bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparative study on the expression of stress‐response protein (srp) 72, srp27, αB‐crystallin and ubiquitin in brain tumours. An immunohistochemical investigation
Authors: Kato S. , Hirano A. , Kato M. , Herz F. , Ohama E.
Published: May 2008

This immunohistochemical study compares the expression of stress‐response (heat‐shock) protein (srp) 72, srp 27, αB‐crystallin and ubiquitin in 86 primary human brain tumours and 21 carcinoma metastases to the central nervous system. Normal brain tissues were included for control purposes. Serial sections of formalin‐fixed, paraffin‐embedded tissues were used. Most meningiomas (17/23), glioblastomas (11/12) and breast carcinoma metastases (9/10) and some astrocytomas (7/13), pituitary tumours (4/9) and lung cancer metastases (5/11) had tumour cells that reacted with one or more of the antibodies used. Around 43% of the meningiomas and 25% of the glioblastomas expressed srp 72 only. Sole expression of srp 2 7, αB‐crystallin or ubiquitin was seen in several tumours. Some meningiomas (3/23) and breast cancer metastases (4/10) co‐expressed srp 72 and srp 27, and 1/3 of the glioblastomas co‐expressed srp 27 and αB‐crystallin. We conclude that primary and metastatic tumours of the brain produce stress‐related proteins and that certain tumours concurrently express two or more srp's.
Selective vulnerability in acute energy deprivation syndromes
Authors: Cavanagh J. B.
Published: May 2008

The topography and cellular events in the experimental lesions caused by chlorosugars, 6‐aminonicotinamide, dinitrobenzene and tribromoimidazole in animals are considered in relation to those features in human acute thiamine deficiency (Wernicke's) encephalopathy and for comparison in Leigh's disease. The topography and cellular changes when closely examined are different and particular to each condition, although there is a basic cellular process common to all. The pathogenesis of each condition must be considered as multifactorial and a search for the factors responsible for the neuronal and cellular selective vulnerability of different regions of the neuraxis will lead us to understanding the pathogenesis of the disease process in each instance. The experimental models offer much for the understanding of the human conditions, particularly in the search for satisfactory therapeutic strategies.
The neurotoxicity of α‐chlorohydrin in rats and mice: II. Lesion topography and factors in selective vulnerability in acute energy deprivation syndromes
Authors: Cavanagh J. B. , Nolan C. C.
Published: May 2008

Mice and rats have been found almost equally susceptible to (R, S)‐α‐chlorohydrin neurotoxicity, but in rats the distribution of lesions in the neuraxis is less widespread. The topography of the brain lesions shows an incomplete relationship to the regional hierarchy of local glucose utilization in rats and local cerebral blood flow in mice, suggesting that other, unknown, factors also play roles in determining this. Evidence suggesting progressive tonotopic selective vulnerability was found in inferior colliculi in rats given five doses of 50 mg/kg/day. Distinct differences in the patterns of damage to brain stem centres found with chlorohydrin by comparison with other acute energy deprivation syndromes, despite the proximity of the metabolic lesions along the energy generation pathway, suggests there are other unrecognized factors that play a role in determining whether a neuronal centre is at risk or not.
Anti‐NKH‐1 antibody specifically stains unmyelinated fibres and non‐myelinating Schwann cell columns in humans
Authors: Forestier N. Le , Lescs M‐C. , Gherardi R. K.
Published: May 2008

Anti‐NKH‐1 antibody recognizes an isoform of the neural cell adhesion molecule (N‐CAM) that is involved in cell‐cell interactions during embryonic stages and has been detected in skin autonomic nerves. The specificity of anti‐NKH‐1 antibody for human unmyelinated fibres (UF) and the distribution of the antigens recognized by this antibody at the ultrastructural level, were evaluated by immunohistochemistry and immunoelectron microscopy on nerve biopsy samples from patients with normal nerve biopsies and a variety of peripheral neuropathies. The anti‐NKH‐1 antibody strongly stained all unmyelinated fibres while no myelinated fibre was stained. Autonomic nerve fibres were visualized at the periphery of blood vessels. Immunoelectron microscopy showed that the antigen recognized by the antibody was located at Schwann cell‐axon interfaces and in portions of joined Schwannian surfaces, i.e. along mesaxons of non‐myelinating Schwann cells. Expression of NKH‐1 was basically similar in normal and diseased nerves as expression of NKH‐1 was similar at the level of apposed plate‐like Schwann cell processes than along normal mesaxons. The extent of labelling of diseased nerves by the anti‐NKH‐1 antibody likely depended on the number of residual Schwann cell columns observed by light microscopy.
A rapid and non‐radioactive PCR based assay for the detection of allelic loss in human gliomas
Authors: von Deimling A. , Bender B. , Louis D. N. , Wiestler O. D.
Published: May 2008

Studies of the loss of allelic heterozygosity (LOH) in tumour tissues have evolved as an important tool for the identification of chromosomal regions which are likely to harbour tumour suppressor genes. The classical procedure to determine LOH has been restriction fragment length polymorphism (RFLP) analysis and Southern blotting, a time consuming method requiring radioisotopes and several micrograms of DNA. Recently, the use of highly polymorphic microsatellites of the CA‐dinucleotide repeat class and polymerase chain reaction (PCR) has considerably advanced and facilitated the detection of LOH in tumour tissues. We here describe a strategy to identify LOH based on PCR amplification of CA‐dinucleotide repeats, denaturing polyacrylamide gel electrophoresis (PAGE) and nucleic acid detection with a sensitive silver staining protocol. In a comparative study of 20 astro‐cytomas, this rapid technique was able to identify all cases of LOH on chromosome 17 p that had previously been found in these tumours by RFLP analysis and Southern blotting. This non‐radioactive PCR based assay has a great potential for LOH studies in human tumours.
Partial reversal of aluminium‐induced neurofibrillary degeneration by desferrioxamine in adult male rabbits
Authors: Savory J. , Herman M. M. , Erasmus R. T. , Boyd J. C. , Wills M. R.
Published: May 2008

J. Savory, M. M. Herman, R. T. Erasmus, J. C. Boyd and M. R. Wills (1994) Neuropathology and Applied Neurobiology 20, 31–37

Partial reversal of aluminium–induced neurofibrillary degeneration by desferrioxamine in adult male rabbits

Desferrioxamine, a chelating agent with a high affinity for aluminium, has been reported to slow the clinical progression of dementia associated with Alzheimer's disease [4], We report here the effects of desferrioxamine treatment on aluminium–induced neurofibrillary degeneration in rabbits. Adult male New Zealand white rabbits received a single injection of aluminium–maltolate into the lateral cerebral ventricle. Three days later, one group of rabbits was treated with intramuscular injections of desferrioxamine twice daily; a second group received saline instead of desferrioxamine. Both groups were sacrificed 4 or 5 days following initiation of desferrioxamine or saline treatment. Minimal neurofibrillary degeneration was found in two of six desferrioxamine–treated rabbits, while all six rabbits treated with saline showed extensive neurofibrillary degeneration, particularly in the ventral horn of the lower spinal cord. Quantitation of the neurofibrillary degeneration in ventral horn neurons of lumbar cord revealed 30% to be affected in saline–treated animals compared to zero affected neurons following desferrioxamine treatment. When sacrificed just 3 days after aluminium treatment, 50% of the rabbits already revealed neurofibrillary degeneration, corresponding to the timepoint when desferrioxamine treatment was begun in the above animals; on quantitation, 7.5% of ventral lumbar cord neurons were involved. These findings indicate a partial reversal of aluminium–induced neurodegeneration by desferrioxamine. Delaying desferrioxamine treatment to 6 days after aluminium administration prevented any reversal of the aluminium effect; all animals had abundant neurofibrillary degeneration as well as a striking basophilic spicular deposit of calcium and argyrophilic material in the leptomeninges, lateral ventricles and brain parenchyma adjacent to these areas. Pre–treatment of rabbits with desferrioxamine did not provide the expected protective effect against aluminium–induced neurofibrillary degeneration. No pathological effects were observed when saline or desferrioxamine were given alone, without aluminium
The Purkinje cell in olivopontocerebellar atrophy. A Golgi and immunocytochemical study
Authors: Ferrer I. , Genist D. , Davalos A. , Bernado L. , Sant F. , Serrano T.
Published: May 2008

Purkinje cells were examined in three familial cases of olivopontocerebellar atrophy (OPCA) by means of the Golgi method, and neurofilament and calcium–binding protein immunocytochemistry. Reduced dendritic arborizations, as seen with different techniques, early formation of axonal spheroids, and abnormal accumulation of phosphorylated neurofilament epitopes in dendrites, somata and axonal spheroids, together with limited formation of proximal spine–like protrusions were the main changes in Purkinje cells. These lesions are unlikely to be the consequence of anterograde degeneration secondary to olivary atrophy, as postulated by some investigators, but probably represent primary damage to Purkinje cells in patients with OPCA. Reduced dendritic arborizations result in a decrease of receptor sites for parallel fibres and deprive granule cells of their main targets. Abnormal accumulation of neurofilaments in somata, dendrites and axonal spheroids may contribute to an abnormal transport and may impair protein turnover in the distal regions of Purkinje cells.
Microsatellite analysis of loss of heterozygosity on chromosomes 9q, 11 p and 17p in medulloblastomas
Authors: Albrecht S. , von Deimling A. , Pietsch T. , Giangaspero F. , Brandner S. , Kleihuest P. , Wiestler O. D.
Published: May 2008

Medulloblastoma (MB) is a primitive neuroectodermal tumour of the cerebellum whose pathogenesis is poorly understood. Previous studies suggest a role for loci on chromosomes 11p and 17p in the pathogenesis of MB. Evidence for another potential MB locus has recently emerged from studies on Gorlin syndrome (GS). an autosomal dominant syndrome with multiple basal cell carcinomas, epithelial jaw cysts, and skeletal anomalies. Since GS can be associated with MB, we examined sporadic (non–GS) cases of MB for evidence of loss of heterozygosity (LOH) on chromosome 9 where a putative GS locus has been localized to band q31. Nineteen paired blood and MB DNA specimens from 16 patients (11 primary tumours, two primary with recurrent tumours, one primary tumour and cell line, two cell lines) were studied by PCR analysis of microsatellites at D9S55 (9pl2). D9S15 (9ql3–q21.1). D9S127 (9q21.1–21.3). D9S12 (9q22.3), D9S58 (9q22.3–q31), D9S109 (9q31), D9S53 (9q31), GSN (9q33), D9S60 (9q33–q34), D9S65 (9q33–q34), ASS (9q34), D9S67 (9q34.3), TH (llpl5.5). D11S490 (llq23.3), D17S261 (17pll.2–12), D17S520 (17pl2), TP53 (17pl3.1). D17S5 (17pl3.3), D17S515 (17q22–qter), and by RFLP analysis at the WT–1 locus (lip 13). Only two tumours had LOH on 9q. One was non–informative at D9S15, D9S65, and GSN but showed LOH at D9S127, D9S12, D9S58, D9S109, D9S53, D9S60, ASS, and D9S67. The other was uninterpretable at D9S65 and non–informative at D9S15, D9S58, D9S53, and D9S67 but exhibited LOH at D9S127, D9S12, D9S109, GSN, D9S60, and ASS. Both these cases were informative at D9S55 without LOH. These results are compatible with loss of most if not all of one copy of 9q in both tumours. None of the 19 specimens had LOH on 11p. Seven tumours showed LOH on 17p including four with LOH at all four 17p loci examined. None of the tumours with LOH on 9q had LOH on 17p and vice–versa. These data suggest that LOH on 9q occurs rarely in sporadic MB. This does not rule out a role for the GS locus in sporadic MB but makes it less likely.
Excitatory amino acids, free radicals and the pathogenesis of motor neuron disease
Authors: Zeman S. , Lloyd C. , Meldrum B. , Leigh P. N.
Published: May 2008

The cause of motor neuron disease (MND) remains unknown, but the pathogenic involvement of excitatory amino acid (EAA) neurotransmitters and related exogenous compounds has been proposed. We discuss current concepts of the mechanisms of action of EAAs and the evidence for links between these neurotransmitters and free radical hypotheses of neuronal damage. These concepts are especially pertinent following reports of mutations in the gene encoding the free radical scavenging enzyme, copper‐zinc superoxide dismutase, in familial MND. New approaches to treatment are suggested by advances in understanding of the disease.
Skeletal muscle involvement in HIV‐infected patients
Authors: Gherardi R. K.
Published: May 2008

Skeletal muscle involvement may occur at all stages of human immunodeficiency virus (HlV)‐infecuon, and represents the first manifestation of the disease in some patients. There have been many controversies about the classification of myopathies related to HIV infection. We usually classify muscle involvement in HIV–infected patients in one of the following categories: (1) HIV–associated myopathy, a myopathy that meets the criteria for polymyositis in a majority of patients, and those for acquired nemaline myopathy in some; (2) zidovudine myopathy, a reversible mitochondrial myopathy; (3) the HIV–wasting syndrome and other AIDS–associated cachexias; (4) opportunistic infections and tumoral infiltrations of skeletal muscle; (5) vasculitic processes and iron pigment deposits. Immunohistology for major histocompatibility complex class I antigen and the histochemical reaction for cytochrome C oxidase are helpful in correctly classifying a myopathy as HIV polymyositis or zidovudine myopathy respectively. Studies of circulating levels and tissue expression of cytokines in HIV–infected patients have yielded new insights into the pathogenesis of the various AIDS–associated muscle disorders.
Primary central nervous system malignant non–Hodgkin's lymphomas from HIV‐infected and non‐infected patients:expression of cellular surface proteins and Epstein‐Barr viral markers
Authors: Auperin I. , Mikol J. , Oksenhendler E. , Thiebaut J. B. , Brunet M. , Dupont B. , Morinet F.
Published: May 2008

The increased incidence of primary central nervous system malignant non–Hodgkin's lymphomas (PCNSL) in HIV– and non–HIV–infected patients and the demonstration of Epstein–Barr virus (EBV) in these tumours may indicate relationships between PCNSL and EBV. Consequently expression of EBV–induced antigens and cellular markers were studied in 11 HIV–infected and seven non–infected patients by in situ hybridization (ISH) and immunocytochemistry in monoclonal B cell PCNSL. In HIV–infected patients EBV genome was present in 9/11 cases, LMP in 11/11 cases and EBNA2 in 10/11 cases. The expression of adhesion and activation molecules was low or absent. In HIV non–infected patients, EBV genome was present in 5/7 cases, with LMP in 4/7 cases. EBNA2 was never detected. All these lymphomas expressed LFAlbeta. Whatever the population, no lytic cycle EBV markers were detected. Compared with other types of EBV lymphomas, our results suggest a different EBV latency state in primary B cell lymphomas of the CNS from HIV–infected or non–infected patients.
CD44 plays a role in adhesive interactions between glioma cells and extracellular matrix components
Authors: Radotra B. , McCormick D. , Crockard A.
Published: May 2008

Glioma invasion is a complex process involving interactions of tumour cells with host cells and extracellular matrix (ECM). The initial event in the process is recognition and attachment of glioma cells to specific ECM molecules prior to migration into proteolytically modified matrix. In comparison with other tissues, brain ECM is a relatively amorphous matrix which contains glycosaminoglycans including hyaluronan (HA). Recently CD44 which is a transmembrane adhesion molecule found on a wide variety of cells, has been suggested as the principal cell surface receptor for HA. In the present in vitro investigation we have analysed the role of CD44 in adhesive interactions between human gliomas and ECM. Our experimental procedures included immunocytochemistry, immunoblotting, in vitro adhesion assay and flow cytometry. CD44 was expressed on the surface of all gliomas analysed (9) and the level of expression showed no correlation with tumour grade. Eighty, 95 and 120 kDa isoforms were demonstrated by immunoblotting. In an adhesion blocking assay it was found that ligation of CD44 with specific antibody resulted in reduced adhesion to hyaluronan. chondroitin sulphate, fibronectin, laminin, collagen IV and Matrigel™. We conclude that CD44 is involved in adhesion of glioma cells to a wide range of ECM components.
How to detect gold, silver and mercury in human brain and other tissues by autometallographic silver amplification
Authors: Danscher G. , Stoltenberg M. , Juhl S.
Published: May 2008

Gold, silver, mercury and zinc bind chemically to sulphide or selenide ions and create crystal lattices that can be detected in histological sections by a silver amplification technique called autometallography (AMG). The technique specifically magnifies such nanometer–sized catalytic crystals. For each metal, a detailed protocol has been worked out. If several different AMG metals/metal molecules are present in the same tissue, it is possible to distinguish one from another. The AMG technique is based on the capability of small crystal lattices of the aforementioned metals and metal molecules to initiate AMG silver amplification. Electrons released from adhering hydroquinone molecules reduce silver ions that are integrally connected with the crystal lattices. In this manner, particles consisting of only a few atoms of, say, gold, or molecules of mercury selenide (Figure 1), can be silver amplified to a size at which they can be detected in the electron microscope, or even further to dimensions that can be observed in the light microscope. Thus the AMG technique opens up the possibility of visualizing gold, e.g. in the nervous system of rheumatic patients who have been treated with aurothiomalate. Mercury can similarly be visualized in tissues from individuals who have been exposed to mercury, either through leaching from amalgam dental fillings, through eating fish, or by occupational exposure, and silver in the central (CNS) and peripheral nervous systems (PNS) and other tissues from individuals exposed to silver in one form or another.

In the future, the possibility of demonstrating vesicular zinc, a particular pool of endogenous zinc that is found in terminals of zinc–enriched neurons (ZEN neurons), might prove valuable for pathological interpretation of diseases such as Alzheimer's disease The vesicular zinc, present in some of the synaptic vesicles of ZEN neuron terminals, is most impressively demonstrated by AMG in telencephalic structures. It is becoming increasingly indisputable that vesicular zinc is related to synaptic activity influencing or modulating facilitatory synapses. ZEN neurons are probably a sub–population of glutaminergic neurons. A technique for the post–mortem demonstration of vesicular zinc in terminals of ZEN neurons in human brains is therefore urgently required.
Transferrin receptors in the Parkinsonian midbrain
Authors: Morris C. M. , Candy J. M. , Omar S. , Bloxham C. A. , Edwardson J. A.
Published: May 2008

Several hypotheses have been put forward to explain the pathogenesis of Parkinson's disease (PD) and recently it has been suggested that alterations in iron homeostasis may be implicated. Because of the central role of the transferrin receptor in providing access of iron to cells, we have studied the distribution and density of transferrin receptors using [3H]–transferrin ([3H]–Tf) binding and tritium film autoradiography in the normal and PD midbrain. High levels of [3H]–Tf binding were found in the dorsal raphé, oculomotor nucleus and periaqueduc tal grey whilst lower levels of [3H]–Tf binding were found in the tegmentum, red nucleus and substantia nigra. Significant reductions in binding were found in the substantia nigra, red nucleus and oculomotor nucleus in PD, the reductions in [3H]–Tf binding being similar to the loss of nigral neurons in PD. The data suggest that the increased iron content of surviving nigral neurons may reflect a compensatory metabolic response rather than abnormal transferrin receptor expression.
Are Schwann cells essential for axonal regeneration into muscle autografts?
Authors: Enver M. K. , Hall S. M.
Published: May 2008

When axons regenerate through frozen–thawed (FT) muscle grafts, they are accompanied by co–migrating Schwann cells derived from the nerve stumps. Although acellular, FT muscle grafts contain an internal scaffold of basal laminae rich in components capable of supporting neurite outgrowth in vitro such as laminin and fibronectin: it is not known whether Schwann cells are essential for axonal regrowth within these grafts. In this paper we test the hypothesis that sarcolemmal basal laminae will support axonal regeneration in the absence of Schwann cells. Two groups of 12 adult Wistar rats were used. All rats received a 0.5 cm FT muscle graft, and 12 rats also received a subperineurial injection of the anti–mi to tic agent mitomycin C (400 μg/ml in physiological saline) prior to grafting. Previous studies have shown that this dose effectively depresses cell proliferation within the endoneurium for 3–4 weeks [17, 18, 28]. Rats were killed (n= 3) 1, 2, 3 or 4 weeks later. The spatio–temporal sequence of axonal regeneration into the grafts was assessed histologically, by immunofluorescence using antibodies against GAP–43; S–100; RT97; laminin and macrophages (EDI), and by transmission electron microscopy. Outgrowth of almost all axons from the mitomycin C–treated proximal stumps was delayed for up to 3 weeks, after which time vigorous regeneration occurred into the persisting tubes of sarcolemmal basal lamina. All axons regenerating within the grafts (irrespective of mitomycin C–treatment) were accompanied by co–migrating Schwann cells. The results suggest that Schwann cells play an important role in axonal regeneration across FT muscle autografts and that sarcolemmal basal laminae alone are insufficient to support axonal regeneration.
Overexpression of the 18A2/mts1 gene and down–regulation of the TIMP–2 gene in invasive human glioma cell lines in vitro
Authors: Merzak A. , Parker C. , Koochekpour S. , Sherbet G. V. , Pilkington G. J.
Published: May 2008

Invasion of the reconstituted extracellular matrix composite, Matrigel, by eight human glioma–derived cell lines and human fetal brain cells was assessed in vitro using 8 um polycarbonate filters in a modified Boyden migration chamber. With the exception of one low grade glioma derived cell line, all lines studied proved to be invasive while normal fetal brain cells failed to invade. This invasive potential was independent of the histological grade of the tumour from which the cell lines originated. In addition, the expression of the metastasis–associated gene 18A2lmts1 as well as the tissue inhibitor of metalloproteinases–2 (TIMP–2) was analysed in each of the glioma–derived cell lines. The 18A2/mtsl was expressed in all the cells studied with the exception of fetal brain cells and the low grade non–invasive glioma derived IPRK–7 cell line. The 18A2/mtsl related genes coding for the S100 subfamily of calcium binding proteins were found to be differentially and overexpressed in invasive cell lines. TIMP–2 was expressed only in noninvasive cell lines. These results suggest that the 18A2/ mtsl and TIMP–2 genes could play an important role in the invasive behaviour of human glioma cells in vitro..
Association of measles virus with neurofibrillary tangles in subacute sclerosing panencephalitis: a combined in situ hybridization and immunocytochemical investigation
Authors: McQuaid S. , Allen I. V. , McMahon J. , Kirk J.
Published: May 2008

Neurofibrillary tangle formation, a cardinal characteristic of Alzheimer's disease, is also a feature of several other neurodegenerative disorders, including subacute sclerosing panencephalitis (SSPE). In the present study the association of measles virus genome with neurofibrillary tangle formation has been studied in five cases of SSPE, using in situ hybridization (measles genome) and immunocytochemistry (tau, ubiquitin and p7A4 amyloid). In two cases with duration of disease less than one year, neurofibrillary tangle formation was not observed. However, in those cases in which the disease was of several years duration, numerous tau– and ubiquitin positive neurofibrillary tangles were demonstrated. In the two cases of longest duration, double–labelling techniques demonstrated the frequent association of neurofibrillary tangle formation with neuronal measles virus genome positivity. Immunocytochemistry for p7A4 amyloid failed to demonstrate amyloid in any of the five cases. These findings support the hypothesis that neurofibrillary tangle formation can occur independently of amyloid formation and that this mechanism may operate in both Alzheimer's disease and in virallyinduced disease.
Iatrogenic Creutzfeldt—Jakob disease in three growth hormone recipients: a neuropathological study
Authors: de Villemeur T. Billette , Gelot A. , Deslys J. P. , Dormont D. , Duyckaerts Ch. , Jardin L. , Denni J. , Robain O.
Published: May 2008

Since 1985, several cases of Creutzfeldt–Jakob disease, occurring after a treatment by human cadaveric hormone have been reported. Three new iatrogenic cases observed in French patients (two children and one young adult) are described here. Neuropathological study displayed the classical aspects of previously reported sporadic cases of Creutzfeldt–Jakob disease in adults, including severe cortical spongiform change with numerous vacuoles within neuronal dendrites, diffuse astrogliosis and neuronal loss. In addition, the iatrogenic cases described here included two more unusual points: (i) they were homozygotic for the PrP gene on codon 129 and therefore a genetic predisposition could be suspected; (ii) numerous kuru plaques were scattered in the cerebral cortex, the subcortical white matter and in the cerebellar cortex. They were decorated with a PrP monoclonal antibody, but not with a βA4 antibody. This last point underlines the similarities between iatrogenic Creutzfeldt–Jakob disease and kuru.
The familial syndrome of proliferative vasculopathy and hydranencephaly‐hydrocephaly: immunocytochemicaI and uItrastructuraI evidence for endothelial proliferation
Authors: Harding B. N. , Ramani P. , Thurley P.
Published: May 2008

This is the fourth report of Fowler‐type hydranencephaly, or proliferative vasculopathy and hydranencephaly‐hydrocephaly (PVHH), and is both the first case in Europe and the first case reported in an Asian family. A 17‐week fetus showed severe arthrogryposis, pterygia and muscular hypoplasia. Massive cystic dilatation of the cerebral ventricles with thin disorganized pallium was associated with calcifications and characteristic glom‐eruloid vasculopathy throughout the CNS. Hydranencephaly in a previous pregnancy was demonstrated ultrasonographically at 13 weeks gestation. The glomeruloid vasculopathy, unique to this disorder, has ill‐defined vascular channels, prominent reticulin network and inclusion‐bearing cells which our immunocytological and ultrastructural studies suggest are endothelial cells. Aetiopathogenesis remains uncertain: previous hypotheses include congenital infection or primary neuro‐ectodermal failure. Our present clinical and morphological findings suggest a primary role for the glomeruloid vasculopathy at the time of vascular invasion of the cerebral mantle during the first trimester. Previous and present case data support autosomal recessive inheritance, in contradistinction to sporadic, encephaloclastic, hydranencephaly from which PVHH can be readily differentiated by microscopic examination.
Oculopharyngeal muscular dystrophy: clinical and morphological follow‐up study reveals mitochondrial alterations and unique nuclear inclusions in a severe autosomal recessive type
Authors: Schröder J. M. , Krabbe B. , Weis J.
Published: May 2008

Oculopharyngeal muscular dystrophy (OPMD) is usually a late onset, autosomal dominant dystrophy that affects extraocular eye muscles, pharyngeal muscles, and the trunk and limb musculature. In the present presumably recessively inherited case, with a clinical history of oculopharyngeal myopathy and distal weakness, paracrystalline mitochondrial inclusions and unique nuclear inclusions were found. In a biopsy obtained from the erector spinae muscle, marked muscle fibre atrophy and hypertrophy, occasional muscle fibre necrosis, and considerable fibrosis of the endomysium were noted. Similar signs of a chronic myopathy could already be detected in a biopsy from the anterior tibial muscle that had been obtained 10 years before. In both muscles, nuclear inclusions were seen in numerous severely affected, atrophic muscle fibres. These inclusions consisted of straight or helically wound 2–4 nm filaments. The outer diameter of the double helix was 12–15 nm and the periodicity of its repeats was about 15 rim, The filaments were often accumulated in clusters with a paracrystalline arrangement. No nuclear inclusions consisting of 8.5 nm tubular filaments, typically found in cases of OPMD, were detected. In addition, paracrystalline inclusions were present in a large number of mitochondria in several muscle fibres of the erector spinae muscle indicating that mitochondria could be primarily involved in the disease.
The proteolipid protein gene
Authors: Griffiths I. R. , Montague P. , Dickinson P.
Published: May 2008

Proteolipid protein (PLP) is the major myelin protein of the CNS and is believed to have a structural role in maintaining the intraperiod line of compact myelin. An isoform. DM‐20. produced by alternative splicing of exon 3B is expressed earlier than PLP in the CNS and may be involved in glial cell development. DM‐20 is also present in myelin‐forming and non‐myelin‐forming Schwann cells, olfactory nerve ensheathing cells, some glial cell lines and cardiac myocytes. Molecular studies suggest the existence of a PLP gene family with sequence similarities between molecules of different species. Such studies also lend credence to the suggestion that PLP and/or DM‐20 may function as a membrane pore. Mutations in the PLP gene occur in several animal species and cause severe pleiotropic effects on myelination. In man this presents as Pelizaeus‐Merzbacher disease (PMD). The phenotype of such mutants is characterized by dysmyelination with myelin of abnormal periodicity, paucity of mature oligodendrocytes and astrocytosis. Duplication of the PLP gene in transgenic animals or in one form of PMD also results in dysmyelination. X‐linked spastic paraplegia (SPG2) is allelic to PMD and is associated with PLP mutations in which the levels of the DM‐20 isoform are probably relatively normal. The effects of PLP gene dosage on CNS myelination can be compared in many ways to the variety of phenotypes in the PNS in hereditary neuropathies of the Charcot‐Marie‐Tooth type in which the peripheral myelin‐22 gene is mutated.
Expression of the proteolipid protein gene in glial cells of the post‐natal peripheral nervous system of rodents
Authors: Griffiths I. R. , Dickinson P. , Montague P.
Published: May 2008

The proteolipid protein (PLP) gene encodes for two proteins, PLP and DM‐20, which are produced by alternative splicing of exon 3B. PLP is the major CNS myelin protein and is postulated to play a structural role at the intraperiod line. Its developmental expression mirrors that of CNS myelination. DM‐20 predominates in the embryo and prior to myelination of the CNS and may be involved in glial cell development. The PLP gene is expressed in the PNS in which DM‐20 is the predominant isoform at all ages. In this study we describe the localization of the two isoforms in the post‐natal rodent PNS using immunostaining and reverse transcriptase PCR. DM‐20 is present in relatively high abundance in non‐myelin‐forming Schwann cells and within cytoplasmic regions of myelinated internodes, particularly the paranodes and Schmidt‐Lanterman incisures and also the outer Schwann cytoplasm and perinuclear cytoplasm. DM‐20 is also located in the perineuronal satellite cells of spinal, cranial and autonomic ganglia and in the ensheathing cells of the olfactory nerve layer of the olfactory bulb. PLP was detected by immunocyto‐chemistry in the perinuclear region of myelinated inter‐nodes: PCR analysis indicated small amounts of PLP mRNA in the other locations but protein was not detected by immunostaining. Neither protein was identified in compact myelin of the PNS. DM‐20 is the predominant product of the PLP gene expressed in a wide variety of peripheral glia. Its presence is not correlated to a myelin‐forming state. Other studies have demonstrated early embryonic expression of the PLP gene throughout the PNS and all these features support the hypothesis that any putative role for DM‐20 is unrelated to myelination but may involve glial cell development.
A case of PelizaeusMerzbacher disease showing increased dosage of the proteolipid protein gene
Authors: Harding B. , Ellis D. , Malcolm S.
Published: May 2008

Clinical, neuropathological and molecular genetic studies in a 9 month old boy with Pelizaeus‐Merzbacher disease are described. The principal clinical features were developmental delay, nystagmus, stridor and seizures. Both brain and spinal cord showed almost complete absence of stainable central myelin, while cranial and spinal root myelin was preserved. Probes for cDNA in the boy and his asymptomatic mother indicated an increase in the dosage of proteolipid protein gene (of at least twofold) compared with controls.
Production and evaluation of syngeneic antibodies showing specificity for the A15 A5 transplantable rat glioma
Authors: Clarke T. M. , Pilkington G. J.
Published: May 2008

Antibodies have been raised which show specificity for the A15 A5 transplantable rat glioma model. Viable, irradiated, colcemid‐treated and microwave‐fixed A1 5 A5 cells were each used to hyperimmunize BDIX rats by subcutaneous inoculation, while viable cells were also injected intracerebrally into syngeneic animals. Specific anti‐A15 A5 antibodies were detected in serum by a modified enzyme‐linked immunoabsorbent assay (ELISA). Immunoperoxidase and immunofluorescence cytochemistry revealed the presence of antigen in paraffin‐wax and frozen sections, respectively, of A15 A5 gliomas. The different methods of immunogen denatur‐ation were found to affect the degree of immunological potency of the cells. This study has shown that A15 A5 cells are immunogenic in a syngeneic host. Intracerebrally transplanted, viable cells produced antibodies of higher titre than subcutaneously‐injected, denatured cells. The anti‐A15 A5 antisera may be used for detection of neoplastic rat astrocytes using immunocyto‐chemistry. These antibodies will prove to be of value in discriminating between neoplastic and normal cells at the tumour/brain interface.
Accumulation of wild‐type p53 in meningiomas
Authors: Ellison D. W. , Lunec J. , Gallagher P. J. , Steart P. V. , Jaros E. , Gatter K. C.
Published: May 2008

The p53 tumour suppressor gene contributes to the regulation of DNA repair and the initiation of apoptosis. Mutations of this gene and nuclear accumulation of its protein product are features of a large variety of turnours. A histological spectrum of meningiomas, including anaplastic examples and a meningosarcoma. was analysed for accumulation of the p53 protein and mutations in exons 4–9 of the p53 gene. No mutations were found, but 9134 (26%) tumours showed accumulation of the p53 protein. The p53‐positive meningiomas came from across the histological spectrum and were not restricted to the anaplastic group. The accumulation of wild‐type p53 in a proportion of meningiomas may reflect this gene's role in DNA repair, or its enhanced stability when bound to cellular proteins such as the mdm‐2 gene product.
Neuronal apoptosis in HIV infection in adults
Authors: Adle‐Biassette H. , Levy Y. , Colornbel M. , Poron F. , Natchev S. , Keohane C. , Gray F.
Published: May 2008

Productive infection of the central nervous system by HIV predominantly involves the white matter and basal ganglia. Involvement of the cerebral cortex with neuronal loss is also described in AIDS patients but not in asymptomatic HIV‐positive patients. The mechanism of neuronal damage is unknown. To enquire whether neuronal loss in AIDS may be due to an apoptotic process, we examined the cerebral cortex from 12 patients who died from AIDS using two different methods: in situ end labelling and gel electrophoresis of DNA to demonstrate DNA fragmentation. None of the patients had cerebral opportunistic infection or tumour. Four patients had no significant neuropathological changes, eight patients had variable cerebral atrophy and four of them also had productive HIV infection of the brain. These patients were compared with four HIV‐positive asymptomatic patients, five seronegative asymptomatic controls, and two seronegative patients with Alzheimer's disease. We demonstrated neuronal apoptosis in the cortex in all AIDS patients, as well as in the Alzheimer's patients. Apoptosis was not observed in the asymptomatic cases whether seropositive or seronegative. Neuronal apoptosis was more severe in atrophic brains, and did not directly correlate with productive HIV infection, suggesting an indirect mechanism of neuronal damage is most likely.
Immortalization and characterization of rat microglial cells
Authors: McLaurin J. , Almazan G. , Williams K. , Antel J. P.
Published: May 2008

Microglial cell lines from rat brain were established by transfer of a temperature sensitive simian virus 40 large tumour antigen by means of a retrovirus. Four weeks after infection, colonies were generated in the presence of neomycin and granulocyte‐macrophage colony stimulating factor (GM‐CSF), and subsequently subcloned. Both bulk cell lines and clones proIiferate actively at 33°C. whereas the rate of division was significantly decreased at 39°C when the large T antigen is non‐functional. At 39°C these cells take on the microglial phenotype as demonstrated by immunoreactivity to ED‐1 (an intra‐cellular antigen), OX‐42 (complement type 3 receptor), W3/25 (CD4 homologue), OX‐6 (MHC class II antigen) and OX‐18 (MHC class I antigen). These cells are capable of active phagocytosis and retain these properties for 10–15 passages. Long‐term culture of these lines and clones, greater than 15 passages, displayed a gradual down‐regulation of all cell surface specific antigens that were not rescued by lipopolysaccharide (LPS), interferon‐gamma (γ‐IFN), GM‐CSF or colony‐stimulating factor‐1 (CSF‐1). The expression of the SV‐40 large T antigen was unaffected. These results demonstrate the feasibility of immortalizing short‐term cell lines with the SV‐40 large T antigen for their use in the characterization of microglial properties.
Neurof ibrillary tangles in chronic alcoholics
Authors: Cullen K. M. , Halliday G. M.
Published: May 2008

Magnocellular neurons in the cholinergic nucleus basalis appear to be vulnerable in a variety of pathological conditions, including chronic alcoholism. While neuro‐fibrillary degeneration of these neurons has been noted in a number of disorders characterized by dementia, the mechanism of cell death in thiamine‐deficient chronic alcoholics has not been identified. In the present post‐mortem investigation, multiple brain regions of seven thiamine‐deficient chronic alcoholics, three neurologically asymptomatic chronic alcoholics and seven non‐alcoholic age matched controls were screened for neurofibrillary pathology using both tau‐immunohistochemistry and a modified Bielschowsky silver stain. In chronic alcoholics with thiamine deficiency, neurofibrillary pathology was found in the nucleus basalis, but not any other brain region. Neurofibrillary tangles were not seen in age‐matched controls and were infrequent in alcoholics without neuropathological signs of thiamine‐deficiency. Neurofibrillary tangles were most numerous in those cases with cell loss in the nucleus basalis. These findings suggest that neurodegeneration of the nucleus basalis in chronic alcoholics proceeds through the formation of neurofibrillary tangles.
Long‐term culture of organotypic multicellular glioma spheroids: a good culture model for studying gliomas
Authors: Kaaijk P. , Troostt D. , Dast P. K. , Leenstra S. , Bosch D. A.
Published: May 2008

Gliomas. as well as other solid tumours. contain tumour stroma composed of connective tissue, macrophages, capillaries and other non‐cellular constituents. Therefore, a homogeneous culture of tumour cells alone, as is often used as a culture model for gliomas, is not ideal to study all aspects of gliomas. In the present study we describe an alternative culture model, i.e. organotypic multicellular spheroids (OMS), that histologically closely resembles the tumour in vivo. Glioma explants. obtained at surgery from five patients, were cultured on agarose to form OMS, which were cultured for up to 16 weeks. At regular intervals. OMS were fured and histological and immunocytochemical analyses were carried out. The histology as well as the immunocytochemical characteristics of the OMS proved to be almost unchanged after a culture period of 16 weeks. In contrast to monolayer cultures, glial fibrillary acidic protein (GFAP) expression in the OMS is preserved after 16 weeks of culture. However, in OMS from three out of five patients, small GFAP‐negative cells appeared in the outer cell layers between 1 and 2 weeks of culture. Furthermore, after about 6 weeks of culture, the capillaries disappeared from the OMS. After prolonged culture, tumour cell heterogeneity, the cellular composition, and the histology of the OMS still closely resembled the tumour in vivo It is suggested that OMS provide a good long‐term culture model for the study of gliomas.
Transthyretin expression in medulloblastomas and medulloblastoma cell lines
Authors: Albrecht S. , Bayer T. A. , Kraus J. A. , Pietsch T.
Published: May 2008

Transthyretin is a protein crucial to the transport of lipophilic molecules such as thyroid hormones and retinoids. In the central nervous system. large amounts of transthyretin are synthesized by the choroid plexus and are secreted into the cerebrospinal fluid. The choroid plexus is the only site of transthyretin synthesis in the brain. Transthyretin is expressed by most benign and malignant choroid plexus tumours while gliomas and meningiomas do not express transthyretin. Other major sites of transthyretin synthesis are the retinal pigment epithelium and hepatocytes. Medulloblastoma is the prototypical primitive neuroectodermal tumour of the cerebellum and can show multiple lines of differentiation, including the expression of retinal markers. In this study, we examined transthyretin expression both at the RNA and protein level in four medulloblastomas and six medulloblastoma cell lines using Northern and Western blot analysis. reverse transcription polymerase chain reaction (PCR). RNA in sitri hybridization, and immuno‐histochemistry. All four medulloblastomas and five of the six medulloblastoma cell lines expressed transthyretin‐mRNA as demonstrated by reverse PCR and iu situ hybridization while three medulloblastomas and one cell line were positive on Northern blot. The medulloblastoma with the most abundant RNA expression was transthyretin‐immunoreactive on cryosections and the medulloblastoma cell line that was positive on Northern blot also expressed transthyretin at levels detectable by Western blot. No transthyretin‐immunoreactivity was seen in 16 additional medulloblastomas studied on paraffin sections. These findings indicate that low‐level expression of transthyretin‐mRNA is common in medulloblastomas and medulloblastoma cell lines.

Expression of transthyretin protein occurs rarely but can reach significant levels. Transthyretin expression in medulloblastoma is consistent with retinal pigment epithelium differentiation in medulloblastomas and reflects their pluripotential nature. Furthermore, the potential for transthyretin‐immunoreactivity in medulloblastoma should be kept in mind when performing immunohistochemical studies on poorly differentiated cerebellar tumours.
Frontal lobe degeneration: novel ubiquitin‐immunoreactive neurites within frontotemporal cortex
Authors: Tolnay M. , Probst A.
Published: May 2008

Ubiquitin‐protein conjugates have been identified in filamentous inclusions in various neurodegenerative disorders. In frontal lobe degeneration (FLD) no distinctive histological features have been reported with the exception of some ubiquitin‐positive intraneuronal inclusions in cases associated with motor neuron disease. In the present study, we investigated five FLD cases without motor neuron disease using immunohistochemistry. A constant feature in all cases consisted of ubiquitin‐positive neurites in layers I—III of the frontotemporal neocortex. These neurites were not argyrophilic, and could not be labelled with various antibodies against tau and neurofilament proteins. Ubiquitin‐protein conjugates were found in distended dendritic branches, in dendritic spines and in smooth slender neurites, probably axons. No ubiquitinated neurites were seen in corresponding areas of the brain in aged controls. The nature of ubiquitinated proteins in FLD and the reason why they are confined to nerve cell processes is unknown but may be understood as part of an ongoing process leading to cell death observed in FLD.
Apoptosis in amyotrophic lateral sclerosis is not restricted to motor neurons. Bcl‐2 expression is increased in unaffected post‐central gyrus
Authors: Troost D. , Aten J. , Morsink F. , de Jong J. M. B. V.
Published: May 2008

We searched for the presence of apoptotic cell death and studied the distribution of bcl‐2, an oncoprotein that counteracts apoptosis, in amyotrophic lateral sclerosis (ALS). Brain and spinal cord specimens from 12 ALS patients were compared with those from six non‐neurological controls. ALS brain tissue was pre‐selected by the presence of reactive cortical damage. Apoptosis was demonstrated by in situ end‐labelling of fragmented DNA, a method that is suitable for formalin‐bed, paraffin‐embedded tissue. All ALS patients exhibited some apoptosis, eight of them did so in each of the three central nervous system (CNS)‐levels studied. Apoptosis was not restricted to the motor system, but also affected other neuronal and non‐neuronal CNS elements. Apoptosis corresponded with cell shrinkage, and neuro‐nophagia in Nissl stains and with small Nissl‐positive bodies. None of the non‐neurological controls showed as much apoptosis as any of the ALS cases. Immunocyto‐chemically, the overall distribution of BcI‐2 did not differ between ALS and non‐neurological controls. In ALS, however, we found variable degrees of increased Bcl‐2 expressed in the nuclei and in the cytoplasm. We found no inverse relationship between apoptosis and bcl‐2 expression.