bluuebunny/crossref_metadata_2025 huggingface dataset:
Coronavirus induced primary demyelination: indications for the involvement of a humoral immune response
Authors: ZIMPRICH F. , WINTER J. , WEGE H. , LASSMANN H.
Published: May 2008

Coronavirus MHV‐JHM infection of rodents can result in demyelinating encephalomyelitis. We analysed histological changes induced by coronavirus MHV‐JHM infection in Lewis rats. Besides an acute disease (AE), chronic panencephalitis (CPE) and subacute demyelinating encephalomyelitis (SDE) were induced. These disease types were differentiated by the incubation period, the localization of lesions, the type of tissue damage and distribution of virus antigen. In AE and CPE, virus antigen was detected in neurons, astrocytes and oligodendrocytes, whereas in SDE neurons lacked virus antigen. Viral nucleocapsid protein (N) was present in the cytoplasm and the spike protein (S) was displayed on the surface of infected neural cells. However, expression of S protein relative to N protein was severely impaired in SDE lesions. Quantitative analysis of infiltrating inflammatory cells revealed that the number of macrophages and T cells were similar in lesions of AE, CPE and SDE. In contrast to that, SDE lesions contained a significantly higher number of IgG† B cells and plasma cells. In addition active demyelinating SDE lesions displayed an enhanced IgG content and deposits of complement C9. These results indicate that virus induced primary demyelination could be a consequence of antibody mediated cytotoxicity. Furthermore, a reduction in the number of cells producing spike protein in the chronic forms of the disease indicates down‐regulation of this protein, possibly mediated by anti‐S antibodies.
The site of the lesion causing hearing loss in bacterial meningitis: a study of experimental streptococcal meningitis in guinea‐pigs
Authors: KAY R.
Published: May 2008

The pathological basis of hearing loss in bacterial meningitis was investigated using an animal model of Streptococcus suis meningitis. Forty guinea‐pigs were infected after their hearing had been assessed by brain stem auditory evoked potentials. In 17 animals, it was possible to repeat the procedure at the onset of meningitis; this included one animal with subclinical disease. Fifteen animals showed evidence of hearing loss, which on subsequent histological examination was found to be associated invariably with suppurative labyrinthitis. The remaining two animals without hearing loss had normal cochleas. It is suggested that cochlear sepsis rather than eighth cranial nerve involvement by meningeal sepsis is primarily responsible for hearing loss in bacterial meningitis, and that bacteria enter the cochlea via the cochlear aqueduct and not the internal auditory canal. The tissue within the lumen of the cochlear aqueduct may act as a barrier against invasion by micro‐organisms, and haemolytic streptococci could cause lysis of this barrier by the exotoxins they produce.
Vascular factors in the neurotoxic damage caused by 1, 3‐dinitrobenzene in the rat
Authors: ROMERO I. , BROWN A. W. , CAVANAGH J. B. , NOLAN C. C. , RAY D. E. , SEVILLE M. P.
Published: May 2008

Using a 3 times 10 mg/kg dose schedule of 1, 3‐dinitrobenzene (DNB) over two days in Fischer rats, we have found the following changes in vascular function and structure during the early phase of the symmetrical brain stem lesions.

1 Marked increase in cerebral blood flow generally but especially in the inferior colliculi, from 6 h after the final dose of DNB.

2 Increasing incidence of petechial haemorrhages in inferior colliculi, cerebellar roof, vestibular and superior olivary nuclei from 12 h.

3 Focal leakage of horseradish peroxidase and many sleeve‐like arteriolar haemorrhages seen in vibratome sections and by scanning electron microscopy (SEM) in these regions from 12 h.

4 Periarteriolar oedema and protein leakage present in step‐serial sections in these regions from 12 h, with astrocyte swelling and occasional small infarcts.

These changes suggest that the vascular bed may play an important role in the pathogenesis of these lesions, perhaps in parallel with early astroglial damage. They are discussed in relation to (i) the known presence of xanthine oxidase in the vascular bed of the brain and the likelihood of ‘useless redox cycling’ with free radical generation from this enzyme's interaction with nitroheterocyclic compounds, and (ii) the possible role of free radical damage to endothelial cells in this intoxication and in the analogous lesions of natural and experimental Wernicke's encephalopathy.
Age‐related ubiquitin deposits in dystrophic neurites: an immunoelectron microscopic study
Authors: MIGHELI A. , ATTANASIO A. , PEZZULO T. , GULLOTTA F. , GIORDANA M. T. , SCHIFFER D.
Published: May 2008

Widespread neuritic dystrophy is a hallmark of Alzheimer's disease (AD) and, in a less severe form, of brain ageing in various mammalian species. By immunohistochemistry, diffuse dot‐like staining for ubiquitin (Ubq), a polypeptide involved in the degradation of abnormal and shortlived proteins, has been associated with human brain ageing. The nature of the Ubq deposits was investigated by immunogold electron microscopy on autopsy samples from aged human and dog brains. Most of the dot‐like staining was localized to the white matter and corresponded to myelinated dystrophic neurites filled by Ubq‐labelled lysosomal dense bodies. They did not contain paired helical filaments or multilamellar bodies. A minority of Ubq deposits was represented by amorphous densities in focal enlargements of the myelin sheaths, Our findings show that the spectrum of Ubq changes in ageing brain is wider than formerly recognized, and support the hypothesis that a defective regulation of the lysosomal system might be involved in the pathogenesis of structural abnormalities both in the ageing brain and in Alzheimer's disease.
The identity of cells expressing MHC class II antigens in normal and pathological human brain
Authors: SASAKI A. , NAKAZATO Y.
Published: May 2008

Major histocompatibility complex class II antigen (Ag) expression in human brain was investigated in autopsied human brain tissues, using anti‐human class II monoclonal antibodies. In normal brains, class II Ag was usually absent or was low in positivity. When it was found immunohistochemically, it appeared more frequently in the meninges (meningeal macro‐phages) and the neurohypophysis (pituicytes) than in the cerebral cortex (microglia and perivascular cells). The identity of the latter cell types was confirmed by immunoelectron microscopy. Class II‐positive microglial cells were usually present in the cerebral white matter, but in senile brains showing numerous senile plaques, their numbers were increased in the grey matter. In diseased brains, numerous reactive microglia and macrophages containing class II Ag were observed in the affected lesions of neural tissue destruction, neuronal degeneration, and inflammation. Astrocytes, which were identified with an antibody to glial fibrillary acidic protein, did not contain class II Ag, although a small number of reactive astrocytes showed an equivocal class II staining. Staining for class II Ag on cerebral endothelial cells was mostly negative; however, class II Ag was microscopically identified in a case of secondary CNS T‐cell lymphoma.
Cerebcal vasculopathy in divers
Authors: PALMER A. C. , CALDER I. M. , YATES P. O.
Published: May 2008

Brains from 12 amateur and 13 professional divers, all but one of whom died accidentally, were examined neuropathologically. Grossly distended, empty vessels (presumably caused by gas bubbles) were found in the brains of 15 out of 22 divers who died from diving accidents. Perivascular lacuna formation was found in cerebral and/or cerebellar white matter in three amateurs and in five professionals. In addition to lacuna formation, hyalinization of vessel walls was present in the brains of three amateurs and five professionals. Necrotic foci in grey matter occurred in seven cases and perivascular vacuolation of white matter occurred in seven cases. The vascular changes probably arose from intravascular gas bubble formation. In one professional diver, there was also unilateral necrosis of the head of the caudate nucleus.
Ultrastructure of neurons containing somatostatin in the dentate hilus of the rat hippocampus after cerebral ischaemia, and a note on their commissural connections
Authors: JOHANSEN F. F. , SØRENSEN T. , TØNDER N. , ZIMMER J. , DIEMER N. H.
Published: May 2008

In a light microscopical study, we previously showed that more than 80% of somatostatin (SS) immunoreactive (‐i) neurons in the hilus of the dorsal part of the rat dentate gyrus are lost4 days after ischaemia. In order to verify that the loss of SS immunostaining is due to an actual loss of the SS‐i neurons and not merely a loss in expression of SS immunoreactivity, we have now performed an ultrastuctural study of these neurons before and 40 h after 20 min of global cerebral ischaemia in adult rats. The normal SS‐i neurons were multipolar and fusiform in shape. The SS‐i product was associated with the endoplasmic reticulum and occasionally the Golgi apparatus. The cell nuclei had indentations of the nucleolemma and contained intranuclear rods. After ischaemia, many SS‐i neurons in the dentate hilus showed increased electron density of both the cell nucleus and the cytoplasm. In addition the cytoplasm was heavily vacuolated with the SS‐i associated with some of these vacuoles. Other SS‐i neurons had, in addition to the vacuoles a more homogeneous, and abnormal electron lucent nucleus and cytoplasm. These ultrastructural changes correspond to previously Reported irreversible, ischaemic cell changes of neurons. Based on this we conclude that the SS immunoreactivity in the dentate hilus of the dorsal hippocampus is lost after ischaemia because of neuronal necrosis. As a minor part of this study, we examined whether the ischaemia‐susceptible SS‐i neurons in dentate hilus had commissural'axonal projections. This was done utilizing double fluorescence microscopy of retrograde axonal transport of the fluorescent dye, Fluoro‐Gold, and the observation that vulnerable SS‐i neurons display homogeneously dispersed immunostaining 40 h after ischaemia. Fluoro‐Gold was injected unilaterally into the dorsal dentate gyrus 5 days prior to ischaemia. Then, 40 h after ischaemia, sections were stained for SS immunofluorescence, and examined, in the dentate hilus contralateral to the injection, for neuronal co‐localization of both events. Cell counts revealed double‐labelling of 13% of all neurons which displayed one of the events. This observation suggests that at least some of the ischaemia‐susceptible SS‐i neurons in dentate hilus do project commissurally. The pathophysiological significance of ischaemic loss of commissurally projecting SS‐i neurons in dentate hilus remains to be determined.
Ultra structure of pre‐synaptic input to motor neurons in Onuf's nucleus: controls and motor neuron disease
Authors: PULLEN A. H. , MARTIN J. E. , SWASH M.
Published: May 2008

Ultrastructural analyses of sphincter motoneurons in Onuf's nucleus at S2 were undertaken in human spinal cord obtained 3–6 h post‐mortem from three subjects with no neurological disease (‘controls’) and five in which death was due to motor neuron disease (MND). Neurons in specified locations within Onuf's nucleus of control subjects ranged between 17.8 and 71.7 pm diameter (mean 38.6 pm). Analyses of synaptology revealed five ultrastructural classes of pre‐synaptic terminal synapsing with the neuronal surface membrane. When classified by size, vesicle morphology, and synaptic site structure these conformed to the S, F, T, M and C‐terminals defining somatic motoneurons. No terminals characteristic of autonomic motoneurons were found. In MND subjects, neurons in Onuf's nucleus at S2 were preserved despite a paucity of neurons in medial and lateral motor nuclei and were of similar size range to those in control subjects. The morphological classes of pre‐synaptic terminal found in controls, also characterized sphincteric motoneurons in MND subjects, including the C‐type terminal. The presence of C‐terminals indicates (i) that sphincteric motoneurons are somatic alpha‐motoneurons, and (ii) that hypotheses explaining the survival of sphincteric motoneurons in MND on the basis of Onuf's nucleus being an extension of the pre‐ganglionic parasympathetic nucleus, or having intrinsic autonomic properties are incorrect.
Cytoskeletal protein abnormalities in patients with olivopontocerebellar atrophy — an immunocytochemical and Gallyas silver impregnation study
Authors: KOBAYASHI K. , MIYAZU K. , KATSUKAWA K. , FUKUTANI Y. , MUKAI M. , NAKAMURA I. , YAMAGUCHI N. , MATSUBARA R. , ISAKI K.
Published: May 2008

A highly sensitive silver technique for glial cytoplasmic inclusions (GCI) in olivopontocerebellar atrophy (OPCA) was applied to tissues from 15 patients with neurodegenerative disorders inluding OPCA, Joseph disease, Alzheimer's disease (AD), Huntington's chorea, Pick disease and three control non‐neurological subjects. Brain tissue from both OPCA and AD impregnated positively. Neurons, astroglia and oligodendroglia in the putamen, pontine nucleus and inferior olivary nucleus all impregnated in addition to white matter oligodendroglia. Neuronal inclusions in the pontine nucleus appeared as compact or fibrillary masses, and GCI‐bearing oligodendroglia and astrocytes showed homogeneously impregnated somata. The myelinated pontocerebellar tract and the white matter surrounding the inferior olivary nucleus contained a small number of impregnated nerve fibres with a hollow structure, which resembled the myelin sheath. Immunocytochemical studies to clarify these argyrophilic structures in the OPCA subjects employed paired helical filament (PHF), microtubule associated proteins (MAPS), MAPl, MAPZ, MAPS, tau, ubiquitin, neurofilament (200 or 70 kilodaltons) and myelin basic protein (MBP) antisera. GCI‐bearing white matter oligodendroglia expressed PHF, tau, MAP5 and ubiquitin immunoreactives and non‐argyrophilic astroglia were positive for MAP5 antiserum alone. In the putamen, pontine nuclei and inferior olivary nuclei, impregnated neurons as well as the GCI‐bearing oligodendroglia immunostained with PHF, tau, MAP5 and ubiquitin antisera and impregnated astroglia were also immunoreactive to these antisera except for being tau negative in the putamen. Silver impregnated nerve fibres showed only MBP immunoreactivity. These findings indicate that the argyrophilia in the OPCA subjects closely correlates with PHF and tau immunoreactivities.
IgG subclass responses in brain and serum in Semliki Forest virus demyelinating encephalitis
Authors: PARSONS L. M. , WEBB H. E.
Published: May 2008

The response of IgG subclasses within the central nervous system (CNS) of the mouse to Semliki Forest virus (SFV), an alphavirus associated with meningoencephalitis and primary immune mediated demyelination, has been measured using immunocytochemistry. The subclass response in serum has been assessed using virus specific enzyme linked immunosorbant assays. In the CNS IgGl was poorly represented throughout the sampling period of 28 days with a maximum of 3% of the total number of positive cells on day 21 after infection. Of the few IgG positive cells present on day 6, 2a and 3 positive cells were dominant. From day 9 onwards the numbers of 2b positive cells rose and by day 28 IgG2a, 2b and 3 subclasses showed roughly equal percentages of total cells counted. By contrast, in serum, anti‐SFV IgG 2a and 2b were the first to appear and were dominant on day 12 and 21. Levels of anti‐SFV IgGl did not rise until after day 12 but rose steeply thereafter. IgG3 was weakly positive at days 9 and 12, rising slightly on day 21, Clearly there are differences in the patterns of subclass response between the CNS and the periphery. This may be important in the context of neurotropic viral infection.
Ubiquitin, PGP 9.5 and dense body formation in trimethyltin intoxication: differential neuronal responses to chemically induced cell damage
Authors: ANDERSON V. E. R. , HAJIMOHAMMADREZA I. , GALLO J. M. , ANDERTON B. H. , UNEY J. , BROWN A. W. , NOLAN C. C. , CAVANAGH J. B. , LEIGH P. N.
Published: May 2008

Ubiquitin in normal cells may be important in degrading or transferring short‐lived or aberrant proteins to lysosomal dense bodies. To examine its role in degrading proteins produced by a chemical insult, changes in the distribution of ubiquitin and the carboxy‐terminal hydrolase, PGP 9.5, have been studied in rat hippocampal neurons and cerebellar Purkinje cells in trimethyltin intoxication. Here tubulovesicular dense bodies (TVBs) form from 12 h onwards associated with vacuolation of the Golgi apparatus. Striking accumulations of lysosomal dense bodies follow in hippocampal pyramidal cells but not in cerebellar Purkinje cells; many of the hippocampal neurons later die, while the Purkinje cells generally survive.

Ubiquitin immunoreactivity was diffusely increased in hippocampal pyramidal and Purkinje cells 6h after dosing. By 12 h both diffuse and granular ubiquitin immunoreactivity was present that intensified over 24 and 48 h. Both by light and electron microscopy TVBs showed ubiquitin immunoreactivity, but dense bodies in hippocampal perikarya did not stain with an anti‐ubiquitin antibody. PGP 9.5 immunoreactivity was not altered in hippocampal cells at any time, while Purkinje and Golgi cell dendrites and perikarya showed intensified labelling at 3 h that reached a peak of 12 h. At 48 h Western blot analysis of hippocampal homogenates showed significant increases in high molecular weight (HMW) ubiquitin conjugates, while cerebellar homogenates showed an increase in ubiquitin‐histone conjugates. Northern blot analyses showed no change in ubiquitin or PGP 9.5 gene expression in hippocampus or cerebellum. These findings suggest that the material in the TVBs in hippocampal cells is not being degraded by the ubiquitin system but passes unubiquitinated into the lysosomal system, while material in Purkinje cell TVBs is degraded by the ubiquitin system, suggesting it may have a different composition in each type of neuron.
Experimental traction injuries of cervical spinal nerve roots: a scanning EM study of rupture patterns in fresh tissue
Authors: LIVESEY F. J. , FRAHER J. P.
Published: May 2008

This study examines the levels at which fresh rat ventral and dorsal C4 to T1 spinal roots rupture under traction stress. Rupture rarely occurs at the CNS‐PNS transitional zone. Despite its delicate appearance this is strengthened in a number of ways, so that it is less vulnerable than the roots and their constituent rootlets and aggregated rootlet bundles (ARBs). Ventral roots commonly rupture either where the rootlets join to form the ARBs, along the course of the latter, or where these in turn join to form the ventral root. Dorsal root rupture shows a similar pattern but has a higher frequency of rupture within the root proper than is the case with the ventral roots. The level of rupture also varies systematically over the series of roots examined: rupture points tend to be located at more distal levels in caudal roots. This may occur because of mechanical differences in the distribution of traction stress along roots, related to their courses through the vertebral canal. Upper roots run transversely and the traction force is transmitted directly to rootlet levels, while more caudal roots run obliquely and tend to rupture where they are drawn taut against the pedicle. Many of the morphological features of ruptured roots would tend to inhibit regeneration of fibres distally. Differences in the pattern of rupture between fresh and fixed roots are examined. The latter tend to rupture at levels closer to the CNS than the former.
Glioma heterogeneity in vitro: the significance of growth factors and gangliosides
Authors: PILKINGTON G. J.
Published: May 2008

Despite renewed attempts by the WHO at updating the system of classification for brain tumours, most of the dynamic biological processes which underlie both the morphological appearances which form the basis for such systems and the malignant potential of gliomas remain an enigma to the neuropathologist. One feature recognized in human gliomas is their phenotypic and genotypic heterogeneity. Such cellular heterogeneity seen in the histological section is retained in vitro, at least during early passage. It is proposed that this heterogeneity is important in the growth and maintenance of the tumour and may be related to the activity of growth factors and gangliosides. Such molecules may not only influence the histoarchitecture of glial neoplasms but may also determine malignant progression and invasive potential. Moreover, there may be an intimate relationship between growth factors and gangliosides constituting an intricate feedback mechanism upon which the biological progression of gliomas depends.
The inflammatory response in the CNS
Authors: PERRY V. H. , ANDERSSON P. B.
Published: May 2008

In recent years it has been recognized that cells of the mononuclear phagocyte lineage, macro‐phages and microglia, are a major component of gliosis. We review here studies on the kinetics of the myelomonocytic response to acute excitotoxin induced neuronal degeneration and following the injection of endotoxin (LPS) into the parenchyma of the central nervous system. These studies have shown that the kinetics of myelomonocytic recruitment to the parenchyma of the central nervous system is quite unlike that of other tissues; the polymorphonuclear cells are largely excluded and monocytes are only recruited after a delay of several days. The unusual nature of the inflammatory response in the central nervous system needs to be considered when drawing parallels with the acute inflammatory response in other tissues.
Genes coding for proteins in central nervous system myelin
Authors: THOMPSON R. J.
Published: May 2008

There has been considerable interest recently in a genetic component as a causative factor in multiple sclerosis, but the identity of putative susceptibility genes is unknown. In the past decade, the primary amino acid sequences of the four proteins making up 90% of the protein content of central nervous system myelin (proteolipid protein, myelin basic protein, 2′,3′‐cyclic nucleotide‐3′‐phosphohydrolase, and myelin‐associated glycoprotein) have been determined in several species. Additionally, the structural genes coding for these proteins have been analysed and their human chromosomal localization determined. We have been analysing these genes for possible variants conferring susceptibility to multiple sclerosis. Recent results have shown that cholera and pertussis toxin substrates and low molecular‐weight GTP‐binding proteins are also present in central nervous system myelin. This implies the presence of signal transducing systems whose purpose is currently obscure. The emerging picture of central nervous system myelin is of a complex dynamic structure composed of many more proteins than was previously thought.
Morphological spectrum, distribution and clinical correlation of white matter lesions in AIDS brains
Authors: SCHMIDBAUER M. , HUEMER M. , CRISTINA S. , TRABATTONI G. R. , BUDKA H.
Published: May 2008

This paper analyses the histopathological characteristics and the topographical distribution of ‘pure’ HIV‐associated white matter lesions of the brain in 18 AIDS patients at autopsy; it includes a time‐controlled correlation of neuropathology to clinical staging of the AIDS dementia complex. Three distinct lesion types can be delineated: 1 Vacuolar myelin damage (n= 15) in the hemispheric and interhemispheric white matter, in projection fibre tracts, and in intracerebral segments of cranial nerves III, VII, and VIII; 2 Angiocentric foci (n= 14), disseminated randomly in the white matter; 3 HIV leukoencephalopathy (n= 14), as previously defined, seen predominantly in the hemispheric white matter. As a sole lesion type, HN leukoencephalopathy is found in two cases, while vacuolar myelin damage and angiocentric foci always occur in combination with one or both other types of pathology. Patients with advanced AIDS‐dementia complex consistently show severe and combined white matter pathologies at autopsy. We conclude that, in addition to the previously defined features of diffuse HIV leukoencephalopathy, vacuolar myelin damage and angiocentric foci are significant and frequent components of white matter pathology in AIDS autopsies. This reflects the multitude of patho‐genetic factors which co‐operate in damaging the brain in AIDS. The advanced AIDS dementia complex correlates with the combined and severe white matter lesions.
An assessment of the proliferative potential of ‘balloon cells’ in focal cortical resections performed for childhood epilepsy
Authors: ROSA M. J. DE , FARRELL M. A. , BURKE M. M. , SECOR D. L. , VINTERS H. V.
Published: May 2008

Cerebral cortical dysplasia is an uncommon pathological substrate of severe intractable childhood epilepsy, sometimes treated by hemispherectomy. Neuropathological findings include abnormal gyrus formation, loss of cortical lamination, unusual giant neurons and ‘balloon cells’ of indeterminate histogenesis similar in appearance to neoplastic gemistocytic astrocytes. In order to investigate the proliferative potential of ‘balloon cells’, we used Crocker's silver impregnation technique to demonstrate nucleolar organizer regions (AgNORs) involved in cellular proliferation, together with immunohistochemical evaluation of proliferating cell nuclear antigen (PCNA) expression. Balloon cells (5.56 ± 0.24) had significantly (P<0.001) greater AgNOR numbers than reactive astrocytes (3.89 ± 0.15), neurons (2.30±0.13) or giant neurons (4.26±0.20). However, when corrected for nuclear size, results showed that ‘balloon cells’ (0.093±0.006) had significantly (P< 0.001) fewer AgNORs/square micrometre of nuclear area than reactive astrocytes (0.225 ± 0.016) and had significantly (P < 0.001) more AgNORs/square micrometre of nuclear area than normal (0.048 ± 0.003) or giant neurons (0.054±0.003). On the assumption that astrocytes are typical interphase cells and that normal neurons are post‐mitotic, the results suggest that ‘balloon cells’ are unlikely to be undergoing proliferative activity and, when adjusted for nuclear size, the number of AgNORslunit of nuclear area is more reflective of cellular ploidy than of proliferative activity in non‐neoplastic neural tissues. The virtual absence of PCNA expression by ‘balloon cell’ nuclei supports such an interpretation of the AgNOR results.
2,5‐hexanedione‐induced intermediate filament aggregates contain ubiquitin‐protein conjugate immunoreactivity and resemble Rosenthal fibres
Authors: TUCKWELL D. S. , LÁSZLÓ L. , MAYER R. J.
Published: May 2008

A number of chronic degenerative disorders including cerebellar astrocytomas and Parkinson's disease are characterized by the presence of cytosolic inclusions which contain intermediate filament (IF) aggregates and ubiquitin‐protein conjugate immunoreactivity. In cerebellar astrocytomas these inclusions are known as Rosenthal fibres. 2,5‐hexanedione (HD) treatment is known to induce IF aggregates in cells in culture. HD‐induced aggregates have therefore been studied as a potential model for the clinical inclusions. Exposure of astrocyte cultures to 2 mm HD for 2 or 4 weeks led to the formation of aggregates of the IFs (glial fibrillary acidic protein and vimentin). The aggregates contained ubiquitin‐protein conjugates, which, on electron microscopy appeared to be localized in a peripheral shell. In addition, ubiquitin mRNA levels were found to be elevated approximately threefold by HD treatment. HD‐induced inclusions and Rosenthal fibres were found to share a number of features. HD administration, therefore, appears to be a suitable model for the production of pathological inclusions.
Early central nervous system changes in human immunodeficiency virus (HIV)‐infection
Authors: Gray F. , Hurtrel M. , Hurtrel B.
Published: May 2008

Early HIV infection of the CNS, as demonstrated by cerebrospinal fluid studies, seems relatively common. However most HIV carriers remain neurologically unimpaired during the incubation period. A few psychometric, radiological, and electrophysiological studies suggest that neurological abnormalities are present at early stages of HIV infection; the findings of these studies are controversial and until recently, they have not been supported by neuropathological data. Early brain changes, including leptomeningitis and vasculitis with myelin pallor and gliosis of the deep white matter are probably secondary to vascular inflammation and opening of the blood‐brain barrier. Such conclusions are drawn from the examination of brains of asymptomatic HIV‐positive individuals who died from unnatural causes, and of rare cases with acute fatal encephalopathy revealing HIV infection. In addition, early experimental simian immunodeficiency virus infection and feline immunodeficiency virus encephalopathy have demonstrated similar changes to those in man. Although small amounts of viral genome were detected by PCR in a few cases, the early changes in the human brain do not seem to result from a productive HIV infection of the CNS, as seen in HIV encephalitis. The occurrence of a usually asymptomatic and transient immunopathological reaction coinciding with early HIV infection of the nervous system appears to be more likely.
The management of carotid artery disease: application of new diagnostic techniques and their neuropathological significance
Authors: Bone I. , Mendelow A.D. , Graham D.I.
Published: May 2008

The early management of patients with carotid artery disease was based on minimal investigative knowledge without much appreciation of its pathophysiological significance. During the last decade, however, the advent of non‐invasive and functional imaging has increased our awareness and the significance of extracranial cervical vascular disease. This has led to more logical management strategies particularly for patients with carotid artery disease. Non‐invasive imaging, in particular, has identified patients at risk and led to the establishment of large randomized trials of medical and surgical treatments, the recent results of which have altered management practice.
Cerebrovascular permeability to azo dyes and plasma proteins in rodents of different ages
Authors: Moos T. , Møllgård K.
Published: May 2008

The often quoted investigation by Behnsen [4] provides some evidence for an increased permeability of the neonatal mouse blood‐brain barrier (BBB) to trypan blue compared to the adult. Trypan blue, which circulates in plasma mainly bound to albumin, is commonly used as a macromolecular tracer, although Behnsen probably injected dyes in amounts exceeding the dye‐binding capacity of plasma proteins. The Cerebrovascular permeability in neonatal and adult mice and rats was investigated using the visual tracers trypan blue and Evans blue and immunocytochemical staining for endogenous plasma proteins. By administering different concentrations of the dyes, the permeability of the BBB was assessed. The presence of the dyes in plasma as either dye‐protein complexes or as free dye was measured by a plasma protein binding assay. When dyes occurred in plasma as macromolecular dye‐protein complexes, dyes and plasma proteins were restricted to CNS regions normally devoid of a BBB in both neonates and adults. When unbound (free) dyes occurred in plasma, dyes were observed intraneuronally in regions without projections beyond the BBB in both neonates and adults corresponding to that observed by Behnsen; intraneuronal accumulation of plasma proteins also occurred in regions with projections confined to the BBB but only in neonates. It is concluded that the BBB to macromolecular tracers is fully developed at birth in mouse and rats. However, when free dye is present in plasma, there is a differential permeability to plasma proteins between neonates and adults.
Ubiquitin immunocytochemistry in human spongiform encephalopathies
Authors: Ironside J. W. , McCardle L. , Hayward P. A. R. , Bell J. E.
Published: May 2008

The distribution of ubiquitin was studied by immunocytochemistry in eight cases of human spongiform encephalopathy and compared with the findings in seven age‐and sex‐matched cases of Alzheimer's disease and six non‐demented control cases. The results were also compared with the immunocytochemical distribution of prion protein and the lysosomal aspartic protease cathepsin D. In the human spongiform encephalopathies, ubiquitin immunoreactivity was found in a punctate distribution at the periphery of prion protein amyloid plaques and in a finely granular pattern in the neuropil around and within areas of spongiform change. Cortical nerve cells contained scanty ubiquitinated dot‐like inclusions, and occasional microglia around the areas of spongiform change also gave a positive staining reaction for ubiquitin, as did multiple irregular thread‐like structures in the neuropil and white matter. The ubiquitin‐containing structures at the plaque periphery in human spongiform encephalopathies resemble the neuritic processes at the periphery of the senile plaque in Alzheimer's disease. The granular positivity for ubiquitin associated with areas of spongiform change closely resembles the pattern of immunostaining seen with the antibodies to the prion protein and cathepsin D, consistent with the reported accumulation of ubiquitinated proteins and prion protein in lysosomes in the murine scrapie model. Further studies are required to investigate the role of lysosomes in this group of disorders, and to study the localization of other cell stress proteins and prion protein in spongiform encephalopathies.
Malignant infiltration of peripheral nerves in the course of acute myelomonoblastic leukaemia: neuropathological study of two cases
Authors: Vital A. , Vital C. , Ellie E. , Ferrer X. , Lagueny A. , Ferrer A. M. , Broustet A. , Gbikpi‐Benissan G.
Published: May 2008

Two patients suffering from acute myelomonoblastic leukaemia developed clinical evidence of peripheral nerve involvement. In both cases, a peripheral nerve biopsy revealed endoneurial cellular infiltrates which were identified as leukaemic cells by immunocytochemistry. Ultrastructural studies showed mainly axonal damage. Moreover, in one patient, a few features of active demyelination were also observed.
Characterization and distribution of phagocytic macrophages in multiple sclerosis plaques
Authors: Li H. , Newcombe J. , Groome N. P. , Cuzner M. L.
Published: May 2008

Populations of phagocytic cells in multiple sclerosis (MS) plaques were examined by quantitative immunocytochemical analysis of macrophage markers and myelin degradation products in serial cryostat sections from 10 cases of MS. Around lesions with ongoing demyelination expression of the Class II antigen HLA‐DQ appeared to be a marker of microglial activation. Alpha l‐antichymotrypsin + monocytes and myelin‐laden macrophages expressing the later differentiation markers Ber‐MAC3 and RFD7 were predominantly perivascular in location. On the basis of the distribution of oil red 0 (ORO)+ phagocytes and myelin loss, plaques were divided into groups representing different stages in lesion development. In early lesions (group 1), there was no apparent myelin loss around ORO+ macrophages although these cells contained material stained with antibodies against myelin basic protein (MBP) epitopes and neoepitopes. However, patchy myelin loss was detectable around the phagocytic macrophages uniformly distributed throughout group 2 plaques. ORO+ macrophages containing MBP peptides were confined to the hypercellular border of group 4 lesions, in which the demyelinating process may be recurrent.
Cerebral amyloid in human prion disease
Authors: Watanabe R. , Duchen L. W.
Published: May 2008

The clinical and neuropathological features of 21 patients with prion disease were reviewed with special reference to the morphology and immunoreactivity of cerebral amyloid. Six cases had a mutation at codon 102 of the prion protein (PrP) gene and in these the characteristic pathology was the formation of multicentric amyloid plaques which were stained with PrP antibody, whereas spongiform changes were absent in one and minimal in two. In one case, with a 216 base‐pair insertion in the PrP gene, there was no spongiform encephalopathy (SE) but cerebellar amyloid was a prominent feature of the pathology. One case with a PrP gene mutation at codon 200 had severe SE but no amyloid. Two iatrogenic and 11 sporadic cases had SE and some form of amyloid was identified in all but three. Amyloid angiopathy and senile neuritic plaques, which stained with antibody to β‐protein, were present in familial as well as in sporadic cases, including some who were rather young to be regarded as having Alzheimer's disease. Cerebellar amyloid and degeneration of granule and Purkinje cells were particularly common findings in sporadic as well as in genetically determined cases. This study serves to emphasize the association between prion disease and amyloid deposition in the brain. PrP is a component of some amyloid plaques in a high proportion of cases with inherited prion disease but may also be found in cases of sporadic SE without known mutations or base‐pair insertions in the PrP gene.
The cellular pathology associated with Alzheimer β‐amyloid deposits in non‐demented aged individuals
Authors: Coria F. , Moreno A. , Rubio I. , García M. A. , Morato E. , Jr F. Mayor
Published: May 2008

In this study, we have compared the cellular pathology associated with β‐amyloid (βA) deposits which characterize Alzheimer's disease (AD) in demented patients with pathologically confirmed AD, with that in non‐demented aged individuals. Brain sections from two severely demented AD cases, six non‐demented individuals with βA deposits, and six age‐matched controls devoid of βA deposits were double‐immunostained with antibodies against βA, and antibody markers for neurofibrillary tangles (NFT), astrocytes and microglial cells. We found that the severely demented patients displayed numerous plaques of variable morphology, most of which were associated with NFT, hypertrophied astrocytes and reactive microglial cells. In contrast, non‐demented patients showed fewer plaques, few or no NFT and less astroglial and microglial reaction. The number of plaques with associated abnormal cellular elements were much lower in non‐demented than in demented cases. Furthermore, classical plaques were more likely to be associated with abnormal cellular elements than diffuse plaques, which were most often devoid of any associated cellular change. These findings suggest that: (i) βA plaques in non‐demented individuals may represent an early stage of AD; (ii) βA deposition is the first recognizable pathological abnormality of AD; and (iii) NFT, and astro‐and microglial proliferation are later features, possibly secondary to the known dystrophic effects of the βA peptide and other fragments of its precursor protein.
Parvalbumin and calbindin D‐28k in the human motor system and in motor neuron disease
Authors: Ince P. , Stout N. , Shaw P. , Slade J. , Hunziker W. , Heizmann C.W. , Baimbridge K.G.
Published: May 2008

Calbindin D‐28k and parvalbumin are neuronal calcium binding proteins of interest in relation to neurodegenerative diseases. Expression of calbindin and parvalbumin may be one of the determinants of selective vulnerability in these disorders. The distribution of these proteins was surveyed in the normal human motor system and in motor neuron disease (MND) using immunocytochemistry in formalin fixed post‐mortem tissues. CNS tissues from 14 MND patients (mean age 61.2 years, mean post‐mortem delay 24.6 h) and seven controls (mean age 62.6 years, mean post‐mortem delay 25.3 h) were studied. Preliminary studies on the effects of fixation were performed. In normal cases upper and lower motor neurons showed absent expression of both proteins.

Several neuronal groups characteristically spared in MND showed varying patterns of immunoreactivity: oculomotor neurons showed parvalbumin staining of the perikaryon; the thoracic preganglionic sympathetic neurons showed calbindin staining in perikarya, Onuf's nucleus showed calbindin staining in the neuropil only. In motor neuron disease a loss of ventral horn interneurons and calbindin immunoreactive processes was observed with no other disease related changes in the spinal cord, brainstem, or motor cortex. These findings are consistent with the hypothesis that the distribution of these proteins is one determinant of selective vulnerability to the neurodegenerative processes in MND acting via disturbance of neuronal calcium homeostasis.
Diminution of dopaminergic neurons in the substantia nigra of sporadic amyotrophic lateral sclerosis
Authors: Kato S. , Oda M. , Tanabe H.
Published: May 2008

The substantia nigra was examined immunohistochemically using the antibody to tyrosine hydroxylase in 15 patients with sporadic amyotrophic lateral sclerosis (ALS). The number of dopaminergic neurons was diminished in the substantia nigra of seven cases. The diminution was not related to the age, duration of the illness or use of respirators. Supranuclear ophthalmoplegia developed in four and dementia in three out of seven patients with reduction of nigral dopaminergic neurons. In addition, five out of the seven patients developed respiratory failure within 2 years after the onset of the illness. The nigral dopaminergic system may be involved in rapidly progressive ALS patients with supranuclear ophthalmoplegia and/or dementia.
Granule cells and the development of synapses with mossy fibres in the cerebellum of the jaundiced Gunn rat
Authors: Takagishi Y. , Yamamura H.
Published: May 2008

The development of granule cells and the formation of synapses with mossy fibres were investigated in cerebella from jaundiced (j/j) Gunn rats with hereditary hyperbilirubinemia. The external granular layer was thinner than that in cerebella from heterozygous (+/j) Gunn rats without hyperbilirubinemia on days 12 and 15 after birth, and it had disappeared in places by day 18. Migrating granule cells decreased in number from days 12 to 18. In the internal granular layer, the paucity of granule cells became apparent on day 12 and a reduction in the number of cells was prominent from day 18 onward. More degenerating cells were found in j/j cerebella than in +/j cerebella on days 12 and 15. Mossy fibre‐granule cell synapses (glomeruli) were immature in appearance in j/j and +/j cerebella from days 7 to 12; small, roundish mossy fibre terminals were in contact with a few dendrites of granule cells. After day 18, the glomeruli were mature in terms of shape in +/j cerebella. By contrast, the mossy terminals remained small and roundish, and the granule cell dendrites that surrounded the mossy terminals did not increase in number nor develop digitiform branches in j/j cerebella. The mossy terminals were partially surrounded by glial processes and were occasionally surrounded by large dendrites of Golgi cells, which made multiple synaptic contacts. Some degenerating mossy terminals were present from days 18 to 30. These anomalous glomeruli may be caused by insufficient synaptic contacts with granule cells.
Absence of neuron‐associated microtubule proteins in the rat C‐6 glioma cell line. A comparative immunoblot and imrnunohistochemical study
Authors: Zientek G. M. , Herman M. M. , Katsetos C. D. , Frankfurter A.
Published: May 2008

Three neuron‐associated microtubule proteins, Class III β‐tubulin isotype, MAP‐2, and tau, were evaluated in a comparative immunoblot and immunohistochemical study of the rat C‐6 glioma cell line maintained for up to 31 days in vitro. Western blots on whole SDS extracts of cells grown: (i) as monolayers on plastic dishes (for 13 and 16 days); (ii) as monolayers on poly‐D‐lysine coated glass coverslips (for 3, 7, and 11 days): and (iii) as explants on Gelfoam matrices (for 10, 30, and 31 days) were probed with monoclonal antibodies (MoAb) specific for the abovementioned microtubule proteins. For these and all other markers employed, immunoperoxidase histochemistry was performed only on the matrix cultures. The immunoblot experiments demonstrated that the Class III β‐tubulin isotype, MAP2, and tau were not expressed by the C‐6 cell line in any of the culture conditions, nor were they found by immunohistochemistry. In contrast, explants from all culture conditions were positive for glial fibrillary acidic (GFA) protein and for a universal anti‐β‐tubulin isotype MoAb by immunoblotting, as well as by immunohistochemistry in Gelfoam matrix cultures maintained in an organ culture system. Both sets of experiments indicate that these markers are not altered under three different conditions of growth over a one‐month period in vitro. The expression of GFA protein and the absence of detectable levels of Class III β‐tubulin, MAP2, and tau are in keeping with the astrocytic phenotype of the C‐6 cell line.
Myopathy in HIV infection: the role of zidovudine and the significance of tubuloreticular inclusions
Authors: Lane R. J. M. , McLean K. A. , Moss J. , Woodrow D. F.
Published: May 2008

Muscle biopsies were obtained from 3 3 consecutive HIV‐infected patients with symptoms suggestive of muscle disorder. Twenty‐three patients had clinical evidence of myopathy; 18 of these had been taking zidovudine (AZT) for between 8 and 28 months, and were found to have a multifocal necrotizing myopathy with little or no inflammation. However, the remaining five clinically myopathic patients, who had never received AZT or had stopped treatment at least 5 months earlier, had either a necrotizing myopathy which appeared indistinguishable for that seen in patients taking the drug, or an inflammatory myopathy. The 10 clinically non‐myopathic patients showed no significant histological abnormalities. Tubuloreticular inclusions (TRI), in capillary endothelial cells, were found in all clinically myopathic cases but were not seen in five out often clinically non‐myopathic cases. We suggest that AZT causes a myopathy only when an underlying HIV‐related inflammatory myopathy is present. The drug appears to substantially reduce the inflammatory reaction in the muscle, but this may recur when the drug is stopped. The appearance of TRI may be the first manifestation of HIV activity in muscle.
Immunocytochemical detection of the microsomal glucose‐6‐phosphatase in human brain astrocytes
Authors: Bell J. E. , Hume R. , Busuttil A. , Burchell A.
Published: May 2008

Using an antibody raised against the catalytic subunit of glucose‐6‐phosphatase, this enzyme was immuno‐localized in many astrocytes in 20 normal human brains. Double immunofluorescence studies showed co‐localization of glial fibrillary acidic protein (GFAP) with glucose‐6‐phosphatase in astrocytes. However, not all GFAP‐positive cells were also glucose‐6‐phosphatase positive, indicating that some astrocytes do not contain demonstrable expression of this enzyme. Reactive astrocytes in a variety of abnormal brains were strongly glucose‐6‐phosphatase positive, but neoplastic astrocytes were often only weakly positive. Expression of the enzyme could not be demonstrated in radial glia, neurons or oligodendroglia. Astrocytes normally contain glycogen and the demonstration that some astrocytes also contain glucose‐6‐phosphatase indicates that they are competent for both glycogenolysis and gluconeogenesis, which may be critical for neuronal welfare.