Primary versus postoperative gamma knife radiosurgery for intracranial benign meningiomas: a matched cohort retrospective study.

OBJECTIVE: The aims of this study were to investigate the long-term outcomes of primary versus postoperative Gamma Knife radiosurgery (GKRS) for benign meningiomas. METHODS: Three hundred and forty meningioma patients underwent GKRS were retrospectively reviewed. Patients in the postoperative GKRS group were matched to those in the primary GKRS group, in a 1:1 ratio. RESULTS: The study consisted of 122 patients, including primary (n = 61) and postoperative (n = 61) GKRS group. Thirty-four patients (27.9%) occurred radiological progression after a median follow-up of 72.5 (range, 24.2-254.5) months. The median time to radiological progression was 85.1 (range, 20.7-205.1) months. The radiological progression-free survival (PFS) was 100%, 93%, 87%, and 49%, at 1, 3, 5, and 10 years respectively. Thirty-one patients (25.4%) occurred clinical progression. The clinical PFS was 92%, 89%, 84%, and 60%, at 1, 3, 5, and 10 years. In combined group, only max diameter ≥ 50 mm was associated with radiological (p = 0.020) and clinical PFS (hazard ratio [HR] = 2.896, 95% confidence interval [CI] = 1.280-6.553, p = 0.011). Twenty-five patients (20.5%) developed GKRS related adverse effects, including radiation-induced edema (n = 21). Non-skull base tumors (HR = 3.611, 95% CI = 1.489-8.760, p = 0.005) and preexisting peritumoral edema (HR = 3.571, 95% CI = 1.167-10.929, p = 0.026) were significantly related to radiation-induced edema in combined group. There was no significant difference in radiological PFS (p = 0.403), clinical PFS (p = 0.336), and GKRS related adverse effects (p = 0.138) between primary and postoperative GKRS groups. CONCLUSIONS: Primary GKRS could provide similar radiological and clinical outcomes, as well as similar complication rate compared with postoperative GKRS. For selective benign meningioma patients (asymptomatic or mildly symptomatic tumors; unfavorable locations for surgical resection; comorbidities or an advanced age), GKRS could be an alternative primary treatment.

Histone deacetylase 6 promotes growth of glioblastoma through the MKK7/JNK/c-Jun signaling pathway.

Histone deacetylase 6 (HDAC6) activity contributes to the malignant proliferation, invasion, and migration of glioma cells (GCs), but the molecular mechanisms underlying the processes remains elusive. Here, we reported that HDAC6 inhibition by Ricolinostat (ACY-1215) or CAY10603 led to a remarkable decrease in the phosphorylation of c-Jun N-terminal kinase (JNK) and c-Jun, which preceded its suppressive effects on glioma cell growth. Further investigation showed that these effects resulted from HDAC6 inhibitor-induced suppression of MAPK kinase 7 (MKK7), which was identified to be critical for JNK activation and exerts the oncogenic roles in GCs. Selectively silencing HDAC6 by siRNAs had the same responses, whereas transient transfections expressing HDAC6 promoted MKK7 expression. Interestingly, by performing Q-PCR, HDAC6 inhibition did not cause a down-regulation of MKK7 mRNA level, whereas the suppressive effects on MKK7 protein can be efficiently blocked by the proteasomal inhibitor MG132. As a further test, elevating MKK7-JNK activity was sufficient to rescue HDAC6 inhibitor-mediated-suppressive effects on c-Jun activation and the malignant features. The suppression of both MKK7 expression and JNK/c-Jun activities was involved in the tumor-growth inhibitory effects induced by CAY10603 in U87-xenograft mice. Collectively, our findings provide new insights into the molecular mechanism of glioma malignancy regarding HDAC6 in the selective regulation of MKK7 expression and JNK/c-Jun activity. MKK7 protein stability critically depends on HDAC6 activity, and inhibition of HDAC6 probably presents a potential strategy for suppressing the oncogenic roles of MKK7/JNK/c-Jun axis in GCs.

Vestibular migraine with Wallenberg syndrome: a case report.

BACKGROUND: Vestibular migraine, a kind of acute vestibular syndrome, leads to both migraines and vertigo symptoms in a single patient. The occurrence of vestibular migraine has shown an obvious increase in female groups based on age. Though it is recognized that migraines may cause ischemic lesions in some brain regions, the relationship between vestibular migraine and cerebral infarction has seldom been reported, especially with no known research reports about vestibular migraine with Wallenberg syndrome. Based on this, the connection of the two diseases needs to be the focus of more research. CASE PRESENTATION: The patient, a 35-year-old lady, came to our department with severe vertigo and headaches for approximately two years. She suffered from migraines which attacked about twice yearly for nearly a decade. The diffusive weighted imaging showed a subacute infarction in the right lateral medullar. The clinical characteristics and MRI findings supported the diagnosis of vestibular migraine with Wallenberg syndrome. Along with the normal routine medication for vestibular migraine with Wallenberg syndrome, we also prescribed migraine therapy at the same time. In a 3-month follow-up, the patient had suffered only one vertigo attack and she reported that the migraines were less common and less intense than she was previously experiencing. CONCLUSIONS: Due to the fact that vestibular migraine is one of the risk factors of cerebral ischemia, we need to pay more attention to this phenomenon. The current case suggests that both routine medication on ischemic stroke as well as treatment for migraines should be used concurrently in vestibular migraine with Wallenberg syndrome.

MDH2 is an RNA binding protein involved in downregulation of sodium channel Scn1a expression under seizure condition.

Voltage-gated sodium channel α-subunit type I (NaV1.1, encoded by SCN1A gene) plays a critical role in the excitability of brain. Downregulation of SCN1A expression is associated with epilepsy, a common neurological disorder characterized by recurrent seizures. Here we reveal a novel role of malate dehydrogenase 2 (MDH2) in the posttranscriptional regulation of SCN1A expression under seizure condition. We identified that MDH2 was an RNA binding protein that could bind two of the four conserved regions in the 3' UTRs of SCN1A. We further showed that knockdown of MDH2 or inactivation of MDH2 activity in HEK-293 cells increased the reporter gene expression through the 3' UTR of SCN1A, and MDH2 overexpression decreased gene expression by affecting mRNA stability. In the hippocampus of seizure mice, the upregulation of MDH2 expression contributed to the decrease of the NaV1.1 levels at posttranscriptional level. In addition, we showed that the H2O2 levels increased in the hippocampus of the seizure mice, and H2O2 could promote the binding of MDH2 to the binding sites of Scn1a gene, whereas ß-mercaptoethanol decreased the binding capability, indicating an important effect of the seizure-induced oxidation on the MDH2-mediated downregulation of Scn1a expression. Taken together, these data suggest that MDH2, functioning as an RNA-binding protein, is involved in the posttranscriptional downregulation of SCN1A expression under seizure condition.

No Overlap among Serum GAD65, NMDAR and AQP4 Antibodies in Patients with Neuromyelitis Optica Spectrum Disorders.

OBJECTIVE: To evaluate whether serum glutamic acid decarboxylase (GAD), N-methyl-D-aspartate-receptor (NMDAR), and aquaporin-4 (AQP4) autoantibodies coexist in patients with neuromyelitis optica (NMO)/NMO spectrum disorders (NMOSD). METHODS: Serum samples were collected from 98 patients with NMO/NMOSD. Serum GAD65, NMDAR and AQP4 antibodies were measured using a cell-based assay. RESULTS: A total of 63 patients (64.3%) had myelitis and optic neuritis and satisfied the revised diagnostic criteria for NMO. Longitudinally extensive transverse myelitis was seen on spinal cord magnetic resonance imaging, showing continuous T2-weighted signal abnormalities in at least three vertebral segments in 26 patients (26.5%); 5 patients (5.1%) had recurrent optic neuritis, and 4 patients (4.1%) had brain syndromes with optic neuritis and myelitis. None of the 98 patients had diabetes, stiff-man syndrome, or epilepsy. All 98 patients tested positive for AQP4 antibody. No patients tested positive for GAD65 and NMDAR antibodies. CONCLUSIONS: In the present study, we found no simultaneous presence of serum GAD65, NMDAR and AQP4 antibodies in patients with NMO/NMOSD.

Y-39983, a selective Rho-kinase inhibitor, attenuates experimental autoimmune encephalomyelitis via inhibition of demyelination.

OBJECTIVE: Rho-associated kinase (ROCK) is a serine/threonine kinase and a major downstream effector of the small GTP-binding protein, Rho. Rho-ROCK triggers an intracellular signaling cascade that controls actin cytoskeleton and is essential for cell motility and adhesion, neurite outgrowth and retraction. In chronic disabling disease, multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE), demyelination and axonal damage are the major pathological changes contributing to neurological disability. We investigated the protective effect of a specific ROCK inhibitor, Y-39983, on demyelination and axonal damage in chronic EAE. METHODS: Western blotting for myelin proteins, electron microscopy and solochrome cyanine staining was performed to evaluate demyelination while neurofilament proteins and cytoskeletal proteins including ß-actin and ß-tubulin were used to determine axonal damage in a chronic mouse model of EAE treated with Y-39983. RESULTS: Y-39983 significantly suppressed clinical symptoms of EAE and prevented its relapse while increasing the amount of myelin proteins. No significant changes in neurofilaments and cytoskeletal proteins were observed compared with control EAE mice. The inhibition of demyelination by Y-39983 was confirmed by solochrome cyanine staining and electron microscopy. To further study the effect of Y-39983 on demyelination in EAE, we tested three major ROCK substrates, including myosin light chain phosphorylation, LIMK2 and collapsin response mediator protein-2. The activity of these molecules was decreased in EAE animals treated with Y-39983. CONCLUSION: The inhibitory effect of Y-39983 on demyelination is probably due to the inactivation of ROCK substrates, which are important for neurite outgrowth, growth cone collapse and demyelination of oligodendrocytes.

Estimation of critical closing pressure using intravascular blood pressure of the common carotid artery.

PURPOSE: Radial artery, femoral artery, and aortic arterial blood pressures (ABPs) can be used to estimate cerebral critical closing pressure (CrCP) and resistance-area product (RAP). However, the use of the common carotid artery (CCA) intravascular blood pressure to estimate CrCP is unclear. Thus, using continuous ABP monitoring, we compared the CrCP and RAP estimated from CCA measurements with the corresponding values acquired from the radial artery. METHODS: In this retrospective cross-sectional study, we analyzed CrCP and RAP estimations from 21 patients with normal cerebral blood vessels between July 23, 2010, and February 9, 2011, using linear regression of the cerebral blood flow velocity-ABP relationship. RESULTS: Bland-Altman analysis showed that the average differences (95% limits of agreement) between the radial artery and the left CCA were -6.3 (-53.1 - 40.6) mmHg and -0.08 (-0.41 - 0.25) mmHg s cm-1 for CrCP and RAP, respectively. CONCLUSIONS: The CrCP and RAP estimated from the CCA measurements are consistent with the corresponding values obtained from the radial artery.

L-3-n-Butylphthalide Effectively Improves the Glymphatic Clearance and Reduce Amyloid-ß Deposition in Alzheimer's Transgenic Mice.

Amyloid-ß (Aß) deposit in the parenchyma is a major characteristic in Alzheimer's disease (AD), and the impaired glymphatic clearance contributes to the Aß accumulation. It was reported that L-3-n-butylphthalide (NBP) showed the potential neuroprotective effect in the rodent models of AD. The effects of NBP on the glymphatic system were explored in this study. In the wild-type mice, both CSF tracer influx and perivascular drainage increased after NBP treatment compared with vehicle treatment. Moreover, NBP promoted the perivascular drainage of Aß via increased cerebral pulsation, which could be inhibited by propranolol. Then, we studied the potential of 3-month NBP treatment on Aß deposits in 8-month-old APP/PS1 transgenic mice. NBP daily treatments remarkably improved cognitive behavior in Morris water maze. Furthermore, NBP could reduce Aß deposition and decrease parenchymal Aß levels. In addition, NBP markedly improved the perivascular AQP4 localization. Our results indicated that NBP could enhance the glymphatic clearance and reduce parenchymal Aß deposit in the APP/PS1 mice, suggesting that it may have potential in the treatment of AD.

Autoimmune inflammatory meningoencephalitis in a patient negative for glial fibrillary acidic protein-specific immunoglobulin G.

BACKGROUND: In this study, we describe clinical findings in a patient with autoimmune inflammatory meningoencephalitis who was negative for antibodies against glial fibrillary acidic protein (GFAP-IgG). METHODS: Serum and cerebral spinal fluid (CSF) samples were collected from the patient as part of a study of 520 patients with neurological syndromes. Antibodies against GFAP and other proteins associated with neurological disorders were measured by rat brain- and cell-based indirect immunofluorescence assays. RESULTS: A 42-year-old female was diagnosed with autoimmune inflammatory meningoencephalitis. She experienced a subacute and relapsing course with decreased vision, fever, headache, ataxia, hemiplegia, and disturbance of consciousness. Brain magnetic resonance imaging showed extensive lesions in the white matter along the ventricle, brainstem, right internal capsule, and meninges. The patient responded well to steroid treatment. Examination of CSF revealed a normal white blood cell count and protein level. Serum and CSF were negative for GFAP-specific antibodies and all other autoantibodies tested. Immunohistochemical staining of a brain biopsy collected during relapse revealed chronic inflammation and severe edema. Extensive and strong staining of CD163+ macrophages were evident throughout the lesions; however, CD3+ cells were rare and CD138+ and CD20+ cells were absent. CONCLUSION: We describe a case of subacute corticosteroid-responsive nonvasculitic autoimmune inflammatory meningoencephalitis in the absence of GFAP-IgG. The pathological features were distinct from those of patients with GFAP-IgG-positive meningoencephalitis, suggesting that nonvasculitic autoimmune inflammatory meningoencephalitis is a heterogeneous neurological syndrome.

dl-3n-butylphthalide prevents stroke via improvement of cerebral microvessels in RHRSP.

The purpose of the study is to establish a model of cold-induced stroke in hypertensive rats, and to study the preventive effect of dl-3n-butylphthalide ( NBP ) on stroke. Stroke-prone renovascular hypertension(RHRSP) was created in Sprague-Dawley rats. The animals were assigned randomly to NBP, aspirin treated and vehicle control group, with administration of the medications for 7 days, and then subjected to cold treatment in an environmentally controlled chamber for 3 days to induce the occurrence of stroke. The incidence of stroke, the volume of the brain lesion, patency of the microvessels by FITC-dextran perfusion and the number of microvessels by immunohisochemical detection of vwF were investigated. Cold induced different types of stroke in RHRSP. The incidence of ischemic stroke and the volume of the infarct were decreased, and the perfused microvessels were increased with NBP pretreatment. Our data suggest that NBP prevents cold-induced ischemic stroke via improvement of cerebral microvessels.

Loss of GCN5 leads to increased neuronal apoptosis by upregulating E2F1- and Egr-1-dependent BH3-only protein Bim.

Cellular acetylation homeostasis is a kinetic balance precisely controlled by histone acetyl-transferase (HAT) and histone deacetylase (HDAC) activities. The loss of the counterbalancing function of basal HAT activity alters the precious HAT:HDAC balance towards enhanced histone deacetylation, resulting in a loss of acetylation homeostasis, which is closely associated with neuronal apoptosis. However, the critical HAT member whose activity loss contributes to neuronal apoptosis remains to be identified. In this study, we found that inactivation of GCN5 by either pharmacological inhibitors, such as CPTH2 and MB-3, or by inactivation with siRNAs leads to a typical apoptosis in cultured cerebellar granule neurons. Mechanistically, the BH3-only protein Bim is transcriptionally upregulated by activated Egr-1 and E2F1 and mediates apoptosis following GCN5 inhibition. Furthermore, in the activity withdrawal- or glutamate-evoked neuronal apoptosis models, GCN5 loses its activity, in contrast to Bim induction. Adenovirus-mediated overexpression of GCN5 suppresses Bim induction and apoptosis. Interestingly, the loss of GCN5 activity and the induction of Egr-1, E2F1 and Bim are involved in the early brain injury (EBI) following subarachnoid haemorrhage (SAH) in rats. HDAC inhibition not only significantly rescues Bim expression and apoptosis induced by either potassium deprivation or GCN5 inactivation but also ameliorates these events and EBI in SAH rats. Taken together, our results highlight a new mechanism by which the loss of GCN5 activity promotes neuronal apoptosis through the transcriptional upregulation of Bim, which is probably a critical event in triggering neuronal death when cellular acetylation homeostasis is impaired.

Brain gadolinium enhancement along the ventricular and leptomeningeal regions in patients with aquaporin-4 antibodies in cerebral spinal fluid.

BACKGROUND: Aquaporin-4 (AQP4) is densely expressed in the ependymal region and leptomeninges, and it is susceptible to pathological responses triggered by antibodies from blood and cerebral spinal fluid (CSF). Therefore, enhancement of these regions may be related to neuromyelitis optica spectrum disorder (NMOSD). METHODS: MRI from a consecutive cohort of 84 subjects (NMOSD=47, multiple sclerosis [MS]=37) with AQP4 antibodies in serum and CSF were analyzed retrospectively. RESULTS: The brain was normal in five of the 47 patients with NMOSD and none of the MS patients showed a normal brain. Twelve patients in each group had parenchymal enhancing lesions. Of these, white matter enhancement was more frequently found in MS patients than in NMOSD patients (12/12 vs 4/12, p=0.001). "Cloud-like" enhancement was found in three NMOSD patients (3/12) and in one MS patient. Nine of the 12 NMOSD patients showed "pencil-thin" ependymal enhancement, whereas one of the 12 MS patients showed ependymal enhancement (p=0.003). Enhancement along the lateral ventricle was more frequently found in NMOSD patients than in MS patients (p=0.027), whereas enhancing lesions around the fourth ventricle tended to be more frequent in NMOSD patients than MS patients (p=0.097). Leptomeningeal enhancement around the brainstem was found in six (12.8%) NMOSD patients and in no MS patients (p=0.032). CONCLUSION: Enhancement of the leptomeninges and ventricular ependymal region more frequently occurs in NMOSD patients than in MS patients. This may be considered as characteristic clue in the diagnosis of NMOSD.

The association baseline NIH Stroke Scale score with ABO blood-subtypes in young patients with acute ischemic stroke.

OBJECTIVES: The presence of the A and B blood group antigens has been associated with risk of arterial thrombosis. The aim of the current study was to design a new simpler form of National Institutes of Health Stroke Scale (NIHSS) for use on admission, and assess the association of blood groups with NIHSS score in young stroke patients. METHODS: We conducted this study in 1311 young Chinese adults with acute ischemic cerebral stroke. The outcome measures included a composite favorable outcome (defined as a modified Rankin Scale (mRS) of 0 or 2) and poor outcome (defined as a modified Rankin Scale score of 3 or 6) at discharge; a minor strokes (NIHSS scores 0-5) and severe strokes (NIHSS scores ≥6). Logistic regression analyses were used to determine the association between ABO blood groups and stroke severity. RESULTS: Regression analysis confirmed in relative to patients with AB subtype, Oxfordshire community stroke project classification (OCSP) subtype and serum white blood cell (WBC) were the major predictors for stroke severity. Meanwhile, diabetes, serum triglyceride and uric acid levels were determined as independent indicators of stroke severity in A, B and O blood subtype respectively. The optimal cutoff score of the baseline NIHSS was ≤5 for patients with non-O subtype, the optimal cutoff score of the baseline NIHSS was ≤7 for patients with blood O subtype. CONCLUSIONS: Our analysis provide compelling information regarding the ABO blood groups differences in predictors of stroke severity and the different validity of NIHSS scores in predicting prognosis at discharge between O subtype and non-O subtype.

Different independent susceptibility markers for first-ever cerebral infarction and myocardial infarction in young patients.

Cerebral infarction (CI) and myocardial infarction (MI) share some common features, but there are other differences in risk factors. The aim of our study is to determine whether there are some significantly independent susceptibility markers for them. All consecutive patients between the ages of 18 and 45 years with first-ever CI and MI during 2001-2010 were recruited to participate in the study. Using multivariate logistic regression modeling, we explore many different data, such as age at onset, sex ratio, numbers of patients with history of hypertension, smoking, drinking, and serum lipid, uric acid, prealbumin (PA), and white blood cell (WBC) count levels. Logistic regression analysis adjusted for confounders confirmed the following independent susceptibility markers for young CI patients: hypertension, admission serum PA levels, daily alcohol [odds ratio (OR), 0.251; 95% confidence interval (CI), 0.097-0.648, p = 0.004; OR, 0.994; 95% CI, 0.988-0.999, p = 0.031; OR, 0.150; 95% CI, 0.047-0.473, p = 0.001], and for MI patients: age at onset, current smoking, serum WBC, and glucose levels (OR, 1.293; 95% CI, 1.146-1.457, p = 0.000; OR, 8.914; 95% CI, 3.575-22.231, p = 0.000; OR, 1.344; 95% CI, 1.169-1.544, p = 0.000; OR, 1.149; 95% CI, 1.022-1.291, p = 0.020). We conclude that there are some significantly different independent susceptibility markers for young CI and MI patients.

The potent different risk factors for cerebral infarction in young patients with and without type 2 diabetes: subanalysis of the Young Cerebral Infarction Study (YCIS).

BACKGROUND: To compare risk factors, stroke characteristics, and short-term prognosis between diabetic and nondiabetic young ischemic stroke patients to provide information for patient management, counseling, and future research in these patient groups. METHODS: All consecutive patients between the ages of 18 and 45 years with first-ever cerebral infarction during 2001-2010 were recruited to participate in the study. Using multivariate logistic regression modeling, demographic characteristics, cerebrovascular risk factors, clinical events, stroke subtypes, and outcome in ischemic stroke patients with and without diabetes were compared. RESULTS: Logistic regression analysis adjusted for confounders confirmed the following independent susceptibility markers: in a substudy of young patients with and without diabetes, the predictors of short-term outcome were more likely to be TOAST subtype, initial stroke severity and serum uric acid, and age at onset, dyslipidemia, initial stroke severity and serum fibron levels correlate with a higher risk for incident stroke in young with diabetes. CONCLUSION: Our findings suggest that diabetic and nondiabetic ischemic stroke patients exhibit a distinct risk-factor and etiologic profile and may help clinicians to assess prognosis more accurately.

[Changes in endothelial cellular adhesion molecule mRNA expressions in the cerebral blood vessels of rats with prestroke condition caused by simulated cold wave].

OBJECTIVE: To study the changes in the mRNA expression of endothelial cellular adhesion molecules in the cerebral blood vessels in rats with prestroke condition caused by simulated cold wave. METHODS: Two-kidney two-clip renovascular hypertension was induced in 48 male SD rats, which were subsequently randomly assigned into cold wave exposure and non-exposed group (n=24). Each group was further divided into 4 sub-groups according to their systolic blood pressure, namely the sham-operated group with blood pressure (BP)<140 mmHg, mild hypertensive group with BP of 160-199 mmHg, moderate hypertensive group with BP of 200-219 mmHg, and severe hypertensive group with BP no less than 220 mmHg. Cold wave exposure was simulated by housing the rats in an artificial climate chamber with 3 cycles of 12 h light at 22 degrees celsius; and 12 h dark at 4 degrees celsius;. The non-exposed group was kept at 22 degrees celsius; throughout the experiment. After the exposure, the rats were sacrificed and the tissues of the frontal lobe were slice into 2.0-mm-thick coronal sections for real-time RT-PCR detection of vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and p-selectin mRNA expressions. The 5.0-microm-thick frozen sections from the bregma section underwent in situ hybridization of VCAM-1, ICAM-1, and p-selectin. The other sections were stained with HE to observe the infarct lesions, and the rats with cerebral infraction were excluded from the statistical analysis. RESULTS: In rats with cold wave exposure-induced prestroke condition and BP <220 mmHg, VCAM-1, ICAM-1, and p-selectin mRNA expressions all increased compared with those in the non-exposed group. In rats with BP>or=220 mmHg and cold exposure, the expressions all decreased to some extent compared with those in the non-exposed treatment. In the non-exposed rats, a positive correlation of BP to VCAM-1, ICAM-1, and p-selectin mRNA expressions were noted, and this correlation was also found in cold-wave-exposed rats with BP <220 mmHg; VCAM-1, ICAM-1, and p-selectin mRNA expressions decreased dramatically in the exposed rats with BP >or=220 mmHg compared with those in rats with BP <220 mmHg. CONCLUSION: Persistent and severe hypertension impairs the modulatory function of the cerebral vascular endothelia, which is a prerequisite for the stroke vulnerability. The modulatory function deteriorates as the BP further increases.