Differential transcription of the repetitive R-element in various mouse cell types.

Clones that contain R-elements separated from the rest of the L1-repeat have been isolated from a mouse genomic DNA library. Spot hybridization of DNA from various species (from mammals to plants) with one representative and well characterized mouse DNA clone shows that at least this sequence hybridizes only with mouse DNA. In addition, we demonstrate that the R-element repeat is transcribed differentially in various tissues or cell types. Furthermore, the amount of R-transcripts is regulated at varying rates in the different cell types of a tissue as shown by in situ hybridization.

Stiff-man syndrome in a woman with breast cancer: an uncommon central nervous system paraneoplastic syndrome.

We report a patient who developed stiff-man syndrome, including disabling shoulder subluxation and wrist ankylosis, in association with breast cancer. Immunologic investigations disclosed autoimmunity directed against not only glutamic acid decarboxylase but also amphiphysin, a 128-kd protein located in the presynaptic compartment of neurons. The patient improved after surgery and corticosteroid treatment and has been stable for nearly 4 years on only anti-estrogenics. The triad of stiff-man syndrome, breast cancer, and autoantibodies against amphiphysin identifies a new autoimmune paraneoplastic syndrome of the CNS.

Expression and immunolocalization of the multidrug resistance proteins, MRP1-MRP6 (ABCC1-ABCC6), in human brain.

Multidrug resistance proteins (MRPs, symbol ABCC) are membrane glycoproteins that mediate the ATP-dependent export of organic anions, including cytotoxic and antiviral drugs, from cells. To identify MRP family members possibly involved in the intrinsic resistance of human brain to cytotoxic and antiviral drugs, we analyzed the expression and localization of MRP1-MRP6 in rapidly frozen perilesional samples of several regions of adult human brain obtained during neurosurgery. Quantitative polymerase chain reaction analysis showed expression of MRP1, MRP2, MRP3, MRP4, and MRP5 mRNA, whereas MRP6 mRNA was below detectability. However, immunofluorescence microscopy of cryosections from human brain showed no reactivity for the MRP2 or MRP3 proteins. The proteins MRP1, MRP4, and MRP5 were clearly localized by confocal laser scanning microscopy to the luminal side of brain capillary endothelial cells. The MRP4 and MRP5 proteins were also detected in astrocytes of the subcortical white matter. Notably, MRP5 protein was present in pyramidal neurons. MRP proteins may, thus, contribute to the cellular efflux of endogenous anionic glutathione or glucuronate conjugates (substrates for MRP1), cyclic nucleotides (substrates for MRP4 and MRP5), or glutathione (co-substrate for MRP1 and MRP4); in addition, they may play an important role in the resistance of the brain to several cytotoxic and antiviral drugs.

Alternative splicing of the beta A4 amyloid gene of Alzheimer's disease in cortex of control and Alzheimer's disease patients.

An S1 nuclease protection assay was designed to study the splicing pattern of the alternatively spliced beta A4 amyloid gene (APP gene) of Alzheimer's disease (AD). We determined the splicing pattern of the APP gene in fetal, adult, aged adult and AD human cortex. The results suggest that alternative splicing of the APP gene in AD is not significantly different from age-matched controls, but distinct from the developing fetal brain.

Cerebellar vermis area in schizophrenic patients - a post-mortem study.

Neuroimaging studies of cerebellar atrophy in schizophrenia have yielded contradictory results. In computer-tomography (CT) studies, cerebellar atrophy was found in up to 40% of schizophrenic patients. However, several recent magnetic resonance imaging (MRI) studies could not replicate these early findings; in addition, contradictory observations of enlargement of vermal structures were reported. In contrast to the number of CT and MRI studies, there are only a few neuropathological reports on this subject. In a post-mortem study we analyzed the midsagittal vermal area of formaldehyde-fixed cerebella of 12 deceased schizophrenic patients and 12 age- and gender-matched control subjects by using morphometrical methods. Statistical analysis using ANOVA revealed no significant group effects, but there were interactions with gender and cerebellar brain weight. In view of the present results, the common concept of cerebellar atrophy in schizophrenic patients appears premature. Gender effects and secondary processes (e.g., relevant alcohol or drug abuse) cannot be excluded as possible factors causing decrease of vermal areas in schizophrenic patients.

"Epi-" and intramedullary neurilemmoma of the spinal cord with denervation atrophy in the related skeletal muscles.

The autopsy of a 68-year-old male who died of cardiac infarction revealed an ep - and intramedullary neurilemmoma of the spinal cord as an associated finding half a year prior to death. The patient had suffered from progressive weakness and sensory disturbances of the lower limbs together with muscular wasting for 6 months. Repeated neurological examinations had led to the diagnosis of an intraspinal space occupation which, however, could not be substantiated by myelography because of its surprisingly small size. The Schwann cell proliferation originated from the adventitia of the epi- and intramedullary vessels of the conus medullaris. The main tumor mass was epi-medullary and extended into the medullary parenchyma via the penetrating vessels forming intramedullary nodules. The special findings in the present case seem to support the hypothesis that intramedullary neurilemmomas originate from the perivascular nerve endings.

The relationship between target, targetoid, and targetoid/core fibers in severe neurogenic muscular atrophy.

In the m. tibialis anterior of a 68-year-old man with rapidly developing denervation atrophy in the legs since 1/2 year prior to death from heart stroke, abundant unifocal concentric fiber changes, such as target, targetoid/core, and targetoid fibers could be observed. Besides, large vacuolized fibers with multiple changes resembling cytoplasmic bodies in the peripheral zone were present as well; they are interpreted as fibers with multicentric target or targetoid formations. The target fibers displayed a broad variation of their outer appearance suggesting a continuous transition to targetoid/core fibers (with a dense center) and targetoid fibers (with a central change to aquous sarcoplasm showing a paucity of fibrillar structures). Very few fibers with a central densification of fibrillar material with or without a thin intermediate zone were fairly akin to core fibers of central core disease; others were more alike the type of targetoid fibers, previously described in the literature, showing a dense target-like center; both were summarized under the term, inaugurated by Engel et al. (1966), "targetoid/core fibers". Simultaneous occurrence of the different kinds of concentric fiber changes suggested a strong relation between all of them in the sense of representing different developmental stages of the same pathogenetic process. Thus, the central core disease, for instance, might be a disorder with a generalization of concentric fiber changes having come to arrest in the earliest stage of development.

Peripheral intraaxonal storage in Tay-Sachs' disease (GM2-gangliosidosis type 1.

Considerable intraaxonal lipid storage was observed in intramuscular nerve fibres mainly of the extraocular muscles and less frequently in limb muscles of a 3-year-old child, which had suffered from Tay-Sachs' disease. Many axons of the small intramuscular nerve twigs and of the terminal and preterminal nerve endings showed spherical and cylindrical enlargements containing granular storage material of the same staining properties as the material in the central nervous system. The identify of the axonal and the neuronal storage material was further confirmed by electron-microscopical demonstration of typical multilamellated cytoplasmic bodies (MCBs) in both of them. In addition, silver impregnation and electron microscopy revealed dystrophic changes with an increase of argyrophilic filamentous material within some of the axonal distensions, indicating that the latter were probably due to both a lipid storage and an unspecific dystrophic process.

Long-term survival of a patient with giant cell glioblastoma. Case report.

The authors report on a patient who had undergone resection of a left-sided temporal giant cell glioblastoma at the age of 69 years and who survived for more than 17 years. This man had not undergone postoperative radiotherapy or adjuvant chemotherapy. He died at the age of 86 years without clinical evidence of tumor recurrence. Histologically, the lesion was characterized by highly pleomorphic tumor cells (including bizarre multinucleated giant cells) with high mitotic activity, large necroses, and prominent mononuclear infiltration. A point mutation in the TP53 tumor suppressor gene (c.524G>A; R175H) and no epidermal growth factor receptor gene amplification were revealed on molecular genetic analysis. No diagnostic chromosomal imbalances were identified on comparative genomic hybridization, although the average ratio profile for chromosome 10 indicated loss of 10p15 in a subpopulation of tumor cells. This patient is exceptional because tumor resection, probably in conjunction with a marked antitumor immune response, apparently resulted in eradication of the lesion.

A correlative study of gliomas using in vivo bromodeoxyuridine labeling index and computer-aided malignancy grading.

An in vivo bromodeoxyuridine (BrdU) labeling index (LI) was estimated in 43 cases of astrocytic tumors and mixed gliomas by one hour intra-operative intravenous infusion at a dose of 200 mg/m2 and correlated with (a) histological grading using a computer aided malignancy classifier TESTAST-268; and (b) histological typing using WHO classification. The lowest BrdU LI was seen in pilocytic and gemistocytic astrocytomas followed by astrocytomas, anaplastic astrocytomas and glioblastoma multiforme in that order. Mixed oligoastrocytomas followed the pattern of their astrocytic counterparts. Tumors of similar histological type showed different BrdU LI values especially amongst astrocytomas and glioblastomas. A statistically significant difference in the BrdU LI was also noted between the higher TESTAST grades of astrocytomas (T III and IV) versus the lower TESTAST grades (T II). Unlike earlier reports in literature, in the present study the category of BrdU LI of <1 contained no case of anaplastic astrocytoma or glioblastoma multiforme (TESTAST grades III and IV). Likewise, the category of BrdU LI >5 contained only anaplastic astrocytoma and glioblastoma multiforme (TESTAST grades III and IV). Maximum spread of cases was seen in the BrdU LI category of 1-5, not only in terms of histological types but also TESTAST grades. Thus there appeared to be a positive trend of increasing BrdU LI values both with histological types and increasing TESTAST grades. Further, an interesting observation was that by using a combination of TESTAST grades and BrdU LI, the histologically homogenous glioblastoma group could be further subdivided into 4 categories which showed a trend towards prognostic correlation. Thus, this study though preliminary with number of cases being small in some groups, highlights the possible usefulness of combined histological typing, TESTAST grading and in vivo BrdU LI for prognostication of gliomas especially glioblastoma multiforme.

"Inverse Chiari type II syndrome" in untreated hydrocephalus and its relationship to typical Arnold-Chiari syndrome.

Two cases of transtentorial upward displacement of the cerebellum in children with untreated hydrocephalus are reported. These cases clearly indicate that the condition is a primary malformation of the hindbrain and not a result of longstanding hydrocephalus treatment, as has been proposed in the past. The second case demonstrates the close relationship of the syndrome to classical Arnold-Chiari malformation.

Multicystic encephalopathy--a polyetiologic condition in early infancy: morphologic, pathogenetic and clinical aspects.

Eleven observations of severe multicystic encephalopathy ( MCE ) in young infants and in a two-year-old child provide the basis for a summing-up and discussion of the various aspects of this characteristic polyetiologic phenomenon occurring in early infancy. In all cases the triggering causes or underlying disorders were different, although in five cases the common pathogenetic mechanism was a disturbance of circulation and/or respiration (acute respiratory distress syndrome). In two cases the basic disorders were a suppurative and a granulomatous meningoencephalitis. Carbon monoxide poisoning had occurred in one and diffuse meningocerebral angiomatosis in another two cases. In the eleventh case, one of a complicated twin birth, the exact cause of the MCE remained obscure. These cases together with those recorded in the literature demonstrate that the surprisingly constant pattern of damage in MCE , which results from different etiologic conditions, should be due to a specific mode of reaction of the infantile brain to a common pathogenetic mechanism. Anoxia with hypercapnia and the formation of brain edema are discussed as the basic events in the pathogenesis of MCE .

Unusual split of the spinal cord in a caudal regression syndrome with myelocystocele.

Report of a newborn infant with a caudal regression syndrome and a large myelocystocele. A small part of the transitional zone between the normal spinal cord and the myelocystocele displayed a triploid cord in cross sections, suggesting a kind of "triastematomyelia," which was, however, finally considered rather to represent a special form of diastematomyelia than a true threefold split of the spinal cord. The probable pathogenetic background of the condition is discussed.

Diagnostic value of the stereotactic approach to focal lesions in the deep brain of children and adolescents.

Since it is relatively harmless, stereotactic biopsy has become in recent years a useful method for the diagnostic assessment of lesions deep in the brain, which are not accessible to open surgery. With the aid of stereotaxis, focal lesions only a few millimeters in diameter can be approached in every location in the brain with high precision. Since stereotaxis does not require general anesthesia, or at most requires only a very shallow anesthesia, it can also be applied to young infants or persons of advanced age. Experience with stereotactic biopsy exploration of lesions of various kinds in the deep brain of 74 children and adolescents, out of a sample of 260 patients of all age groups who received stereotactic biopsy, is reported. Our aim is to demonstrate and discuss the advantage of this contemporary method for child neurology and neurosurgery. In many medical centers in the world where stereotactic tumor biopsy has been established, it has become an important criterion for the choice of treatment.

Childhood progressive spinal muscular atrophy with facioscapulo-humeral predominance, sensory and autonomic involvement and optic atrophy.

A female child of healthy parents developed rotary nystagmus at the age of 15 months. Ophthalmoscopy disclosed incomplete optic atrophy. Blood tests, EEG and CT scans were normal. At 20 months progressive muscular weakness and wasting with limb-girdle distribution commenced, followed later by disturbance of gait. From muscle and nerve biopsy the diagnosis of a peripheral neuropathy with neurogenic muscular atrophy was made. No mental change occurred. At 23 months she sustained cardiac arrest and was resuscitated; thereafter, she remained in a vegetative state and expired 9 months later. Her brain was markedly atrophic and firm. Diffuse old ischemic necroses and neuronal loss with gliosis were found in the cortex, the neostriatum, the thalamus, parts of the lower brainstem, and the cerebellum. Her optic nerves and tracts showed complete atrophy. The spinal cord exhibited degeneration and loss of motor neurons with cervical accentuation. The intermediolateral nuclei, the dorsal nuclei and the spinal ganglia were also involved. There was demyelination of the posterior funiculi, the pyramidal tracts, and the sciatic, peroneal, sural, and superior frontal nerve. The voluntary muscles exhibited large group atrophy with liposclerotic change and limb-girdle predominance. The neck, tongue and ocular muscles were also involved, as were, to a less extent, the lower limbs. Although the loss of motor neurons in the spinal cord and at the bulbar level with the typical pattern of neurogenic muscular atrophy, as well as its distribution, resemble the facioscapulo-humoral type of heredity motor neuropathy (HMN), early onset, rapid course, sensory and autonomic involvement, and atrophy of the optic nerve do not fit this or any one type of HMN.

Telencephalosynapsis (synencephaly) and rhombencephalosynapsis with posterior fossa ventriculocele ('Dandy-Walker cyst'): an unusual aberrant syngenetic complex.

Agenesis of the cerebellar vermis (paleocerebellar agenesis) with fusion of the cerebellar hemispheres (rhombencephalosynapsis) is a rare malformation of the central nervous system (CNS). Its combination with synencephaly (telencephalosynapsis), telencephalic ventricular aplasia, aqueductal atresia and cystic fourth ventricle has not yet been described, as far as we know. Here, we report this combination in a 23-weeks' gestation male fetus who was aborted to a 24-year-old diabetic mother. In this fetus with cerebral and cerebellar hemispheric fusion, vermian agenesis was associated with a Dandy-Walker-like posterior fossa cyst, in spite of the fusion of the hypoplastic cerebellar hemispheres. The CNS malformations were further accompanied by dysmorphic facial stigmata such as unilateral atresia of the external ear, ocular hypertelorism and a broad nasal bridge. Preaxial polydactyly and contractures of the upper limbs were the only associated non-cranial abnormalities. Cytogenetic studies revealed a numerically and structurally normal male (46, XY). The malformation complex described in this fetus of a mother with antedating pregnancy diabetes appears to represent a previously undescribed aberrant syngenetic CNS phenotype, some basic teratogenetic aspects of which will be discussed in this paper.

Rapid anaplastic transformation in gliomas of adulthood. "Selection" in neuro-oncogenesis.

Rapid change of the phenotypical expression is reported in three adult cases of benign or malignant gliomas. Cases with phenomenologically similar thorough alterations have only infrequently been reported in the literature. In all cases the alteration resulted in uniformly small undifferentiated and aggressive cell populations, which would not have permitted diagnosis of the original tumor. Remnants of the latter and the new undifferentiated portions were blended with each other. In two cases the clinical course was characterized by a rapid deterioration within a few months, following as slowly progressive course or periods with only mild symptoms over many years. In his studies of mammary tumors Foulds (1956) found similar phenomena of circumscribed phenotypical changes, to which he applied the term "focal progression". He outlined progression as a basic mechanism in oncogenesis. Later on it has been interpreted as the result of selection of genetically changed subpopulations of tumor cells with an altered, i.e. enhanced malignant expression. They are favoured due to their less demanding behaviour as to environmental conditions. Thus they gradually or rapidly overgrow the original tumor, changing its phenotype. The author believes that the present observations may be interpreted as examples of rapid focal progression in gliomas in terms of Foulds, with "selection" acting as a basic developmental mechanism.

Malignant intracerebral granular cell tumor reacts positively with anti-alpha-1-antichymotrypsin and the MB2 antibody: a clue to the histogenesis of the brain granular cell?

A 50-year-old man developed a granular cell tumor (GCT) of the right hemisphere (parieto-occipital) with visual deterioration and headache. Two months after surgery the tumor relapsed with diffuse infiltration of the right hemisphere, the corpus callosum and the adjacent left hemisphere. Subsequently, radiotherapy (5000 rads) was applied. Controls two and four months after the radiotherapy did not show any signs of the tumor in the computerized tomogram (CT). Light- and electronmicroscopy showed typical type I (small) and type II (large) granular cells with irregularly rounded or oval nuclei, abundant cytoplasm and PAS positive granules. Immunohistochemistry was positive with anti-alpha-1-antichymotrypsin (ACT) and the MB2 antibody. A survey of the relevant literature is given with special emphasis on the impact of the results of immunohistochemistry on the histogenesis of the CNS granular cell. Finally, some aspects of the therapy of GCTs will be discussed.

Neuronal ubiquitin and neurofilament expression in different lysosomal storage disorders.

We studied various lysosomal storage disorders such as Tay-Sachs' disease, Niemann-Pick's disease, and Hunter's disease for their immunoreactivity with antibodies against ubiquitin (Ub) and neurofilaments (NF). We found that in all cases, irrespective of the nature of the storage material or disorder, only a minor proportion of neurons (20-30% at most), as a rule, moderately reacted with the Ub antibody, while the majority of the distended neurons neither expressed Ub nor NF epitopes. These findings suggest that the UB dependent proteolytic pathway may play a secondary role in the lysosomal storage disorders, at least in the advanced stages which are observed at autopsy. It seems that the Ub expression of a minor proportion of neurons should be regarded as an unspecific epiphenomenon rather than as a mechanism of major significance in the basic metabolism of these disorders, in which the inclusions consist of membrane-bound lipid material.

GM2D gangliosidosis B1 variant in a boy of German/Hungarian descent.

After the introduction of 4-methylumbelliferyl-2-acetamido-2-deoxy-beta A-D-glucopyranoside (4MUG) and its sulfated form (4MUGS) in the pre- and postnatal diagnosis and carrier identification of gangliosidosis genotypes, infrequent forms of the GM2 gangliosidosis Type B (Tay-Sachs disease) have been observed which show normal activity of Hexosaminidase A (Hex A) isoenzyme with the substrate 4MUG but absent or deficient activity against the sulfated form 4MUGS. Here we report the observation of a German/Hungarian boy aged 12 when he died with a prolonged course of a neurodegenerative disorder, later biochemically identified as a GM2 gangliosidosis B1-variant which is characterized by a deficient Hex A activity only against 4MUGS. The first clinical symptoms had occurred after the age of 14 months with a clear manifestation of the disease at age 3, when he presented disturbances of movement and tended to fall down. The slowly progressive course with brain atrophy, seizures and severe mental deterioration resulted in death after almost 9 years. At autopsy, the typical light microscopic neuronal changes of a "lysosomal storage disorder" were found, with multilamellar concentric bodies (MCB) and Zebra bodies in the neuronal cytoplasm at the electron microscopic level.