuronal lineage. Moreover, the decreased BMP-4 expression within the dysplastic cortex was confirmed by western blot analysis. In conclusion, the downregulation and altered cellular distribution of BMP-4 protein observed in MCDs suggests that BMP-4 may be involved in the pathogenesis of abnormal cortical development.

Tuberous sclerosis complex (TSC) and focal cortical dysplasia type IIb (FCDIIb) are recognized as causes of intractable epilepsy. Transient receptor potential vanilloid receptor 1 (TRPV1), a member of the transient receptor potential family, is the capsaicin receptor and is known to be involved in peripheral nociception. Recent evidence suggested that TRPV1 may be a contributing factor in epileptogenicity. Here, we evaluated the expression of TRPV1 in the cortical lesions of TSC and FCDIIb relative to normal control cortex. TRPV1 was studied in epilepsy surgery cases with TSC (cortical tubers; n=12) and FCDIIb (n=12) using immunocytochemistry, confocal analysis, and Western blotting (WB). Immunohistochemical location of the TRPV1 was predominately detected in the abnormal cell types, such as dysmorphic neurons, balloon cells (BCs) and giant cells. Co-localization assays further revealed that cells expressing TRPV1 mainly had a neuronal lineage, apart from some BCs in FCDIIb, which obviously were of astrocytic lineage. The increased TRPV1 expression within the dysplastic cortex of TSC and FCDIIb was confirmed by WB. Interestingly, both immunohistochemical and WB data indicated that TRPV1 might have both cytoplasm and nuclear distribution, suggesting a potential nuclear role of TRPV1. The over-expression of TRPV1 in cortical lesions of TSC and FCDIIb suggested the possible involvement of TRPV1 in the intrinsic and increased epileptogenicity of malformations of cortical development associated epilepsy diseases and may represent a potential antiepileptogenic target. However, the current data are merely descriptive, and further electrophysiological investigation is needed in the future., (Copyright © 2012 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Focal cortical dysplasias (FCDs) are increasingly recognized as important causes of medically intractable epilepsy. To understand the potential role of the interleukin 17 (IL-17) system in the epileptogenesis of FCDs, we studied the expression patterns of the IL-17 system in 15 FCD type Ia (FCDIa), 12 FCD type IIa (FCDIIa), and 12 FCD type IIb (FCDIIb) cortical lesions and compared the results with those in cerebral cortex from 10 control patients. Protein levels of IL-17, IL-17 receptor (IL-17R), and downstream factors of the IL-17 pathway (nuclear factor-κB activator 1 [NFκB; ACT1] and NFκB-p65) were markedly elevated in FCDIa, FCDIIa, and FCDIIb. Moreover, protein levels of IL-17 and IL-17R positively correlated with the frequency of seizures in FCD patients. Immunostaining indicated that IL-17 and IL-17R are highly expressed in neuronal microcolumns, dysmorphic neurons, balloon cells, astrocytes, and vascular endothelial cells. Nuclear factor-κB activator 1 and NFκB-p65 were diffusely expressed in FCDs. In addition, we detected a few IL-17-positive, CD4-positive T lymphocytes in FCDIIa and FCDIIb but not in FCDIa. Taken together, these findings suggest that the overexpression of the IL-17 system and the activation of the IL-17 signal transduction pathway may be involved in the epileptogenicity of cortical lesions in FCDs, thus representing a novel potential target for antiepileptic therapy.

Transient receptor potential vanilloid type-1 (TRPV1) is a ligand-gated nonselective cation channel that has been well characterized in peripheral pain pathway. Recent evidence from animal models of temporal lobe epilepsy (TLE) has supported the important role of TRPV1 in epileptogenesis. In this study, we investigated the expression and cellular distribution of TRPV1 in the temporal cortex (CTX) and hippocampus (HPC) from 26 patients with mesial TLE (MTLE) compared with 12 histologically normal samples. Reverse transcription-PCR and Western blotting revealed up-regulated mRNA and protein levels of TRPV1 in the MTLE group versus the control group. Immunohistochemistry data demonstrated that TRPV1 was mainly distributed in the cell bodies and dendrites of neurons. Double-labeled immunofluorescence further revealed that TRPV1 was localized on NeuN-positive neurons and GFAP-positive astrocytes, but not on HLA-positive microglia. In addition, its co-localization with glutamate and gamma-aminobutyric acid (GABA) indicated that TRPV1 was distributed on both glutamatergic and GABAergic neurons. Moreover, nerve growth factor, a sensitizing factor for TRPV1, was showed a higher expression pattern in MTLE patients. Taken together, our findings suggest that the overexpression and distribution patterns of TRPV1 might be involved in the pathogenesis and epileptogenesis of human MTLE.

The reticulon protein Nogo-A is an important regulator of neurite growth, axonal plasticity, and cell migration in the central nervous system. Previous studies have shown markedly elevated levels of Nogo-A in human temporal lobe epilepsy. In the present study, we examined the expression pattern of the Nogo-A system in cortical lesions of pediatric patients with tuberous sclerosis complex and focal cortical dysplasia type IIb. These disorders are characterized by malformations of cortical development and are frequently associated with intractable epilepsy. We found that the messenger RNA and protein levels of the Nogo-A receptor (NgR) and the downstream targets of Nogo-A, LINGO-1, TROY, and RhoA but not P75 were upregulated in the cortices of patients compared with autopsy control samples. Immunohistochemical analyses indicated that Nogo-A and NgR were strongly expressed in misshapen cells, particularly dysmorphic neurons, balloon cells, and giant cells. TROY was diffusely expressed in the malformations of cortical development. Most of theNogo-A/NgR-positive misshapen cells were colabeled with neuronal rather than astrocytic markers. Taken together, our results suggestthat the activation of Nogo-A via the NgR/LINGO-1/TROY signal transduction pathways, but not NgR/LINGO-1/P75, may be involved in the development and/or seizure activity of cortical lesions in tuberous sclerosis complex and focal cortical dysplasia type IIb.

Background: Choroid plexus carcinoma (CPC) is an uncommon, aggressive, malignant, central nervous system neoplasm that typically occurs in children, presenting with the signs and symptoms of intracranial hypertension and cerebrospinal fluid obstruction., Case Report: We report the case of a 2.5-year-old girl with CPC. The tumor was subtotally removed by microsurgery, followed by gamma knife radiosurgery for the residual lesion. H&E staining indicated that this was a rare case of CPC. Neuropathological studies, assayed by immunohistochemical staining, showed that the tumor sample was positive to antibodies against S-100, CgA, AE1/AE3 (cytokeratin), Ki-67, INI1 and TP53, and was negative to antibodies against Nestin, GFAP, CD133, EMA and AFP. Moreover, stainings for transthyretin and vimentin were focally positive. Interestingly, direct DNA sequencing of the paraffin-embedded tumor sample identified a novel R248Q mutation in the TP53 gene. In contrast to previous reports suggesting that TP53 germline mutations were associated with the pathogenesis of CPC, here we provide a rare case of CPC with TP53 somatic mutation, as evidence that the peritumoral tissue possesses the non-mutant TP53 allele., Conclusions: Our finding suggests that TP53 somatic mutations, in addition to its germline mutations, may also be involved in the pathogenesis of pediatric CPC.

Cortical tubers are malformations of cortical development in patients with tuberous sclerosis complex (TSC), and highly associated with pediatric intractable epilepsy. Recent evidence has shown that signaling mediated through vascular endothelial growth factor-C (VEGF-C) and its receptors, VEGFR-2 and VEGFR-3, has direct effects on both neurons and glial cells. To understand the potential role of VEGF-C system in the pathogenesis of cortical tubers, we investigated the expression patterns of VEGF-C signaling in cortical tubers compared with age-matched normal control cortex (CTX). We found that VEGF-C, VEGFR-2 and VEGFR-3 were clearly upregulated in tubers at both the mRNA and protein levels, compared with CTX. The in situ hybridization and immunostaining results demonstrated that VEGF-C, VEGFR-2 and VEGFR-3 were highly expressed in dysplastic neurons (DNs), giant cells (GCs) and reactive astrocytes within tubers. Most DNs/GCs expressing VEGF-C and its receptors co-labeled with neuronal rather than astrocytic markers, suggesting a neuronal lineage. In addition, protein levels of Akt-1, p-Bad and ERK1/2, the important downstream factors of the VEGF-C pathway, were significantly increased in cortical tubers, indicating involvement of VEGF-C-dependent prosurvival signaling in cortical tubers. Taken together, our results suggest a putative role for the VEGF-C signaling pathway in the pathogenesis of cortical tubers., (© 2011 The Authors. Brain Pathology © 2011 International Society of Neuropathology.)

Tuberous sclerosis complex (TSC) and focal cortical dysplasia type IIb (FCDIIb) are characterized by epilepsy-associated cerebral cortical malformations. To understand the potential role of the inflammatory cytokine interleukin 6 (IL-6) in the pathogenesis of these lesions, we analyzed the IL-6 system in TSC and FCDIIb cortical lesions and in control cortex (CTX). Greater messenger RNA and protein levels of IL-6 and of its receptors (i.e. IL-6 receptor [IL-6R] and glycoprotein 130 [gp130]) were observed in TSC and FCDIIb lesions versus CTX. Immunohistochemical analyses indicated that IL-6 and IL-6R were strongly expressed in misshapen cells, namely, dysmorphic neurons, giant neurons, and balloon cells. Glycoprotein 130 was diffusely expressed in nearly all cell types. Most IL-6/IL-6R+ misshapen cells colabeled with neuronal rather than astrocytic markers, suggesting a neuronal lineage; most IL-6/IL-6R+ balloon cells in FCDIIb expressed glial fibrillary acidic protein. Protein levels of Janus kinase 2 and phosphorylated signal transducer and activator of transcription 3 were greater than in CTX, suggesting involvement of the gp130-Janus kinase 2-signal transducer and activator of transcription 3 pathway in IL-6 signal transduction. Soluble IL-6R, but not soluble gp130, was greater in TSC and FCDIIb lesions than in CTX, indicating activation of this trans-signaling pathway. These results suggest that overexpression in the IL-6 system and activation of IL-6 signal transduction pathways may contribute to the pathogenesis of cortical lesions in TSC and FCDIIb.

The molecular mechanisms and potential clinical applications of neural precursor cells have recently been the subject of intensive study. Dlx5, a homeobox transcription factor related to the distal-less gene in Drosophila, was shown to play an important role during forebrain development. The subventricular zone (SVZ) in the adult brain harbors the largest abundance of neural precursors. The anterior SVZ (SVZa) contains the most representative neural precursors in the SVZ. Further research is necessary to elucidate how Dlx5-related genes regulate the differentiation of SVZa neural precursors. Here, we employed immunohistochemistry and molecular biology techniques to study the expression of Dlx5 and related homeobox genes Er81 and Islet1 in neonatal rat brain and in in vitro cultured SVZa neural precursors. Our results show that Dlx5 and Er81 are also highly expressed in the SVZa, rostral migratory stream, and olfactory bulb. Islet1 is only expressed in the striatum. In cultured SVZa neural precursors, Dlx5 mRNA expression gradually decreased with subsequent cell passages and was completely lost by passage four. We also transfected a Dlx5 recombinant plasmid and found that Dlx5 overexpression promoted neuronal differentiation of in vitro cultured SVZa neural precursors. Taken together, our data suggest that Dlx5 plays an important role during neuronal differentiation.

Although abundant evidence indicates mutual regulation between the immune and the central nervous systems, how the immune signals are transmitted to the brain is still an unresolved question. In a previous study we found strong expression of proinflammatory cytokine receptors, including interleukin (IL)-1 receptor I and IL-6 receptor alpha in the rat carotid body (CB), a well-known arterial chemoreceptor that senses a variety of chemostimuli in the arterial blood. We demonstrated that IL-1 stimulation increases intracellular calcium ([Ca(2+)](i)) in CB glomus cells, releases ATP, and increases the discharge rate in carotid sinus nerve. To explore the effect of IL-6 on CB, here we examine the effect of IL-6 on [Ca(2+)](i) and catecholamine (CA) secretion in rat CB glomus cells. Calcium imaging showed that extracellular application of IL-6 induced a rise in [Ca(2+)](i) in cultured glomus cells. Amperometry showed that local application of IL-6 evoked CA release from glomus cells. Furthermore, the CA secretory response to IL-6 was blocked by 200 microM Cd(2+), a well-known Ca(2+) channel blocker. Our experiments provide further evidence for the responsiveness of the CB to proinflammatory cytokines and indicate that the CB might play a role in inflammation sensing and transmission of such information to the brain.

PC12 cell line has been widely used in a diverse array of neurophysiological studies including in exploration of oxygen-sensing mechanism. In present study, we first identified with immunocytochemistry and Western blot methods that interleukin-1 receptor type I was expressed in the PC12 cells. We then demonstrated with patch clamping technique that extracellular application of IL-1beta dose-dependently inhibited the outward voltage-dependent and TEA-sensitive potassium currents (I(K)) in the PC12 cells, and pre-incubation with the interleukin-1 receptor antagonist almost completely abolished this inhibitory effect. In addition, application of IL-1beta shifted steady-state inactivation of I(K) in hyperpolarizing direction, but did not alter its steady-state activation. Furthermore, IL-1beta-induced inhibition of I(K) led to a membrane depolarization and a transient increase of [Ca(2+)](i) in PC12 cells. Taking together, the present study elucidates that PC12 cells bear interleukin-1 receptor and response to IL-1beta stimulation.

Increasing evidence indicates that there exists a reciprocal communication between the immune system and the brain. Interleukin 1beta (IL-1beta), a proinflammatory cytokine produced during immune challenge, is believed to be one of the mediators of immune-to-brain communication, but how it gets into the brain is unknown because of its large molecular weight and difficulty in crossing the blood-brain barrier. Our previous work has demonstrated that IL-1 receptor type I is strongly expressed in the glomus cells of rat carotid body (CB), a well characterized polymodal chemoreceptive organ which serves not only for the detection of hypoxia, hypercapnia and acidity, but also for low temperature and blood glucose. The present study was designed to test whether IL-1beta could stimulate the CB glomus cells and alter the discharge properties in the carotid sinus nerve, the afferent nerve innervating the organ. The results from whole-cell patch-clamp recordings and calcium imaging showed that extracellular application of IL-1beta significantly decreased the outward potassium current and triggered a transient rise in [Ca(2+)](i) in the cultured glomus cells of rat CB. Furthermore, by using extracellular recordings and pharmacological intervention, it was found that IL-1beta stimulation of the CB in the anaesthetized rat in vivo significantly increased the discharge rate in the carotid sinus nerve, most probably mediated by ATP release. This experiment provides evidence that the CB responds to cytokine stimulation and proposes the possibility that the CB might play a role in immune-to-brain communication.

Purpose: We hypothesize that changes in the transcription of up-regulated genes are biologically meaningful and may be linked to variations in tumor behavior and clinical features. This study aimed to find individual up-regulated genes responsible for clinicopathologic variations in human colorectal cancer., Experimental Design: Genes up-regulated concurrently in four microarray experiments were taken as candidate genes; 20 candidate genes were verified using real-time reverse transcription-PCR in these four experiments, along with 27 new samples. The presence or absence of up-regulation of these genes was correlated with 10 clinicopathologic variables from 31 patients. The mRNA transcript levels of these 20 candidate genes in the 31 paired samples were also correlated with each other to disclose any expression relationship., Results: Forty percent (8/20) of the candidate genes were verified by real-time reverse transcription-PCR to have a tumor/normal expression ratio > 2. Up-regulation of THY1 and PHLAD1 was associated with the presence of anemia in colon cancer patients (P = 0.036 and 0.009, respectively). Up-regulation of HNRPA1 was more significant in cancer growing in the right-sided colon than the left side (P = 0.027). Up-regulated GPX2 was related to a higher degree of tumor differentiation (P = 0.019). c-MYC was significantly over-expressed in specimens from male compared with female colon cancer patients (P = 0.012). GRO1 was significantly up-regulated in patients younger than 65 years old (P = 0.010) and was found to be frequently over-expressed when cancers were less invasive. In addition, we found that normalized transcript levels of HNRPA1 were tightly associated with that of c-MYC (r = 0.948)., Conclusions: Validation of microarray data using another independent laboratory approach is mandatory and statistical correlation between gene expression status and the patient's clinical features may reveal individual genes relevant to tumor behavior and clinicopathologic variations in human colorectal cancer.

This report describes the case of a 42-year-old alcoholic man who developed advanced squamous-cell carcinoma of the esophagus following an endoscopic examination showing grossly normal mucosa only 8 months previously. We believe this is the first case report providing endoscopic images illustrating a progression from grossly normal mucosa to advanced carcinoma of the esophagus in only 8 months.

Congenital cystic dilatation of the intrahepatic biliary ducts (Caroli's disease), until recently, has been infrequently recognized. It is often associated with autosomal recessive polycystic kidney disease (ARPKD) and congenital hepatic fibrosis (CHF). We hereby report a case with Caroli's disease, polycystic kidney disease (PKD), and CHF: This 24-year-old female patient initially presented with acute bacterial nephritis (ABN). Renal ultrasonography revealed bilateral enlarged kidneys with multiple cysts. Because her parents showed no renal cyst on ultrasonographic examination, she received further studies. Abdominal ultrasonography showed cystic dilatation of the biliary tree. Computed tomography (CT) with meglumine lotroxinate (biliscopin) infusion study and hepatobiliary scintigraphy confirmed the diagnosis of Caroli's disease. Liver biopsy revealed CHF: The radiographic and scintigraphic pictures are hereby illustrated and CT with biliscopin infusion study is emphasized. We conclude that if radiologic evidence of renal cystic lesions is absent in the parents of patients with PKD, the coexistence of Caroli's disease and CHF should be considered. The clinical pictures of ABN in this patient are also discussed. As far as we know, this is the first reported case of ABN in a patient with PKD and Caroli's disease, and it showed good response to antibiotic therapy.