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S Brandner

Publications and source records attributed to S Brandner.

72 records · Page 4Linked to original sources
PubMed1996

Neuroectodermal grafting: a new tool for the study of neurodegenerative diseases.

Transgenic and knockout mice have contributed much to our current understanding of the role played by single genes during development and in pathological processes of the CNS, such as neuro-degeneration. However, embryonic lethality resulting from the disruption of important genes has often hindered the interpretation of such experiments. Grafting of immature cells from genetically modified organisms into healthy recipients promises to efficiently bypass this problem. We have used neural transplantation techniques which allow us to keep CNS tissue of knockout and transgenic mice viable for a prolonged period of time in the brain or in the kidney capsule of healthy recipients. We have characterized biological parameters such as growth, proliferation and differentiation and also the formation of an intact blood-brain barrier (BBB) after grafting of wild-type telencephalic anlage in this system. We have also employed this technique to study the longterm properties of neuroepithelial tissue derived from knockout mice. The results of our studies are discussed in the context of neurodegenerative diseases.

Adenosine Triphosphatases↗
PubMed1995

Transgenic and gene disruption techniques in the study of neurocarcinogenesis.

Transgenic technologies have come of age, and the field of carcinogenesis has profited extensively from the availability of these methods. Both the inappropriate expression of dominant oncogenes in specific tissues and the ability to "knock out" tumor suppressor genes in mammalian organisms have enabled substantial advancements of our understanding of development and progression of the neoplastic phenotype. In the first part of this article, we review the most popular techniques for modification of the mammalian genome in vivo, i.e. microinjection of fertilized eggs, retrovirus-mediated gene transfer, and targeted gene deletion through homologous recombination. Subsequently, we attempt a critical evaluation of the available models of neurocarcinogenesis, and discuss their impact and future potential for the study of cancer in the nervous system.

Animals↗
PubMed1995

The AMOG/beta 2 subunit of Na,K-ATPase is not necessary for long-term survival of telencephalic grafts.

Adhesion molecule on glia (AMOG) represents the beta 2-subunit of murine Na,K-ATPase. Mice carrying a targeted deletion of the AMOG/beta 2 gene exhibit tremor and limb paralysis at postnatal day (P) 15 and die 2 days after the onset of symptoms. The brains of these mice show edema and swelling of astrocytic end feet. However, the cause of death has remained unclear. To identify long-term consequences of AMOG/beta 2 deficiency, we have grafted parts of the embryonic telencephalic anlage of AMOG/beta 2-deficient mice into the caudoputamen of wild-type mice and analyzed the grafts up to 500 days after transplantation. Histological, immunocytochemical, and in situ hybridization techniques were applied to examine histoarchitecture, proliferation, differentiation, and long-term survival of grafts. AMOG/beta 2-deficient telencephalic grafts develop normally and form solid neural tissue that cannot be distinguished from control grafts by morphological features or with immunocytochemical stains for neuronal and glial markers. No signs of degeneration can be found. Expression analysis, however, revealed that no AMOG/beta 2 protein of possible host origin can be detected in AMOG/beta 2-deficient grafts. Graft-borne astrocytes express neither the AMOG/beta 1 nor the AMOG/beta 2 subunit of Na,K-ATPase as examined with immunocytochemistry and in situ hybridization. These findings indicate that AMOG/beta 2 is not necessary for long-term survival of telencephalic graft tissue.

Adenosine Triphosphatases↗
PubMed1995

Secondary manifestation of medulloblastoma: metastases and local recurrences in 66 patients.

Although primary treatment of medulloblastoma is now successful in a high percentage of patients, its secondary manifestations still bear a poor prognosis. Thorough studies of secondary manifestations are therefore pivotal to plan therapeutic approaches for the long-term management of medulloblastoma. Here we describe the incidence of secondary tumour manifestations in 66 patients of a single centre who underwent surgery for medulloblastoma between 1975 and 1990. No patient was excluded due to a poor postoperative course. Thirty-five patients showed evidence of secondary tumour growth. Of these, 17 suffered from local recurrence, and 27 developed metastastatic disease. The median latencies for secondary manifestations were 25 months for local recurrence (n = 17), 11 months for spinal metastases (n = 10), 15 months for supratentorial metastases (n = 8), 8 months for subleptomeningeal dissemination (n = 6), and 23 months for systemic metastases (n = 8). Two patients developed primary metastatic spread to the posterior fossa. Of 8 patients with supratentorial metastases, 6 developed fronto-basal lesions. In our patients, 89% of secondary lesions occurred within less than 3 years after primary diagnosis. 85% of patients with extra-axial tumour spread had been treated with a permanent shunt. Radical tumour resection and radiotherapy with 30 Gy to the neuraxis and 20 Gy boost to the posterior fossa was an important prognostic factor in this series. Patients with additional chemotherapy did not benefit significantly from this treatment. We conclude that optimal management of the primary lesions should aim at (i) total resection, (ii) avoid permanent shunting, and (iii) completion of the radiotherapy with inclusion of the medial frontobasal cisterns in the radiotherapeutic regimen. Our analysis suggests that adequate postoperative screening programmes should consist of 3-monthly scans of the neuraxis in the first three postoperative years and 6-monthly scans thereafter.

Adolescent↗
PubMed1995

Shared allelic losses on chromosomes 1p and 19q suggest a common origin of oligodendroglioma and oligoastrocytoma.

Loss of heterozygosity (LOH) in specific chromosomal regions, which are likely to harbor tumor suppressor genes, has been associated with human gliomas. In this study we have analyzed astrocytic and oligodendroglial tumors for LOH on chromosomes 1 and 19. By microsatellite analysis LOH was found on chromosome arm 1p in 6/15 oligodendrogliomas WHO grade II and III, 12/25 oligoastrocytomas WHO grade II and III, 6/79 glioblastomas WHO grade IV, 5/44 astrocytomas WHO grade II and III and 0/23 pilocytic astrocytomas WHO grade I. The high incidence of LOH on chromosome arm 1p in oligodendrogliomas and oligoastrocytomas indicates that a putative tumor suppressor gene in this region is involved in the formation of gliomas with oligodendroglial features. Furthermore, the frequent involvement of chromosome arm 1p in oligodendrogliomas and oligoastrocytomas, but not in astrocytomas, suggests that genetically oligoastrocytoma is more similar to oligodendroglioma than to astrocytoma. In order to support this hypothesis, oligodendroglial and astrocytic areas in three mixed oligoastrocytomas were examined differentially for LOH 1p and for LOH 19q, the second genetic region believed to be affected in these tumors. All three tumors had LOH of 1p and LOH of 19q in both areas of oligodendroglial and of astrocytic differentiation. These findings show that the astrocytic and oligodendroglial portions of oligoastrocytoma share molecular genetic features and probably are of monoclonal origin.

Alleles↗
PubMed1995

Symptomatic cerebellar metastasis and late local recurrence of a cauda equina paraganglioma. Case report.

This case report contains a description of a 61-year-old patient who presented with a progressive truncal ataxia 22 years after complete removal of a small paraganglioma of the cauda equina. Magnetic resonance imaging of the neuraxis revealed a large cystic lesion in the cerebellar midline, three small cortical-to-subcortical nodular tumors in the posterior fossa, and local recurrences of the paraganglioma of the cauda equina. Pathological examination showed the cerebellar midline lesion to be a paraganglioma, most likely a metastasis from the cauda equina localization.

Adult↗
PubMed1995

Activation of HIV transcription by human foamy virus in transgenic mice.

BACKGROUND: Although infection by HIV-1 is the primary cause of AIDS, cofactorial agents of an infectious nature may be involved in the pathogenesis of the disease. The present work addresses the cofactorial potential of human foamy virus (HFV) in AIDS. It has been suggested that HFV seroprevalence reaches 5% in East Africa, and HFV seroprevalence in East African patients suffering from AIDS and AIDS-related complex may be as high as 20%. Although the pathogenic potential of HFV in humans has not yet been investigated in detail, HFV transgenic mice develop an encephalopathy reminiscent of some of the features of HIV-associated brain diseases. EXPERIMENTAL DESIGN: We set out to investigate the possibility that the regulatory genes of HFV may act as transcriptional cofactors of HIV. To study the effects of bel1, the transcriptional activator of HFV, on the HIV-1 LTR, we generated double transgenic mice for bel1 and for the HIV-1 LTR linked to a lacZ reporter gene. Moreover, to identify the cis-acting elements mediating bel1 action on the HIV LTR, we analyzed the consequences of deletions in the negative regulatory element or in the NF-kappa B binding sites. RESULTS: We demonstrate that bel1 is capable of activating the transcription of HIV-1 LTR in vivo. Such transactivational activity, however, was observed exclusively in a subset of hippocampal neurons, whereas cortical neurons expressing bel1 did not show transactivation. Transactivation was completely abolished by the deletion of the NF-kappa B binding sites. In contrast, deletion of the negative regulatory element region seems to enhance transactivation of bel1 on HIV-1 LTR over a prolonged period of time. CONCLUSIONS: Our study indicates that transcriptional transactivation of HIV-1 by HFV can be accomplished in vivo and is dependent on NF-kappa B binding sequences. Therefore, transcriptional transactivation is a potential mechanism of cooperation between HFV and HIV. It is conceivable that this phenomenon attains clinical significance in a situation of coinfection with both viruses.

Animals↗
PubMed1994

Behavioral and anatomical deficits in mice homozygous for a modified beta-amyloid precursor protein gene.

The beta-amyloid precursor protein (beta APP) gene of the mouse was disrupted by inserting into exon 2 a cassette containing a neomycin resistance gene and a putative transcription termination sequence. Contrary to expectation, brain and other tissues from mice homozygous for the insertion still contained beta APP-specific RNA, albeit at a level 5- to 10-fold lower than wild type and lacking the disrupted exon, which had been spliced out. The brain contained shortened beta APP-specific protein at a low level. Mutant mice were severely impaired in spatial learning and exploratory behavior and showed increased incidence of agenesis of the corpus callosum.

Amyloid beta-Protein Precursor↗
PubMed1994

Microsatellite analysis of loss of heterozygosity on chromosomes 9q, 11p and 17p in medulloblastomas.

Medulloblastoma (MB) is a primitive neuroectodermal tumour of the cerebellum whose pathogenesis is poorly understood. Previous studies suggest a role for loci on chromosomes 11p and 17p in the pathogenesis of MB. Evidence for another potential MB locus has recently emerged from studies on Gorlin syndrome (GS), an autosomal dominant syndrome with multiple basal cell carcinomas, epithelial jaw cysts, and skeletal anomalies. Since GS can be associated with MB, we examined sporadic (non-GS) cases of MB for evidence of loss of heterozygosity (LOH) on chromosome 9 where a putative GS locus has been localized to band q31. Nineteen paired blood and MB DNA specimens from 16 patients (11 primary tumours, two primary with recurrent tumours, one primary tumour and cell line, two cell lines) were studied by PCR analysis of microsatellites at D9S55 (9p12), D9S15 (9q13-q21.1), D9S127 (9q21.1-21.3), D9S12 (9q22.3), D9S58 (9q22.3-q31), D9S109 (9q31), D9S53 (9q31), GSN (9q33), D9S60 (9q33-q34), D9S65 (9q33-q34), ASS (9q34), D9S67 (9q34.3), TH (11p15.5), D11S490 (11q23.3), D17S261 (17p11.2-12), D17S520 (17p12), TP53 (17p13.1), D17S5 (17p13.3), D17S515 (17q22-qter), and by RFLP analysis at the WT-1 locus (11p13). Only two tumours had LOH on 9q. One was non-informative at D9S15, D9S65, and GSN but showed LOH at D9S127, D9S12, D9S58, D9S109, D9S53, D9S60, ASS, and D9S67. The other was uninterpretable at D9S65 and non-informative at D9S15, D9S58, D9S53, and D9S67 but exhibited LOH at D9S127, D9S12, D9S109, GSN, D9S60, and ASS. Both these cases were informative at D9S55 without LOH.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1994

Transgenic and knock-out mice: models of neurological disease.

Besides providing useful model systems for basic science, studies based on modification of the mammalian germ line are changing our understanding of pathogenetic principles. In this article, we review the most popular techniques for generating specific germ line mutations in vivo and discuss the impact of various transgenic models on the study of neurodegenerative diseases. The "gain of function" approach, i.e., ectopic expression of exogenous genes in neural structures, has deepened our understanding of neurodegeneration resulting from infection with papova viruses, picorna viruses, and human retroviruses. Further, inappropriate expression of mutated cellular molecules in the nervous system of transgenic mice is proving very useful for studying conditions whose pathogenesis is controversial, such as Alzheimer's disease and motor neuron diseases. As a complementary approach, ablation of entire cell lineages by tissue-specific expression of toxins has been useful in defining the role of specific cellular compartments. Modeling of recessive genetic diseases, such as Lesch-Nyhan syndrome, was helped by the development of techniques for targeted gene deletion (colloquially termed "gene knock-out"). Introduction of subtle homozygous mutations in the mouse genome was made possible by the latter approach. Such "loss of function" mutants have been used for clarifying the role of molecules thought to be involved in development and structural maintenance of the nervous system, such as the receptors for nerve growth factor and the P0 protein of peripheral myelin. In addition, these models are showing their assets also in the study of enigmatic diseases such as spongiform encephalopathies.

Alzheimer Disease↗
PubMed1994

[Morphology and development of neural transplants of AMOG-deficient mice].

The adhesion molecule on glia (AMOG) has been reported to function as cell adhesion molecule and also to constitute the beta 2-subunit of the murine Na,K-ATPase. In order to elucidate these functions in vivo, Magyar et al. have generated mice carrying a targeted deletion of the AMOG gene. These mice exhibit behaviourally normal development till postnatal day P16. At this time, they develop muscular weakness, incoordination, and tremor. Death invariably occurs 24-36 hours after onset of the symptoms. Histological and ultrastructural examination of brain sections show enlarged ventricles, brain edema, and swelling of astrocyte end feet. However, no disturbances of the architecture or cell migration in the brain can be detected. In order to identify long-term consequences of AMOG deficiency which might not yet be detectable at the time of death, we have established a CNS grafting model. The embryonal brain anlage (E10.5-E13.5) was grafted into the caudoputamen of wild type mice. The graft recipients are sacrificed up to 7 months after the procedure. Both wild type and AMOG deficient grafts develop and form solid neural tissue with neurons, myelinated axons, glial cells, and ventricular structures, as shown by histological and immunocytochemical analysis. However, no differences in grafts derived from wild type, heterozygous, and AMOG-deficient donors can be detected. Proliferation has been examined by BrdU immunocytochemistry. The blood-brain barrier as examined by repeated magnetic resonance imaging after injection of Gadolinium-DTPA has been shown to be largely reconstituted five weeks after grafting.

Adenosine Triphosphatases↗
PubMed1991

Functional organization of the auditory thalamus in the guinea pig.

The auditory thalamus of the guinea pig was investigated with microelectrode mapping techniques. Pure tones of varying frequencies and amplitudes were used as acoustic stimuli, and frequency tuning curves were recorded from 840 multi-units or single cells. The neurons in ventral nucleus of the medial geniculate body (MGv) respond vigorously to pure tones; they have mostly narrow frequency tuning curves and short response latencies (8-12 ms). The MGv is tonotopically organized: High frequencies (16-21 kHz) are located rostrally; the intermediate frequencies (2.8-11 kHz) lie caudomedial of the high frequencies, while the low frequencies (0.5-2.8 kHz) run as a continuous band from rostrolateral to caudomedial. These data confirm a model of tonotopy of the guinea pig MGv which was based on anatomical data from previous tract-tracing experiments. In these experiments, thalamocortical connections were investigated with retrogradely transported tracers (horseradish peroxidase, fluorescent dyes, Redies et al. 1989b). Dorsal, lateral and in part also ventral to MGv, the neuronal responses to pure tones were often less vigorous than in MGv. Many neurons had broad frequency tuning curves, and in nearly all recordings from this region, the response latencies were longer than 12 ms. A tonotopic organization was not apparent here. From the response properties and the location relative to MGv, we concluded that this area corresponds to the shell nucleus of the MG.

Acoustic Stimulation↗
PubMed1990

The projection from medial geniculate to field AI in cat: organization in the isofrequency dimension.

The topography of the anatomical projection from isofrequency contours (IFCs) in auditory thalamus to IFCs in primary auditory cortex (field AI) was investigated in the cat. In each experiment, a best-frequency map of AI was obtained with electrophysiological recording techniques. Then, different retrogradely transported tracers (HRP, fluorescent dyes) were introduced into AI. In some experiments, different parts (e.g., dorsal, central, and ventral) of a previously mapped IFC were injected, each part with a different tracer. In other experiments, 2 or 3 rows of tracer injections were made at different dorsoventral levels of AI, over a large frequency range (5-38 kHz); each injection row was oriented orthogonal to the IFCs and contained a different tracer. The main mass of the labeled thalamic cells was found in the ventral nucleus of the medial geniculate body (MGv). The MGv cells projecting to a limited sector (1-2 mm in length in most experiments) of an IFC in AI form one or several densely packed neuron clusters of variable shape. The cells labeled by a given tracer are largely separated in space from cells labeled by a different tracer. Thus, different sectors of a cortical IFC receive input from different portions of the corresponding thalamic IFC. As a general rule, cells labeled from dorsal (ventral) injections are centered rostrally (caudally) in the part of MGv innervating AI. However, the topographic details are variable between individuals, and the rostrocaudal gradient is complicated by numerous irregularities and gradients. Previous studies of the auditory thalamocortical projection in the cat have not recognized the topographic order in the isofrequency dimension. Instead, it was believed that different sectors of a cortical IFC were innervated by coincident thalamic populations.

Animals↗
PubMed1989

Anatomy of the auditory thalamocortical system of the guinea pig.

We investigated the projection from the medial geniculate body (MG) to the tonotopic fields (the anterior field A, the dorsocaudal field DC, the small field S) and to the nontonotopic ventrocaudal belt in the auditory cortex of the guinea pig. The auditory fields were first delimited in electrophysiological experiments with microelectrode mapping techniques. Then, small quantities of horseradish peroxidase (HRP) and/or fluorescent retrograde tracers were injected into the sites of interest, and the thalamus was checked for labeled cells. The anterior field A receives its main thalamic input from the ventral nucleus of the MG (MGv). The projection is topographically organized. Roughly, the caudal part of the MGv innervates the rostral part of field A and vice versa. After injection of tracer into low or medium best-frequency sites in A, we also found a topographic gradient along the isofrequency contours: the dorsal (ventral) part of a cortical isofrequency strip receives afferents from the rostral (caudal) portions of the corresponding thalamic isofrequency band. However, it is not so obvious whether such a gradient exists also in the high-frequency part of the projection. A second, weaker projection to field A originates in a magnocellular nucleus that is situated caudomedially in the MG and was therefore named the caudomedial nucleus. The dorsocaudal field DC receives input from the same nuclei as the anterior field, but the location of the labeled cells in the MGv is different. This was demonstrated by injection of different tracers into sites with like best frequencies in fields A and DC, respectively. After injection of HRP into the 1-2-kHz isofrequency strip in field A and injection of Nuclear Yellow (NY) into the 1-2-kHz site in field DC, the labeled cells in the MGv form one continuous array that runs from caudal to rostral over the whole extent of the MGv. The anterior part of this array consists of NY-labeled cells; i.e., it projects to field DC. The caudal part is formed by HRP-labeled cells; i.e., it innervates field A. These findings indicate that there is only one continuous tonotopic map in the MGv. This map is split when projected onto the cortex so that two adjacent tonotopic fields (A and DC) result. The cortical maps are rotated relative to the thalamic map in that rostral portions of the MGv project to caudal parts of the tonotopic cortex and vice versa.(ABSTRACT TRUNCATED AT 400 WORDS)

Afferent Pathways↗
PubMedDate not supplied

Primary Candida albicans empyema associated with epidural hematomas in craniocervical junction.

The case of a 27-year-old patient with chronic candida empyema in the craniocervical junction is presented. Occlusive hydrocephalus at admittance, primary subdural candida empyema, and recurrent epidural bleedings are the outstanding features in the clinical course. Despite intact immunity this patient acquired primary candidosis of CNS. Pathological changes in dura, ventricular system, and CSF required multiple shunt revisions. Antimycotic therapy was performed with a combination of 3 antimycotics. The clinical improvement was prolonged by several complications.

Adult↗