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In inflammatory CNS conditions such as multiple sclerosis (MS), current options to treat clinical relapse are limited, and more selective agents are needed. Disruption of the blood-brain barrier (BBB) is an early feature of lesion formation that correlates with clinical exacerbation, leading to edema, excitotoxicity, and entry of serum proteins and inflammatory cells. Here, we identify astrocytic expression of VEGF-A as a key driver of BBB permeability in mice. Inactivation of astrocytic Vegfa expression reduced BBB breakdown, decreased lym-phocyte infiltration and neuropathology in inflammatory and demyelinating lesions, and reduced paralysis in a mouse model of MS. Knockdown studies in CNS endothelium indicated activation of the downstream effector eNOS as the principal mechanism underlying the effects of VEGF-A on the BBB. Systemic administration of the selective eNOS inhibitor cavtratin in mice abrogated VEGF-A-induced BBB disruption and pathology and protected against neurologic deficit in the MS model system. Collectively, these data identify blockade of VEGF-A signaling as a protective strategy to treat inflammatory CNS disease., Introduction The blood-brain barrier (BBB) acts as a selective interface insulating the CNS parenchyma from the circulation (1). It exists at the level of microvascular endothelial cells (MVECs), which restrict [...]

A genomewide linkage scan is performed using 10-cM-resolution microsatellite markers in order to identify new Meckel syndrome (MKS). The results have identified a fourth locus for MKS (MKS4) and the CEP290 gene, which are responsible for MKS.

Polysialic acid (PSA), a large cell-surface carbohydrate that regulates ceil interactions, is used during vertebrate development to promote precursor cell migration and axon path-finding. The induction of PSA expression in damaged adult CNS tissues could help them to rebuild by creating conditions permissive for architectural remodeling. This possibility has been explored in two contexts, the regeneration of axons and the recruitment of endogenous neural precursors to a lesion. Glial scars that form at CNS injury sites block axon regeneration. It has been found that transfection of scar astrocytes by a viral vector encoding polysialyltransferase leads to sustained expression of high levels of PSA. With this treatment, a substantial portion of severed corticospinal tract axon processes were able to grow through a spinal injury site. In the studies of precursor cell migration to a cortical lesion, it was found that induced PSA expression in a path extending from the subventricular zone to a lesion near the cortical surface increased recruitment of BrdU/nestin-positive ceils along the path and into the injury site. These displaced precursors were able to differentiate in a regionally appropriate manner. These findings suggest that induced PSA expression can be used as a strategy for promoting tissue repair involving both replacement of cells and rebuilding of neural connections. astrocyte | axon regeneration | brain lesions | plasticity | progenitor migration

Serotonergic and dopaminergic systems, and their functional interactions, have been implicated in the pathophysiology of various CNS disorders. Here, we use recombinant serotonin (5-HT) 2A (5-[HT.sub.2A]) receptors to further investigate direct interactions between dopamine and 5-HT receptors. Previous studies in Xenopus oocytes showed that dopamine, although not the cognate ligand for the 5-[HT.sub.2A] receptor, acts as a partial-efficacy agonist. At micromolar concentrations, dopamine also acts as a partial-efficacy agonist on 5-[HT.sub.2A] receptors in HEK293 cells. Like 5-HT, dopamine also induces receptor-internalization in these cells, although at significantly higher concentrations than 5-HT. Interestingly, if the receptors are first sensitized or 'primed' by subthreshold concentrations of 5-HT, then dopamine-induced internalization occurs at concentrations [approximately equal to]10-fold lower than when dopamine is used alone. Furthermore, unlike 5-HT-mediated internalization, dopamine-mediated receptor internalization, alone, or after sensitization by 5-HT, does not depend on PKC. Dopamine-internalized receptors recycle to the surface at rates similar to those of 5-HT-internalized receptors. Our results suggest a previously uncharacterized role for dopamine in the direct activation and internalization of 5-[HT.sub.2A] receptors that may have clinical relevance to the function of serotonergic systems in anxiety, depression, and schizophrenia and also to the treatment of these disorders. receptor priming | receptor recycling

Background: T2 hyperintensities (T2H) on MRI are the most common CNS lesions in individuals with neurofibromatosis type 1 (NF1). Objectives: The aim was to determine the frequency, signal characteristics and localization of T2H at different ages. In addition, we examined the sensitivity of different MR imaging sequences in detecting these lesions. Materials and methods: We studied prospectively a cohort of children, adolescents and young adults with NF1 using T2-volume (T2-V) and conventional MRI sequences. Lesions were designated as either discrete or diffuse, and the region of signal abnormality was recorded. A total of 103 patients were studied (age range 8.0-25.4 years, mean 13.9 years). Results: The frequency, size, and intensity of T2H decreased with age in the basal ganglia (BG) and the cerebellum/brainstem (CB/BS). The majority of thalamic and CB/BS lesions were diffuse. Of the total cohort, 80% had diffuse bilateral hippocampal hyperintensities and 18.4% had hemispheric lesions best demonstrated on FLAIR; there was no significant difference in the frequency or signal intensity of hemispheric lesions with age. Conclusion: Lesions in the cerebral hemispheres and hippocampus imaged by MR do not change in prevalence over time, suggesting a different pathological basis from the lesions in the in BG and CB/BS that resolve with age. FLAIR and T2-V sequences are more sensitive in detecting lesions than standard T2-weighted sequences. Keywords Neurofibromatosis type 1 * MRI * Hippocampus

Abstract: Magnetic Resonance Spectroscopy is based on the chemical shift property of the atom nuclei when a magnetic field is applied. This technique offers invaluable information about living tissues with [...]

Increased IgG and oligoclonal bands are found in cerebrospinal fluid of humans with chronic infectious CNS disease. Studies have shown that these oligoclonal bands are antibodies directed against the agent that causes disease. Laser-capture microdissection was used to isolate individual CD38+ plasma cells from the brain of a patient with subacute sclerosing panencephalitis, and single-cell RT-PCR was used to analyze individual IgG heavy and light chains expressed by each cell. Based on overrepresented IgG sequences, we constructed functional recombinant antibodies (recombinant IgGs) and determined their specificities. Five of eight recombinant IgGs recognized measles virus, the cause of subacute sclerosing panencephalitis. These results demonstrate that overrepresented IgG sequences in postmortem brains can be used to produce functional recombinant antibodies that recognize their target antigens. This strategy can be used to identify disease-relevant antigens in CNS inflammatory diseases of unknown etiology. oligoclonal bands | recombinant antibodies

Byline: Bao Quan Qi (1), Spencer W. Beasley (1), Dejan Arsic (1) Keywords: Anorectum; Imperforate anus; Vertebral; Rachischisis; Ethylenethiourea Abstract: Lumbosacral vertebral abnormalities are a common association of anorectal malformations (ARMs) and are one of the determinants of the eventual level of fecal continence that can be achieved. This study used a fetal rat model to investigate the spectrum of axial skeletal maldevelopment that may occur with ARMs. Time-mated pregnant rats received 125 mg/kg of 1% ethylenethiourea (ETU) (experimental group) or vehicle only (control). Their fetuses were examined for external malformations and prepared for staining of their skeletons using Alcian blue and Alizarin red S. ARMs developed in 67/68 (98%) of ETU-exposed fetuses, of which 28 (42%) also developed rachischisis, mainly involving the lumbosacral vertebrae. No skeletal abnormality was found in control fetuses. ETU-exposed fetuses with ARMs and rachischisis had abnormal ossification of the vertebral centrum, abnormal fusion between the neural arches of vertebrae, localized narrow or interrupted thoracic vertebral canal, a widely open vertebral canal in the lumbosacral area (rachischisis), and absence of the lower two sacral and coccygeal vertebrae. Rib abnormalities included absence of two to three floating ribs, abnormal fusion of adjacent proximal segments, and abnormal ramification, irregularity, and angulation of their distal segments. The vertebral and rib abnormalities found in ETU-exposed fetuses with ARMs but no rachischisis were much less severe. In addition to the lumbosacral anomalies that are common with ARMs, severe abnormalities of the thoracic vertebrae and their corresponding ribs may occur also. Fetuses with both ARM and rachischisis tend to have more extensive and severe vertebral and rib anomalies. These observations imply a possible common aetiology for ARMs and vertebral anomalies and are consistent with our understanding of the perceived role of the notochord in axial development. Author Affiliation: (1) Department of Paediatric Surgery, Christchurch Hospital, Private Bag 4710, Christchurch, New Zealand Article History: Registration Date: 29/04/2004 Accepted Date: 02/02/2004 Online Date: 16/06/2004

The central nervous system is the most vulnerable of all body systems to developmental injury. This review focuses on developmental processes by which the nervous system is formed and how those processes are known or suspected to be injured by toxic agents. The processes discussed are establishment of neuron numbers; migration of neurons; establishment of connections, neurotransmitter activity, and receptor numbers; deposition of myelin; and 2 processes that are prominent in postnatal development, trimming back of connections and postnatal neurogenesis. Our knowledge of the risks of exposure to environmental hazards in childhood and adolescence is minimal. Most of our information concerns the effects of neurotoxicants in prenatal and early postnatal life. More worrisome than our lack of data regarding later stages of development is the minimal effort that we have mounted to protect the public from known neurotoxic agents and that regulations for testing new drugs and chemicals still do not require any assessment of neuroteratologic effects. Pediatrics 2004;113:1076-1083; CNS development, teratology, critical periods, gene-environment interactions., Of all of the body systems, the central nervous system (CNS) is the one for which we have the most information on normal development and developmental injury, yet it is [...]

Byline: Dieta Brandsma (1), Gerard H. Jansen (2), Wim Spliet (3), Kathelijne Nielen (1), Martin J. B. Taphoorn (1) Keywords: meningeal or intracerebral plasma cell granuloma; Rosai-Dorfman disease; central nervous system B-cell lymphoma; meningioma; pachymeningitis Abstract: Abstract. Meningeal and intracerebral plasma cell granulomas are uncommon inflammatory lesions of unknown etiology. In this paper the diagnostic difficulties in two patients with meningeal plasma cell granuloma and one patient with intracerebral plasma cell granuloma are described. The first patient had an intracranial extra-axial lesion, which was first diagnosed as a meningioma. One and a half years later she underwent a second resection for recurrent tumor growth and the diagnosis of a meningeal plasma cell granuloma was made. The second patient was treated for a central nervous system B-cell lymphoma but proved to have an intracerebral plasma cell granuloma in retrospect 11 years later. In the third patient tuberculous meningitis was considered to be the most likely diagnosis because infratentorial contrast-enhanced thickened meninges (pachymeningitis) were found together with a high protein level in the cerebrospinal fluid and a positive Mantoux test. However, pathological examination of an extra-axial, cervical lesion that was operated upon revealed a meningeal plasma cell granuloma. These cases show the importance of diagnosing a meningeal or intracerebral plasma cell granuloma correctly, since it has both therapeutical and prognostic implications. Author Affiliation: (1) Dept. of Neurology, G03.228, University Medical Center Utrecht, 85500, 3584 CX, Utrecht, The Netherlands (2) Dept. of Laboratory, Medicine Ottawa, Ontario, Canada (3) Dept. of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands Article History: Registration Date: 01/01/2003 Received Date: 30/01/2003 Accepted Date: 24/06/2003

Byline: Rolf-Detlef Treede (1) Keywords: laser evoked potentials; somatosensory system; touch; pain; temperature; sensory testing Abstract: Abstract. Standard clinical neurophysiological assessment of somatosensory pathways by sensory evoked potentials (SEPs) is limited to the tactile and proprioceptive systems consisting of large fibers in the peripheral nerve, the dorsal columns of the spinal cord and the medial lemniscus in the brainstem. This limitation means that about half of the lesions in the somatosensory system will not be detectable. In recent years, many clinical studies have confirmed that laser evoked potentials (LEPs) allow the assessment of the other half of the somatosensory system. Rapid heating of the skin by infrared laser pulses specifically activates the nociceptive and thermoreceptive pathways consisting of small fibers in the peripheral nerve and the anterolateral spinothalamic tract in the spinal cord and brainstem. Owing to the large degree of convergence of the somatosensory pathways on to common thalamic nuclei, the differential use of LEP vs. SEP is less evident for thalamocortical lesions. In contrast to standard SEPs, the LEP technique can be applied to non-glabrous skin in any dermatome. This review summarizes the principles of clinical neurophysiological studies of pain pathways and the findings obtained in patients with peripheral and central nervous system disorders. These data provide a rational basis for developing clinical indications for LEP testing. Author Affiliation: (1) Institute of Physiology and Pathophysiology, Johannes Gutenberg-University, Saarstr. 21, 55099, Mainz, Germany Article History: Received Date: 17/07/2003 Accepted Date: 23/07/2003

Byline: Takaki Emura (1), Kohei Hashizume (1), Makoto Asashima (2) Keywords: Split notochord syndrome Gastrointestinal duplication Enteric cyst Split cord malformation Embryogenesis Abstract: The theory of gastrointestinal duplication and enteric cyst embryogenesis was verified by examining the developmental process of this experimentally induced anomaly. In Cynopus pyrrhogaster (amphibian) embryos (stage 18), the dorsal midline structures (including the neural plate and notochord) were split regionally to induce partial separation of the notochord and gut anlage endoderm herniation between the split elements of the notochord. Following this procedure, the embryonic development was traced morphologically and histologically. Control embryos were cultured without the procedure. Following the incubation and breeding period, gastrointestinal duplication and enteric cysts were observed with vertebral anomaly, spina bifida, split cord malformation and subcutaneous manifestations in the mature animals. The combination of anomalies that was observed in these experimental animals is consistent with that found in 'split notochord syndrome.' No abnormal morphology or histology was observed in the control group. The embryogenetic theory of gastrointestinal duplication and enteric cysts was thus verified by simulating the partial separation of the notochord, which induced split notochord syndrome in laboratory animals. The results indicate that gastrointestinal duplication and enteric cysts may arise through a process of herniation of the gut anlage endoderm between split elements of the notochord. Author Affiliation: (1) Department of Pediatric Surgery, Graduate School of Medicine, University of Tokyo, Tokyo, Japan (2) Department of Life Science, CREST Project, Graduate School of Arts and Sciences, University of Tokyo, Tokyo, Japan Article note: Electronic Publication

Byline: E. G. Potyagailo (1), V. M. Pokrovskii (1) Abstract: Parameters of cardiorespiratory synchronization were determined in children with different types of nervous system, under conditions of psychoemotional stress and in gastrobiliary disease. These parameters were found to be significant in characterizing the regulatory and adaptive potential of children. Author Affiliation: (1) Kuban' State Medical Academy, ul. Sedina 4, Krasnodar, 350640, Russia Article History: Registration Date: 11/10/2004

Neurocysticercosis appears to be on the rise in the United States, based on immigration patterns and published cases series, including reports of domestic acquisition. We used a collaborative network of [...]

Byline: V. A. Ilyukhina (1), N. Yu. Kozhushko (1), Yu. K. Matveev (1), V. M. Shaitor (2) Abstract: Central disorders that determine a decrease in stress resistance and compensatory-adaptive possibilities of six- to eight-year-old children with remote consequences of a perinatal hypoxic-ischemic CNS injury were comprehensively characterized on the basis of literature data and results of the complex psychophysiological and neurophysiological examination using complementary integral indices. The main factors responsible for constraints of adaptive possibilities of such children at a preschool age and aggravation of the central regulatory disorders during the transition to school period of their life were revealed. Author Affiliation: (1) Institute of the Human Brain, Russian Academy of Sciences, ul. Akad. Pavlova 9, St. Petersburg, 197022, Russia (2) Medical Academy of Postgraduate Education, Russian Ministry of Public Health, St. Petersburg, Russia Article History: Registration Date: 12/10/2004

Disruption of the tight junctions (TJs) of the blood-brain barrier (BBB) is a hallmark of many CNS pathologies, including stroke, HIV encephalitis, Alzheimer's disease, multiple sclerosis and bacterial meningitis. Furthermore, systemic-derived inflammation has recently been shown to cause BBB tight junctional disruption and increased paracellular permeability. The BBB is capable of rapid modulation in response to physiological stimuli at the cytoskeletal level, which enables it to protect the brain parenchyma and maintain a homeostatic environment. By allowing the `loosening' of TJs and an increase in paracellular permeability, the BBB is able to `bend without breaking'; thereby, maintaining structural integrity.

Abstract A few patients with an affected CNS involving abnormalities in copper metabolism have been described that do not fit any known nosological entities such as Wilson's disease or Menkes' [...]

Byline: N. A. Losseff (1), L. Wang (1), D. H. Miller (1), A. J. Thompson (1) Keywords: Key words Multiple Sclerosis; MRI; Spinal Cord; Disability; T1 hypointensity Abstract: It has recently been shown in multiple sclerosis (MS) that the volume of T1 hypointense lesions in the brain explains more of the variance in disability amongst patients than T2 lesion volume. T1 hypointense lesions may therefore represent areas of underlying pathology likely to be of functional significance, such as axonal loss. The spinal cord is a common area of involvement in MS and its dysfunction is likely to be responsible for much of the motor disability seen. Hence it serves as a useful model by which to examine the functional relevance of differing imaging sequences. We have therefore examined the relationship between T1 signal intensity in the spinal cord and disability in 60 patients with MS. We have also examined the relationship between T1 signal intensity and atrophy of the cord, as the latter is another potential marker of axonal loss. Sixty patients with MS underwent spinal cord imaging with a T1 weighted sequence to acquire axial sections of the cord at the C2 level. These sections were histogram matched to allow comparison of image intensity and a manual outlining technique was applied from which the mean cord intensity was calculated. Within the patient group there was a significant relationship between T1 signal intensity and disability as measured with the EDSS (r = -0.4, p &lt 0.005) and also between T1 signal intensity and atrophy (r = 0.36, p &lt 0.005). This study demonstrates that disability and atrophy are associated with a generalised reduction in cord signal on T1 weighted images. A lower T1 signal intensity in the spinal cord may be more pathologically specific than T2 hyperintensity and may represent underlying axonal loss, although gliosis and predominant white matter atrophy are alternative possibilities. Author Affiliation: (1) NMR Research Unit, Institute of Neurology, Queen Square, London WC1N 3BG, UK Tel.: +44-0171-8373611 ext 4152 Fax: +44-0171-8136505, GB Article note: Received: 7 April 2000, Received in revised form: 29 December 2000, Accepted: 10 January 2001

Byline: Erich Schmutzhard (1) Keywords: Key words Viral encephalitis; Herpesviridae Abstract: Within the past decade the management of acute HSV I encephalitis has been improved dramatically by the advent of the polymerase chain reaction (PCR), a method which has become the gold standard of diagnosis of HSV I encephalitis, replacing diagnostic uncertainties and, avoiding, in particular, invasive brain biopsy. Early detection of HSV II in the neonate is mandatory however, prevention by Caesarean section and/or prenatal therapy of the mother are for this the best option. Very recently the causative agent of Mollaret's meningitis has proved to be, at least in part, HSV I or II. So far prospective randomized therapeutic trials are awaited for the treatment of Mollaret's meningitis using intravenous acyclovir or the more modern oral forms of virostatics (famciclovir, valaciclovir). For decades the causative agent of facial palsy (Bell's palsy) has been sought only with the advent of PCR has this question been answered. Although one single study indicates the superiority of a combination of acyclovir plus prednisone, this finding has to be confirmed by a large scale prospective randomised double blind study. Nevertheless, if other causes for the clinical/neurological syndrome of peripheral facial palsy have been excluded, a combination therapy with acyclovir plus prednisone seems to be indicated in a patient with Bell's palsy. Author Affiliation: (1) Department of Neurology, University Hospital Innsbruck, Anichstrasse 35, 6020 Innsbruck, Austria Tel.: +43-512504-3853 Fax: +43-512504-4243 e-mail: erich.schmutzhard@uibk.ac.at, AT Article note: Received: 2 February 2001, Accepted: 8 February 2001

Byline: Brigitte Wildemann (1), Olav Jansen (2), Juergen Haas (1), Maria-Elisabeth Vogt-Schaden (1), Brigitte Storch-Hagenlocher (1) Keywords: Key words Demyelinating disease; Central nervous system lymphoma; Polymerase chain reaction; Complementarity determining region 3IgH; Gene scanning Abstract: Polymerase chain reaction (PCR) based automated high-resolution fragment analysis of rearranged immunoglobulin heavy-chain genes is a highly sensitive means for identifying clonal B-cell responses. We used this technique to distinguish polyclonal inflammatory from monoclonal neoplastic B-cell populations in the cerebrospinal fluid (CSF) of three patients with acute demyelinating disorders of the central nervous system whose clinical, magnetic resonance imaging (MRI) and CSF features did not permit unequivocal exclusion of primary central nervous system lymphoma (pC-NSL). This approach is highly suitable for detecting CNS inflammation particularly when lymphomatous involvement cannot be ruled out by noninvasive diagnostic procedures alone. Author Affiliation: (1) Department of Neurology, University of Heidelberg, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany, Tel.: +49-62 21-56 75 04, Fax: +49-62 21-56 54 61, e-mail: brigitte_wildemann@med.uni-heidelberg.de, DE (2) Department of Neuroradiology, University of Heidelberg, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany, DE Article note: Received: 31 May 2000 / Received in revised form: 14 August 2000 / Accepted: 22 August 2000

Byline: M. Gary Hadfield (1), Martha M. Quezado (1), Robert L. Williams (2), Vivian Y. Luo (2) Keywords: Key words: central nervous system, Ewing's family of tumors, prognosis and treatment, molecular pathology and genetics Abstract: This review consolidates information gleaned from several case reports and larger series on Ewing's sarcoma family of tumors (EFT) involving structures related to and found in the central nervous system (CNS). These tumors involve the skull, the spinal column, adjacent soft tissues, the meninges, and the brain. We have separated the cases by skull region and spinal column level, and we discuss the attendant differences in prognosis following treatment by neurosurgery, radiation, and chemotherapy. Light and electron microscopic features can be used to differentiate EFT from other small round blue cell tumors that involve the CNS (central primitive neuroectodermal tumor, lymphoma, etc.). Recent molecular and genetic findings in EFT provide new diagnostic methods. We conclude that EFT involving the CNS and adjacent structures is not so rare as previously stated and that the prognosis is more favorable, as a rule, than for the more common examples arising in the long bones and pelvis. Author Affiliation: (1) Division of Neuropathology, Medical College of Virginia Campus/Virginia Commonwealth University, Richmond, VA 23298, USA, US (2) Department of Pathology, Medical College of Virginia Campus/Virginia Commonwealth University, Richmond, VA 23298, USA, US Article note: Received February 3, 1999 accepted November 22, 1999.

The pathogenesis of tuberculous meningitis, a devastating complication of tuberculosis in man, is poorly understood. We previously reported that rabbits with experimental tuberculous meningitis were protected from death by a combination of antibiotics and thalidomide therapy. Survival was associated with inhibition of tumor necrosis factor c[Alpha] (TNF-[Alpha]) production by thalidomide. To test whether cerebrospinal fluid (CSF) levels of TNF-[Alpha] correlated with pathogenesis, the response of rabbits infected in the central nervous system (CNS) with various mycobacteriai strains was studied. CNS infection with Mycobacterium bovis Ravenel, M. bovis bacillus Calmette-Guerin (BCG) Pasteur, and M. bovis BCG Montreal were compared. M. bovis Ravenel induced the highest levels of TNF-[Alpha] in the CSF in association with high leukocytosis, protein accumulation, and severe meningeal inflammation. BCG Pasteur had intermediate effects, and BCG Montreal was the least virulent. In addition, M. bovis Ravenel numbers were highest in the brain and CSF and the bacilli also disseminated more efficiently to distant organs, compared with BCG Pasteur and BCG Montreal. In subsequent experiments, rabbits were infected with either recombinant M. bovis BCG Montreal (vector), or BCG Montreal expressing the murine gene for TNF-[Alpha] (BCG mTNF-[Alpha]). BCG Montreal was rendered virulent by the expression of murine TNF-[Alpha], as demonstrated by high CSF leukocytosis, high protein accumulation, severe meningeal inflammation, persistent bacillary load, and progressive clinical deterioration. Taken together, these results demonstrate that the level of TNF-[Alpha] produced during mycobacterial CNS infection determines, at least in part, the extent of pathogenesis.

Feline immunodeficiency virus (FIV) is a lentivirus of domestic cats that causes a spectrum of diseases remarkably similar to AIDS in HIV-infected humans. As part of this spectrum, both HIV-1 and FIV induce neurologic disorders. Because astrocytes are essential in maintaining the homeostasis of the central nervous system, we analyzed FIV for the ability to infect feline astrocytes. Through immunocytochemistry and reverse transcriptase activity, it was demonstrated that two molecular clones of FIV (FIV-34TF10 and FIV-PPR) produce a chronic low level productive infection of feline astrocyte cultures. To investigate the consequences of this infection, selected astrocyte functions were examined. Infection with FIV-34TF10 significantly decreased the ability of astrocytes to scavenge extracellular glutamate (with a peak inhibition of 74%). The effects of the infection did not appear to be a result of toxicity but rather were more selective in nature because the glucose uptake function of the infected astrocyte cultures was not altered. Our data demonstrate that FIV productively infected, at a low level, feline astrocyte cultures, and as a consequence of this infection, an important astroglial function was altered. These findings suggest that a chronic low grade infection of astrocytes may impair the ability of these cells to maintain homeostasis of the central nervous system that, in turn, may contribute to a neurodegenerative disease process that is often associated with lentivirus infections.

Immortalized multipotent neural stem and progenitor cells have emerged as a highly convenient source of tissue for genetic manipulation and ex vivo gene transfer to the CNS. Recent studies show that these cells, which can be maintained and genetically transduced as cell lines in culture, can survive, integrate and differentiate into both neurons and glia after transplantation to the intact or damaged brain. Progenitors engineered to secrete trophic factors, or to produce neurotransmitter-related or metabolic enzymes can be made to repopulate diseased or injured brain areas, thus providing a new potential therapeutic tool for the blockade of neurodegenerative processes and reversal of behavioural deficits in animal models of neurodegenerative diseases. With further technical improvements, the use of immortalized neural progenitors may bring us closer to the challenging goal of targeted and effective CNS repair.

Bovine spongiform encephalopathy (BSE) and human Creutzfeldt-Jakob disease (CJD) are among the most notable central nervous system degenerative disorders caused by priors. CJD may present as a sporadic, genetic, or infectious illness. Prions are transmissible particles that are devoid of nucleic acid and seem to be composed exclusively of a modified protein ([PrP.sup.Sc]). The normal, cellular prion protein ([PrP.sup.C]) is converted into ([PrP.sup.Sc]) through a posttranslational process during which it acquires a high Β-sheet content. It is thought that BSE is a result of cannibalism in which faulty industrial practices produced prior-contaminated feed for cattle. There is now considerable concern that bovine prions may have been passed to humans, resulting in a new form of CJD., During the past two decades, a previously unknown mechanism of disease has been described in humans and animals. Several fatal illnesses, often referred to as the prion diseases and including [...]

We have studied T-cell apoptosis in animal models of human autoimmune disorders of the nervous system and in other tissues devoid of specialized immune-defense mechanisms. Our data suggest that the CNS has high potential for elimination of T-cell-dependent inflammation, whereas this mechanism is less effective in the PNS, and is almost absent in other tissues such as muscle and skin. Interestingly, several conventional and novel immunotherapeutic approaches, such as glucocorticosteroid and high-dose antigen therapy, induce T-cell apoptosis in situ. In vitro experiments suggest different scenarios for the mechanisms by which specific cellular and humoral elements in the nervous system synergize and sensitize T cells for apoptosis in vivo. We also discuss regulatory, proapoptotic mechanisms, such as the Fas-FasL system and galectin-I, that have been utilized in other tissues to mediate immune protection.

Immune cells invading the central nervous system (CNS) in response to Borna disease virus (BDV) antigens are central to the pathogenesis of Borna disease (BD). We speculate that the response of the resident cells of the brain to infection may be involved in the sensitization and recruitment of these inflammatory cells. To separate the responses of resident cells from those of cells infiltrating from the periphery, we used dexamethasone to inhibit inflammatory reactions in BD. Treatment with dexamethasone prevented the development of clinical signs of BD, and the brains of treated animals showed no neuropathological lesions and a virtual absence of markers of inflammation, cell infiltration, or activation normally seen in the CNS of BDV-infected rats. In contrast, treatment with dexamethasone exacerbated the expression of BDV RNA, which was paralleled by a similarly elevated expression of mRNAs for egr-1, c-fos, and c-jun. Furthermore, dexamethasone failed to inhibit the increase in expression of mRNAs for tumor necrosis factor [Alpha], macrophage inflammatory protein 1[Beta], interleukin 6, and mob-1, which occurs in the CNS of animals infected with BDV. Our findings suggest that these genes, encoding transcription factors, chemokines, and proinflammatory cytokines, might be directly activated in CNS resident cells by BDV. This result supports the hypothesis that the initial phase of the inflammatory response to BDV infection in the brain may be dependent upon virus-induced activation of CNS resident cells.

Cytokines are now recognized to play important roles in the physiology of the central nervous system (CNS) during health and disease. Tumor necrosis factor a (TNF-[alpha]) has been implicated in the pathogenesis of several human CNS disorders including multiple sclerosis, AIDS dementia, and cerebral malaria. We have generated transgenic mice that constitutively express a murine TNF-[alpha] transgene, under the control of its own promoter, specifically in their CNS and that spontaneously develop a chronic inflammatory demyelinating disease with 100% penetrance from around 3-8 weeks of age. High-level expression of the transgene was seen in neurons distributed throughout the brain. Disease is manifested by ataxia, seizures, and paresis and leads to early death. Histopathological analysis revealed infiltration of the meninges and CNS parenchyma by [CD4.sup.+] and [CD8.sup.+] T lymphocytes, widespread reactive astrocytosis and microgliosis, and focal demyelination. The direct action of TNF-[alpha] in the pathogenesis of this disease was confirmed by peripheral administration of a neutralizing anti-murine TNF-[alpha] antibody. This treatment completely prevented the development of neurological symptoms, T-cell infiltration into the CNS parenchyma, astrocytosis, and demyelination, and greatly reduced the severity of reactive microgliosis. These results demonstrate that overexpression of TNF-[alpha] in the CNS can cause abnormalities in nervous system structure and function. The disease induced in TNF-[alpha] transgenic mice shows clinical and histopathological features characteristic of inflammatory demyelinating CNS disorders in humans, and these mice represent a relevant in vivo model for their further study.

Byline: Satish. Khadilkar, Ashish. Bhutada, Chetan. Chaudhari, Vernon. Velho, Shilpa. Domkundwar, Girish. Muzumdar Mrs. G.S., a 45-year-old lady, presented with 3 month history of throbbing, continuous bilateral headaches. She developed [...]

Protease Nexin-II (Amyloid β-Protein Precursor): A Platelet α-Granule Protein THE AMYLOID β-PROTEIN IS A 4.2-kD peptide that is deposited in neuritic plaques and the cerebrovascullature in Alzheimer's disease, Down syndrome, [...]

Author(s): Claude P. Genain [1]; Scott S. Zamvil [1] In the late 1980s, neuroimmunologists used the concept of major histocompatibility complex (MHC)-restricted T-cell recognition of antigens to define the immunopathogenesis [...]

Significant progress has been made over recent years in identifying the genetic features of some diseases of the central nervous system and in understanding pathogenic mechanisms. It should eventually be possible to establish new therapeutic targets and to design new treatments. Researchers are now using model systems for molecular and cell biological investigations of pathogenic mechanisms and to identify new therapeutic targets. These models will be used to test new drugs.

Bacterial meningitis is a disease primarily affecting children two years of age or younger. The condition is rare in older children, who account for approximately four percent of all cases. An ll-year study was performed to review the characteristics of the disease in 25 previously healthy children who were six years of age or older. The most significant neurological symptoms were headache, altered consciousness, and neck pain. Other symptoms included nuchal rigidity (abnormal stiffness of the neck with pain and spasm on passive motion), lethargy, somnolence (sleepiness), petechiae (skin spots); less frequently noted were stupor or coma. Eleven of the patients had no fever when they were first examined. In the 22 patients who survived, any fever that was present responded to antibiotics, either immediately or within 48 hours. The organisms primarily responsible for the disease were Haemophilus influenzae type B (10 cases); Neisseria meningitides (9 cases) and streptococcus pneumoniae (6 cases). (Consumer Summary produced by Reliance Medical Information, Inc.)

The article presents the neuron-glial interactions in blood brain barrier of invertebrates and vertebrates and evolvement into an endothelial barrier system. More research is suggested for the blood brain barrier in treatment of central nervous system diseases.

Although multiple metabotropic glutamate (mglu) receptor subtypes were cloned in the early 1990s, progress in the characterization of these receptors has been slow because of difficulties in obtaining subtype-selective ligands. However, in the past few years exciting progress has been made on the [mglu.sub.5] receptor subtype following the identification of selective non-amino-acid-like ligands that implicate the [mglu.sub.5] receptor as a potentially important therapeutic target, particularly for the treatment of pain and anxiety.

Schizophrenia is a serious brain disease of uncertain etiology. A role for retroviruses in the etiopathogenesis of some cases of schizophrenia has been postulated on the basis of clinical and epidemiological observations. We found sequences homologous to retroviral pol genes in the cell-free cerebrospinal fluids (CSFs) of 10 of 35 (29%) individuals with recent-onset schizophrenia or schizoaffective disorder. Retroviral sequences also were identified in the CSFs of 1 of 20 individuals with chronic schizophrenia. However, retroviral sequences were not identified in any of the CSFs obtained from 22 individuals with noninflammatory neurological diseases or from 30 individuals without evidence of neurological or psychiatric diseases ([chi square] = 19.25, P [is less than] 0.001). The nucleotide sequences identified in the CSFs of the individuals with schizophrenia or schizoaffective disorder were related to those of the human endogenous retroviral (HERV)-W family of endogenous retroviruses and to other retroviruses in the murine leukemia virus genus. Transcription of RNA homologous to members of the HERV-W family of retroviruses also was found to be up-regulated differentially in the frontal cortex regions of brains obtained postmortem from individuals with schizophrenia, as compared with corresponding tissue from individuals without psychiatric diseases. The transcriptional activation of certain retroviral elements within the central nervous system may be associated with the development of schizophrenia in at least some individuals. The further characterization of retroviral elements within the central nervous system of individuals with schizophrenia might lead to improved methods for the diagnosis and management of this disorder.

In 1988, the World Health Assembly resolved that by the year 2000 paralytic poliomyelitis would be wiped off the face of the Earth. The global eradication campaign is now moving [...]

Perinatal exposure to infectious agents and toxins is linked to the pathogenesis of neuropsychiatric disorders, but the mechanisms by which environmental triggers interact with developing immune and neural elements to create neurodevelopmental disturbances are poorly understood. We describe a model for investigating disorders of central nervous system development based on neonatal rat infection with Borna disease virus, a neurotropic noncytolytic RNA virus. Infection results in abnormal righting reflexes, hyperactivity, inhibition of open-field exploration, and stereotypic behaviors. Architecture is markedly disrupted in hippocampus and cerebellum, with reduction in granule and Purkinje cell numbers. Neurons are lost predominantly by apoptosis, as supported by increased mRNA levels for pro-apoptotic products (Fas, caspase-1), decreased mRNA levels for the anti-apoptotic bcl-x, and in situ labeling of fragmented DNA. Although inflammatory infiltrates are observed transiently in frontal cortex, glial activation (microgliosis [is greater than] astrocytosis) is prominent throughout the brain and persists for several weeks in concert with increased levels of proinflammatory cytokine mRNAs (interleukins 1[Alpha], 1[Beta], and 6 and tumor necrosis factor [Alpha]) and progressive hippocampal and cerebellar damage. The resemblance of these functional and neuropathologic abnormalities to human neurodevelopmental disorders suggests the utility of this model for defining cellular, biochemical, histologic, and functional outcomes of interactions of environmental influences with the developing central nervous system.

After damage to the central nervous system (CNS), patients will usually undergo a period of rehabilitation on the assumption that many repeats of a behavior will instruct the CNS to [...]

Wollerian degeneration of the inferior cerebellar peduncle has never been demonstrated on imaging studies. We describe a case in which it was depicted by thin slice diffusion weighted imaging. Location [...]