Biomedical subjects

H D Mennel

Publications and source records attributed to H D Mennel.

At least 37 records · Page 2Linked to original sources

PubMed1999

Molecular genetic characterisation of intracerebrally transplanted brain tumours.

The aim of the present study was the characterisation of genetic alterations in two different experimental gliomas, induced in rats from the inbred strain BDIX by transplacental ethylnitrosourea with subsequent serial transplantation. The genes investigated have been shown previously to be altered during human glial tumour progression and include the gene for the epidermal growth factor receptor (EGFR), the genes for the cell cycle regulators cyclin dependent kinase 4 (CDK4), cyclinD1 (cycD1), the p16 gene (MTS1/INK4) and the retinoblastoma gene (RB). Using a semi-quantitative PCR-based screening method no gross alterations could be detected in these genes, demonstrating that nitrosourea-induced glial tumours of rats do not harbour those genetic changes which typically arise in human malignant gliomas. Thus, the use of this tumour model for gene therapy trials is questionable.

Animals↗

PubMed1999

Amphetamines induce apoptosis and regulation of bcl-x splice variants in neocortical neurons.

Amphetamineanalogs have emerged as popular recreational drugs of abuse. The number of reports of these substances producing severe acute toxicity and death is increasing. In 'Ecstasy' -associated deaths, focal necrosis in the liver and individual myocytic necrosis has been reported. Furthermore, serotonergic and dopaminergic neuronal cell damage has been observed in experimental amphetamine intoxication in laboratory animals. Here we demonstrate that subchronic exposure to D-amphetamine, methamphetamine, methylenedioxyamphetamine, and methylenedioxymethamphetamine ('Ecstasy') results in significant neurotoxicity in rat neocortical neurons in vitro. This neuronal cell death is accompanied by endonucleosomal DNA cleavage and differential expression of anti- and proapoptotic bcl-xL/S splice variants. In addition, we observed pronounced induction of cell stress-associated transcription factor c-jun and translation initiation inhibitor p97 after amphetamine treatment. These data support that the neurotoxic effects of different amphetamines are extended to rat neocortical neurons and that apoptotic pathways are involved in amphetamine-induced neurotoxicity.

3,4-Methylenedioxyamphetamine↗

PubMed1998

Comparative genomic in situ hybridization discloses chromosomal copy number changes in a transplanted brain tumor line of the rat (Rattus norvegicus).

We investigated chromosomal copy number changes in ethylnitrosourea-induced and serially transplanted gliomas of the rat by flow cytometry and Comparative Genomic in situ Hybridization (CGH). CGH analysis of a primary and four transplanted tumors revealed several genomic aberrations, including whole chromosome and subchromosomal gains and losses. Gains involved rat Chromosomes (RNO) 2, 3, 4, 5, 7, 9, 11, 12, 13, and Y, whereas losses affected RNO5, 13, 20, and Y. The primary tumor exhibited gain of RNO2q31qter and gain of RNO4. While gain of RNO2 was seen in nearly all investigated passages, gain of RNO4 was apparent in the primary tumor and in passage 2 and 5 tumors. Chromosomal alterations detected as single events were restricted to the transplanted tumors and included gain of RNO3q11, 3q41qter, 5q36, 7q34qter, 9q37, 11q, and Y, and loss of RNO5, 13, and 20q. Flow cytometry disclosed different aneuploid cell clones in the tumors investigated. The results are discussed in analogy to findings in human glial tumors.

Animals↗

PubMed1998

Electron microscopy and capillaroscopically guided nailfold biopsy in connective tissue diseases: detection of ultrastructural changes of the microcirculatory vessels.

The aims of the study were to describe and compare the frequency and nature of histologically detectable microvascular lesions in patients with various connective tissue diseases (CTD). An electron microscopic examination of specimens obtained by the technique of capillaroscopically guided nailfold biopsy was performed in 52 patients with CTD [nine systemic lupus erythematosus (SLE), eight mixed CTD, 18 scleroderma, 17 undifferentiated CTD] and 27 controls. The microvascular changes most frequently observed by electron microscopy were multilayering of the basal lamina (approximately 70% of the CTD patients), an increased amount of perivascular connective tissue, perivascular oedema formation, and an increased number of perivascular fibroblasts and mast cells (each in 30-37% of the CTD patients). In contrast, no particular histopathological feature was found in > 25% of the controls, multilayering (22.6%) being the most frequently observed. Comparing the different conditions studied, there were distinct differences in the frequency and nature of the histologically observed microvascular changes. In particular, SLE seems to be based on a separable type of vasculopathy consisting of significantly less frequent microvascular abnormalities. In conclusion, ultrastructural abnormalities of the microvascular system are a frequent finding in CTD. Electron microscopic examination of specimens obtained by capillaroscopically guided nailfold biopsy is able to disclose histopathological differences between defined entities. Therefore, this approach may be a useful tool to gain further insights into potentially separable aetiopathological mechanisms of the various types of CTD.

Adult↗

PubMed1997

Early morphological findings in experimental high pressure neurological syndrome.

HPNS (high pressure neurological syndrome) is considered to be reversible condition of the nervous system caused by elevated (atmospheric) pressure. Clinical observations and experimental findings gave rise to the belief that this syndrome at least partly functions as a model of a dopamin dependent psychosis. Morphological alterations during or after HPNS in man and animals have not been reported so far. We treated rats for three hours with an increasing pressure of helium-oxygen mixture up to 61 ATA in a pressure chamber. This pressure was subsequently maintained for one hour and then released to zero within twenty seconds. The rats died within the first three seconds of pressure release due to complete deoxygenation. Brains were immediately removed and either cooled in liquid nitrogen or fixed in formalin. In both instances the central nervous tissue was excellently preserved. In paraffin embedded formalin fixed specimens, dark neurons in different brain regions were found, especially within parts of the dentate gyrus, the CA 4 subfield of the ammons horn, in dopaminergic brainstem nuclei and in some cortical pyramidal cells. In dopaminergic cells, tyrosine hydroxylase was found to be absent in cells transformed into dark neurons. These dark neurons which have long been recognized in neuropathology, probably represent reversibly damaged neurons transformed into the dark configuration by aldehyde fixation. They may correspond to early apoptosis or they may be the consequence of cytoskeletal disruption.

Animals↗

PubMed1996

Intravital microscopy and capillaroscopically guided nail fold biopsy in scleroderma.

OBJECTIVES: To describe the frequency, extent, and nature of microvascular lesions in patients with scleroderma by means of capillaroscopy and capillaroscopically guided nail fold biopsy, and to determine the diagnostic value of the two methods and the pathophysiological significance of the lesions described. METHODS: A cohort study was made of 24 consecutive patients with scleroderma and 10 healthy controls, using standardised clinical, serological, capillaroscopic, and histological (nail fold biopsy) techniques. RESULTS: All patients with scleroderma had distinct lesions of the microvascular system. Capillaroscopy revealed more than 90% of the patients to have the typical scleroderma pattern. Histologically, these changes most frequently consisted of splitting of the basal lamina, broadening of the perivascular connective tissue, perivascular round cell infiltrations, and immunoglobulin deposits (each in 60-75% of the patients). Electron microscopy was the most sensitive method of histological examination, detecting abnormalities in 87.5% of patients; with light microscopy and immunohistochemical techniques, abnormalities were revealed less frequently (83.3% and 75%, respectively). In contrast, normal findings were observed in most of the healthy controls: capillaroscopy = 90%; histology = 80%. CONCLUSIONS: Microvascular lesions are a predominant feature in scleroderma and seem to have a central pathogenetic role in the disease. Capillaroscopy is able to identify this microangiopathy noninvasively, and capillaroscopically guided nail fold biopsy can detect the frequency and nature of the underlying ultrastructural changes. This may therefore be a useful tool in describing the pathogenetic role of the microvascular system in scleroderma.

Adult↗

PubMed1995

Malignant transformation of benign gliomas during interstitial irradiation.

Interstitial curietherapy with 125-Iodine is an effective therapeutic option in the treatment of low grade gliomas. Four cases with astrocytoma grade II are presented, where tumour growth characteristics have changed to anaplasia during interstitial irradiation after a primary period of tumour regression. Anaplastic transformation could be due to a radiation effect or an insufficient therapeutic influence of interstitial irradiation on natural tumour progression of glioma growth due to genetic events.

Adult↗

PubMed1995

Quantitative DNA analysis of an intracerebrally transplanted brain tumour model after experimental chemotherapy with BCNU and CCNU.

In the present study we investigated the susceptibility of high passages of the rat glial transplantation tumour G-XIII to chemotherapy using nitrosourea compounds. We observed a significant increase in lifespan (ILS) of animals treated with BCNU (37%, p < 0.01) and CCNU (27%, p < 0.01). There were no difference in the efficiency between these two substances. Using a semi-quantitative score system no histopathological changes were observed which were associated with the response to therapy. The only predicative parameter in the present study was the quantitative DNA distribution pattern. There was a close correlation between treatment and the occurrence of unimodal DNA distribution patterns indicating clonal regrowth of recurrent tumours. Moreover, we also observed a correlation of the DNA distribution pattern of recurrent tumours with the result of experimental chemotherapy. Survival times of animals suffering from tumours containing unimodal DNA histogram was significantly longer than survival times of rats with multimodal DNA distribution, i.e. bimodal or broad DNA histograms. A unimodal, near-diploid stem line was only present in treated animals suggesting that these clones are more resistant against therapy using nitrosourea compounds. Our data indicate DNA cytophotometry as comprehensive tool for the monitoring of therapy response and the design of experimental chemotherapy using rat glial tumours.

Animals↗

PubMed1995

Vascular morphology and angiogenesis in glial tumors.

Intracranial tumor classification is paralleled by a grading system that empirically compares tumor entities with "progression stages" of supratentorial gliomas of the adult. This grading system is an integral part of the WHO classification. Glioma progression has originally been defined by descriptive morphology. In this respect, morphological key features of high-grade gliomas (WHO grades III and IV) are microvascular proliferation and the formation of tumor necroses. Glioma progression is now more accurately defined on the molecular genetic level by a stepwise accumulation of oncogene activation and/or tumor suppressor gene inactivation. Angiogenesis occurs during development and progression of glial tumors. Pathological vessels are a hallmark of malignant glioma and it has therefore been suggested that malignant glioma cells are able to induce neovascularization. Despite the exuberant neovascularisation, however, vascular supply may not be sufficient for tumor areas with high cell proliferation, and necroses may develop. Malignant transformation of blood vessel itself is a rare event but may be the underlying mechanism of gliosarcoma development. The recently purified vascular endothelial growth factor (VEGF) is at present the only mitogen known to selectively act on endothelial cells. Growing evidence suggests that VEGF is the key regulator of developmental and pathological angiogenesis. In vivo, VEGF mRNA is upregulated in a subpopulation of malignant glioma cells adjacent to necroses. Since VEGF is hypoxia-inducible, hypoxia may be an important regulator of VEGF mRNA expression and tumor angiogenesis in vivo. Two tyrosine kinase receptors for VEGF are expressed in vessels which invade the tumor, suggesting that tumor angiogenesis is regulated by a paracrine mechanism.(ABSTRACT TRUNCATED AT 250 WORDS)

Brain Neoplasms↗

PubMed1995

Effect of lazaroid U-74389G on iron-induced reduction of striatal dopamine metabolism.

The substantia nigra of parkinsonian brains is reported to contain increased amounts of iron as compared with age-matched controls. Since iron might be cytotoxic via radical mechanisms, we analyzed the effect of intranigral iron infusion on the dopaminergic activity in the striatum of the rat. The striatal dopamine metabolism of the rat was followed 1, 3, and 6 weeks after unilateral intranigral iron (III) (1.5 micrograms) application. A progressive decrease of extraneuronal 3,4-dihydroxyphenylacetic acid (DOPAC) levels was observed in the ipsilateral striatum by means of in vivo pulse voltammetry. The significant reduction of the DOPAC signal could be attenuated by pretreatment of the animals with the lazaroid U-74389G, applied ip 20 minutes before unilateral intranigral iron application. Our data indicate that a single iron application into the substantia nigra leads to a progressive loss of dopaminergic activity in the striatum, also observed in Parkinson patients. Furthermore, the Lazaroid U-74389G seems to be beneficial in this model of Parkinson's disease.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1994

Vascular endothelial growth factor and glioma angiogenesis: coordinate induction of VEGF receptors, distribution of VEGF protein and possible in vivo regulatory mechanisms.

We have previously suggested that tumor angiogenesis in human gliomas is regulated by a paracrine mechanism involving vascular endothelial growth factor (VEGF) and flt-1 (VEGF-receptor 1). VEGF, an endothelial-cell-specific mitogen, is abundantly expressed in glioma cells which reside along necrotic areas, whereas flt-1, a tyrosine-kinase receptor for VEGF, is expressed in tumor endothelial cells, but not in endothelial cells in normal adult brain. Recently, a second tyrosine-kinase receptor which binds VEGF with high affinity, designated KDR or flk-1, has been described. We performed in situ hybridization for VEGF mRNA, flt-1 mRNA and KDR mRNA on serial sections of normal brain, low-grade and high-grade glioma specimens. We show that KDR mRNA is co-expressed with flt-1 in vascular cells in glioblastoma but not in low-grade glioma. Since flt-1 and KDR are not expressed in endothelial cells in the normal adult brain, the coordinate up-regulation of 2 receptors for VEGF appears to be a critical event which controls tumor angiogenesis. Immunocytochemistry with a monoclonal anti-VEGF antibody revealed significant amounts of VEGF protein in the same glioma cells that expressed VEGF mRNA. The largest amount of VEGF immunoreactivity, however, was detected on the vasculature of glioblastomas, the site where VEGF exerts its biological functions. These findings suggest that VEGF is produced and secreted by glioma cells and acts on tumor endothelial cells which express VEGF receptors. To further characterize VEGF-producer cells in vivo, we investigated cellular proliferation, immunoreactivity to the p53 tumor-suppressor gene product and epidermal-growth-factor-receptor (EGFR) expression on serial sections by immunocytochemistry. VEGF-producer cells did not show increased cellular proliferation, p53 immunoreactivity or EGFR immunoreactivity as compared with glioma cells which did not express VEGF. Our studies therefore do not demonstrate evidence for a growth advantage of VEGF-producer cells in vivo or VEGF induction by p53 mutation or EGFR over-expression.

Brain Neoplasms↗

PubMed1994

Endoscopic anatomy of the third ventricle.

42 cadaver brains in situ were examined endoscopically to work out topographical anatomical landmarks for orientation. The endoscopic route from the chosen precoronal trepanation point to the defined ventricular landmarks has been measured in 22 cases. The identification and measurements of the anatomical landmarks are helpful for safe and atraumatic endoscopical navigation within the ventricular system. Furthermore this article describes and discusses cerebral lesions during ventriculoscopy.

Brain Mapping↗

PubMed1994

Glycosphingolipid component profiles of human gliomas correlate with histological tumour types: analysis of inter-individual and tumour-regional distribution.

Three types of glycosphingolipid (GSL) component profiles have been established for human intracranial gliomas. GSL-type I shows only Glac- and lacto-series-sialoglycolipids. Type II consist of Glac- and Gtri-gangliosides, whereas only GSL-type III contains sulphatide and, as a major neutral glycolipid, galactocerebroside, besides gangliosides of the Glac-, Gtri-, and Gtet-families. Whole gliomas of malignancy grading I/II, III and IV, display GSL-Types III, II, and I, respectively. Thus, the GSL component distribution of the samples taken after surgery from three individual gliomas and two biopsies correlate closely with the general diagnosis of these tumours. Arthrobacter ureafaciens sialidase was used for the characterization of gangliosides. GSL-type analysis of multiple regional samples, taken from necropsy and biopsy, were determined by microanalysis of microscopic cryostat section, and shown to be in good agreement with their histology. The results validate the relevance of tumour ganglioside analysis for the characterization and diagnosis of gliomas.

Biomarkers, Tumor↗

PubMed1994

AgNOR content and PCNA expression in transplanted malignant neurinoma in rats.

Malignant neurinomas can be induced in BD IX rats by transplacental application of ethylnitroso-urea during pregnancy. Tumors develop in the offspring in trigeminal and spinal nerves and can be easily transplanted upon rats of the same strain. During the first passages a considerable shortening of subsequent induction periods takes place. Concurrently, silver stained Nucleolar Organizer Regions (AgNORs) increase in number and other measured AgNOR parameters change in a similar way. The number of cells that express the proliferation marker PCNA equally becomes more frequent during the first subcutaneously transplanted generations. There is high correlation between AgNOR parameters, number of PCNA expressing cells, induction times and passage. It is concluded that the first generations of the transplantation model of these tumors can be used to test the validity of proliferation indicators. Our results show further that AgNORs in fact belong to the group of markers of proliferation.

Animals↗

PubMed1994

Morphometric investigation on nuclear and nucleolar arrangement and AgNOR content in the rat hippocampus under normal and ischemic conditions.

A morphometric analysis of constituents of the rat hippocampus was performed in the different hippocampal regions that are known to be vulnerable in various degrees to experimental global ischemia. In the hippocampus formation of the normal Fisher rat the number and areas of neuronal nuclei and of their constituents, nucleoli and AgNOR particles, were counted and measured. Nuclear and nucleolar size were different in the various parts of the Ammon's formation. AgNORs, i.e. silver stainable proteins that represent actively rRNA transcribing genes, equally varied in number and extension in the different hippocampal subfields. In granule cells of the dentate gyrus and in pyramidal cells of CA 1, CA 3 and CA 4, AgNORs usually occupy half of the nucleolar area. Using the determined values an estimate of the length and volume of the neuronal layers within the different parts of the rats Ammon's horn was performed. After the development of delayed ischemia all measured structures were significantly smaller despite the fact that only nuclei with well preserved outlines could be analysed. They represent only 5-10% of controls. Nuclear sizes were reduced between 20 and 55%. The strongest reduction was observed in the transition zone between CA 1 and CA 3, the least in CA 3. Nucleoli and AgNORs equally were considerably smaller than in normal cells. For AgNORs a skewed distribution to the left resulted, whereas the nuclear size had normally distributed shape with peak at lower values. We conclude that an architecture of both nucleoli and AgNORs exists in the hippocampal subfields in addition to the known cytological architecture. Under ischemic conditions, even the healthy looking cells remain damaged to a variable extent in the different subfields corresponding to their selective vulnerability. There are some indications that damage to nucleoli and AgNORs is earlier and stronger than to nuclei. A time course of AgNOR damage can be constructed.

Animals↗

PubMed1994

Chemical carcinogenesis in the nervous system: past and future.

The model of experimental tumors of the nervous system has greatly contributed to our understanding of growth and management of intracranial tumors, but has been somewhat neglected in the last years, because a wealth of new data concerning oncogenic action came from viral oncogenesis. These new issues led to a much better insight into human tumor induction and promotion. Yet one example of the impact of oncogenic transformation stems from the "neurooncogenic" model: the discovery of the neu oncogene and its product as a putative differentiation receptor in the cell membrane of experimental Schwann cell derived tumors. In the light of this unique finding the history of the "neurooncogenic" model and the morphological and "clinical" result of tumors produced within the model are reviewed. There is a large open field for future investigation both in basic and applied science.

Animals↗

PubMed1994

Nucleolar organizer regions (AgNORs) in primary and recurrent gliomas. A retrospective study.

To assess the diagnostic and prognostic relevance of nucleolar organizer regions (AgNORs) the silver-stained AgNOR structures of 46 human gliomas (22 primary gliomas, 21 first and 3 second recurrences) from 28 patients were counted and measured. Surgical specimens of two neuropathological centres were included in this retrospective study. The tumours were classified into 8 groups according to WHO criteria of diagnosis and grading and their state of recurrence: 1: primary glioma grade II; 2: primary glioma grade III; 3: glioblastoma grade IV; 4: first recurrence of glioma grade II; 5: first recurrence of glioma grade III; 6: first recurrence of glioblastoma grade IV; 7: second recurrence of glioma grade II and 8: second recurrence of glioma grade III. AgNOR numbers demonstrated a positive correlation with increasing histological grade. Similarly, higher levels of AgNORs were in general found in recurrent tumours compared to primary tumours with few exceptions in groups, in which few numbers only could be analyzed. The present study demonstrates the utility of evaluating AgNOR in assessing malignant gliomas and indicates that recurrences have a higher proliferative potential than original tumours. The problems of standardization of the AgNOR technique are especially crucial for the retrospective evaluation of fixed and embedded pathological material.

Adult↗

PubMed1994

"Stereology" of intracranial lesions.

Endoscopy of the intracranial space requires a new understanding of the anatomy and pathology of pertinent structures. This meets with the new development of imaging methods which equally require three dimensional interpretation of intracranial pathology. The stereological arrangement of intracranial lesions is examplified on three neuropathological conditions: brain tumours, territorial infarction and mass displacement.

Brain↗