Italiano Farmacia on line: comprare cialis senza ricetta, acquistare viagra internet.

N81067.qxd

Acta Neuropathol (2005) zzz:zzz–zzzDOI 10.1007/s00401-005-1067-8 50th Annual Meeting of the German Society of Neuropathology and Neuroanatomy Clinical Neuropatology – State of the Art Graz, Austria, October 5–8, 2005President: Reinhold Kleinert Regression of synapses in the cerebellar dentate nucleus
Olfactory pathology in aging and Alzheimer disease
of patients with multiple sclerosis
Johannes Attems, Kurt A. Jellinger, Felix Lintner Albert M1, Antel J2, Prineas JA3, Palkovits M4, Wolff JR5, Institute of Clinical Neurobiology, A-1070 Vienna, Austria Brück W1, Stadelmann C11 Department of Neuropathology, Georg August University Goet- Background: Hyposmia is a common feature in Alzheimer (AD) tingen, Germany; 2Department of Neurology and Neurosurgery, and Parkinson disease (PD). threads/neurofibrillary tangles McGill University Montreal, Canada; 3Institute of Clinical Neuro- (NTs/NFTs), plaques (SPs) and α-synuclein (AS) lesions occur- sciences, Department of Medicine, University of Sydney, Australia; ring in their olfactory system (OS). Material and methods: 185 4Department of Anatomy, Histology and Embryology, Semmel- autopsy cases (113 female, 92 male, aged 55-103, mean 83.5±8.66 weis University Budapest, Hungary; 5Center of Anatomy, Georg SD years) underwent semiquantitative assessment of tau and AS in the olfactory bulb/nerve and AD using established criteria in-cluding Braak staging. Seven were PD (n=3) with dementia (PDD; Multiple sclerosis (MS) is characterised by a relapsing-remitting n=4). Results: All definite AD cases (Braak stages 5/6; n=57) re- disease course that eventually leads to cumulative motor and sen- vealed large numbers of NT and NFT (tau scores 3-6), amyloids in sory deficits. Recent studies demonstrated focal demyelination of 42% in the OS. Braak stages 4 (n=46), 3 (n=41) and 2 (n=19) cortical areas including the motor cortex in patients with chronic showed olfactory tau in 89, 41.5, and 26.5%, respectively (de- MS. Our study aimed at investigating the synaptic contacts in the creasing OS tau scores (0.5-1.0 in Braak stage 2), with amyloid cerebellar dentate nucleus, one of the relay stations of the cerebel- deposits in 4%. Braak stages 0/1 (n=22) were all negative. The OS lar motor control. Density and morphology of synapses were in- tau scores showed highly significant correlations with neuritic vestigated in post-mortem brain tissue samples from longstanding Braak stages; both scores showed significant but low correlations MS patients by light and electron microscopy. with age. All PD brains showed olfactory AS-pathology; PDD 9/18 MS patients examined harboured demyelinated lesions in (Braak 4-5) had moderate, PD no tau lesions. Conclusion: Our the dentate nucleus. The density of synapses was determined by data confirm previous studies demonstrating abundant tau patholo- synaptophysin (SYN) immunhistochemistry and counting of SYN- gy in the OS in all definite AD cases, in two-thirds of limbic AD, positive clusters on the soma membrane of dentate neurons. There and in over a quarter in MCI or nondemented elderly (Braak stage was a substantial loss of axosomatic synaptic contacts in all MS 2). Olfactory and limbic systems are strongly correlated, both with patients examined. Synapses on the stem and peripheral dendrites, similar increase in severity. Clinical dementia correlated with both however, appeared well preserved. Subpopulations of neurons Braak and OS tau scores. In single cases of severe AD, tau de- were affected to a variable degree. Dissociation of boutons from posits were observed in olfactory mucosa, while olfactory AS pa- the soma membrane occurred irrespective of the lesional border; moreover it could be found in sections, where no demyelinated le-sions were recognised. Sections processed for electron microscopyrevealed synaptic stripping. Neuron loss and axonopathy in transgenic mouse models
In summary, we found evidence for regression of synaptic con- for Alzheimer disease
tacts in the cerebellar dentate nucleus. Detachment of synapses Thomas A. Bayer, Oliver Wirths, Christoph Schmitz, seems to be synapse selective, neuron selective, and presumably André Delacourte, Luc Buée, Joachim Weis region selective. Synaptic degradation also occurs outside of the Universität des Saarlandes Psychiatrie, Abtl. Neurobiologie 66421 demyelinated area. Electron microscopy reveals synaptic stripping as a mechanism of synapse elimination. Our data indicate that syn-aptic degradation takes place in patients with long standing MS.
Accumulating evidence points to an important role of intraneu-ronal Aß in Alzheimer’s disease (AD). A major problem with theprevailing ß-amyloid hypothesis is the lack of correlation betweenneuron loss and plaque load in AD brain. Transgenic animal mod-els overexpressing human mutant amyloid precursor protein(APP) producing numerous plaques in an age-dependent mannerexhibit no significant or only mild neuron loss. We investigatedbi- transgenic mice expressing human mutant amyloid precursor protein APP751 (KM670/671NL and V717I) and presenilin-1 S100 and 42% of metastatic adenocarcinomas are S100-positive.
(overexpressing M146L; or knocked-in M233T and L235P muta- We thus investigated 28 CPT (13 male, 15 female; 0.4-70 years; tions, PS1KI) showing a marked elevation in Aß42 levels. The ra- mean age 33.9 years) including 21 choroid plexus papillomas tio of Aß42 to total Aß is: 0.2 in APP751SL, 0.4 in APP751SLx- (CPP), 4 atypical CPP and 3 choroid plexus carcinomas (CPC) PS1M146L and 0.85 in APP751SLxPS1KI mice at 3 months of regarding their expression of the excitatory amino acid trans- age. Hippocampal neuron loss was only observed in APP751SLx- porter-1 (EAAT-1). Additionally, 38 metastatic carcinomas (24 PS1M146L at 16 months of age (25%) and in APP751SLxPS1KI male, 14 female; 47-80 years; mean age 61 years) deriving from at 10 months of age (50%). In the spinal cord, prominent axonopa- different organs were examined. EAAT-1 expression in CPT was thy like axonal dilatations, spheroids (immunohistochemically significantly age-dependent with the proportion of EAAT-1 immu- positive for neurofilament, APP and ubiquitin). Electron micros- noreactive tumor cells increasing with age, but not sex-dependent.
copy revealed distended axons containing condensed fibrils, fila- However, there was a significant difference between EAAT-1 ments and organelles, remyelinated axons and degenerated axons.
expression in CPT and in metastatic carcinomas even if pediatric Intraneuronal Aß accumulation has again be observed to precede CPT were included. 22/28 CPT (78%) but none of the metastatic plaque formation in axonopathy also in spinal cord. As has been carcinomas expressed EAAT-1. However, numbers and distribu- shown in Tau transgenic mice, the bigenic mice in the present tion of EAAT-1-positive cells in CPT varied. 12/28 CPT (43%) study also have motoric deficits. These mouse models clearly indi- showed immunoreactivity in less than 10% of tumor cells. All cate that axonopathy and neuron loss is independent from extra- atypical CPP and 2/3 CPC expressed EAAT-1 but one atypical cellular amyloid deposition and identifies intraneuronal Aß as a CPP and two CPC showed less than 10% immunoreactive tumor major neurotoxic risk factor for the integrity of neurons.
cells. Our findings indicate that the vast majority of CPT showsEAAT-1 immunoreactivity, especially in adult cases. Thus, EAAT-1may be useful in differentiating CPT from metastatic carcinomas.
A novel bispecific small molecule tyrosine kinase inhibitor
enhances the effects of an experimental radiotherapy in
human malignant glioma cells

Neuropathologisches Epilepsie-Register: Update 2005
S. Berezowska (1), A. Grosu (2) and J. Schlegel (1) (1) Division of Neuropathology, TU München and GSF-Forschungs- Universität Erlangen, Neuropathologie, 91054 Erlangen zentrum Neuherberg; (2) Department of Radiotherapy, TU München.
In Deutschland, Österreich und der Schweiz werden im Jahr It has been shown previously that human glioblastomas co- ca. 500 Epilepsie-chirurgische Behandlungen durchgeführt. Allen expresses EGFR and HER2 receptors. We hypothesize that target- Epilepsie-chirurgischen Operation wird ein extensives prächirurgi- ed blockade of EGFR/HER2 heterodimeric receptor complexes sches Monitoring zur Definition des epileptogenen Areals und den will prove to be an attractive and valuable therapeutical approach.
möglichen postoperativen kognitiven Leistungseinbußen vorange- Two cell lines derived from primary human glioblastomas with stellt. Die histopathologische Untersuchung dieser zum Teil sehr different amounts of EGFR and HER2 receptors were treated with ausgedehnten Resektate stellt eine besondere Herausforderung für novel bispecific small molecule TKIs (kindly provided by den Neuropathologen dar, da das Spektrum der Läsionen vielfältigNOVARTIS) and Tyrphostin AG1478 in equimolar concentra- ist, detaillierte klinisch-neuropathologische Verlaufsuntersuchun- tions, and irradiated with a single dose of 6 Gy. The three TKI gen kaum verfügbar sind und international keine einheitlichen showed different effects on proliferation and clonogenic survival Klassifikationsschemen und Bewertungskriterien vorliegen. Für in the cell lines examined. Proliferation of LN229 cells was effi- die systematische Erforschung von Ursachen pharmakoresistenter, ciently and uniformly blocked at low concentrations, whereas fokaler Epilepsien sowie der Etablierung einheitlicher histopatho- growth inhibition of LN18 cells was achieved at substantially logischer Kriterien wurde im Mai 2003 ein neuropathologisches higher concentrations only. Bispecific TKI proved significantly Epilepsie-Register eingerichtet. Mit der Arbeit des Epilepsie-Re- more efficient than AG1478. We have attributed the differing ef- gisters, welchem Ärzte und Wissenschaftler aus den Fachdiszipli- fects of the three TKI to their distinct inhibition of EGFR and nen Neuropathologie, Neurologie, Neuropädiatrie, Neurochirurgie HER2, respectively. The immediate response of LN229 cells to all und Neuroradiologie angehören, verbinden sich folgende Ziele: three TKI can be explained by their early arising inability to form 1. Einrichtung einer Gewebe- und Datenbank zur einheitlichen heterodimers after their comparably low number of EGFR has Dokumentation Epilepsie-chirurgischer Resektate. 2. kostenloser been inhibited. LN18 cells are quite resistant to EGFR inhibition referenzpathologischer Konsiliardienst für die DGNN. 3. Regel- due to their higher levels of EGFR, but experience drastic effects mäßige Fortbildungsveranstaltungen und Workshops. Die 2750 after their comparably low amount of HER2 receptors is inhibited bislang erfassten Fälle gliedern sich wie folgt: Hippocampusskle- and thus shut off from heterodimerisation with EGFR, at higher rose: 896; Fehlbildungen: 350; Epilepsie-assoziierte Tumoren concentrations of bispecific TKI. Taken together our results indi- (LEAT): 810; duale Pathologie: 137; Enzephalitis: 45; Glianarben: cate the importance of EGFR/HER2 heterodimeric receptor com- 150; vaskuläre Läsionen: 162; in 200 Fällen konnte keine eindeu- plexes for cell proliferation and survival.
tige Pathologie festgestellt werden. Wir danken den einsendendenKollegen aus Bonn (PD Dr. Becker), Bielefled-Bethel (PD Dr.
Hans), Freiburg (Prof. Volk), Berlin (Prof. von Deimling), Greifs- Choroid plexus tumors differ from metastatic carcinomas
wald (Prof. Warzock), Göttingen (Prof. Brück), Würzburg (Prof.
by expression of EAAT-1
Roggendorf); Köln (Perof. Deckert), Münster (Prof. Paulus), und R. Beschorner, J. Schittenhelm, J.R. Iglesias-Rozas, T. Herberts, München (Prof. Kretzschmar) für Ihre Unterstützung. Das Epilep- H. Schimmel, H. Schlaszus1, R. Meyermann, M. Wehrmann sie-Register ist für registrierte Benutzer online verfügbar unterwww.epilepsie-register.de.
Institut für Hirnforschung, 72076 Tübingen Tumors of the choroid plexus (CPT) are rare neoplasm’s of neuro-ectodermal origin usually arising in pediatric cases. However,CPT may occur at any age and their distinction from metastaticcarcinomas is often difficult in adult cases. Frequently, S100 im-munoreactivity is designated to distinguish CPT from metastaticcarcinomas. However up to 56% of CPT has been reported to lack Spinocerebellar ataxias (SCA): evidence for microglial
Hypermethylation and reduced expression of SOCS-1
activation
in pituitary adenomas
1K. Bürk, 1M. Mittelbronn, 2R. de Vos, 3J. Büttner-Ennever, R. Buslei, J. Kreutzer, B. Hofmann, V. Schmidt, F. Siebzehnrübl, E. Hahnen, I.Y. Eyupoglu, R. Fahlbusch, I. Blümcke 1Institute of Brain Research, University of Tübingen, Tübingen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Lehrstuhl für Germany; 2Laboratorium Pathologie Oost Nederland, Enschede, Neuropathologie, 91054 Erlangen, Deutschland The Netherlands; 3Institute of Anatomy, Ludwig-Maximilians-University, Munich, Germany; 4Institute of Clinical Neuroana- Cytokine signaling of the gp130/JAK/STAT pathway plays a piv- tomy, University of Frankfurt, Frankfurt, Germany otal role in pituitary development and is implicated in tumorigene-sis of various cell progenies. Gatekeeper in the physiological con- The spinocerebellar ataxias (SCA) are a group of dominantly in- trol of this pathway is the suppressor of cytokine signaling herited neurological disorders characterised by progressive ataxia (SOCS) family of proteins and their encoding genes. Eight SOCS that results from degeneration of the cerebellum and its afferent proteins have been identified so far. Their expression levels appear and efferent connections. The most frequent SCA mutations – to be epigenetically regulated, i.e. by promoter methylation. We SCA1, SCA2, and SCA3 – have been shown to be unstable CAG have investigated the CpG island methylation status of SOCS-1 in trinucleotide repeat expansions present within coding regions of a cohort of pituitary adenomas (PA; n=57), craniopharyngiomas the respective genes. The pathogenesis of the polyglutamine disor- (CP; n=30) and normal pituitary tissue (NP; n=11) using methyla- ders is not yet fully understood. In the CNS, inflammation is tion specific PCR (MSP), methylation sensitive single-strand con-mediated by microglial cells. In other neurodegenerative disorders formation analysis (MS-SSCP) and direct sequencing. SOCS-1 such as Alzheimer´s disease (AD) or Parkinson´s disease (PD), hypermethylation was identified in 51% (29/57) of surgical speci- there is evidence for activation of microglia cells. In an animal mens obtained from PA patients. 83% of these tumors lack model of SCA3, gene expression profiling yielded upregulation of hormone secretion. In contrast, no methylation of SOCS-1 was ob- inflammatory genes. Therefore, two SCA1, two SCA2 and two served in CPs or NPs. Quantitative real-time PCR confirmed re- SCA3 and six control brains were screened for the presence of duced SOCS-1 expression in pituitary adenomas (11/15) comparedactivated microglia by immunolabeling of inflammatory proteins to normal pituitary gland tissue. Eight of these samples showed a (CD68, IL-16, macrophage inhibitory factor-related protein 8 distinct hypermethylation in the examined CpG islands. Western (MRP8), allograft-inflammatory factor 1 (AIF-1), endothelial blot analysis confirmed reduced SOCS-1 protein levels in these tu- monocytes activating polypeptide II (EMAP-II), cyclooxygenase mor samples. Epigenetic silencing of the SOCS-1 gene appears toI and II (COX I and II)). Only the number of CD68 positive significantly contribute to the pathogenesis of PA, in particularmicroglial cells was found to be increased in the cerebellar white those characterized by a hormone-inactive status, and may result matter of SCA brains. Nevertheless, it is not yet clear, whether in enhanced responsiveness of tumor cells to growth stimulating neuroinflammation and microglial activation are beneficial or Accumulation of amyloid ß protein causes a hierarchical
Common mutations of b-catenin in adamantinomatous
degeneration of commissural neurons in the frontal cortex
craniopharyngiomas but not in other tumours originating
E. Capetillo-Zarate(1); D. Abramowski(2); M. Staufenbiel(2); from the sellar region
Rolf Buslei, Michael Nolde, Bernd Hofmann, Stephan Meissner, (1) Department of Neuropathology, University of Bonn, D-53105 Ilker Y. Eyupoglu, Florian Siebzehnrübl, Eric Hahnen, Jürgen Bonn, Germany; (2) Novartis Institutes for Biomedical Research Basel, Basel, Switzerland; (3) Biochemistry, Adolf-Butenandt Friedrich-Alexander-Universität Erlangen-Nürnberg, Lehrstuhl für Neuropathologie, 91054 Erlangen, Deutschland Neuronal degeneration is one of the hallmarks of Alzheimer’s dis- Dysregulation of the Wnt signalling pathway contributes to develop- ease (AD). In mouse models of AD overexpressing mutant amy- mental abnormalities and carcinogenesis of differnet tumour types.
loid precursor protein (APP) neuronal loss has been described.
Here, we examined b-catenin and APC by mutational analysis in pi- Since these studies reported general neuronal loss in the hippo- tuitary adenomas (n=60) and a large series of craniopharyngiomas campal formation it is not clear whether there is selective vulnera- (n=41). Furthermore, the expression pattern of b-catenin was im- bility of specific types of neurons. To address this question we munohistochemically analysed in a cohort of tumours and cysts of quantified the number of traced commissural neurons after im- the sellar region including pituitary adenomas (n=58), craniopharyn- plantation of DiI tracer into the left frontocentral cortex of APP23 giomas (n=57), arachnoidal cysts (n=8), Rathke’s cleft cysts (n=10) transgenic mice overexpressing mutant human APP and littermate and xanthogranulomas (n=6). Whereas APC mutations were not de- controls at 3, 5, 11, and 15 months of age. Quantification of the tectable in either tumour entity, b-catenin mutations were present in DiI-traced commissural neurons in the layer III of the right fronto- 77% of craniopharyngiomas, exclusively of the adamantinomatous central cortex allowed us to differentiate three types of commissu- subtype. All mutations affected exon 3, which encodes the degrada- ral neurons: 1) heavily ramified pyramidal neurons, 2) sparsely tion targeting box of b-catenin compatible with an accumulation of ramified pyramidal neurons, and 3) non pyramidal neurons. No nuclear b-catenin protein. In addition a novel 81bp deletion of this significant differences in number of these types of commissural exonic region was detected in one case. Immunohistochemical anal- neurons were shown between controls and APP23-mice at ysis confirmed a shift from membrane-bound to nuclear accumula- 3 months of age. Heavily ramified pyramidal neurons were redu- tion of b-catenin in 94% of the adamantinomatous tumors. Aberrant ced in number in 5 months old APP23-mice as well as in 11 and distribution patterns of b-catenin were never observed in the other tu- 15 months old animals. The total Aß-levels in the brain did not mour entities under study. We conclude that b-catenin mutations and/ differ among 3 and 5 months old APP23-mice. The only diffe- or nuclear accumulation serve as diagnostic hallmarks of the rence between these mice was the beginning of the deposition of adamantinomatous variant, setting it apart from the papillary variant fibrillar Aß in 5 months old animals. Significant reduction of spar- sely ramified pyramidal neurons was observed in 15 months oldAPP23-mice exhibiting already numerous Aß-plaques. In summa-ry, our results showed a hierarchical involvement of different ty- pes of commissural neurons in Aß-induced neurodegeneration in one in children. Detection of aluminum should be pursued in each APP23-mice. The degeneration of these neurons starts with the affected individual. (3) As MMF is a focal process, its myopathol- occurrence of the first Aß-fibrils in the brain. Support: DFG ogy may actually obscure any generalized neuromuscular disorderwhich had led to the original biopsy. Thus, as muscles recentlyneedled by electromyography should not be biopsied, those sub- Posttranslational prenylation, carboxyl methylation,
jected to vaccines, i.e. deltoid in adults and quadriceps in children, and neurofibrillary degeneration
should only be used for biopsy when preceding vaccination has R. Distl, V. Komkov, N. Holtkamp, S. Treiber-Held, F. Albert, been included into history-taking and biopsy site selection.
V. Meske, Th. G. Ohm, A. v. DeimlingCharité Universitätsmedizin Berlin, Institut für Neuropathologie, Statins induce neuronal differentiation of neuroblastoma
cells via activation of EGFR
Neurofibrillary degeneration occurs as tangles in Alzheimer’s se- M.E. Evangelopoulos, J. Weis, A. Krüttgen nile dementia and in the juvenile dementia and cholesterol storage Universitätsklinik RWTH Aachen, Institut für Neuropathologie, disorder Niemann-Pick type C (NPC). Tangles consist of hyper- phosphorylated tau. We found elevated cholesterol levels in tan-gle-bearing neurons in both diseases. This was more pronounced Neuroblastoma cell lines are commonly used as models to study in NPC. Previously, we could induce tau hyperphosphorylation in neuronal differentiation as they retain the capacity to differentiate primary rat neurons by inhibiting geranylgeranylation of protein into a neuronal-like phenotype. Cholesterol synthesis blockers (so rhoA. Geranylgeranylation and farnesylation are two forms of called “statins”) trigger neuroblastoma differentiation and are con- posttranslational prenylation of small guanyltriphosphatases rho, sidered as candidate drugs for the treatment of neurodegeneration, ras, and ras-related in brain (rab). The prenyl moieties are prod- as they i.e. induce neurogenesis in experimental models of stroke.
ucts of the cholesterol biosynthesis pathway. Prenylation is a pre- Our aim was to reveal the molecular mechanisms involved in neu- requisite for the membrane localisation and correct function of ronal differentiation triggered by statins. We found that treatment guanyltriphosphatases in dendritic differentiation and membrane with mevastatin induced neuronal differentiation of Neuro2a neu- transport. In our experiment, tau hyperphosphorylation was asso- roblastoma cells grown in medium containing full serum, with ciated with reduced membrane localisation of protein rhoA. We neurites appearing as soon as 6 hours after statin treatment. The also found tau hyperphosphorylation in cerebella of an NPC morphological differentiation of neuroblastoma cells was associat- mouse model. Tau hyperphosphorylation correlated with the Pur- ed with the upregulation of the neuronal marker protein NeuN.
kinje cell loss that appears regularly from the 42nd postnatal day Surprisingly, Neuro2a differentiation after addition of mevastatin onward. By SSH (subtraction suppressive hybridisation) we analy- could be blocked by addition of geranygeranyl-pyrophosphate sed differential gene expression in cerebella of NPC and control (GGPP) and farnesyl-pyrophosphate (FPP), but not by addition of mice on postnatal day 35. Among the differentially expressed the direct cholesterol precursor squalene. This result suggests that genes were isoprenylcysteine carboxyl methyltransferase (Icmt), a small GTPases inhibit neuroblastoma differentiation, as small GT- rab guanyldiphosphate dissociation inhibitor (Gdi3), and a ras Pases depend on farnesylation of geranylgeranylation for their guanyl releasing protein (Rasgrp1). We could show by quantita- activity. We subsequently examined the signal transduction path- tive polymerase chain reaction (PCR) that the Icmt transcript was ways leading to statin-induced neuroblastoma differentiation. reduced 68±18% in diseased cerebella at postnatal day 28. Icmt Addition of mevastatin to neuroblastoma cells was associated with carboxyl methylates prenylated proteins. Our results point towards induced phosphorylation of EGFR (Tyr-1068), ERK1/2 and Akt.
a role of prenylation and carboxyl methylation in the development Inhibition of EGFR, PI3K and MEK blocked neuroblastoma dif- ferentiation induced by mevastatin. In summary, our study is thefirst to show that a well established HMG-CoA reductase inhibitortriggers activation of the receptor tyrosine kinase EGFR leading to Macrophagic myofasciitis
neuroblastoma differentiation. Further studies will give mechanis- Soroush Doostkam1, Jürgen R.E. Bohl1, Peter F. Schmidt2, tic insight into the signalling pathways triggered by statins.
Harald D. Müller1, Clemens Sommer1 and Hans H. Goebel11Department of Neuropathology, Johannes Gutenberg University Expression profiling analysis in epilepsy-associated
Mainz, 55131 Mainz, Germany; 2Institute for Medical Physics and gangliogliomas
Biophysics, Westfälische Wilhelms-University, Münster, Germany Jana Fassunke, Volker Schick, Achim Tresch, Phillip Koch, Macrophagic myofasciitis (MMF) has recently been identified as a Claudia Ullmann, Christian E Elger, Johannes Schramm, focal – and, perhaps, even as a general – inflammatory process Albert J Beckerafter injection of aluminum-containing vaccines. Many such pa- Universitätsklinik Bonn, Institut für Neuropathologie, 53105 Bonn, tients have now been encountered in France. Objective This is a report on the experience with MMF in a single (non- French) sur-vey. Material and Methods Muscle biopsy specimens from four The comprehensive analysis of disease-related gene transcripts adults and three children were assessed by histological, electron gains increasing importance for understanding the molecular basis microscopic, enzyme- and immunohistochemical techniques as of human diseases. Gangliogliomas constitute the most frequent well as by the LAMMA method to identify aluminum in their tis- glioneuronal tumor entity occurring in patients with pharmacore- sues. Results Over a period of four years, encompassing muscle sistant epilepsy. We here report first results of a microarray-based biopsy specimens from 1537 patients, three deltoid muscle speci- expression profile analysis in gangliogliomas. Microarray analysis mens retrieved from four different hospitals showed classic citeria (Affymetrix U133A) was carried out comparing expression pat- of MMF and two quadriceps muscle specimens from unrelated terns in ganglioglioma vs. adjacent normal control tissue (n= 6 pa- children. Conclusions (1) Even outside of France, MMF does not tients). Real time RT-PCR analysis was performed to validate dif- seem to be as rare a disease contrary to common impression. In- ferential gene expression patterns. A total number of 95 genes was creasing awareness may certainly furnish additional muscle biopsy found to be differentially expressed in gangliogliomas vs. controls.
specimens. (2) The deltoid muscle is the preferential vaccinated Stratification by gene ontology analysis revealed several differen- muscle in adults whereas the quadriceps muscle is the preferential tially expressed genes related to neuronal differentiation and mi- gration. In particular, protein kinase C, beta 1 type as well as its findings demonstrate that axon outgrowth appears to be promoted binding partner NELL2 are significantly reduced in expression in by estradiol in a wide range of estrogen concentrations. In con- gangliogliomas. Gene chip technologies open new avenues for the trast, proliferation and apoptosis in the hippocampus are balanced identification of candidate molecules and mechanisms involved in in a restricted range of concentration as provided by hippocampus- the pathogenesis of gangliogliomas. Current experiments focus on functional analyses of candidate genes using siRNA approaches.
Supported by DFG (SFB TR3) and BONFOR Creutzfeldt Jakob disease in Austria: 10 years of surveillance
Ellen Gelpi, Romana Höftberger, Ursula Unterberger, Thomas
Digital virtual microscopy – a new method in diagnostics
Ströbel, Till Voigtländer, Edita Drobna, and Herbert Budka und education
Institute of Neurology, Medical University of Vienna, and Austrian Reference Centre for Human Prion Diseases (ÖRPE) Universitätsklinikum des Saarlandes, Institut für Neuropathologie, Klinisches Institut für Neurologie der Medizinischen Universität Light microscopy is the standard tool in diagnostic and scientific The Austrian Reference Centre for Human Prion Diseases (ÖRPE) pathology as well as in medical education. Digital technology in was established in 1996 as an active surveillance programme for microscopy was restricted, up until now, because the field of view prion diseases. Since then, 802 referrals were analysed by ÖRPE.
of any camera is limited for any given magnification. Using new Postmortem investigation of brain tissue is mandatory in every intercoordinated components (“.slide” – system; Olympus / SIS) suspected case of transmissible spongiform encephalopathy. Since like the microscope with motor stage and a workstation with 1996, more than 800 analyses of 14.3.3 protein in CSF have beenspecial software components it is now possible to scan the entire performed. Sequencing of the prion protein gene (PRNP) has been slide at the resolution required. Integrated focus routines make performed since 1999. The total of diagnosed TSE cases is 189.
sure that the images are always in sharp fucus. The single images From 1969 to 1996, 88 definitive TSE cases occurred with an are automatically mounted together into a large overview image.
average annual incidence of 0,43 per million, whereas the average This “virtual slide” is displayed on the monitor as an overview and incidence for the period 1996 to 2005 is 1,4 per million. This additionally, in the upper-left corner, as thumbnail. Based on the increase reflects most likely improved case ascertainment due to overview or thumbnail image, detail image segments can be higher awareness of the medical community. Since 1996, 85% ofselected and zoomed in or out like an actual glass slide under the definitive TSE cases were classified as sporadic CJD. Of these, microscope. Because the images are saved in web-based galleries, 6 cases did not meet the clinical surveillance diagnostic criteria of the virtual slide is to be published on the web or archived on probable nor possible. Alternative clinical and/or neuropathologi- DVD. Thus, the virtual microscopy may promote education and cal diagnoses in suspect cases included Alzheimer’s or diffuse diagnostic cyto- and histopathology especially in getting another Lewy body disease, vascular encephalopathy, viral or limbic encephalitis, Hashimoto or metabolic encephalopathies. A total of19 genetic cases and 2 iatrogenic cases (dural graft) were docu-mented. No cases of variant CJD have been documented. There is Neuroprotective effects in hippocampal neurons vary
no regional or professional clustering of cases, and no common with estrogen concentrations
risk factors have been detected. (ÖRPE is funded by the Austrian Lars Fester, Christian von Schassen, Veronica Ribeiro-Gouveia, Ministry for Health and Women. It gratefully acknowledges the Janine Prange-Kiel, Christina Lohse, Cornelia Huber, Gabriele M.
continuous support by Austrian neurologists, neuropathologists and other clinical personnel without whom CJD surveillancewould be impossible).
Universtätsklinikum Hamburg Eppendorf, Institut für Anatomie I:Zelluläre Neurobiologie, 20246 Hamburg, BRD Primary leptomeningeal primitive neuroectodermal tumor
Neuroprotective effects of estrogens on cell survival and regenera- with subseqent development of a glioblastoma.
tion have frequently been shown. Here, we have studied the effects of low, gonad- derived serum estrogen concentrations, of Gies U., Pekrun A., Neubauer U., Bergmann M.
intermediate concentrations, which are provided by hippocampal Klinikum-Bremen-Ost, Neuropathologie, 28325 Bremen, Deutsch- cells, and of high doses of estrogen on proliferation, apoptosis, and axon outgrowth of rat hippocampal neurons. No effects of lowconcentrations were found, neither in vitro nor after ovariectomy Introduction: Primitive neuroectodermal tumors (PNET) are neo- in vivo. To study the effects of hippocampus-derived estradiol plasms of high malignancy which occur predominantly duringwe inhibited estrogen synthesis by treatment of hippocampal cell childhood. Secondary leptomeningeal dissemination ist a frequent cultures with letrozole, an aromatase inhibitor. Alternatively, we complication. Primary leptomeningeal PNET´s without a solid tu- used siRNA against Steroidogenic acute regulatory protein mor are very rare. Case report: A 9-year-old boy suffered from (StAR). Axon outgrowth as shown by quantitative immunohisto- headache and vomiting of 4 weeks duration. Papilledema was the chemistry of growth associated protein 43 and by measurements only abnormality. MRT showed disseminated contrast enhance- of axon length was significantly downregulated in response to ment of the leptomeninges. On liquor analysis slight lymphocytic letrozole and in siRNA-StAR transfected cells. Similarly, counting pleocytosis and elevated protein concentration were the only find- of Ki67-positive cells, a parameter of proliferation revealed a de- ings. No tumor cells were detected. Leptomeningeal biopsy crease in the number of proliferative cells. The number of TUNEL showed a small cell malignant neoplasm, which expressed NSE and of caspase-3 positive cells, parameters of apoptosis, increased and synaptophysin and was classified as primary leptomeningeal in response to inhibition of estrogen synthesis. Application of PNET. Radiochemotherapy resulted in complete remission. 5 years high, supraphysiological doses of estradiol promoted axon out- later a cystic tumor developed during a few months in the right growth but did not affect proliferation and apoptosis. The estrogen frontal lobe. The tumor was resected. Histological examination receptor antagonist ICI 182,780 antagonized estrogen-induced showed a typical glioblastoma. During the following chemothera- axon outgrowth but had no effect on proliferation, suggesting dif- py according the HIT-scheme the tumor revealed an increasing ferent pathways of estrogen signaling in neuroprotection. Our contrast enhancement. Conclusion: Our case is an example of a primary leptomeningeal PNET, which is very rare and has to be ly, the tumor cells expressed glial proteins. Comparative genomic differentiated from the other causes of meningitis. For the subse- hybridization (CGH) showed few, dissimilar chromosomal aberra- quent evolution of a glioblastoma radiotherapy could be a factor, tions in the two tumors. Although sharp demarcation and mono- because malignant gliomas occur as a complication of cerebral ra- morphic architecture of both tumors are reminiscent of a primitive diation after a latency of 5 – 10 years.
neuroectodermal tumor (PNET), the tumor cell histology and im-munohistochemical glial differentiation refer to a glial origin. Toour knowledge the features of the described tumors are not in ac- Repeated Lipopolysaccharide Administration Induces
cordance with any so far recognized glioma variant. Therefore, we Hyperalgesic Tolerance, but Enhances Glial Activation
propose these tumors as distinct glioma subtype and suggest the in Rat Spinal Cord
designation of “infantile minigemistocytic glioma”.
Liang-Hao Guo, Katrin Trautmann, Hermann J. SchluesenerEberhard Karls Universität Tübingen, Institut für Hirnforschung, Therapy of Spinal Muscular Atrophy using Suberoylanilide
Hydroxamic Acid, a second generation Histone Deacetylase
Inhibitor

Glial cells produce a various inflammatory molecules in responseto signals derived from immune system generated within the cen- Eric Hahnen, Ilker Y. Eyüpoglu, Lars Brichta, Kirsten Haastert, tral nervous system (CNS). The role of glial cell in the pathologi- Christian Tränkle, Florian A. Siebzehnrübl, Markus Riessland, cal pain process becomes emerged recently. In the present study, Irmgard Hölker, Peter Claus, Johann Romstöck, Rolf Buslei, we have analyzed activations of astrocytes and microglia in spinal cord during repeated lipopolysaccharide (LPS) injection induced Universität Köln, Institut für Humangenetik, 50931 Köln, Germany inflammatory pain. Male Lewis rats were treated intraperitoneallywith a single or 7 injections of LPS (5mg/kg) or vehicle. Mechani- Amongst a panel of histone deacetylase (HDAC) inhibitors inves- cal hyperalgesia, measured as rat hindpaw withdraw thresholds tigated, suberoylanilide hydroxamic acid (SAHA) evolved as a (PWTs), was observed within the first 48 hours after single LPS potent and non-toxic candidate drug for the treatment of Spinal injection. Behavioral effects of LPS tolerance developed by re- muscular atrophy (SMA), an alpha-motoneuron disorder caused peated injections indicated as reduction of PTWs. Activation of by insufficient survival motor neuron (SMN) protein levels. We astrocytes and microglia were evaluated by immunohistochemistry show that SAHA elevates SMN levels at low micromolar concen- with specific antibodies glial fibrillary acidic protein (GFAP) and trations in several neuroectodermal tissues, including rat hippo- ED1 respectively. A single LPS elicited persisted microglial acti- campal brain slices and motoneuron-rich cell fractions, and con- vation. Although behavioral hyperalgesic tolerance was observed, firm its therapeutic capacity using a novel human brain slice cul- long-term repeated LPS injection induced an dramatically in- ture assay. SAHA activates the survival motor neuron gene creased microglia activation in whole spinal cord. Furthermore, 2 (SMN2), the target gene for SMA therapy, and inhibits histone this elicited microglial activation was confirmed by expression of deacetylases at submicromolar doses, giving evidence that SAHA P2X4 receptor (P2X4R) and endothelial monocytes activating is more efficient than the HDAC inhibitor valproic acid, which is polypeptide II (EMAP-II). However, effects either single or multi- currently under clinical investigation for SMA treatment. In con- ple LPS treatments on astrocytes activation was modest. In trast to SAHA, the compounds CBHA, SBHA and M344 displayconclusion, this is the first demonstration of glial activation in hy- unfavourable toxicity profiles, while MS-275 fails to increase peralgesic effect of LPS tolerance. This indicates that chronic SMN levels. Clinical trials revealed that SAHA, which has beenexposure to LPS can alter CNS-mediated inflammatory response developed for cancer treatment, has a good oral bioavailability and during chronic pain, and spinal glia might be a potential target in is well tolerated, allowing to achieve in vivo concentrations shown to elevate SMN levels. Since SAHA crosses the blood-brain barri-er, oral administration may be useful to decelerate progressive alpha-motoneuron degeneration by epigenetic SMN2 gene activa- Infantile minigemistocytic glioma: a distinct glioma variant,
report of two cases.
Christine Haberler, Irene Slavc, Thomas Czech, Daniela Prayer,
Christine Pirker, Herbert Budka, Johannes A. Hainfellner
Supratentorial tanycytic ependymoma associated with
childhood epilepsy – report of three cases.

Medizinische Universität Wien, Klinisches Institut für Neurologie,A-1097 WIEN, Österreich Volkmar H. Hans1, Raffael Villagrán1, Markus Bergmann3, Ingrid E. Tuxhorn2, Friedrich G. Wörmann2, Heinz W. Pannek2 The identification and definition of brain tumors with distinct clin- 1Institut für Neuropathologie and 2Epilepsie-Zentrum Bethel, ico-histopathological features that differ from established tumor Evangelisches Krankenhaus Bielefeld, D-33617 Bielefeld; 3Insti- entities is important to optimize postoperative patient treatment.
tut für Neuropathologie, Klinikum Bremen-Ost, D-28325 Bremen We report two cases of supratentorial tumors in infants with dis-tinct histopathological features. In the first patient a temporal Introduction Focal epilepsies are associated with low grade tu- paraventricular space-occupying lesion was diagnosed in the 28th mours, not commonly presenting with other clinical signs. A spe- gestational week. The boy was delivered in the 34th gestational cial rare finding is tanycytic ependymoma. We report on three week and the tumor was operated 10 days after birth. The second young patients operated on for this tumour. Cases 1. Boy, 6 years patient, a 30-month-old male infant had a paraventricular left fron- old, right temporal tumour, temporal lobe and mesial resection, to-central tumor. Both tumors were gross totally resected and the Engel 1A two years postoperatively. 2. Girl, 9 years old, left tem- children received postoperative chemotherapy. At the last follow poral lesion, lesionectomy, Engel 1A two years postoperatively. 3.
up 14 (patient 1) and 6 months (patient 2) postoperatively, both Boy, 17 years old, left perisylvic lesion, biopsy, ongoing radiation patients were in continuous complete remission. Histologically, and chemotherapy, Engel 1A 8 months postoperatively. Histology the tumors were sharply demarcated from the adjacent CNS paren- showed a partly fascicular tumour of moderate cellularity inter- chyma and displayed a highly cellular monomorphic tumor tissue.
mingled with preexisting neurons. Well differentiated tumour cells Tumor cells were small and showed a distinct minigemistocytic infiltrated along small vessels, forming perivascular peudorosettes shape. Abundant mitotic figures and small areas of necrosis with- in solid areas. Spindle-formed, piloid cells had an eosinophilic cy- out nuclear pseudopalisading were present. Immunohistochemical- toplasm, within a dense fibrillary matrix. Ovoid and elongated small nuclei showed a finely stippled chromatin with small nucle- 2 different NF2 mutations were observed. No NF2 mutation was oli. Mitoses, necroses as well as microvascular proliferations were found in 33 secretory-, 7 microcystic-, 2 lymphoplasmacyte-rich-, absent. All tumours showed immunoreactivity for vimentin, pro- 1 rhabdoid- and 1 metaplastic meningioma. In the control group tein S100, and GFAP, with some cytoplasmic dots positive for of 25 fibroblastic meningiomas 11 cases were identified that carry EMA. Low proliferative activity reached focally up to 3% a NF2 mutation. These results support the concept of different (MIB1). Staining was absent for MAP2, synaptophysin, neurofila- molecular subgroups of meningiomas which overlap with histo- ment, CD34, and p53. One case analyzed ultrastructurally showed typical microvilli, microlumina, and cilia. Conclusion Tanycyticependymoma is a rare variant of tumours showing ependymal dif-ferentiation. Whereas mostly described in a spinal location, supra- Microarray-based identification of novel diagnostic markers
tentorial cases seem to be associated with focal epilepsy. One has for ependymomas
to be aware of this diagnosis in epilepsy neurosurgery in order not Martin Hasselblatt, Lars Tatenhorst & Werner Paulus to confuse it with WHO grade I tumours (ganglioglioma, pilocytic Institute of Neuropathology, University Hospital Münster, Germany astrocytoma) which may well be mimicked.
The diagnosis of ependymoma is straightforward if perivascularpseudorosettes or ependymal rosettes are abundantly present.
Multimodal impact of DCC and Netrin-1 on human fetal
However, diagnostic difficulties may arise in cases where ependy- brain stem development.
mal differentiation is less obvious. Apart from distinct punctate or P. Harter1, B. Bunz1, H. Schlaszus1, R. Meyermann1, ring-shaped epithelial membrane antigen (EMA) staining, diag- nostic markers for epithelial differentiation are missing. Therefore, 1Institute of Brain Research, University of Tuebingen, Germany gene expression profiles obtained from ependymal lining laser mi-crodissected from human autopsy tissue (n=6) were compared DCC and its ligand netrin-1 exert functions in cellular survival via to that of whole hippocampal tissue (n=9) using DNA microarrays a dependence receptor pathway and bifunctional axonal guidance.
in order to identify genes highly and specifically expressed in Both features are required for regular embryonic and fetal CNS ependymal cells. Data analysis yielded a number of 52 genes with development. To evaluate DCC and netrin-1 expression in human >10-fold overexpression in ependymal cells. Another 48 genes fetal brain stems, we investigated brain stem specimens deriving were found to be highly expressed in ependymal lining but absent from 23 fetuses by immunohistochemistry. Strongest intensity and in hippocampal tissue. In addition to genes involved in cilia func- highest frequency of DCC and netrin-1 expression could be tion (e.g. axonemal dynein heavy polypeptide 9 and intermediatedetected in subependymal germinal layers as well as in the exter- polypeptide 2 as well as sperm-associated antigens 1 and 6), these nal granular layer of the cerebellum. These findings parallel the included genes coding for ion channels (e.g. potassium inwardly- expression of MIB-1-positive cells indicating proliferative activi- rectifying channel Kir 5.1), proteins involved in glucose metabo- ty. Furthermore strong DCC and netrin-1 expression was seen in lism (glycogenin 2, glucose transporter GLUT10) and glycopro- most brain stem nuclei as well as in the choroid plexus. A selec- tein synthesis (SLC35D2, GalNAc-T3) as well as genes involved tive strong netrin-1 intensity could be observed at anterior pontine in proliferation and development (e.g. epithelial membrane protein mid-line crossing axons as well as on endothelial cells. The find- 1, glypican-4). Antibodies directed against differentially expressed ings of high expression rate of DCC and netrin-1 in proliferative gene products are currently evaluated for their sensitivity and areas indicate their probable anti-apoptotic role in the human fetal specificity using tissue arrays representing a variety of glial tu- brain. Additional, DCC and netrin-1 seems to be partly responsi- mors and might complement EMA staining in the diagnosis of ble for the fetal cellular survival off all brain stem nuclei and the choroid plexus. Furthermore, the selective strong netrin-1 expres-sion around pontine mid-line crossing axons could reflect an spe-cific upregulation in CNS areas where considerable directional Granulocyte-Colony Stimulating Factor (G-CSF) reduces
changes in axonal growth are necessary. Upregulation of netrin-1 infarct volume upon delayed application in middle cerebral
on endothelial cells without DCC expression is in accordance to artery occlusion in rats and is expressed along with neuronal
prior findings that netrin-1 induced angiogenesis is mediated by G-CSF receptors upon acute ischemic stroke in the human
brain
Martin Hasselblatt, Armin Schneider & Wolf-Rüdiger Schäbitz
NF2 mutations in secretory and other rare variants
Universitätsklinikum Münster, Institut für Neuropathologie, 48149 of meningiomas
Christian Hartmann, Jennifer Sieberns, Claire Gehlhaar, Matthias Granulocyte-colony-stimulating factor (G-CSF) is a hematopoietic Simon, Werner Paulus, Andreas von Deimling growth factor that enhances survival and differentiation of my- Charité – Humboldt Universität, Institut für Neuropathologie, eloid lineage cells. G-CSF receptors are also expressed in the rat brain. Here, early administration of G-CSF provides neuroprotec-tion upon ischemic stroke. Because G CSF is a promising candi- The WHO classification defines different histological variants of date for neuroprotective trials in humans, we investigated if (1) the meningiomas. Mutations of the tumor suppressor gene NF2 on beneficial effect of G CSF on infarct volume is still preserved 22q have been described in 30 to 60 % of sporadic meningiomas.
upon delayed administration in a rat model of ischemic stroke and However, the vast majority of the meningiomas which have been (2) if G-CSF and the G CSF receptor are also expressed in human subject to NF2 analysis belong to the most frequent variants.
stroke brains. In rats subjected to middle cerebral artery (MCA) Within these subtypes, transitional and fibroblastic meningiomas occlusion, G CSF treatment (Neupogen®, 60 µg/kg i.v.) initiated harbour significantly more NF2 mutations than meningothelial 2 h after onset of ischemia reduced infarct volume by 37% as meningiomas, indicating molecular subsets of these tumors. To compared to vehicle-treated animals (n=7 10; p<0.01). In forma-determine whether rare meningioma variants carry NF2 mutations lin-fixed paraffin-embedded brain samples obtained from patients, we analyzed 80 tumors. In 5/14 psammomatous-, 1/9 angioma- that had died 2, 3 and 5 days upon MCA infarction, an up-regula- tous-, 2/9 clear cell-, 1/3 chordoid- and 1/1 papillary meningioma tion of neuronal G-CSF receptor immunoreactivity was observed NF2 mutations were detected. In the single papillary meningioma in the periinfarct area as compared to the contralateral cortex and normal control brains. G CSF staining was observed in endothelial Memory acquisition in humans critically correlates with
cells and appeared to be more pronounced in small vessels in the hippocampal granule cell loss
vicinity of the infarct area. At later time-points, G-CSF receptor Michelle Hildebrandt, Johann Romstöck, Hermann Stefan, Ingmar immunoreactivity was restricted to glial cells. To conclude, the re- duction of infarct volume even upon delayed administration in ananimal model of ischemic stroke along with the observed up-regu- FAU Erlangen, Lehrstuhl für Neuropathologie, 91054 Erlangen, lation of neuronal G-CSF receptors upon acute ischemic stroke in humans further underscore the potential of G-CSF, a well-charac- The hippocampal formation is essentially involved in the forma- terized and safe compound, for the treatment of human ischemic tion of conscious memories for facts and events and neurological diseases affecting the hippocampus associate with severe memorydeficits, i.e. temporal lobe epilepsies. We studied the degree of Intracerebral mature teratoma in a case of Delleman
declarative memory dysfunction in 27 human subjects, suffering syndrome
from unilateral mesial temporal lobe epilepsy, using the uniquepossibility to access memory performance of each isolated hippo- Hey K., Spranger S., Meyer H., Neubauer U., Bergmann M.
campus by intracarotid amobarbital anaesthesia (IAT). Subse- Klinikum-Bremen-Ost, Neuropathologie, 28325 Bremen, Deutsch- quently, hippocampal specimens from the same patients were available for neuropathological analysis following surgical treat-ment of intractable seizures. Neuronal cell in dentate gyrus and in Introduction: In 1981 Delleman and Oorthys described a new syn- all hippocampal subfields especially CA2 correlated with memory drome with oculo-cerebro-cutaneous malformations. Minimal di- decline. Moreover, multiple regression and partial correlation agnostic criteria are CNS-malformations, orbital cysts or microph- analyses identified neuronal cell loss within the internal limb of thalmia and focal skin appendages. About 40 cases have been de- the dentate gyrus, a developmentally distinct subregion of the hip- scribed in the Englisch literature, which sometimes had additional pocampal formation known to generate new neurons throughout cranial, vertebral or cardial malformations.
life, as highly significant predictor for the patient’s ability to learn Case report: This 3-year-old male ist the fourth child of non- and recall memories. The data is compatible with recent animal consanginous parents with three other normal children. Pregnancy studies, proposing that memory formation critically depends on was uncomplicated but the child was born in the 41 week by ce- the capability of the hippocampus to maintain and recruit new sarean section because the CTG worsened. The infant weighed neurons into the dentate gyrus, and suggest a similar mechanism 4610 g, measured 58 cm with a head circumference of 39,5 cm.
Apgar was 9-9-9. Microphthalmia/ Anophthalmia was present onthe left side, whereas the right eye seemed normaly developed.
The nasal canal was narrow (choanal atresia?). The nasal ridge Volumetric and neuropathological examination reveals
was broadened and there were multiple skin tags around the left hemispheric hypoplasia in children with severe epilepsy
eye, the nose and both ears. A lipoma-like tumor lay in the left and focal cortical dysplasia type I
cheek and posteriorly in the midline two elastic skin swellings M. Hildebrandt; T. Pieper; P. Winkler; D. Kolodziejczyk, were seen. Cranial MRI disclosed microphthalmia on the left, cal- losal agenesis, pachy- polymicrogyria in both hemispheres, an oc-cipital meningoencephalocele and a cystic tumor in the left frontal FAU Erlangen, Lehrstuhl für Neuropathologie, 91054 Erlangen, lobe. Further radiological investigation disclosed rib anomalies on both sides and an atrial septal defect. Karyotype was XY, 46. Three-dimensional MR-volumetry points to unilateral hypoplasia Because the tumor increased significantly in size, it was subtotally of cerebral hemispheres in children with severe epilepsy and psy- resected. Histologically the tumor was a mature teratoma. The chomotor retardation. Extensive lobular resection strategies are re- skin tags were trichoepitheliomas and the tumor of the left cheek quired to achieve seizure control in this particular cohort of young was an epidermoid cyst. Conclusion: Our case is an example of patients. Systematic neuropathological examination of surgical Dellemans syndrome, which features ocular, cerebral and skin specimens identified significant alterations in cortical architecture malformations and is therefore named as oculocerebrocutaneous including smaller cortical layers, increased cell densities and syndrome. Cerebral malformations are callosal agensis, gyral abundance of microcolumns, in an earlier study classified as FCD abnormalities and cerebral cysts (porencephalic cysts, meningoen- type I (Hildebrandt et al., 2005). Moreover, we found a significant cephaloceles, Dandy-Walker-cysts etc.). Although a cystic tumor correlation between decreased cortical thickness, increased neuro- without histological verification was seen once, no cerebral terato- nal density and abundance of microcolumns in the affected speci- ma has to our knowledge been reported up to now. The spectrum mens. These alterations are detectable in all cortical areas, presur- of clinical symptomes in Delleman´s syndrome is very wide and gically characterized by MRI or EEG abnormalities. MR-volume- the prognosis with regard to life span and psychomotor develope- try showed a high inter-individual variance, but individual patients ment is usually poor. Genetic counseling can be relieving as no showed a significant volume reduction in affected hemisphere.
cases of recurrence in a family have been reported up to now. This However, we have not observed a significant correlation between syndrome has to be differentiated from similar syndromes, such as individual volumetric measurements and histopathological analy- Goldenhar syndrome, focal dermal hypoplasia and encephalo- sis of corresponding cortical specimens. Nevertheless, apparently cranio-cutaneous lipomatosis (Haberland syndrome). hypoplastic cortical volume can be histopathologically character-ized by architectural disorganization which is compatible with delayed maturation of cortical development and which may be regarded as underlying cause of catastrophic epilepsy and mentalretardation in young children.
Ex vivo therapy of malignant melanomas transplanted into
Lymphocytic infiltration in human brain metastasis
organotypic brain slice cultures using inhibitors of histone
investigated with the Network SOM and HneT2000.
deacetylases
José R. Iglesias-Rozas and John Sutherland Annett Hölsken, Florian A. Siebzehnrübl, Ilker Y. Eyüpoglu, Mike Institut für Pathology, Katharinenhospital, Stuttgart, Germany and Lueders, Christian Tränkle, Detlef Dieckmann,Rolf Buslei, Eric ANDCorporation, Toronto, Ontario, Canada.
Hahnen, and Ingmar BlümckeUniversität Erlangen, Neuropathologie, 91054 Erlangen The functional and temporal correlation of the lymphocytic infil-tration in human brain metastasis with other histological features Disease progression in patients with malignant melanomas is often is an expression of genotypic variability of the metastasis and of determined by metastatic spreading into the brain. Here we pres- variability of the tumor-brain-tissue interactions. The temporal ent an experimental ex vivo model using a malignant melanoma variation of the lymphocytic infiltration into the brain tissue how- mouse cell line (B16/F10) transplanted into rat hippocampal slice ever, cannot be investigated directly with conventional histologi- cultures. This model was employed to study the chemotherapeutic cal methods. One thousand one hundred and thirteen human brain propensity of inhibitors of histone deacetylases (HDAC) within metastasis were selected for study. In all tumors 50 histological the organotypic brain environment. In monolayer cell cultures, the and immunohistological characteristics, age and gender were ex- second generation of HDAC inhibitors M344, MS-275 and amined by SOM, which is a powerful tool for analyzing and visu- suberoylanilide hydroxamic acid (SAHA) inhibited tumor cell alizing complex data set without prior statistical knowledge.
growth at low micromolar levels (ranging from an IC90 for M344 HneT2000 SL Platform is based upon one cell assembly similar to = 2.88 µM to IC90 = 12.9 µM for MS-275), whereas valproic acid the CNS. Lymphocytic infiltration was manifested in 589 cases reduced tumor cell growth only at milimolar concentrations (IC90 (52.92%) in various grades: intense in 188, less intense in 189 cas- for VPA = 4.47mM). The cell cycle regulating protein p21WAF1 es and minimal in 212 cases. The cluster windows of SOM dis- was significantly increased after treatment, which was in accor- played a colored map of 5 clusters of human brain metastasis. A dance with an increased G1 arrest of tumor cells as shown by cluster may be regarded as a map area containing similar vectors cytofluorometric analysis. Anti-tumor efficacy of HDAC in- or similar histological features of metastasis delimited by separa- hibitors was confirmed in the ex vivo organotypic slice culture tors. The component windows represent the average component model. Tumor progression of eGFP – transfected B16/F10 mela- value of each feature. Cluster C1 contained 316 cases of metasta- noma cells transplanted into hippocampal slice cultures could be sis, of which 194 (51.45%) manifested middle and intense lym- significantly inhibited by administration of 12.9, 25.8 and 38.7 µM phocytic infiltration. Windows with adenocarcinomas showed MS-275 (3 fold IC90) over a period of 8 days. In contrast, SAHA similar component window. The topology of graphs of HneT2000 treatment was less efficient to inhibit tumor cell growth ex vivo.
permitted to view a threedimensional surface of the features, using Considering the ability of MS-275 to cross the blood-brain-barrier, the time axis to display a third stimulus variable (age). The lym- our experimental model identifies the benzamide MS-275 as a phocytic infiltrations manifested a complex temporal process in promising therapeutic compound targeting epigenetic chromatin modulation for systemic treatment of metastatic melanomas.
Prognostic implications of atypical histological features
Transgenic expression of TIMP 1 in the CNS recruits
in choroid plexus papilloma
lymphocytes and prolongs clinical symptoms in EAE
Astrid Jeibmann, Martin Hasselblatt & Werner Paulus Institute of Neuropathology, University Hospital Münster, Germany Dept. Neuropathology, University of Freiburg The prognostic significance of atypical histological features in Tissue inhibitors of metalloproteases (TIMPs) are a family of pro- choroid plexus papillomas remains uncertain and clear diagnostic teins that inhibit matrix metalloproteases (MMPs) in a 1:1 stoichi- criteria for atypical choroid plexus papilloma have not been estab- ometry. Moreover, some TIMPs have effects on proliferation and lished. Therefore, a series of 29 choroid plexus papillomas was apoptosis in vitro and in vivo. While TIMPs 2, 3 and 4 are consti- evaluated for the presence of atypical histological features, i.e. mi- tutively expressed at different levels in most organs the expression totic activity, increased cellular density, nuclear polymorphism, of TIMP 1 is tightly regulated. Strong upregulation is observed in blurring of the papillary growth pattern or necrosis. Choroid plex- the course of various inflammatory disorders and in certain tu- us carcinomas were excluded according to WHO criteria. The in- mors. We have shown in the EAE model that TIMP 1 is induced in fluence of each of these factors on tumor-free survival was investi- gemistocytic astrocytes in the vicinity of inflammatory lesions in gated using univariate analysis. A number of 14 papillomas (48%) the spinal cord. To further investigate the role of TIMP 1 for the displayed at least one atypical feature. Mitotic activity (n=8, CNS, we established transgenic mice that expressed TIMP 1 under 28%), increased cellular density (n=8, 28%), nuclear polymor- control of the GFAP promoter in astrocytes. Several lines of trans- phism (n=6, 21%), and solid growth (n=4, 14%) were observed.
genic mice revealed expression of TIMP 1 at different amounts in No choroid plexus papilloma displayed necrosis. Three recur- specific areas of the CNS. High expression of TIMP 1 in the hind rences were observed upon a median observation time of brain led to lymphocytic inflammation, calcification and cerebel- 42 months. All of the recurrences occurred in tumors displaying lar hypoplasia. Lower transgene expression in several other lines mitotic activity. On Kaplan-Meyer analysis, mitotic activity did not cause overt pathological alterations. However, mice ex- (p=0.001) and high cellularity (p=0.007), but not nuclear polymor- pressing TIMP 1 predominantly in the spinal cord showed faster phism or solid growth pattern were associated with recurrence. To onset of disease symptoms in the EAE model. Importantly, 50% of conclude, the results from this pilot study suggest that mitotic wildtype animals showed complete clinical remission while only activity and high cellularity are atypical histological features asso- 10% of the transgenic mice recovered from EAE. Our results ciated with recurrence in choroid plexus papillomas. We would demonstrate that constitutive expression of TIMP 1 in the CNS like to invite other centers to contribute cases in order to validate can promote the recruitment to and prolong the presence of lym- our observations in a larger set of patients.
Expression and function of glioma invasion related genes
Recurrence in meningiomas: predictive value of histological,
in Drosophila glia cells
clinical, and cytogenetical data
Astrid Jeibmann, Hanna Witte, Christian Klämbt, Werner Paulus Yoo-Jin Kim1, Ralf Ketter2, Wolfram Henn3, Klaus D. Zang3, Institutes of Neuropathology and Neurobiology, University Hospi- tal and Westfälische Wilhelms University, Münster, Germany 1Institute of Neuropathology, University of Saarland, School of Med-icine, Homburg/Saar, Germany; 2Clinic for Neurosurgery, University In order to learn whether genes mediating glioma invasion are of Saarland, School of Medicine, Homburg/Saar, Germany; 3Institute evolutionary conserved, and to better understand the function of of Human Genetics, University of Saarland, School of Medicine, these genes, we examined whether fly homologs of human glioma invasion genes are expressed and functionally involved in devel-opment of the embryonic nervous system of Drosophila. In a Introduction: The object of this study was to identify independentprevious DNA microarray study we found 56 genes associated predictors for recurrence in meningiomas among histological and with velocity of glioma cell migration (Brain Pathol 15: 46-54, clinical parameters as well as cytogenetic findings. Material and 2005), of which 30 had a Drosophila homolog according to Methods: 189 patients with meningiomas resected at the Clinic for BLAST search. Expression of these genes was examined by using Neurosurgery were followed up. Histological parameters (growth in situ hybridization of Drosophila embryos. Eight genes (Ice, pattern, activity of alkaline phosphatase (AP), and Ki-67 labeling- Pvf1, CG 5226, Pkc 98 E, Ts, Lan A, Tf 2, Fur1) were expressed index [LI]), clinical data (age, gender, and tumour site), and cyto- in the embryonic CNS by either glial cells or neurons and glial genetic findings were investigated in regard to prediction of recur- cells. To reveal possible glia migration defects, flies harboring de- rence by means of univariate analysis (Chi- Square). The estimat- ficiencies and mutations have been analysed by staining for glial ed risk for recurrence was expressed as odds ratio and correspond- cells. In another previous study using human U373MG glioma ing 95% confidence interval (OR, 95% CI). Variables univariately cells and primary glioblastoma cells we found that RGS3 and correlated with recurrence were included in the multivariate model RGS4, which are homologs of the Drosophila glia gene loco in- (multiple linear regression). Results: Within the mean follow up crease migration in vitro (J Neuropathol Exp Neurol 63: 210-22, period of 45 months (range 2-196 months) fourteen patients suf- 2004). In two mutants of the Drosophila homolog loco, fered tumor recurrence after total resection. Multivariate analysis loco&#8710;13 and locoL1, a subtype of lateral glial cells did not revealed patternless growth (OR 14.2, 2.9-69.7), anaplasia (OR reach its correct position at the end of embryonic CNS develop- 135, 15-1215.7), brain invasion (OR 21.1, 5.6-80.3), and loss of ment and stopped more lateral, which could reflect a glia migra- chromosome 1p [1p-] (OR 15.2, 5.6-80.3) as independent risk fac- tion defect. In conclusion, homologous molecular mechanisms un- tors for recurrence. On univariate analysis, “fibroblastic” pheno- derlying both glioma invasion and Drosophila brain development type (“storiform” growth pattern), loss of AP, higher proliferative appear to be rare, while these rare genes are amenable to detailed activity (Ki-67 LI >10%), age > 65 years, and tumor site (convexi- functional analysis using Drosophila as a model system.
ty or posterior cranial fossa) have been shown to correlate signifi-cantly with recurrence. Conclusion: Sheeting, anaplasia, brain in-vasion, and 1p- are independent predictors for recurrence in Tau and alpha-synuclein brainstem pathology in Alzheimer
meningiomas. In practice, the pathologist can reliably estimate the risk for recurrence by considering histomorphology, tumor site, Institute of Clinical Neurobiology, A-1070 Vienna, Austria Neuropathology of mevalonic aciduria (Neuropathologie der
Background: Association between extrapyramidal signs (EPS) in Mevalonazidurie)
Alzheimer disease (AD) with tau and alpha-synuclein (AS) aggre-gation in substantia nigra (SN) have been reported (Burns et al, T. Kirchner*, H. Woelk*, D. May#, B. Ruf+, K. Kuchelmeister*, Neurology 2005;64:1397). Material and methods: 112 autopsy cases (78 female, 34 male, aged 61-99, mean 84.5±7.6 years; *Institut für Neuropathologie, # Institut für Pathologie, +Abtei- 24.5% with clinically reported EPS) underwent immunohisto- lung Neonatologie am Zentrum für Kinderheilkunde und Jugend- chemical assessment of AD pathology, tau and AS lesions in brainstem. Results: All cases of definite AD (Braak stages 5/6) revealed neuronal loss, threads and tangles in SN and locus coeru- Mevalonic aciduria is an inborn error of cholesterol and nonsterol leus (LC), in pontine tegmentum (PT, 86%); AS lesions in SN/ LC isoprenoid biosynthesis caused by mevalonate kinase deficiency.
and amygdala (33% each). Braak 4 (n=24) showed SN/LC tau (87 The disorder is extremely rare with only a few cases reported in and 66.6%), in PT (42%); AS pathology in 32% (SN/LC), stage 3 the literature. Patients with this enzyme defect (which is located at (n=5) had SN/ LC (80%) without AS lesions; stage 2 tau lesions in the beginning of the cholesterol biosynthesis pathway) show a LC; stage 0/1 (n=3) were negative. Higher Braak stages were as- wide range of symptoms which depend on the degree of reduction sociated with increasing brainstem tau and AS in brainstem and of mevalonate kinase activity. In mild forms of the disease only amygdala. 54% of definite AD with EPS revealed brainstem AS recurrent febrile crises occur while in cases with severe enzyme pathology. Those without clinically reported EPS (n=86), had tau defect several neurologic symptoms like developmental delay and inclusions in SN/LC (95%), PT (51%), brainstem AS lesions cerebellar atrophy have been described. We report on a case of an (29%) (7% oblongata), limbic areas and amygdala (11-16%). AD 11-month-old girl, premature birth of the 27th gestational week, with and without EPS showed no differences in SN/LC tau pathol- with mevalonic aciduria who died of pneumonia. Neuropathologi- ogy, while the first group had higher Braak stages. Conclusions: cal examination showed a severe microcephaly with leukoenceph- Our data confirm frequent tau aggregates in brainstem, increasing alopathy with myelination deficit. Cholesterol is an important with AD patholoy, and AS pathology in around one-third of component of myelin sheets and so defects in its biosynthesis duepatients with and without clinically reported EPS. Both lesions, in- to metabolic disturbances are likely to cause leukoencephalopathy.
dicating synergistic relations between tau and AS, suggest their To our knowledge, this is the first neuropathologic autopsy case of role for increasing frequency of EPS as AD progresses, but they also occur in AD patients without clinically reported EPS.
Genetic alteration and aberrant expression of the
Neurodegenerative changes following induction of the
phosphoinositol-3-kinase/Akt pathway genes PIK3CA
interferon pathway by intraventricular delivery of synthetic
and PIKE in glioblastomas
siRNA in rat brain.
C. B. Knobbe, A. Trampe-Kieslich and G. Reifenberger Frank K.H. van Landeghem, Nina Kaempfe, Stefan Angermair, Department of Neuropathology, Heinrich-Heine-University, Düssel- Matthias Truss1, Anja Elstner, Stefan Schreiber, Arpad Von Moers2, Christian Hagemeier1, Christian Woiciechowsky3 and Andreas von Deimling Glioblastomas frequently demonstrate genetic alterations that re- Institute of Neuropathology; 1Department of Pediatric Molecular sult in an aberrant activation of the phosphoinositol-3-kinase Genetics; 2Department of Neuropediatrics; 3Department of Neuro- (Pi3k) / protein kinase B (Akt) signalling pathway. These include surgery, Charité-Universitätsmedizin Berlin, 13344 Berlin most notably PTEN mutation, EGFR amplification and rearrange-ment, as well as CTMP hypermethylation [Knobbe et al., J Natl Inhibition of endogenous gene expression in the central nervous Cancer Inst 2004; 96: 483-486]. In the present study, we investi- system (CNS) can be induced by intraventricular delivery of short gated two further Pi3k/Akt pathway genes, namely PIK3CA interfering RNAs (siRNAs). Recently, it has been shown in vitro (3q26.3) and PIKE (CENTG1, 12q14), for genetic alteration and that inhibition of gene expression by siRNAs induces the interfer- aberrant expression in a series of 97 primary glioblastomas. We on pathway. Here we demonstrate that siRNAs directed against identified somatic mutations of PIK3CA in 5 tumors (5%) by us- class III ß-tubulin can concentration-dependently provoke an in- ing single strand conformation polymorphism (SSCP) analysis fol- terferon response in adult rat CNS causing acute neurodegenera- lowed by direct DNA sequencing. Twelve glioblastomas (12%) tion. Following administration of siRNA or poly I:C, protein lev- showed amplification of the PIKE gene. All 12 tumors had also els of both phosphorylated interferon inducible double stranded amplified the adjacent CDK4 gene. The tumors with PIKE ampli- RNA-dependent protein kinase (PKR) and eukaryotic initiation fication as well as the vast majority of glioblastomas without am- factor 2 alpha (elF2a) were elevated. This response as well as the plification demonstrated increased expression of PIKE-A but not observed neurodegenerative changes were reversed by application PIKE-S/L transcripts as compared to non-neoplastic brain tissue.
of the nonsteroidal antiinflammatory agent ibuprofen. The obser- In summary, our data support an important role of PIK3CA and vation that siRNAs can induce neurodegenerative off-target effects PIKE gene alterations in the molecular pathogenesis of glioblas- should be carefully considered in experimental human study de- tomas and further stress the paramount importance of aberrations in Pi3k/Akt pathway genes in these tumors.
Alpha2-macroglobulin (A2M) and neutrophil elastase (NE)
Generation of Stably Proliferating Neural Precursors from
differently participate in the evolution of atherosclerotic
Human Embryonic Stem Cells
plaques in the circle of Willis
Philipp Koch, Julia Ladewig, Andrea Biegler, Barbara Steinfarz S. Larionov1, O. Dedeck1, G. Birkenmeier2, M. Orantes3, D.R. Thal1 1Department of Neuropathology, University of Bonn Medical Cen- Institute of Reconstructive Neurobiology, University of Bonn Life ter, Bonn, Germany; 2Department of Biochemistry, University of Leipzig, Leipzig, Germany; 3Department of Pathology, MunicipalHospital Offenbach, Offenbach am Main, Germany Controlled differentiation into homogenous somatic cell types aswell as efficient strategies for genetic manipulation are essential to Cerebrovascular atherosclerosis (AS) is currently regarded as a fully exploit the biomedical potential of human embryonic stem complex multifactorial disease of the arterial wall triggered by (hES) cells. We have developed protocols for the derivation of gene-gene and gene- environment interactions and a major cause proliferative PSA-NCAM-positive neural precursors from hES of cerebrovascular infarction. NE plays a pathogenic role in AS by cells. In the presence of EGF and FGF2, these cells can be contin- digesting elastin and collagen fibers, and has a proatherogenic uously propagated as adherent population for at least 50 passages.
function in lipid metabolism. The role of the pan- proteinase inhi- In addition to PSA-NCAM, they show strong expression of nestin, bitor A2M throughout the evolution of AS-plaques in cerebral musashi and A2B5. During proliferation, spontaneous differentia- arteries is still not fully understood. The expression of A2M and tion into beta-III-tubulin(+) neurons and S100-beta(+) astrocytes NE in AS-plaques in the arteries of the circle of Willis from 80 pa- is restricted to less than 1%. Furthermore, the cells can be frozen tients of both genders, aged 61 to 91 years, was examined micros- and thawed without significant loss of their proliferation potential.
copically. Paraffin sections of AS-plaques were immunostained Upon growth factor withdrawal, they consistently give rise to a with antibodies directed against A2M and NE. A2M occurred in dominant fraction of inhibitory, GABAergic neurons and smaller AS-plaques of all stages in the development of AS, NE became fractions of astrocytes and oligodendrocytes. During proliferation, detectable first in the fatty streak lesions as well as in later stages the hES cell-derived neural precursors are readily amenable to ge- of AS-plaques evolution. A2M was seen in the luminal part of the netic manipulation such as transient or stable transfection and plaque, i.e., in the area of intima proliferation whereas NE was retroviral infection. Transfection and subsequent selection enabled mainly located abluminally near the lipid core. There was no co- the generation of stable populations expressing reporter genes or localization of both proteins. A2M and NE were predominantly selectable markers in a cell type-specific pattern. Following trans- found in the extracellular space. The A2M/NE ratio decreased plantation into rat hippocampal slice cultures, the cells were found with increasing histopathological grade of AS. In other words, to migrate and incorporate into the host tissue. Stably proliferating while the amount of A2M remained stable in the AS-plaque the le- neural precursors derived from hES cells may provide a useful vel of NE increased. The marked increase of NE throughout the tool for studying mechanisms of lineage segregation and nervous evolution of AS-plaques indicates a dynamic change of the A2M- NE-equilibrium presumably contributing to vessel wall destructi-on by NE and, in so doing, may explain AS-plaque rupture as wellas ulceration of late-stage plaques. Support: BONFOR-0.154.0041(DRT).
Granular cell tumor of the infundibulum with follicular
Characterisation of neuroblast-dissemination in the injured
lymphatic hyperplasia – case report
and non-injured adult human brain
S. Loeser1, M. Scholz2, R. Pawaresch3, G. Reifenberger1 Jadranka Macas1, Christian Nern1, Josefine von Randow1, 1Institut für Neuropathologie, Heinrich-Heine-Universität, Düssel- Alina Woszczyk2, Kea Franz2, Volker Seifert2, Karl Plate1,
dorf; 2Neurochirurgische Klinik, Knappschaftskrankenhaus, Ruhr- Universität, Bochum; 3Institut für Hämatopathologie, Universität Edinger Institute, Department of Neuropathology1, Department of Neurosurgery2, University Hospital Frankfurt, D-60528 Frankfurt,Germany.
Granular cell tumor of the infundibulum is a rare entity with littleover 50 cases being documented in the literature. Here we report Neurogenesis has been shown to occur throughout life in different on the unique case of a 66-year-old female patient with a history species including humans. Numerous studies describe the contri- of several years of a suprasellar tumor involving the infundibu- bution of endogenous neural stem cells to ongoing neurogenesis as lum. On MRI, the tumor appeared as an isointense and well cir- well as the signals governing this process. Furthermore, there is cumscribed lesion that enhanced after contrast media application.
increasing evidence for the contribution of neural stem/progenitor Because the tumor slowly increased in size over the years, it was cells in the regeneration of the CNS after injury.
decided to perform a surgical resection. Histologically, the tumor In contrast to the rodent brain, the cellular architecture of neu- specimens corresponded to a granular cell tumor composed of en- rogenic regions, but also the properties of migrating neuroblasts larged cells with abundant eosinophilic, granular, strongly PAS- within the adult human brain are much less understood. In our positive cytoplasm and isomorphic small nuclei. Mitotic activity study we are characterising the quantity and dissemination of was low and other signs of anaplasia were absent. Immunohisto- PSA-NCAM expressing migrating neuroblasts in injured and non- chemistry revealed widespread positivity for protein S100 and a injured human brains. We provide evidence, that the adult human MIB1 index of < 2%. However, the tumor featured extensive lym- brain displays a strong response to different types of lesions, in- pho-plamacytic infiltration with formation of typical secondary cluding ischemia and brain tumors, suggesting a previously unrec- lymph follicles. Immunohistochemistry and molecular genetic analysis confirmed the polyclonal nature of the infiltrate. Thus, thefinal histological diagnosis of an infundibular granular cell tumorwith follicular lymphatic hyperplasia and hyperplasia of the mar- Mutational and immunohistochemical analysis of ezrin-,
ginal zone was made. It may be speculated that the marked lym- radixin-, moesin (ERM) molecules in epilepsy associated
pho-plasmacellular infiltration of the tumor tissue reflects a hyper- glioneuronal lesions.
immune reaction against unknown tumor-associated antigens.
Michael Majores1, Volker Schick1, Gudrun Engels1, Jana Fassunke1, Christian E. Elger2, Johannes Schramm3, IngmarBlümcke4, Albert J. Becker1 Prognostic value of MGMT promoter hypermethylation,
TP53 mutation, MDM2, EGFR and CDK4 amplification

Depts. of 1Neuropathology; 2Epileptology and 3Neurosurgery, in malignant glioma patients
University of Bonn Medical Center, Bonn, Germany; 4Dept. ofNeuropathology and Neuropathological Reference Center for Epi- S. Loeser1, C. Luyken2, , B. Blaschke1, S. Köhler2, A. Kreuzmann2, lepsy Surgery, Erlangen Univ., Erlangen, Germany S. Seghrouchni2, G. Reifenberger1, M. Sabel2Departments of 1Neuropathology and 2Neurosurgery, Heinrich- Glio-neuronal lesions are frequently observed in biopsy specimens obtained from patients with pharmacoresistant epilepsies, com-prising focal cortical dysplasias (FCD) and gangliogliomas. The response of malignant gliomas to chemotherapy with alkylat- Recent findings characterize the phosphoinositide 3-kinase (PI3K) ing drugs such as temozolomide varies from patient to patient. The pathway and tuberin/hamartin signaling cascade to be compro- present study investigates the significance of tumor-associated ge- mized in these lesions. Ezrin, radixin and moesin (ERM-/band-4.1 netic aberrations in the TP53, MDM2, EGFR and CDK4 genes, as proteins) genes represent downstream effectors of the PI3K-path- well as the methylation of the MGMT promoter for response to way, are involved in cytoskeleton-membrane interference, cell therapy and survival of 65 patients with malignant gliomas. 61.5% growth, migration and differentiation and harbor tumor suppressor of the patients were males and median age at surgery was 54.4 motifs. Accumulation of band-4.1 proteins has been identified in years. Median survival was 1.6 years for 49 glioblastoma (GBM) cortical tubers of tuberous sclerosis patients, which share neu- patients and 5.3 years for 16 anaplastic glioma (AG) patients. A ropathological similarities with FCD and gangliogliomas. Here, median number of 8 cycles of temozolomide was administered.
we have studied the immunohistochemical distribution pattern of Grade 3 or 4 toxicity occurred in 6 patients. Therapy was termi- ERMs as well as allelic variants occurring in gangliogliomas nated due to tumor progression in 41 patients (5 AG, 31%; (n=20) and focal cortical dysplasias (FCDIIa, n=8; FCDIIb, n=37).
36 GBM, 73%). Statistical analyses revealed that MGMT hyper- Aberrant accumulation of ERMs was observed in dysplastic neu- methylation was significantly associated with longer survival rons of FCDs and gangliogliomas as well as in balloon cells. Ad-(p (log-rank)<0.0001) in the entire patient group. Separate analy- jacent brain tissue without structural abnormalities was used as sis of the GBM group showed a significantly longer time to tumor control and showed only faint neuropil staining. Mutational recurrence or progression under treatment when MGMT was hy- screening revealed silent polymorphisms in the ezrin gene in two permethylated. The percentage of GBM patients showing evidence individuals suffering from FCDIIb. A transition from G to A of of response to temozolomide on neuroimaging was significantly radixin exon 2 resulted in an exchange of valine by isoleucine higher in patients with MGMT methylated GBMs (p=0.0196).
at codon 50 in an additional FCDIIb specimen. Such sequence Neither EGFR, MDM2 and CDK4 amplification nor TP53 muta- alterations were not found in controls. The present data suggest tion were significantly correlated to survival or response to thera- accumulation of ERM expression in dysplastic cellular compo- py. In line with recent publications from other groups, our study nents but do not favor mutational events of ERM in the pathogen- suggests MGMT hypermethylation as a molecular marker that is esis of FCDs or gangliogliomas. Aberrant expression of ERMs is, associated with a higher likelihood for positive response to temo- however, compatible with a compromised PI3K- pathway in glio- zolomide treatment in patients with malignant gliomas. In con- neuronal lesions characterized by abnormal cellular differentiation trast, genetic alterations in the TP53, MDM2, EGFR and CDK4 genes appear to be less important as prognostic factors. Mitochondrial tRNA-Leu(UUR) mutation causes Leigh-like
general, however, inflammatory infiltrates were less dense when encephalopathy in dogs
compared with white matter lesions even in the stage of ongoing Kaspar Matiasek, Sabine Hofmann, Kerstin Baiker, Andrea demyelination. In conclusion, MOG-induced EAE in the common Fischer, Susanne Medl, Wolfgang Schmahl, Klaus-Dieter Gerbitz, marmoset shares key histomorphological features of human corti- cal MS lesions and therefore represents a suitable tool to study thepathogenesis, impact and putative treatment of cortical pathology LS für Neuropathologie, Institut für Tierpathologie – LMU, 80539 Leigh syndrome is the eponym of a subacute necrotizing encepha- CCR2 expression on myeloid cells is sufficient for disease
lopathy (SNE) that results from sporadic or inherited mutations development in a mouse model of multiple sclerosis.
in nuclear or mitochondrial genes responsible for pyruvate dehy- Alexander Mildner, Hauke Schmidt, Harald Pruess, Josef Priller drogenase or respiratory chain complexes I, II, IV or V. Neu- ropathologically, it is characterized by a bilaterally symmetrical,V-shaped, non-contiguous cavitary necrosis of brain stem, thala- Universitätsklinikum Göttingen, Abteilung Neuropathologie, 37075 mus and basal ganglia with both glial decay and proliferation, vas- cular prominence and a remarkable neuronal sparing. Amongstnon-human mammals an encephalopathy with almost identical The β-chemokine monocyte chemoattractant protein-1 (MCP-1,pathology had been observed in Alaskan huskies and Yorkshire CCL2) and its receptor, CCR2, have been implicated in the chron- terriers where mitochondrial aetiology could only be suspected ic inflammatory disease multiple sclerosis (MS) and experimental upon assessment of mitochondrial deformation. In order to uncov- autoimmune encephalomyelitis (EAE), the animal model of MS.
er the molecular pathogenesis of canine Leigh-like encephalopa- EAE is mediated by neuroantigen-specific CD4+ Th1 cells and by thy we investigated 13 affected Yorkshire terriers and 1 Alaskan mononuclear cell infiltrates. Monocyte recruitment to the CNS by husky via muscle biochemistry and genetic testing. Our biochemi- chemokine receptors is a necessary step for EAE development cal analyses revealed combined deficiency of respiratory chain since CCR2-/- mice develop a significant reduced disease. How- complexes I and IV in two animals indicating a mitochondrial ever, CCR2 is broadly expressed on CNS cells such as astrocytes, tRNA defect. Further molecular genetic screening of all 22 mtR- neurons and endothelia as well as on most hematopoietic cells but NAs demonstrated an A-G transition at np 2683 in four Yorkshire the cell-specific role of CCR2 for disease is largely unknown. terriers and the Alaskan husky. The pathogenic role Using bone marrow (BM) chimeric mice our data suggest that theof this tRNA-Leu(UUR) mutation is supported by heteroplasmic lack of CCR2 on radioresistant CNS-resident cells modulates only mutation loads and the fact that corresponding human A3243G slightly disease course whereas hematopoietic CCR2 expression is mutation is associated with mitochondrial multisystem disorders crucial for disease manifestation. To target CCR2 expression only such as MELAS, MERFF, MELAS+MERFF, PEO and HCM.
on myeloid cells we created mixed BM chimeras with BM from Thus, A2683G mutation has been proven causative for SNA in RAG1- /-xCCR2-/-mice. These chimeras were highly susceptible dogs, and provides a valuable model to develop therapeutic strate- to disease similar to wild-type -> wild-type mice indicating that CCR2 on T and B lymphocytes is dispensable for disease. Theseresults clearly indicate a critical function of CCR2 on myeloidcells during autoimmune inflammatory diseases of the CNS.
Extensive cortical demyelination in MOG-induced EAE
in the common marmoset

P0106-125 is a neuritogenic epitope of the peripheral myelin
Doron Merkler1, Barthel Schmelting2, Boldizsár Czéh2, protein P0 and induces autoimmune neuritis in C57BL/6 mice
Eberhard Fuchs2,3,4, Wolfgang Brück 1,3, Christine Stadelmann1 Hrvoje Miletic, Olaf Utermöhlen, Christoph Wedekind, 1Department of Neuropathology, Georg-August University Göttin- Manuel Hermann, Werner Stenzel, Hans Lassmann, Dirk Schlüter, gen, Germany; 2Clinical Neurobiology Laboratory, German Pri- mate Center, Göttingen, Germany; 3Institut für Multiple-Sklerose-Forschung, Bereich Humanmedizin der Universität Göttingen und Universität zu Köln, Abteilung für Neuropathologie, 50931 Köln, Gemeinnützige Hertie-Stiftung, Göttingen, Germany; 4Department of Neurology, Georg-August University Göttingen, Germany The present study describes a new model of autoimmune neuritis Recent studies revealed an important involvement of the cerebral in C57BL/6 mice induced by immunization with the novel neuri- cortex in multiple sclerosis (MS) patients. Different types of le- togenic epitope P0106-125, derived from mouse peripheral myelin sions were proposed according to lesional topography. In addition, protein P0. Immunization with this peptide in combination with cortical lesions in MS were found to be less inflammatory and less pertussis toxin induced high levels of peptide-specific CD4+ destructive than white matter lesions. With regard to cortical T cells in spleen and popliteal lymph nodes. Clinical symptoms ofpathology, there is currently no animal model available which autoimmune neuritis started with a flaccid tail at day 10 post reflects the histopathological features of cortical lesions in MS immunization (p.i.), progressed to moderate paraparesis at day patients. The experimental autoimmune encephalomyelitis (EAE) 15 p.i., declining thereafter with undetectable symptoms at day model is the most widely investigated animal model of MS. Due 40 p.i. Clinical disease activity paralleled decreased sciatic nerve to the structural and functional similarity to human, induction of motor conduction and histopathological alterations of sciatic EAE in the common marmoset (Callithrix jacchus) has turned out nerves. These included inflammatory infiltrates, mainly consisting to be an attractive non-human-primate model for multiple sclero- of iNOS+ macrophages and CD4+ T cells. These data fit into the sis. In the present study we investigated the presence of cortical pathogenetic concept of murine autoimmune neuritis as a CD4+ pathology in common marmoset EAE upon immunization against TH1 cell-mediated immunopathology. Our new mouse model pro- myelin oligodendrocyte glycoprotein (MOG). Immunohistochemi- vides an attractive tool to identify critical factors, which regulate cal staining against myelin basic protein (MBP) revealed exten- the severity of autoimmune responses in the peripheral nervous sive cortical demyelination in diseased animals which reflected the topographically distinct lesion types described in MS patients.
Actively demyelinating lesions of cerebral cortex were mainlycomposed of MRP14+ macrophages/microglia and few T-cells. In Increase of macrophage migration inhibitory factor (MIF)
Multiple thromboembolic events in fetofetal transfusion
expression in human malignant glioma may contribute to
in monochorionic triplets explaining pathogenesis
immune escape and proliferation.
of hydranencephaly.
M. Mittelbronn1, R. Meyermann1, M. Weller2, J. Wischhusen2 M. Mittelbronn1, B. Goeppert1, R. Meyermann1, 1Institute of Brain Research, University of Tuebingen, Germany; 2Department of General Neurology and Hertie-Institut für Clinical 1Institute of Brain Research, University of Tuebingen, Germany; Brain Research, University of Tuebingen, Germany 2Department of Gynecology, University of Bern, Switzerland;3Department of Gynecology, University of Tuebingen, Germany; Macrophage migration inhibitory factor (MIF) has been suggested 4Institute of Pathology, University of Tuebingen, Germany to suppress anti-tumor immune surveillance, to inhibit p53-medi-ated apoptosis and to promote tumor angiogenesis. The biological Much argument about the pathogenesis of hydranencephaly arose role in human glioblastoma has not been defined. We examined over the last 180 years. The disputants favourised infectious, MIF expression in 200 gliomas and 15 normal control brains by aplastic and vascular etiology respectively. Here, we report the immunohistochemistry and in 12 glioma cell lines by quantitative case of monochorionic triplets of the 22nd week of gestation with RT-PCR and Western blot. MIF RNA expression in glioma cell fetofetal transfusion syndrome of which two fetuses developed lines was elevated up to 1000-fold in malignant gliomas in qRT- almost similar hydranencephaly histologically characterized by PCR compared with normal brain. These data correlated with the tissue necrosis, macrophage invasion, endothelial proliferation protein levels measured in western blots. Immunohistochemistry (and partially the pattern of polymicrogyria) in both cases while showed a clear de novo MIF protein expression beginning in one exhibited the features of a fetus papyraceus. In the monochori- WHO grade II glioma, persisting also in higher grades (III-IV). Of onic triamnial placenta, multiple arterio-venous anastomoses in note, all wild-type p53-retaining glioma cell lines showed high the chorionic plate and in the villi were present leading to visceralexpression levels of MIF which may be explained by the previous- infarcts in kidney, lung and spleen in one fetus (in fetus II). The ly described role of MIF as a negative regulator of wild-type p53 pathogenesis of hydranencephaly in both fetuses is most likely signaling in tumor cells. Natural killer (NK)–cell-mediated lysis of induced by a thromboembolic vascular disorder as well as the glioma cells was inhibited by the pretreatment of activated NK infarcts in lung, kidney and spleen of fetus II. These findings con- cells with recombinant MIF. In conclusion, we show that human tribute to the understanding of the pathogenesis of hydranencen- gliomas express MIF in vitro and in vivo and we provide prelimi- phaly as a vascular pathology at least in cases of fetofetal transfu- nary evidence that MIF contributes to the immune escape of ma- lignant gliomas by counteracting NK cell-mediated tumor immunesurveillance.
Influences of Activated Microglia on the Membrane
Resting Potential and the Gap Junction Communication

Elevated HLA-E levels in grade IV but not in grade II
of an Astroglial Cell Line
and III human glioma correlate with infiltrating CD8+
Caroline Möller, Aiden Haghikia, Katharina Heupel, Daniel cytotoxic/NK-cells.
Hinkerohe, Dirk Smikalla, Dominika Szlachta, Rolf Dermietzel M. Mittelbronn1, B. Bunz1, P. Harter1, H. Schlaszus1, A. Schleich1, D. Capper1, B. Goeppert1, R. Meyermann1, J. Wischhusen2, Abteilung für Neuroanatomie und Molekulare Hirnforschung, Ruhr-Universität Bochum, 33790 Halle (Westf.), Deutschland 1Institute of Brain Research, University of Tuebingen, Germany;2Interdisciplinary Centre for Clinical Research, Department of Astrocytes are essential for proper brain functions by providingGynecology, University of Wuerzburg, Germany; 3Department of an optimal extracellular environment for neurons. Under inflam- Sports Medicine, University of Tuebingen, Germany.
matory conditions, microglia, the resident brain macrophages,are activated and produce proinflammatory cytokines which can Natural killer (NK) and cytolytic T-cells express human leukocyte disturb the electrophysiological functions of astrocytes. We stud- antigen (HLA) class I-specific inhibitory receptors. Their ligand, ied the influence of activated microglia on the membrane resting the nonclassical MHC-I protein HLA-E is known to be responsi- potential (MRP) and the intercellular coupling of a rat glial cell ble for the tumor escape from T- and NK-cell immune surveil- line (wild-type Sprague-Dawley rat). The astroglial cells were lance. Until now, no data concerning the situation in human glio- cocultured with microglia. In addition some samples were incu- ma in vivo is available. Therefore, we investigated 200 human bated with Lipopolysaccharide (LPS), a cell wall component of gliomas of WHO I to IV for their HLA-E-expression by tissue gram-negative bacteria, to activate microglia. The MRP andmicro array (TMA). Furthermore, infiltrating cytolytic T- and functional dye-coupling were measured with patch clamp tech-NK-cells were immunohistochemically assessed by a monoclonal nique. Microglia activation and expression of the gap junction antibody directed against human CD8 alpha chain which is ex- protein Connexin 43 (Cx43) were detected using immunofluores- pressed on both cell types. Our results show that the tumor cells cence. A significant depolarisation of the MRP was measured at significantly increase their HLA-E expression in high grade glio- cells which were cocultured with microglia under all tested con- ma compared to WHO grade II glioma and normal brain. In addi- ditions. This effect was strongest at samples which had addition- tion, tumor groups dichotomized by the absence or presence of ally been incubated with LPS for 24 hours. In contrast, incuba- CD8+ cells revealed significantly higher HLA-E expression levels tion of the cell line with LPS in the absence of microglia did not for WHO grade IV but not for grade II and III tumors infiltrated cause a significant depolarisation. The functional coupling and by T-/NK-cells. As HLA-E is known to be upregulated by gamma Cx43 expression of the cell line were not affected under the test- interferon, one can assume that increasing HLA-E levels in human ed conditions. We conclude that activated microglia are impor- glioblastomas are at least partly due to infiltrating immune cell tant to mediate inflammatory influences on the electrophysiolog- populations. These findings suggest that overexpression of HLA-E ical functions of astrocytes. In vivo the depolarisation of astro- mediates resistance to immune surveillance in human malignant cytes’ MRP could cause disturbance of astrocytic voltage depen- glioma as a secondary effect only observed in glioblastomas by dent functions like spatial buffering of potassium or uptake of counteracting cytotoxic T- and NK-cell infiltration.
glutamate and may thus lead to clinical symptoms like seizuresor psychomotoric slowing in various inflammatory diseases ofthe CNS.
Molecular genetic alterations detected in a myxopapillary
Morphological findings of muscles, nerves and spinal cord
ependymoma with malignant transformation
in a severe case of spinal muscle atrophy (SMA type I)
Camelia-Maria Monoranu, Inna Lukashova-v. Zangen, Giles K. Müller1, Ch. Müller2, J. Kirschner2, S. Rudnik-Schöneborn3,

Source: http://www.dgnn.de/kongress2005/download/2005Abstracts.pdf

anzoc.org.au

Policy for Assessment and Recognition of Overseas Assessment and Regulatory Authorities Preamble The Osteopathy Board of Australia (OBA) wishes to offer a Competent Authority Pathway (CAP) for registration of osteopaths who have qualifications gained outside Australia and New Zealand. Overseas assessing authorities may offer, or have offered, more than one pathway to registration.

Untitled

A new breath of life for anoxia Emmanuelle Pucéat UMR CNRS 5561 Biogéosciences, Université de Bourgogne, 6 bd. Gabriel, 21000 Dijon, France The middle of the Cretaceous (120–80 Ma) was one of the warmest named “Demerara bottom water mass.” Local exchange with aeolian or periods of the past 300 m.y., with tropical sea-surface temperatures well riverine particles weathered from the

Copyright © 2010-2014 Drugstore Pdf Search