bluuebunny/crossref_metadata_2025 huggingface dataset:
A quantitative histological study of early clinical and preclinical Alzheimer's disease
Authors: HUBBARD B. M. , FENTONM G. W. , ANDERSON J. M.
Published: May 2008

Brains from 70 unselected general hospital necropsy cases aged. 60–95 years were surveyed histologically for changes of Alzheimer's disease using Congo Red‐Gallocyanin preparations. Counts were made of neurofibrillary tangles in two areas of the neocortex, the hippocampal formation and the substantia innominata. Neurons were counted in the subiculum of the hippocampus, the substantia innominata and the locus coeruleus. In addition, a retrospective enquiry was made concerning the mental health of the patients in the study; cognitive performance was graded on the Global Deterioration Scale (GDS 1–7).

Four cases (5.7%) had clinical and pathological changes amounting to early Alzheimer's disease. Tangles were very numerous in all areas and there was a 30% deficit or more of neurons in at least two of the structures counted. Although the diagnosis of Alzheimer's disease was not recorded during life, all had shown signs of early cognitive decline (GDS grades 3–6).

A further six cases (8.6%) showed excessive tangle accumulation which may represent preclinical Alzheimer's disease. Tangles were present in the temporal neocortex (Brodmann area 22), whereas they were absent in the remainder of the survey. Tangle density in the hippocampal formation (>50 tangles in a 10 μm section) was also above the baseline level of the majority of cases. However, neuron loss was not widespread in these cases and none had shown evidence of cognitive impairment.

The findings confirm that the early stages of Alzheimer's disease commonly occur amongst general hospital necropsies. The emergence of clinical signs of dementia appears to be related to the loss of a critical volume of neurons and not to tangle accumulation alone.
Investigation of the expression of epidermal growth factor receptor and blood group A antigen in 110 human gliomas
Authors: JONES N. R. , ROSSI M. L. , GREGORIOU M. , HUGHES J. T.
Published: May 2008

Investigation of the expression of epidermal growth factor receptor and blood group A antigen in 110 human gliomas. The presence of epidermal growth factor receptor (EGF‐R) and blood group A antigen was studied immunohistochemically in a series of 110 malignant gliomas using monoclonal antibodies. Fifty‐seven percent of the tumours strongly expressed EGF‐R on the malignant cells. Although blood group A antigen is present on EGF‐R of A431 cells (a cell line derived from a human epidermoid carcinoma), in gliomas it was found only on vascular endothelial cells of tumours from blood group A patients. The results suggest that the EGF‐R present in gliomas differs from that in A431 cells in the type or amount of the carbohydrate chains. This is in contrast to previous reports which have suggested that A antigen is present on EGF‐R in gliomas. This has relevance in the choice of monoclonal antibodies used to study the EGF‐R, as those directed against the A antigen component of the A431 cell EGF‐R will not recognize EGF‐R elsewhere and may cause normal blood group A antigen to be mistaken for EGF‐R.
Human herpes virus infections and Alzheimer's disease
Authors: DEATLY A. M. , HAASE A. T. , FEWSTER P. H. , LEWIS E. , BALL M. J.
Published: May 2008

Human herpes virus infections and Alzheimer's Disease. Herpes viruses cause acute and chronic diseases of the peripheral and central nervous systems and have been implicated in the aetiology of Alzheimer's disease (AD). In this investigation the relevance of human herpes virus infection to AD was assessed by in situ hybridization. The abundant latency associated transcript(s) of herpes simplex virus type 1 (HSV‐1) were detected at a significantly higher incidence in the trigeminal ganglia of individuals with AD than in controls. But we could find no evidence of viral RNA in the central nervous system (CNS), looking specifically in the hippo‐campal cortex of demented individuals with extensive neuropathological changes of AD. These studies solve one problem in testing the viral hypothesis of causation, i.e. the sensitivity of the methods used in the search for latent infection. But the central issue remains unresolved because of necessity, only the end stage of a prolonged pathophysiological process has been examined. Our conclusions are qualified accordingly.
Early degeneration and sprouting at the rat neuromuscular junction following acrylamide administration
Authors: DeGRANDCHAMP R. L. , LOWNDES H. E.
Published: May 2008

Early degeneration and sprouting at the rat neuromuscular junction following acrylamide administration. Prolonged acrylamide administration produces motor nerve‐terminal branch degeneration and impairs axonal outgrowth following nerve crush. It is unclear how early terminal branch degeneration is initiated and whether there is a compensatory regenerative response at the neuromuscular junction (NMJ). A modified Pestronk and Drachman silver‐acetylcholinesterase strain was used to carry out a detailed morphometric analysis of the NMJ in soleus and lumbrical muscles. Rats were given 3, 5, or 10 doses of acrylamide, 35 mg/kg/day, by intraperitoneal injection, 5 days/week, and killed 4, 7, or 14 days after the first dose, respectively. Degenerating terminal branches were evident in soleus NMJ after only three doses of acrylamide. Diminished synaptic vesicle content, neurofilament accumulations and tubulo‐vesicular profiles were evident after three doses. At later time points, degenerating terminals contained few synaptic vesicles and were engorged with neurofilaments. Endplate lengthening, indicative of denervation supersensitivity, accompanied degeneration. Terminal sprouting proliferated after 3 and 5 doses but was less prominent after 10 doses. Although similar changes occurred in the lumbrical muscle, they were not initiated until after 5 doses. These experiments reveal that pathological changes in terminal branches commence earlier and after a lower cumulative dose of acrylamide than previously reported and suggest that acrylamide exerts a primary effect at motor nerve‐terminal branches. Eariy, vigorous terminal sprouting indicates that acrylamide does not prevent the initiation of regeneration, but with prolonged treatment does cause degeneration of maturing sprouts.
Pathology of Streptococcal meningitis following intravenous intracisternal and natural routes of infection
Authors: WILLIAMS A. E. , BLAKEMORE W. F.
Published: May 2008

The distribution of pathological lesions present in 20 cases of naturally‐occurring Streptococcus suis type 2 meningitis and 20 cases of the disease induced experimentally by intravenous or intracisternal inoculation was examined. It was found that the distribution of lesions was similar; mild lesions were present at the choroid plexuses whilst the most dense cellular accumulations were found at sites of cerebrospinal fluid (CSF) efflux, such as arachnoid villi and olfactory nerve sheaths. The distribution of changes was considered to reflect the dynamics of CSF flow rather than indicate the site of entry of the organisms into the CSF compartment.
Multifocal vacuolar leucoencephalopathy: a distinct HIV‐associated lesion of the brain**
Authors: SCHMIDBAUER M. , BUDKA H. , OKEDA R. , CRISTINA S. , LECHI A. , TRABATTONI G. R.
Published: May 2008

A 20–year‐old male AIDS patient developed rapidly progressive dementia for more than 3 months prior to death. Autopsy showed, in addition to adrenal cytomegalovirus (CMV) infection and focal cerebral necrosis due to toxoplasmosis, multifocal subcortical white matter lesions of the brain which were strikingly similar to the histopathology of vacuolar myelopathy in AIDS. These distinct lesions contained macrophages which were rarely multinucleated and expressed HIV antigens by immunocytochemistry. The distribution of lesions mimics extrapontine myelinolysis and progressive multifocal leucoencephalopathy (PML); PML was excluded by the absence of papovaviruses by immunocytochemistry and by in situ DNA hybridization. Tissue damage in multifocal vacuolar leucoencephalopathy is different from hitherto characterized HIV‐specific neuropathology such as HIV encephalitis and HIV leucoencephalopathy, and should be included in the list of conditions with damage of the brain white matter in AIDS.
Ultrastructural localization of Factor VIII–related antigen in endothelial proliferations of malignant gliomas*
Authors: MIGHELI A. , ATTANASIO A. , MOCELLINI C. , SCHIFFER D.
Published: May 2008

The ultrastructural localization of Factor Vlll–related antigen (FVIII/RAg) in the endothelial cells of malignant gliomas was studied with immunogold labelling on thin sections of LR White–embedded tissue. FVIII/RAg was localized in Weibel–Palade bodies (WPBs) as well as in cytoplasmic vacuoles and vesicles, and in extracellular spaces. Stained WPBs were found both in cells surrounding vascular channels and in several proliferating cells of solid buds and glomeruli. Our results confirm previous ultrastructural observations on non–neural tissues that FVIII/RAg is produced by endothelial cells and stored in WPBs. The presence of FVIII/RAg–stained WPBs in capillary buds and tufts indicates that at least some of the proliferating cells are endothelial in origin rather than pericytes. Thus, the contribution of endothelial cells to new vessel formation seems to be more substantial than previously Reported.
Neurotoxic acrylamide and neurotrophic melanocortin peptides–can contrasting actions provide clues about modes of action?
Authors: EDWARDS P. M. , SPOREL‐OZAKAT E. , GISPEN W. H.
Published: May 2008

Experimental acrylamide neuropathy has been studied as a model of degenerative neurological disorders of the ‘dying‐back’ type for over 30 years. Functional, histological, ultrastructural, electrophysiological and biochemical aspects of acrylamide neuropathy have been described and several hypotheses concerning the mode of action proposed. However, the mechanism whereby acrylamide causes axonal degeneration and inhibits nerve sprouting remains unknown. By analogy with agonist/antagonist comparisons used by the pharmacologist, we have reconsidered the acrylamide problem in the light of the opposite effects summarized in Table 1, of neurotrophic peptides related to ACTH/MSH (collectively termed melanocortins). The contrasting effects on sprouting and the eventual quality of repair of mechanically lesioned nerves have suggested a mechanism whereby sprouting may regulate perikaryal adjustments to injury. We have also posed the question as to whether a common biochemical mechanism, namely selective proteolysis of neurofilament protein may underlie the opposing effects of acrylamide and melanocortins on nerve sprouting. This possibility implies a hitherto unknown role for neurofilament protein turnover in neuronal maintenance and repair, a suggestion that may provoke further research and discussion.
Cell proliferation in intracranial tumours: selective silver staining of nucleolar organizer regions (AgNORs). Application to surgical and experimental neuro‐oncology
Authors: PLATE K. H. , RUSCHOFF J. , MENNEL H. D.
Published: May 2008

A novel tool in diagnostic and experimental pathology, the AgNOR‐technique, which consists of visualization of ribosomal gene activity by selective silver staining, was applied to 144 cytological specimens of human tumours of the nervous system. The number of silver‐stained nucleolar organizer regions (AgNORs) was correlated with the biological behaviour of the tumours investigated; low AgNOR numbers were observed in benign neoplasms such as meningiomas and schwannomas and higher AgNOR numbers in glioblastomas and metastases. The mean AgNOR number per cell was 3.15 in astrocytomas, 4.5 in anaplastic astrocytomas and 5.86 in glioblastoma multiforme. Benign and malignant lesions showed different distribution patterns of AgNORs, with few but centrally located AgNORs in benign, and multiple but scattered AgNORs in malignant tumours. AgNOR number per cell and AgNOR area revealed an inverse relationship (correlation coefficient –0.15, linear regression). In addition to the human tumours, two JV‐nitroso‐iV‐ethyl‐urea (NEU) induced tumours in BD‐IX rats, a mixed glioma (G‐XIII) and a malignant schwannoma (N‐XII), were investigated. Twelve G‐XIII gliomas revealed homogenous AgNOR‐counts (standard error of the mean < 10%), with absolute values between the values obtained for human glioblastomas and metastases. Seven N‐XIII subcutaneously transplanted schwannomas revealed higher AgNOR values than human schwannomas, but lower than experimental gliomas. It is concluded that the AgNOR method, as a technique for visualization of ribosomal gene activity, is valuable for assessing proliferative activity and malignancy in both diagnostic and experimental neuropathology.
Hurler's disease with diastematomyelia
Authors: KEOHANE C. , O'LEARY J. , O'NEILL M. , KEARNEY P. J.
Published: May 2008

A case of Hurler's disease is Reported in a child with a gibbous deformity of the lumbar vertebrae L1/L2 and a localized diastematomyelia of the spinal cord at L1/L3. The association of an enzyme disorder affecting connective tissue with spinal cord dysraphism has not been Reported before, and may be fortuitous. However, as each condition is rare, the occurrence of both gibbous deformity due to Hurler's and diastematomyelia in the same child, makes it unlikely to be a chance association. We suggest that defective neurulation in this case may be related to mesodermal damage associated with mucopolysaccharidosis.
Reversible Schwann cell hypertrophy in lead neuropathy
Authors: MONTON F. , CORIA F.
Published: May 2008

Schwann cell hypertrophy is an early change observed in lead‐induced neuropathy in the rat. In order to quantify this cell hypertrophy, a morphometric analysis of Schwann cell cytoplasmic and nuclear areas and their relationship to the cross‐sectional area of the associated myelinated fibre was performed. The study was carried out on sural and peroneal nerves from three groups of adult rats. Group I was intoxicated with 4% lead acetate in the drinking water for 6 weeks; group II animals were treated as in group I and then restored to standard laboratory conditions for 30 days; and group III were controls. The results showed that: (a) after 6 weeks of lead exposure, cytoplasmic and nuclear areas were significantly greater in intoxicated, compared with control rats; (b) after 30 days recovery, Schwann cell cytoplasmic and nuclear areas did not differ from control rats.
Multiple sclerosis: a pivotal role for the T cell in lesion development
Authors: RAINE C. S.
Published: May 2008

The recognition of an increasing number of similarities between the immunologic anomalies associated with multiple sclerosis (MS) and the T cell‐mediated demyelinating model, experimental autoimmune encephalomyelitis (EAE), has resulted in considerable focusing of investigative approaches. It appears that irrespective of the elucidation of the nature of the putative aetiological factor (presumed to be viral) in MS, the arrest and reversal of T cell‐related events within the CNS in this devastating condition represent feasible goals and should remain a major target for some time to come. This short review summarizes the current major areas of activity as they relate to T cell involvement in the immunopathology of MS (and EAE) and presents them in the context of potential therapeutic relevance. In the light of laboratory experiments in which ablation or counteraction of the inflammatory response within the central nervous system (CNS) appears to lead to cessation of immune‐mediated disease and encouragement of CNS remyelination, the prospects of similar strategies being applied to MS are becoming increasingly strong.
Animal models of muscular dystrophy – what can they teach us?
Authors: PARTRIDGE T.
Published: May 2008

The discovery and characterization of the X‐linked gene which is defective in Duchenne muscular dystrophy (DMD) and of its protein product, dystrophin, has led to the identification of biochemical homologues of this disease in the mouse, the dog and the cat. All three animal models resemble DMD in that they lack dystrophin and that their skeletal muscle fibres undergo spontaneous necrosis and regeneration. In the dog and man, the degenerative and fibrotic aspects predominate, leading to a progressive loss of muscle structure and function, and to severe clinical disability. By contrast, in the mouse and the cat there is little fibrosis and the regenerative process seems to overcompensate, producing a true muscle hypertrophy and little or no clinical deficit. This interspecies variation in pathological response limits the usefulness of these animals as models for therapeutic testing, calling into question the strength of linkage between a given biochemical lesion and a particular pattern of pathology. However, these differences do give a valuable perspective to the pathology of the dystrophin‐deficiency diseases, permitting identification of the immediate and secondary consequences of the lack of dystrophin. Moreover, the dystrophic mouse and dog are readily bred as colonies, thus providing consistent material for investigating the function of dystrophin and for testing methods of replacing its function or compensating for the absence of this function in the muscles of DMD patients. The fact that a lack of dystrophin is compatible, in some species, with only minor muscle dysfunction, raises hopes for an effective therapy in man.
A method to quantitate axonal injury
Authors: CROOKS D. A.
Published: May 2008

The quantitation of diffuse axonal injury provides a more objective approach to the assessment of tissue damage in head injuries. The method designed in this study takes into account the anisotropy and structural inhomogeneity of the brain, and the distribution of lesions in diffuse axonal injury. The number of counts required for the statistical analysis is inversely proportional to the square of the desired accuracy, specified as the percentage of the mean value of the axonal balloons since the true mean is unknown from the outset. The number of fields are examined using an indexed‐squares graticule in 10 different areas of the brain. Silver‐stained sections from the brains of head injured patients that survived longer than 12 h must be used with this method. Difficulties may arise when patients of different survival times are compared since it takes some time for the axonal balloons to develop. A correlation with the survival time can be established with the quantitative data collected. The morphometric principles and the statistical rationale on which this methodology is based are briefly presented.
Herpes simplex virus latency in the nervous system – a new model
Authors: STEINER I. , KENNEDY P. G. E.
Published: May 2008

Permissive herpes simplex virus (HSV) infection in tissue culture results in host cell destruction. Latent HSV infection in vivo occurs in neurons of peripheral sensory ganglia (PSG) and it therefore can not take place in neurons in which the virus has completed a lytic replication cycle similar to that present in vitro. Our hypothesis, based on experimental data and observations in humans, suggests that establishment of latent infection and reactivation of HSV‐1 does not involve neuronal cell loss. Latency is established in neurons in which the virus does not replicate and is determined, in part, by the tissue levels of a herpes transactivating protein (Vmw65) that is a component of the viral tegument. We also suggest that reactivation of latent infection does not involve destruction of neurons and is due to replication of virus at the peripheral mucocutaneous tissues to where virus or viral DNA have been transported from the nervous tissue. Alternatively, reactivation is initiated in the PSG using a replication cycle which does not involve irreversible damage to neurons. This model explains the lack of damage to neurons which continue to serve as permanent reservoirs of latent virus for the entire life of the host.
Neuropathological findings in chronic relapsing experimental allergic neuritis induced in the Lewis rat by inoculation with intradural root myelin and treatment with low dose cyclosporin A
Authors: McCOMBE P. A. , van der KREEK S. A. , PENDER M. P.
Published: May 2008

Experimental allergic neuritis (EAN) was induced in Lewis rats by inoculation with bovine intradural root myelin and adjuvants. Rats treated with subcutaneous cyclosporin A (CsA) (4 mg/kg on 3 days per week from the day of inoculation until day 29) developed a chronic relapsing course. Tissues from the spinal cord, nerve roots, dorsal root ganglia and sciatic nerve of CsA‐treated rats sampled during relapses and remissions were studied by light and electron microscopy. Control rats that were not treated with CsA were studied during or after episodes of acute EAN. Both control and CsA‐treated animals studied in the first episode of EAN had evidence of inflammation and primary demyelination of the nerve roots and dorsal root ganglia. In control and CsA‐treated animals that had recovered from the first episode there was evidence of remyelination. In CsA‐treated animals in the second episode there was severe inflammation and demyelination and remyelination of the nerve roots and dorsal root ganglia, and in addition there was significant demyelination and remyelination in the spinal nerves and sciatic nerves and dorsal columns of the spinal cord, particularly in later stages of disease. In later episodes there was less inflammation, but there was continuing demyelination and onion bulbs were present. In animals sampled after recovery from chronic relapsing EAN onion bulbs were present. Occasional small onion bulbs were also observed in control animals that were inoculated with higher doses of myelin. Plasma cells were present in the inflammatory lesions of later episodes. Mast cells were also observed at different stages of the disease. We conclude that the CsA form of chronic relapsing EAN has clinical and pathological similarities with the human disease, chronic inflammatory demyelinating polyradiculoneuropathy.
Ballooned neurons in several neurodegenerative diseases and stroke contain αB crystallin
Authors: LOWE J. , ERRINGTON D. R. , LENNOX G. , PIKE I. , SPENDLOVE I. , LANDON M. , MAYER R. J.
Published: May 2008

αB crystallin is a protein which has homology with the small cell stress proteins. A characterized antibody to residues 1–10 of αB crystallin was used to immunostain tissues containing ballooned (chromatolytic, achromasic) neurons. The tissues included two cases of classical Pick's disease, one case of dementia with swollen achromasic neurons in the cortex, two cases of Alzheimer's disease with large numbers of ballooned neurons, two cases of motor neuron disease, four cases of cortico‐basal degeneration, and four cases with areas of brain showing swollen neurons adjacent to recent cerebral infarcts. The anti‐αB crystallin showed strong diffuse cytoplasmic immunoreac‐tivity of swollen cortical neurons in all the diseases. Astrocytes and oligodendroglial cells were also stained in normal tissues as previously described. Weak diffuse immunoreactivity with an antibody to ubiquitin‐conjugates was also seen in the swollen neurons from cases of neurodegenerative disease but not following infarction. Ballooned neurons have been shown to contain phosphorylated neurofilament epitopes not normally present in the perikaryonal region. The presence of αB crystallin in ballooned neurons, together with previous data which also indicate its close association with intermediate filaments, suggest that αB crystallin may be involved in aggregation and remodelling of neurofilaments in disease. The presence of αB crystallin in neurons at the edge of areas of cerebral infarction is likely to reflect cells which are regenerating following damage; its detection may therefore be a marker for such cells. On a practical level, the antibody greatly facilitates the localization of such abnormal neurons in diagnostic histology.
Schwann cell endocytosis: a role in nerve regeneration?
Authors: BESWETHERICK J. T. , LANE P. A. , ALLT G.
Published: May 2008

Schwann cell plasma membrane vesicles have been shown to increase in numerical density after nerve injury but their function is unclear. In this study, ultra structural tracers were micro‐injected in vivo into crushed rat sciatic nerves after various time intervals to ascertain whether plasma membrane vesicles of Schwann cells are involved in the uptake and utilization of molecules from the endoneurium during axonal regeneration and remediation. Horseradish peroxidase (HRP), a tracer of fluid‐phase endocytosis, was taken up by macrophages and fibroblasts but remained external to Schwann cells throughout the study. After 14–16 days of crush injury, HRP was present within vessel lumina and in cytoplasmic vesicles of pericytes and vascular endothelia. Low‐density lipoprotein‐gold, which is primarily internalized by receptor‐mediated endocytosis, and bovine serum albumin‐gold, proposed as a tracer for fluid‐phase endocytosis, were internalized by macrophages and fibroblasts but were not taken up by Schwann cells. Although Schwann cells formed pits in the plasma membrane and vesicles were evident in the cytoplasm, none of the tracers used were internalized by Schwann cells. It is suggested that Schwann cell plasmalemmal and cytoplasmic vesicles have a cellular role unrelated to endocytosis or alternatively the Schwann cell basal lamina may function as a diffusion barrier to the tracers employed.
Expression of glial fibrillary acidic protein (GFAP) by cultured angiofibroma stroma cells from patients with tuberous sclerosis
Authors: KATO M. , KATSUMOTO T. , OHNO K. , KATO S. , HERZ F. , TAKESHITA K.
Published: May 2008

Large dendritic cells were cultured from facial angiofibromas of six patients with tuberous sclerosis. The cells were examined immunocytochemically for expression of selected cyto‐skeletal and non‐structural proteins and the results compared with the staining profiles obtained with normal skin fibroblasts and normal glial cells. In similarity to normal glia, the angiofibroma stroma cells expressed glial fibrillary acidic protein (GFAP). Conversely, by analogy to fibroblasts, the abnormal stroma cells produced fibronectin and did not react with the antibody to S‐100 protein. By immunogold labelling it was established that GFAP and vimentin were co‐localized in intermediate filaments of the angiofibroma cells.
The effects of pre‐natal exposure to methylazoxymethanol acetate on microglia
Authors: ASHWELL K. W. S.
Published: May 2008

The effects of exposure to a cytotoxic agent, methylazoxymethanol acetate (MAM Ac), on the distribution, density and quantitative morphology of microglia in the rat forebrain have been examined with the aid of a peroxidase‐conjugated lectin derived from Griffonia simplicifolia. Following exposure to MAM Ac (25 mg/kg maternal body weight) on embryonic day 13 (E13), round microglia were concentrated around the areas of induced cell death at the outer margins of the ventricular germinal zone, particularly in the striatopallidal angle and dorsal thalamus. By E19, there were no detectable differences in microglia distribution between experimental and control animals. The increase in number of microglial cells in the neocortex and caudatoputa‐men on exposure to MAM Ac lasted foi only 4 to 6 days. Subsequently, the number of microglia dropped below control values in both regions. The density of microglia in these areas was similar in control and experimental animals from 6 days after exposure. The proportion of microglia relative to all other cells was also similar at post‐natal day 17 (P17) in both experimental and control animals. These results suggest that the distribution and final size of the microglial population is determined by the microenvironment and not by the extent of cell death which may have acted as the initial stimulus to microglial invasion.
The use of azathioprine to ameliorate post‐treatment encephalopathy associated with African trypanosomiasis
Authors: HUNTER C. A. , JENNINGS F. W. , KENNEDY P. G. E. , MURRAY M.
Published: May 2008

The treatment of human African sleeping sickness is complicated by a post‐treatment meningo‐encephalitis that may be fatal. Using a mouse model this study assesses the use of the non‐steroidal anti‐inflammatory drug, azathioprine, in the management of this post‐treatment reaction. Female NIH mice treated with the trypanocidal compound diminazene aceturate (40 mg/kg), 28 days after infection, developed a similar post‐treatment reaction to that seen in humans. Administration of azathioprine (100 mg/kg) for 5 days before and 5 days after trypanocidal chemotherapy abrogated the pathology in the central nervous system although this returned approximately 15 days after cessation of azathioprine. Activated astrocytes associated with the later stages of the infection did not appear to be affected by the use of azathioprine.
Neural tube defects in the parietal region of human embryos: failure to close or closure‐reopening?
Authors: Smith M. S. R. , Upfold J. B. , Shiota K.
Published: May 2008

This is a follow‐up study to earlier investigations on neural tube defects (NTD) in the Kyoto collection of human embryos. It includes an extensive examination of abnormal embryos which have been photographed and serially sectioned following routine histological preparation. Two new types of NTD are described in the parietal region (the roof of the third ventricle) which had previously been overlooked. These anomalies were found most commonly in embryos at the developmental period, Carnegie stage [CS] 16–23 (embryonic days 38–52). Hypotheses are advanced regarding the genesis of NTD and whether encephaloceles and NTD are part of a spectrum of malformation. This study also reinforces evidence that the occurrence of NTD is significantly higher in the embryonic period than at birth. Animal studies, using the guinea‐pig are discussed with regard to the investigation of hypotheses put forward to explain the genesis of NTD.
A four‐layered ‘lissencephalic’ cortex induced by prenatal X‐irradiation in the rat
Authors: Ferrer I. , Alcántara S. , Martí E.
Published: May 2008

A four‐layered cortex is produced in the dorsal region of the rat brain, after 200 cGy X‐irradiation at embryonic day 16. The layer 1 is the molecular layer; layer 2 is the upper cellular layer which is in continuity with normal layers V and VI in the lateral cortex; layer 3 is a sparsely cellular layer; and layer 4 is the inner cellular layer which is composed of neurons normally committed to the upper cortical layers. This failure of neuroblast migration to the upper layers is associated with reduced numbers, and morphological abnormalities, of radial glial cells in the dorsal cortex. This further supports the idea that abnormal interactions between neuroblasts and radial glial cells result in abnormal migratory patterns. Since a similar four‐layered organization is found in human lissencephaly type I, the present results bring new data that can serve our better understanding of human cortical malformations.
Hippocampal damage in fatal paediatric head injury
Authors: Kotapka M. J. , Graham D. I. , Adams J. Hume , Doyle D. , Gennarelli T. A.
Published: May 2008

The hippocampus is known to be frequently involved in head injury. In adults, such hippocampal lesions frequently include regions of selective neuronal necrosis. The present report examines the frequency and distribution of hippocampal damage in 37 cases of fatal head injury in children. Damage to the hippocampus was noted in 27 of 37 cases (73%). Lesions were often focal areas of selective neuronal necrosis located in the CA‐1 subfleld. Other subfields of the hippocampus were involved to lesser degrees. The frequency and distribution of hippocampal damage in fatal childhood head injury is similar to that reported for fatal head injuries of all ages. Pathological evidence of high intracranial pressure and/or hypoxic brain damage in other anatomical locations was present in the majority of cases. Clinical seizures prior to death occurred in 22% of the cases studied. However, these factors could not account for all cases of hippocampal damage in the present report. Thus, the hippocampus is frequently damaged in fatal head injury in children. The mechanisms involved in the production of such damage may involve hypoxia, raised intracranial pressure and altered cerebral perfusion. However, other, yet to be elucidated, mechanisms may be involved.
Intracranial lipoma of the Sylvian region
Authors: Cserni G.
Published: May 2008

The incidental autopsy finding of an intracranial lipoma in the left Sylvian region is reported. This is a rare location for an uncommon lesion. A recent theory on its pathogenesis as a congenital lesion is presented and current methods of diagnosis and treatment are discussed.
Ependymal cells of the choroid plexus express tumour necrosis factor‐α1
Authors: Tarlow M. J. , Jenkins R. , Comis S. D. , Osborne M. P. , Stephensl S. , Stanley P. , Crocker J.
Published: May 2008

Tumour necrosis factor‐alpha (TNFa) is a major proinflammatory cytokine which appears in the cerebrospinal fluid very early after endotoxin challenge, and is likely to be produced locally. Following in vivo and in vitro challenge with endotoxin, we have demonstrated immunocytochemically and by in situ hybridization that pig and guinea‐pig choroid plexus ependymal cells can produce TNFa. Immuno‐electron microscopy shows that this protein is localized within ependymal cells to the cytoplasm and microvilli. We suggest that this TNFa may be important in the initiation of the inflammatory response in bacterial meningitis.
Distinction between artefactually shrunken and truly degenerated ‘dark’ neurons by in situ fixation with microwave irradiation
Authors: Løberg E. M. , Torvik A.
Published: May 2008

Dark, shrunken neurons frequently occur as artefacts in immersion fixed tissue. Perfusion fixation will prevent artefacts of this type. However, morphologically identical neurons have been described as truly degenerated cells in perfusion fixed brains in various pathological conditions. Since adequate perfusion is difficult to obtain in some pathological conditions, the question still remains whether the dark neurons found in some of these situations are true in vivo phenomena or artefacts caused by inadequate fixation. In the present study rat brains with cryogenic lesions were fixed in situ by microwave irradiation. With this method no artefactually changed dark neurons were observed in the normal parts of the brains. In the cryogenic lesions, however, a narrow rim of dark, shrunken neurons occurred adjacent to the normal cortex. This zone was identical to that observed in perfusion fixed tissue. Since inadequate fixation due to uneven perfusion of the damaged tissue is prevented with this method, we suggest that the neuronal changes represent true in viva phenomena. Fixation with microwave irradiation can thus be used to differentiate between artefactually changed and truly degenerated dark neurons in various pathological conditions.
Cellular changes in the cerebellar granular layer in AIDS‐associated PML*
Authors: Kuchelmeister K. , Bergmann M. , Gullotta F.
Published: May 2008

Six cases of AIDS‐associated progressive multifocal leukoencephalopathy (PML) exhibited peculiar cellular changes in the cerebellar granular layer. These cells without discernible cytoplasm showed hypochromatic nuclei about twice as large as those of normal granule cells. They were restricted exclusively to the granular layer and always surrounded PML foci. An astrocytic, leukocytic or macrophage/microglial nature was largely excluded by immunocytochemistry. Human immunodeficiency virus (HIV) antigen p 24 could not be found in these cells and there was no unequivocal detection of JC virus (JCV) DNA and no ultrastructural evidence of papovavirus particles in them. They possibly represent altered cerebellar granule cells abortively or latently infected with JCV.
Meeting report
Authors: Weller R. O.
Published: May 2008

8th Wye College Symposium on Neuropathology (Wye College, near Canterbury, Kent, July 5–9, 1993)
Effect of infection with rubella virus on the development of rat cerebellar cells in culture
Authors: Natale V. A. I. , Caffrey J. F. , Sheahan B. J. , Atkins G. J.
Published: May 2008

Immunogold‐silver staining of mixed rat cerebellar neuron/glial cell cultures, using Ranscht monoclonal antibody, resulted in labelling of neuronal processes and oligodendrocytes. This antibody was originally believed to react with galactocerebroside alone, and it was concluded that labelling by it resulted from the presence of myelin [2]. Electron microscopic examination of the cultures did not reveal myelination. Infection of such cultures with rubella virus resulted in a cytopathic effect. This effect was initially characterized as a disaggregation of neuronal processes, and the disruption of a layer of membranous material covering both cell bodies and processes. The virus causes disruption of cultures of pure glial cells, but there is no evidence of virus multiplication or cytopathic effect in pure neuron cultures. The cytopathic effect in mixed neuron/glial cell cultures is concluded to be glial cell mediated.
Autosomal dominant arteriopathic leuko‐encephalopathy and Alzheimer's disease*
Authors: Gray F. , Robert F. , Labrecque R. , Chrétien F. , Baudrimont M. , Fallet‐Bianco C. , Mikoi J. , Vinters H. V.
Published: May 2008

A 49–year–old man suffered from progressive dementia and seizures leading to death after 2 years. CT scans showed severe cortical–subcortical atrophy and hypodensity of the white matter. His father had died at about the same age with similar clinical signs. Two sisters and one brother were also affected. Neuropatho–logical study revealed predominant involvement of the cerebral white matter with myelin loss, gliosis and type I lacunes. The small arteries and arterioles of the white matter and basal ganglia, and, to a lesser extent those of the subarachnoidal space, displayed fibrosis and replacement of the media by an eosinophilic, PAS positive, Congo Red negative, granular substance. Electron microscopy showed swollen myocytes surrounded by collagen, elastin and a compact electron–dense material. Immunofluorescence using antibodies against IgA, IgG, IgM, Clq and C3 stained the abnormal media weakly. In the cortex, there were diffuse senile plaques and neurofibrillary tangles. Imrnunohistochemistry demonstrated β7A4 positive material in cortical senile plaques but not in arterial walls. Adventitial macrophages were, however, immunoreactive for gamma–trace. Systemic arterioles were normal. The vascular changes and leuko–encephalopathy are comparable to those described in ‘Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy’ (CADASIL). Similar vascular changes were also observed in non–familial cases. An association with Alzheimer changes in the cortex has not been described previously. The relationship between both diseases and the role of each in the causation of the dementia is unclear.
Absence of coxsackie viruses in idiopathic inflammatory muscle disease by in situ hybridization
Authors: Hilton D. A. , Fletcher A. , Pringle J. H.
Published: May 2008

The role of coxsackie virus infection in the pathogenesis of idiopathic inflammatory muscle disease (HMD) has been investigated by many workers with conflicting results. This study uses in situ hybridization, with digoxigenin–labelled oligonucleotide probes complementary to the coxsackie B virus genome, to investigate the presence of virus RNA in muscle biopsies from 26 patients with HMD. In the five cases of inclusion body myositis studied, there was focal probe–binding to nuclei and cytoplasm, and in nine cases probe–binding to mast cells was seen. In both of these instances probe–binding was non–specific and not due to hybridization. None of the cases showed the presence of coxsackie virus RNA within muscle and it is concluded that lytic infection of myocytes by coxsackie virus does not occur in IIMD.
Expression of utrophin (dystrophin–related protein) during regeneration and maturation of skeletal muscle in canine X–linked muscular dystrophy
Authors: Wilson L. A. , Cooper B. J. , Dux L. , Dubowitz V. , Sewry C. A.
Published: May 2008

The regulation of utrophin, the autosomal homologue of dystrophin, has been studied in the canine X–linked model of Duchenne muscular dystrophy. Dystrophic muscle has been shown to exhibit abnormal sarcolemmal expression of utrophin, in addition to the normal expression at the neuromuscular junction, in peripheral nerves, vascular tissues and regenerating fibres. To establish whether this abnormal presence of utrophin in dystrophic muscle is a consequence of continued expression following regeneration, or is attributable to a disease related up–regulation, the expression of utrophin was compared immunocytochemically with that of dystrophin, β–spectrin and neonatal myosin in regenerating normal and dystrophic canine muscle, following necrosis induced by the injection of venom from the snake Notechis scutatis. In normal regenerating muscle, sarcolemmal utrophin and dystrophin were detected concomitantly from 2–3 d post–injection, prior to the expression of β–spectrin. Down–regulation of utrophin was apparent in some fibres from 7 d, and it was no longer present on the extra–junctional sarcolemma by 14 d. Neonatal myosin was still present in all fibres at this stage, but dystrophin and β–spectrin had been fully restored. In dystrophic regenerating muscle, downregulation of utrophin occurred from 7 d, although it persisted on some fibres until 28 d, longer than in normal muscle. At 42 d, however, utrophin in dystrophic muscle was only detected in a population of small fibres thought to represent a second cycle of regeneration, with no immunolabelling of mature fibres. The results show that most utrophin is down–regulated in regenerating dystrophic fibres, prior to neonatal myosin, thus abnormal sarcolemmal expression of utrophin in dystrophic muscle is unlikely to be a continuation of the maturational process. Persistence of both utrophin and neonatal myosin, however, suggest a delay in the maturation of dystrophic muscle. In addition, a second cycle of degeneration and regeneration in dystrophic muscle does not occur whilst utrophin is still present, suggesting it may have a protective role against fibre damage and necrosis.
Lewis rat EAN is suppressed by the 21–aminosteroid tirilazad mesylate (U–74006F)
Authors: Feasby T. E. , Hahn A. F. , Lovgren D. , Wilkie L.
Published: May 2008

Lewis rat experimental allergic neuritis (EAN) was treated with the 21–aminosteroid, tirilazad mesylate (U–74006F). High doses of tirilazad mesylate, begun just before the onset of clinical signs, reduced the clinical and pathological severity of the disease. In rats immunized with a high dose of myelin, axonal degeneration was a major pathological feature. Tirilazad mesylate reduced the amount of axonal degeneration but had little effect on the other pathological features of EAN, such as inflammation and demyelination. Tirilazad mesylate may block axonal degeneration by inhibiting lipid peroxidation of axonal membranes. Inhibition of axonal degeneration is an important goal in the treatment of human neuropathies.
Demonstration of mitochondrial ribosomal RNA in frozen and paraffin–embedded sections of skeletal muscle by in situ hybridization
Authors: Hilton D. A. , Love S. , Goodwin T. , Pringle J. H.
Published: May 2008

We have used in situ hybridization with synthetic oligonucleotide probes to the 16S sub–unit of mitochondrial ribosomal RNA to detect mitochondrial accumulations in biopsies of skeletal muscle from 16 patients with mitochondrial myopathies. In all cases, the distribution of the hybridization signal matched the pattern of succinate dehydrogenase activity in adjacent cryostat sections. In situ hybridization also allowed visualization of mitochondrial accumulations in paraffin–embedded sections of skeletal muscle that had been fixed in either De Castro's solution or formalin. DNase pre–treatment did not significantly diminish the intensity of hybridization signal, suggesting that the hybridization is predominantly to RNA. The advantages of this technique are that it allows the investigation of mitochondrial disorders when only paraffin–embedded tissue is available and should also facilitate the demonstration of mitochondrial accumulations in tissues other than skeletal muscle.
Characterization of T–cell subclasses and NK–cells in lysosomal disorders by immuno–electron microscopy
Authors: Kieseier B. C. , Goebel H. H.
Published: May 2008

Previous studies have shown that B and T lymphocytes are affected in lysosomal disorders. The aim of this study was to investigate the involvement of subclasses of T lymphocytes and natural killer cells in lysosomal diseases. CD4 +, CD8 +, and CD56+ cells were immunomagnetically separated from peripheral blood mononuclear cells in 10 patients with various lysosomal diseases – including one patient each with infantile, late infantile, and juvenile neuronal ceroid–lipfuscinoses, two patients with mucopolysaccharidosis (MPS) type I and four patients with MPS type HI, and one patient with mucolipidosis type II; all lymphocytes were studied by light and electron microscopy. Respective vacuolar or non–vacuolar lysosomal inclusions were identified in CD4 +, CD8 +, and CD56+ cells. Subclass–specific abnormal lysosomes could not be found. Both subclasses of T lymphocytes investigated showed nearly the same ratio of affected to non–affected cells. These results were obtained by studying a small number of different lysosomal disorders. Nevertheless, they suggest that lysosomal storage in these subclasses of immunocompetent cells might also be found in other forms of lysosomal disease.
Microglial aggregation in the dentate gyrus: a marker of mild hypoxic‐ischaemic brain insult in human infants
Authors: Bigio M. R. Del , Beckery L. E.
Published: May 2008

There are many reports in experimental animals indicating that microglia are activated in the dentate gyrus and hippocampus following hypoxic‐ischaemic brain injury. The hippocampi of brains removed at autopsy from 178 children were studied retrospectively and the quantity of microglia in the polymorphous layer of the dentate gyrus was assessed. Up to the age of 8–9 months, patients with proven hypoxic or hypotensive episodes due to perinatal asphyxia, congenital heart defects, or chronic pulmonary dysfunction often had a dense infiltrate of microglial cells. A comparable microglial infiltrate was seen in most children dying under circumstances consistent with sud den infant death syndrome. Children under 9 months of age dying of other acute causes, for example trauma or sepsis either suddenly or with survival of less than 4 days in the intensive care unit, had significantly fewer microglia. After the age of 9 months a dense microglial infiltrate was never seen regardless of the cause of death. We conclude that the presence of abundant microglia in the polymorphous layer of the dentate gyrus of human infants is a marker of chronic illness or mild hypoxic‐ischaemic brain injury which takes several days to develop.