Immunoregulation of Theiler's virus-induced demyelinating disease by glatiramer acetate without suppression of antiviral immune responses.

While most disease-modifying drugs (DMDs) regulate multiple sclerosis (MS) by suppressing inflammation, they can potentially suppress antiviral immunity, causing progressive multifocal leukoencephalopathy (PML). The DMD glatiramer acetate (GA) has been used for MS patients who are at high risk of PML. We investigated whether GA is safe for use in viral infections by using a model of MS induced by infection with Theiler's murine encephalomyelitis virus (TMEV). Treatment of TMEV-infected mice with GA neither enhanced viral loads nor suppressed antiviral immune responses, while it resulted in an increase in the Foxp3/Il17a ratio and IL-4/IL-10 production. This is the first study to suggest that GA could be safe for MS patients with a proven viral infection.

Interruption of perivascular sympathetic nerves of cerebral arteries offers neuroprotection against ischemia.

Sympathetic nervous system activity is increased after cardiopulmonary arrest, resulting in vasoconstrictor release from the perivascular sympathetic nerves of cerebral arteries. However, the pathophysiological function of the perivascular sympathetic nerves in the ischemic brain remains unclear. A rat model of global cerebral ischemia (asphyxial cardiac arrest, ACA) was used to investigate perivascular sympathetic nerves of cerebral arteries via bilateral decentralization (preganglionic lesion) of the superior cervical ganglion (SCG). Decentralization of the SCG 5 days before ACA alleviated hypoperfusion and afforded hippocampal neuroprotection and improved functional outcomes. These studies can provide further insights into the functional mechanism(s) of the sympathetic nervous system during ischemia. NEW & NOTEWORTHY: Interruption of the perivascular sympathetic nerves can alleviate CA-induced hypoperfusion and neuronal cell death in the CA1 region of the hippocampus to enhance functional learning and memory.

Variations in the cerebrospinal fluid proteome following traumatic brain injury and subarachnoid hemorrhage.

BACKGROUND: Proteomic analysis of cerebrospinal fluid (CSF) has shown great promise in identifying potential markers of injury in neurodegenerative diseases [1-13]. Here we compared CSF proteomes in healthy individuals, with patients diagnosed with traumatic brain injury (TBI) and subarachnoid hemorrhage (SAH) in order to characterize molecular biomarkers which might identify these different clinical states and describe different molecular mechanisms active in each disease state. METHODS: Patients presenting to the Neurosurgery service at the Louisiana State University Hospital-Shreveport with an admitting diagnosis of TBI or SAH were prospectively enrolled. Patients undergoing CSF sampling for diagnostic procedures were also enrolled as controls. CSF aliquots were subjected to 2-dimensional gel electrophoresis (2D GE) and spot percentage densities analyzed. Increased or decreased spot expression (compared to controls) was defined in terms of in spot percentages, with spots showing consistent expression change across TBI or SAH specimens being followed up by Matrix-Assisted Laser Desorption/Ionization mass spectrometry (MALDI-MS). Polypeptide masses generated were matched to known standards using a search of the NCBI and/or GenPept databases for protein matches. Eight hundred fifteen separately identifiable polypeptide migration spots were identified on 2D GE gels. MALDI-MS successfully identified 13 of 22 selected 2D GE spots as recognizable polypeptides. RESULTS: Statistically significant changes were noted in the expression of fibrinogen, carbonic anhydrase-I (CA-I), peroxiredoxin-2 (Prx-2), both α and ß chains of hemoglobin, serotransferrin (Tf) and N-terminal haptoglobin (Hp) in TBI and SAH specimens, as compared to controls. The greatest mean fold change among all specimens was seen in CA-I and Hp at 30.7 and -25.7, respectively. TBI specimens trended toward greater mean increases in CA-I and Prx-2 and greater mean decreases in Hp and Tf. CONCLUSIONS: Consistent CSF elevation of CA-I and Prx-2 with concurrent depletion of Hp and Tf may represent a useful combination of biomarkers for the prediction of severity and prognosis following brain injury.

Multiple Sclerosis Epidemiology in East Asia, South East Asia and South Asia: A Systematic Review.

BACKGROUND: Multiple sclerosis (MS) is one of the most common chronic immune-mediated diseases of the human central nervous system and an important cause of non-traumatic neurologic disability among young population in several countries. Recent reports from East Asia, South East Asia and South Asia have proposed a low to moderate prevalence of MS in these countries. METHODS: A literature review search was carried out in December 2014 in Medline, Embase, Scopus and Cochrane library to recover original population-based studies on MS epidemiology in East Asia, South East Asia and South Asia countries published between January 1, 1950 and December 30, 2014. We intended search strategies using the key words: multiple sclerosis, prevalence, incidence and epidemiology. Based on our inclusion criteria, 68 epidemiologic studies were included in this systematic review. RESULTS: The most extensively used diagnostic criteria in the studies were McDonald's criteria. Most studies were performed in a multi-center hospital setting. The female to male ratio varied and ranged from 0.7 in India to 9.0 in China. The mean age at disease onset ranged from the lowest age of 25.3 in Iran to the highest age of 46.4 in China. MS prevalence ranged from 0.77 in 100,000 populations in Hong Kong (1999) to 85.80 in 100,000 in Iran (2013). CONCLUSIONS: Advances in MS registries around the globe allow nationwide population-based studies and will allow worldly comparisons between the prevalence and incidence in different regions that are provided to monitor estimation.

Prevalence of multiple sclerosis in Iranian emigrants: review of the evidence.

Iran has the highest prevalence of multiple sclerosis (MS) in the Middle East and Asia. Rate of emigration has been significantly raised among Iranians and though, multiple studies have been published on prevalence of MS among Iranian emigrants. Here we systematically reviewed these publications. We performed a comprehensive literature search was performed on April 30, 2015 in data bases of MEDLINE, EMBASE, Scopus and Google Scholar for the terms 'multiple sclerosis', 'incidence', 'prevalence', 'epidemiology', 'migration', 'emigrant', 'immigrant', 'Iran', 'Parsis' and 'Persian'. Study location, prevalence day or period, and age of at disease onset were recorded for all the included publications. Nine publications from Sweden, Canada, Norway, UK, and India were included. Only three reported age-adjusted prevalence and six reported age of disease onset. MS prevalence among Iranian emigrants varied from 21 per 100,000 people in Bombay, India in 1985 to 433 per 100,000 people in British Columbia, Canada in 2012. Five studies reported the prevalence in the region of interest, ranging from 1.33 in Bombay, India to 240 in British Columbia, Canada. Five studies also reported the prevalence of MS in the population of the destination country, and in all of them, the prevalence of MS was higher in Iranian immigrants compared to native people. Prevalence studies performed in Iran and also on Iranian emigrants indicate roles for both genetic and environmental factors in MS susceptibility. Data might indicate that living in a high-risk area increases the susceptibility to MS.

Exploration of screening practices for obstructive sleep apnea in stroke medical community: A pilot study.

BACKGROUND: Frequency of sleep-disordered breathing (SDB) among stroke and transient ischemic attack (TIA) patients ranges from 30-80% and is associated with poor neurological outcomes. Per current stroke prevention guidelines from American Heart Association/American Stroke Association (AHA/ASA), SDB is included in the list of modifiable risk factors for stroke and TIA prevention. Goal of our study is to determine screening practices for SDB in stroke medical community. METHODS: A web-based survey was sent to physicians taking care of stroke patients across North America and Europe. RESULTS: Among 112 total responses, 91 (81%) were stroke physicians, nine (8%) were general neurologists, nine (8%) were from other specialties and three (3%) were sleep medicine physicians. Majority of physicians (72%, n=81) do not use SDB screening questionnaires in their stroke patients. Epworth sleepiness scale is the most used among SDB questionnaires (24%, n=25/105), followed by Berlin sleep questionnaire (10%) and STOP-BANG questionnaire (7%). Only 13% of physicians use screening questionnaires in both in-patients and outpatients, whereas 21% use only in outpatients and 5% use only in acute stroke setting. Only 50% (n=56/111) of physicians would refer their stroke patients to a sleep medicine specialist when patients screen positive for SDB on questionnaires. CONCLUSION: Despite being an independent risk factor for stroke and TIA, majority of physicians in the pilot targeted cohort of medical professionals, who are involved in the management of stroke and TIA, do not screen these patients for SDB. Further work involving systematic, more detailed standardized surveys are needed to be developed to objectively evaluate and improve screening practices for SDB in national and international stroke medical communities.

From trash to treasure: The untapped potential of endothelial microparticles in neurovascular diseases.

Discovered in 1947, microparticles (MP) represent a group of sub-micron cell-derived particles isolated by high speed centrifugation. Once regarded as cellular 'trash', in the past decade MP have gained tremendous attention in both basic sciences and medical research both as biomarkers and mediators of infection, injury and response to therapy. Because MP bear cell surface markers derived from parent cells, accumulate in extracellular fluids (plasma, serum, milk, urine, cerebrospinal fluid) MP based tests are being developed commercially as important components in 'liquid biopsy' approaches, providing valuable readouts in cardiovascular disease and cancer, as well as stroke, Alzheimer's disease and Multiple Sclerosis. Importantly, MP have been reported as mobile transport vectors in the intercellular transfer of mRNAs, microRNAs, lipids and proteins. Here we discuss MP structure, properties and functions with particular relevance to neurological and neurovascular diseases.

A recombinant inhibitory isoform of vascular endothelial growth factor164/165 aggravates ischemic brain damage in a mouse model of focal cerebral ischemia.

Vascular endothelial growth factors (VEGF) are a Janus-faced family of growth factors exerting both neuroprotective and maladaptive effects on the blood-brain barrier. For example, VEGFs are beneficial in promoting postischemic brain angiogenesis, but the newly formed vessels are leaky. We investigated the role of the naturally occurring murine inhibitory VEGF isoform VEGF165b in a mouse model of focal cerebral ischemia by middle cerebral artery occlusion and reperfusion (I/R) in male C57BL/6 mice. We investigated the roles of VEGF164/165 and VEGF165b in both brain and nonbrain endothelial barrier, angiogenesis, and neutrophil migration using oxygen glucose deprivation and reoxygenation as in vitro model. We investigated the role of VEGF165b in brain edema, neutrophil infiltration, ischemic brain damage, and neuronal death in vivo using an adenovirus encoding a recombinant VEGF164b isoform. Neither VEGF164/165 nor VEGF165b significantly altered brain endothelial barrier or angiogenesis in vitro. However, treatment of brain endothelial cells with VEGF165b increased neutrophil migration in vitro and exacerbated stroke injury by aggravating neutrophil infiltration and neurodegeneration in vivo. Our results indicate that alterations in the delicate balance in the relative levels of pro- and antiangiogenic VEGF isoforms can result in either adaptive or detrimental effects, depending on the VEGF isoform levels and on the duration and extent of injury.

Neuronal and astrocytic interactions modulate brain endothelial properties during metabolic stresses of in vitro cerebral ischemia.

Neurovascular and gliovascular interactions significantly affect endothelial phenotype. Physiologically, brain endothelium attains several of its properties by its intimate association with neurons and astrocytes. However, during cerebrovascular pathologies such as cerebral ischemia, the uncoupling of neurovascular and gliovascular units can result in several phenotypical changes in brain endothelium. The role of neurovascular and gliovascular uncoupling in modulating brain endothelial properties during cerebral ischemia is not clear. Specifically, the roles of metabolic stresses involved in cerebral ischemia, including aglycemia, hypoxia and combined aglycemia and hypoxia (oxygen glucose deprivation and re-oxygenation, OGDR) in modulating neurovascular and gliovascular interactions are not known. The complex intimate interactions in neurovascular and gliovascular units are highly difficult to recapitulate in vitro. However, in the present study, we used a 3D co-culture model of brain endothelium with neurons and astrocytes in vitro reflecting an intimate neurovascular and gliovascular interactions in vivo. While the cellular signaling interactions in neurovascular and gliovascular units in vivo are much more complex than the 3D co-culture models in vitro, we were still able to observe several important phenotypical changes in brain endothelial properties by metabolically stressed neurons and astrocytes including changes in barrier, lymphocyte adhesive properties, endothelial cell adhesion molecule expression and in vitro angiogenic potential.

Early-onset Alzheimer's disease in two Iranian families: a genetic study.

BACKGROUND: Early-onset Alzheimer's disease (EOAD) represents less than 5% of all AD cases. Autosomal dominant EOAD has been defined as the occurrence of at least three cases in three generations. Mutations in the amyloid precursor protein (APP), presenilin-1 and presenilin-2 genes have been recognized to be the cause of EOAD. OBJECTIVE: We investigated the genotype of EOAD in two generations of two families with EOAD living in an Iranian village. METHODS: The polymerase chain reaction method was used to study the presenilin-1 and APP genes in 25 subjects of these generations. RESULTS: A guanine-to-adenine transition in exon 17 of the APP gene resulting in a valine-to-isoleucine substitution at codon 717 was detected in 14 subjects including 6 patients with EOAD. CONCLUSION: This mutation demonstrates the importance of γ-secretase, the necessity of early detection of patients with memory decline in the susceptible population and raising public awareness of consanguinity marriages.

The Human Gut Microbiota: A Dynamic Biologic Factory.

The human body constitutes a living environment for trillions of microorganisms, which establish the microbiome and, the largest population among them, reside within the gastrointestinal tract, establishing the gut microbiota. The term "gut microbiota" refers to a set of many microorganisms [mainly bacteria], which live symbiotically within the human host. The term "microbiome" means the collective genomic content of these microorganisms. The number of bacterial cells within the gut microbiota exceeds the host's cells; collectively and their genes quantitatively surpass the host's genes. Immense scientific research into the nature and function of the gut microbiota is unraveling its roles in certain human health activities such as metabolic, physiology, and immune activities and also in pathologic states and diseases. Interestingly, the microbiota, a dynamic ecosystem, inhabits a particular environment such as the human mouth or gut. Human microbiota can evolve and even adapt to the host's unique features such as eating habits, genetic makeup, underlying diseases, and even personalized habits. In the past decade, biologists and bioinformaticians have concentrated their research effort on the potential roles of the gut microbiome in the development of human diseases, particularly immune-mediated diseases and colorectal cancer, and have initiated the assessment of the impact of the gut microbiome on the host genome. In the present chapter, we focus on the biological features of gut microbiota, its physiology as a biological factory, and its impacts on the host's health and disease status.

Venous endothelial injury in central nervous system diseases.

The role of the venous system in the pathogenesis of inflammatory neurological/neurodegenerative diseases remains largely unknown and underinvestigated. Aside from cerebral venous infarcts, thromboembolic events, and cerebrovascular bleeding, several inflammatory central nervous system (CNS) diseases, such as multiple sclerosis (MS), acute disseminated encephalomyelitis (ADEM), and optic neuritis, appear to be associated with venous vascular dysfunction, and the neuropathologic hallmark of these diseases is a perivenous, rather than arterial, lesion. Such findings raise fundamental questions about the nature of these diseases, such as the reasons why their pathognomonic lesions do not develop around the arteries and what exactly are the roles of cerebral venous inflammation in their pathogenesis. Apart from this inflammatory-based view, a new hypothesis with more focus on the hemodynamic features of the cerebral and extracerebral venous system suggests that MS pathophysiology might be associated with the venous system that drains the CNS. Such a hypothesis, if proven correct, opens new therapeutic windows in MS and other neuroinflammatory diseases. Here, we present a comprehensive review of the pathophysiology of MS, ADEM, pseudotumor cerebri, and optic neuritis, with an emphasis on the roles of venous vascular system programming and dysfunction in their pathogenesis. We consider the fundamental differences between arterial and venous endothelium, their dissimilar responses to inflammation, and the potential theoretical contributions of venous insufficiency in the pathogenesis of neurovascular diseases.

Inflammation induces neuro-lymphatic protein expression in multiple sclerosis brain neurovasculature.

BACKGROUND: Multiple sclerosis (MS) is associated with ectopic lymphoid follicle formation. Podoplanin+ (lymphatic marker) T helper17 (Th17) cells and B cell aggregates have been implicated in the formation of tertiary lymphoid organs (TLOs) in MS and experimental autoimmune encephalitis (EAE). Since podoplanin expressed by Th17 cells in MS brains is also expressed by lymphatic endothelium, we investigated whether the pathophysiology of MS involves inductions of lymphatic proteins in the inflamed neurovasculature. METHODS: We assessed the protein levels of lymphatic vessel endothelial hyaluronan receptor and podoplanin, which are specific to the lymphatic system and prospero-homeobox protein-1, angiopoietin-2, vascular endothelial growth factor-D, vascular endothelial growth factor receptor-3, which are expressed by both lymphatic endothelium and neurons. Levels of these proteins were measured in postmortem brains and sera from MS patients, in the myelin proteolipid protein (PLP)-induced EAE and Theiler's murine encephalomyelitis virus (TMEV) induced demyelinating disease (TMEV-IDD) mouse models and in cell culture models of inflamed neurovasculature. RESULTS AND CONCLUSIONS: Intense staining for LYVE-1 was found in neurons of a subset of MS patients using immunohistochemical approaches. The lymphatic protein, podoplanin, was highly expressed in perivascular inflammatory lesions indicating signaling cross-talks between inflamed brain vasculature and lymphatic proteins in MS. The profiles of these proteins in MS patient sera discriminated between relapsing remitting MS from secondary progressive MS and normal patients. The in vivo findings were confirmed in the in vitro cell culture models of neuroinflammation.

Neurosarcoidosis: clinical features, diagnosis, and management.

Sarcoidosis is a multisystemic granulomatous disease, which uncommonly affects nervous system. However, when present, it may affect both central and peripheral nervous systems and potentially mimics other chronic diseases of the nervous system. Pathogenesis of neurosarcoidosis remains largely unknown, and its diagnosis and management pose serious challenges to clinicians. Early diagnosis and aggressive treatment of neurosarcoidosis are necessary to produce satisfactory clinical outcomes. This review discusses clinical manifestations, current diagnostic studies, and currently available modalities for management of neurosarcoidosis.

Effect of magnesium supplementation on carotid intima-media thickness and flow-mediated dilatation among hemodialysis patients: a double-blind, randomized, placebo-controlled trial.

OBJECTIVES: The aim of the present study was to determine the efficacy of oral magnesium (Mg) supplementation on endothelial function through evaluation of carotid intima-media thickness (cIMT), brachial artery flow-mediated dilatation (FMD), and C-reactive protein (CRP) among hemodialysis (HD) patients. METHODS: This randomized, controlled, double-blind clinical trial consisted of 54 patients on HD. One group was treated orally with 440 mg of Mg oxide 3 times per week for 6 months (n = 29). The control group (n = 25) was given placebo using the same administration protocol. cIMT, FMD, serum calcium levels, phosphorus, lipid, CRP, and bicarbonate were measured at baseline and at 6 months in both groups. RESULTS: At 6 months, cIMT was significantly decreased in the Mg group (0.84 ± 0.13 mm at baseline and 0.76 ± 0.13 mm at 6 months, p = 0.001). However, in the placebo group, cIMT was significantly increased (0.73 ± 0.13 and 0.79 ± 0.12 mm, respectively, p = 0.003). When hypertension, diabetes mellitus, smoking, hyperlipidemia, and systemic lupus erythematosus were controlled for in the analysis, the effect of Mg remained significant in both groups (p = 0.000). CONCLUSION: Our results indicate that Mg might not improve endothelial function (CRP level and FMD) and that a decreased cIMT as a marker of atherosclerosis may be due to the inhibition of calcification through the regulation parathormone, calcium, and phosphorus.

Immunopathological patterns from EAE and Theiler's virus infection: Is multiple sclerosis a homogenous 1-stage or heterogenous 2-stage disease?

Multiple sclerosis (MS) is a disease which can presents in different clinical courses. The most common form of MS is the relapsing-remitting (RR) course, which in many cases evolves into secondary progressive (SP) disease. Autoimmune models such as experimental autoimmune encephalomyelitis (EAE) have been developed to represent the various clinical forms of MS. These models along with clinico-pathological evidence obtained from MS patients have allowed us to propose '1-stage' and '2-stage' disease theories to explain the transition in the clinical course of MS from RR to SP. Relapses in MS are associated with pro-inflammatory T helper (Th) 1/Th17 immune responses, while remissions are associated with anti-inflammatory Th2/regulatory T (Treg) immune responses. Based on the '1-stage disease' theory, the transition from RR to SP disease occurs when the inflammatory immune response overwhelms the anti-inflammatory immune response. The '2-stage disease' theory proposes that the transition from RR to SP-MS occurs when the Th2 response or some other responses overwhelm the inflammatory response resulting in the sustained production of anti-myelin antibodies, which cause continuing demyelination, neurodegeneration, and axonal loss. The Theiler's virus model is also a 2-stage disease, where axonal degeneration precedes demyelination during the first stage, followed by inflammatory demyelination during the second stage.

Metabolic modulation of cytokine-induced brain endothelial adhesion molecule expression.

OBJECTIVE: Cytokines contribute to cerebro-vascular inflammatory and immune responses by inducing ECAMs' expression. Ischemic insults can be separated into aglycemic and hypoxic components. However, whether aglycemia, hypoxia or OGD plays a major role in dysregulating BBB or promotes immune cell infiltration via ECAMs' expression is not clear. We investigated how expression of ICAM-1, VCAM-1, MAdCAM-1, PECAM-1, E- and P-selectin in response to TNF-α, IL-1ß and IFN-γ was altered by aglycemia (A), hypoxia (H) or combined oxygen glucose deprivation (OGD). METHODS: A cell surface enzyme linked immunoabsorbent assay (cell surface ELISA) was used to analyze ECAM expression. RESULTS: We observed that ICAM-1 and PECAM-1 expressions were insensitive to hypoxia, aglycemia or OGD. Conversely, VCAM-1 and E-selectin were increased by hypoxia, but not by aglycemia. MAdCAM-1 and P-selectin were induced by hypoxia, and decreased by aglycemia. Patterns of cytokine-regulated ECAMs' expression were also modified by metabolic conditions. CONCLUSIONS: Our results indicate that patterns of inflammation-associated ECAMs represent cumulative influences from metabolic stressors, as well as cytokine activation. The expression of ECAMs following tissue injury reflects mechanistic interactions between metabolic disturbances, and alterations in tissue cytokines. Normalization of tissue metabolism, as well as cytokine profiles, may provide important targets for therapeutic treatment of inflammation.

Cesarean delivery may increase the risk of multiple sclerosis.

BACKGROUND: Prenatal and perinatal factors are believed to contribute to the risk of developing multiple sclerosis (MS). OBJECTIVE: This study was designed to evaluate whether mode of delivery (vaginal versus cesarean section), as a perinatal factor, affects susceptibility to MS. METHODS: MS patients were recruited from the MS registry of Isfahan Multiple Sclerosis Society (IMSS) and were compared with their healthy siblings. Data regarding mode of delivery, birth order, and gestation week of birth were obtained through a specially designed questionnaire. Preterm or post term deliveries were excluded. We used conditional logistic regression statistics and adjusted for gender and birth order. RESULTS: This study included 1349 participants (449 MS patients and 900 controls). Subjects who were born by cesarean section had significant risk of MS (odds ratio, OR = 2.51; 95% confidence interval, CI: 1.43-4.41; p = 0.001). There was significant MS risk for females who were born by cesarean section (OR = 2.69, 95% CI: 1.30-5.58; p = 0.008), but not for males (OR = 2.25, 95% CI: 0.90-5.63; p = 0.082). The mean age at onset was lower in MS patients born by cesarean section (24.58 ± 6.33) compared with that of patients born by vaginal delivery (27.59 ± 7.97; p = 0.041). There was no significant difference between the two groups for birth order (p = 0.417). CONCLUSION: Our results suggest that those born by vaginal delivery are at a lower risk of subsequent MS. These preliminary findings will need to be addressed in a much larger and preferably prospective study.

Leptomeningeal Metastatic Prostate Cancer Imitating a Subdural Hematoma.

Metastases to the dura and adjacent parenchyma occur in 1%-2% of patients with prostate cancer. Dural metastases manifest as subdural fluid collections and present as a chronic subdural hematoma. We present a patient with advanced prostate cancer who experienced a fall and a traumatic brain injury. Computer tomography (CT) of the brain revealed a bilateral subdural hematoma (SDH). During the follow-up examination, the patient's mental status declined, and a follow-up brain CT showed an expansion of the SDH. Brain MRI with contrast demonstrated dural lesions suspicious for metastasis to the dura. Histopathologic examination of the lesions confirmed metastatic prostate adenocarcinoma. While uncommon, leptomeningeal-dural metastatic lesions stemming from prostate adenocarcinoma should be suspected in patients with known prostate cancer who present with subdural collections. This is even more significant if the patient with prostatic adenocarcinoma has sustained a recent head injury and presents with a subdural hematoma on neuroimaging. Brain MRI provides more data towards the differential diagnosis of these lesions and should be an essential part of the diagnostic workup. Biopsy and histopathologic examination of these lesions are indicated in the diagnostic workup of these uncommon lesions.

Gliovascular and cytokine interactions modulate brain endothelial barrier in vitro.

The glio-vascular unit (G-unit) plays a prominent role in maintaining homeostasis of the blood-brain barrier (BBB) and disturbances in cells forming this unit may seriously dysregulate BBB. The direct and indirect effects of cytokines on cellular components of the BBB are not yet unclear. The present study compares the effects of cytokines and cytokine-treated astrocytes on brain endothelial barrier. 3-dimensional transwell co-cultures of brain endothelium and related-barrier forming cells with astrocytes were used to investigate gliovascular barrier responses to cytokines during pathological stresses. Gliovascular barrier was measured using trans-endothelial electrical resistance (TEER), a sensitive index of in vitro barrier integrity. We found that neither TNF-α, IL-1ß or IFN-γ directly reduced barrier in human or mouse brain endothelial cells or ECV-304 barrier (independent of cell viability/metabolism), but found that astrocyte exposure to cytokines in co-culture significantly reduced endothelial (and ECV-304) barrier. These results indicate that the barrier established by human and mouse brain endothelial cells (and other cells) may respond positively to cytokines alone, but that during pathological conditions, cytokines dysregulate the barrier forming cells indirectly through astrocyte activation involving reorganization of junctions, matrix, focal adhesion or release of barrier modulating factors (e.g. oxidants, MMPs).