Biomedical subjects

R Meyermann

Publications and source records attributed to R Meyermann.

At least 37 records · Page 2Linked to original sources

PubMed2001

Loss of heterozygosity at 11p15 and p53 alterations in malignant gliomas.

PURPOSE: Malignant gliomas are the most frequent primary brain tumors. Recent studies defined several genetic markers, which might characterize molecular-biological subsets of glioblastomas with prognostic implications. In the later steps of tumor-progression, deletions on chromosome 11p15 and mutations of the tumor suppressor gene p53 were determined for different malignancies. To elucidate the involvement of 11p15 deletions in the tumorigenesis of malignant gliomas, we analyzed a series of 50 glioblastomas for loss of heterozygosity (LOH). METHODS: Paired tissue and blood samples from 50 patients with glioblastoma multiforme were included. Microsatellite markers located on 11p15.1-11p15.5 were used for LOH analysis. Additionally, mutation analysis of the tumor suppressor gene p53 was performed, which might correlate with favorable survival in glioblastomas. RESULTS: The region 11p15.4-5 was deleted heterozygously in 28% of cases representing 15 cM. Twenty-six glioblastomas did not show allelic loss for any locus. Our data revealed close association of LOH 11p15 with p53 mutations, and survival analysis showed a trend indicating better prognosis in glioblastomas characterized by LOH 11p15. CONCLUSION: In the tumorigenesis of malignant gliomas, p53 mutations and 11p15 deletions seem to indicate a genetic subset of tumors with favorable prognostic value.

Brain Neoplasms↗

PubMed2001

Serine proteases and brain damage - contribution of the urokinase- plasminogen activator system.

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Animals↗

PubMed2001

IL-16 is differentially expressed in the developing human fetal brain by microglial cells in zones of neuropoesis.

Microglial cells are regulators of tissue homeostasis in the adult central nervous system and readily participate in pathological processes, orchestrating tissue remodeling. Cytokines produced by microglial cells are markers of cell activation and contribute to reactive processes. In this paper, we have studied the expression of IL-16 (leukocyte chemoattractant factor), a natural soluble ligand to the CD4 molecule, in human fetal brains from the 11th to the 20th(.) week of gestation by immunohistochemistry. Interleukin (IL)-16(+) cells were detected already at the 11th gestational week, accumulating with aging in cortical layers (P<0.0001) at the 16th and 19th week, and reaching maximum numbers in the 20th week. Most IL-16(+) microglia (>80%) revealed morphological hallmarks of activated microglia. We observed that IL-16 cells coexpress LCA (>80%) and MRP-8, an activation-associated Ca(2+) binding S-100 family member (>80%). In contrast, only few IL-16(+) cells proliferated (PCNA(+), 20-40%) or co-expressed the HLA-DR, -DP, or -DQ antigen (<10%), and rare coexpression with CD68 (20-40%) was detected until 17th week. No coexpression with CD4, CD8 or CD20 was detected. Furthermore, we observed accumulation of IL-16(+) microglia in zones of neuronal proliferation, migration and differentiation. Increasing numbers of IL-16(+) cells were detected in bordering zones adjacent to the basal ganglia. Our data suggests that the early presence of IL-16(+) microglia exert a CD4-independent function-mediating activation, and chemotaxis of microglia precursors during neuronal development. In addition, IL-16 immunoreactivity might be a helpful tool to determine distinct developmental stages of microglial cells during fetal central nervous system ontogeny.

Antigens, Differentiation↗

PubMed2001

Galectin-3: cellular distribution and correlation with WHO-grade in human gliomas.

In order to elucidate the reason for conflicting results that have been published previously on galectin-3 expression in human gliomas, we used single labeling and double labeling immunohistochemistry experiments to identify cellular origin and extent of galectin-3 positivity in 53 glioma-samples (16 glioblastomas, 21 anaplastic astrocytomas, 16 low-grade astrocytomas). Galectin-3 positivity was observed in neoplastic astrocytes, macrophages/microglial cells. endothelial cells and some B- and T-lymphocytes. The quantitative analysis showed that the percentage of galectin-3 positive cells was significantly higher in the tumor parenchyma of glioblastomas than in anaplastic (p = 0.0371) and low-grade astrocytomas (p = 0.0042). Single labeling with anti-CD68 antibodies revealed a significant correlation between CD68 and galectin-3 immunoreactivity (p = 0.0092). Endothelial cells were labeled in all low-grade and anaplastic astrocytomas, but only in 10/16 glioblastomas (p = 0.0003). This detailed analysis demonstrates that galectin-3 positivity in human gliomas is considerably influenced by tumor-infiltrating macrophages. The differential expression on endothelial cells raises the question if galectin-3 plays a role in tumor angiogenesis of human gliomas.

Antigens, CD↗

PubMed2001

Macrophage/microglial cell subpopulations in glioblastoma multiforme relapses are differentially altered by radiochemotherapy.

Following surgical removal of glioblastoma multiforme (GBM), radiochemotherapy impedes neoplastic outgrowth and relapse formation. Macrophages/microglial cells are believed to be potent mediators of the host defense system in GBM. However, little is known about their alteration by postsurgical therapies. We have now analyzed expression of LCA (leucocyte common antigen), CD68 (phagocytic cells), HLA-DR, -DP, -DQ (MHC class II), MRP-8 (myeloid-related protein, S100A8), MRP-14 (S100A9), LCF (lymphocyte chemoattractant factor, IL-16) and NOS II (inducible nitric oxide synthase) in macrophages/microglial cells in 39 GBM relapses and their matched primary tumors. Following surgery of the primary tumors, 15 patients received irradiation and chemotherapy, 17 irradiation and 7 no treatment. In irradiated relapses, we observed significantly more macrophages/microglial cells expressing MRP-14 compared to untreated GBM relapses. Furthermore, we observed a significant increase of CD68 expressing macrophages/microglial cells in patients without postsurgical treatment, but not in those with radiochemotherapy. In conclusion, our findings suggest that radiochemotherapy alters the number of MRP-14 expressing cells. The lacking increase of CD68 expressing cells in patients with radiochemotherapy suggests depletion of this cell type by postsurgical therapy.

Adult↗

PubMed2001

Differential cellular accumulation of connective tissue growth factor defines a subset of reactive astrocytes, invading fibroblasts, and endothelial cells following central nervous system injury in rats and humans.

In brain injury, the primary trauma is followed by a cascade of cellular and molecular mechanisms resulting in secondary injury and scar formation. Astrogliosis and expression of transforming growth factor beta (TGF-beta) are key components of scar formation. A cytokine mediating the effects of TGF-beta is connective tissue growth factor (CTGF), a fibrogenic peptide encoded by an immediate early gene with suggested roles in tissue regeneration and aberrant deposition of extracellular matrix. In order to investigate CTGF in traumatic lesions, we evaluated 20 human brains with traumatic brain injury (TBI) and 18 rat brains with stab wound injury. Compared to remote areas and unaltered control brains, CTGF+ cells accumulated in border zones of the traumatic lesion site (p < 0.0001). In the direct peri-lesional rim, CTGF expression was confined to invading vimentin+, GFAP- fibroblastoid cells, endothelial and smooth muscle cells of laminin+ vessels, and GFAP+ reactive astrocytes. In the direct peri-lesional rim, CTGF+ astrocytes (>80%) co-expressed the activation associated intermediate filaments nestin and vimentin. In injured rat brains, numbers of CTGF+ cells peaked at day 3 and 7 and decreased to almost base level 3 weeks postinjury, whereas in humans, CTGF+ cells remained persistently elevated up to 6 months (p < 0.0001). The restricted accumulation of CTGF+-reactive astrocytes and CTGF+ fibroblastoid cells lining the adjacent laminin+ basal lamina suggests participation of these cells in scar formation. Furthermore, peri-lesional upregulation of endothelial CTGF expression points to a role in blood-brain barrier function and angiogenesis. In addition, CTGF appears to be a sensitive marker of early astrocyte activation.

Adult↗

PubMed2001

Recombinant measles viruses expressing altered hemagglutinin (H) genes: functional separation of mutations determining H antibody escape from neurovirulence.

Measles virus (MV) strain CAM/RB, which was adapted to growth in the brain of newborn rodents, is highly neurovirulent. It has been reported earlier that experimentally selected virus variants escaping from the monoclonal antibodies (MAbs) Nc32 and L77 to hemagglutinin (H) preserved their neurovirulence, whereas mutants escaping MAbs K71 and K29 were found to be strongly attenuated (U. G. Liebert et al., J. Virol. 68:1486-1493, 1994). To investigate the molecular basis of these findings, we have generated a panel of recombinant MVs expressing the H protein from CAM/RB and introduced the amino acid substitutions thought to be responsible for antibody escape and/or neurovirulence. Using these recombinant viruses, we identified the amino acid changes conferring escape from the MAbs L77 (377R-->Q and 378M-->K), Nc32 (388G-->S), K71 (492E-->K and 550S-->P), and K29 (535E-->G). When the corresponding recombinant viruses were tested in brains of newborn rodents, we found that the mutations mediating antibody escape did not confer differential neurovirulence. In contrast, however, replacement of two different amino acids, at positions 195G-->R and 200S-->N, which had been described for the escape mutant set, caused the change in neurovirulence. Thus, antibody escape and neurovirulence appear not to be associated with the same structural alterations of the MV H protein.

Animals↗

PubMed2001

In vivo expression of insulin-like growth factor-binding protein-2 in human gliomas increases with the tumor grade.

Human central nervous system tumors and glioma cell lines highly express the insulin-like growth factor-binding protein (IGFBP)-2. As IGFBP-2 can affect tumor growth, we studied the relationship between IGFBP-2 expression and the malignancy of brain tumors in vivo. To do so, we investigated by immunohistochemistry the accumulation of IGFBP-1, -2, and -3 in 50 human gliomas classified by the WHO Malignancy Scale. Double labeling using anti-CD68 (monocytes/macrophages), antiglial fibrillary acidic protein, and anti-CD3 (T cells) antibodies was performed to further characterize the IGFBP-1, -2, and -3(+) cells. The expression of IGFBP messenger RNAs (mRNAs) was tested by RT-PCR in tumor samples from nine gliomas of different grades and in eight cell lines representing the cellular composition of human glioma. As controls, the accumulation of IGFBP-2 was investigated in normal brain and in the rat C6 glioblastoma model. IGFBP-1 and -3 accumulated in endothelial and macrophage/microglial cells. IGFBP-2(+) macrophage/microglial and glioma cells clustered in the immediate vicinity of focal necrosis of the human gliomas as well as of the rat C6 glioblastoma. The labeling score of IGFBP-1 accumulation in endothelial cells correlated negatively (P: = 0.0229), and that of IGFBP-2 accumulation in glioma cells correlated positively (P: < 0.0006) with the tumor grade of the gliomas. In addition, RT-PCR analysis confirmed mRNA expression of IGFBP-1, -2, and -3 by the gliomas and glial cells. Small amounts of IGFBP-1 and -3 mRNA, but high amounts of IGFBP-2 mRNA, were detectable in macrophage-like and glioma cell lines. The results suggest cell type-specific accumulation of IGFBP-1, -2, and -3 in human glial tumors of the brain. The increase in IGFBP-2 expression with this malignancy suggests a role of IGFBP-2 in the biology of human gliomas.

Adult↗

PubMed2000

Cyclooxygenase (COX)-1 expressing macrophages/microglial cells and COX-2 expressing astrocytes accumulate during oligodendroglioma progression.

Cyclooxygenases (COX, prostaglandin endoperoxide synthases, PGG/H synthases) are potent mediators of edema, impeding blood flow and immunomodulation in the pathologically altered brain. Two COX iso-enzymes have been associated with brain disease, the constitutively expressed COX-1 and the cytokine-inducible COX-2. We have used single and double labeling immunohistochemistry to analyse COX-1 and COX-2 expression in twenty-six primary WHO grade II oligodendrogliomas, sixteen primary WHO grade III anaplastic oligodendrogliomas, twenty-seven matched recurrences and ten neuropathologically unaltered brains. COX-1 immunoreactivity was predominantly observed in macrophages/microglial cells. The number of COX-1 expressing macrophages/microglial cells was significantly lower in primary oligodendrogliomas than in primary anaplastic oligodendrogliomas (P<0.0001) and in anaplastic oligodendroglioma relapses (P=0.011). Patients with low COX-1 labeling scores in the primary tumors had significantly longer time to progression and overall survival (P=0.0285) than those with high COX-1 labeling scores. COX-2 immunoreactivity was predominantly observed in disseminated neurons and astrocytes. In glioblastoma multiforme relapses, accumulation of COX-2 expressing astrocytes was observed surrounding areas of focal necrosis. The number of COX-2 expressing astrocytes was significantly (P=0.0471) lower in primary oligodendrogliomas than in high grade oligodendroglioma relapses. These data provide convincing evidence for the differential accumulation of cyclooxygenase isoforms during oligodendroglioma progression in vivo.

Adult↗

PubMed2000

Heme oxygenase (HO)-1 expressing macrophages/microglial cells accumulate during oligodendroglioma progression.

Heme oxygenase (HO-1, HSP32) catalyzes the oxidation of heme to biliverdin and carbon monoxide, a putative neurotransmitter. In the brain, HO-1 expression has been associated with neuroprotection during oxidative stress and hypoxia. However, consecutive downstream mediation is involved in neoangiogenesis and consequent neoplastic outgrowth. We have analyzed HO-1 expression in 69 oligodendroglioma tissue samples, in rat intracranially transplanted C6 gliomas, and neuropathologically unaltered control brains by immunohistochemistry. Double labeling experiments confirmed the nature of HO-1 expressing cells. Reverse transcription-polymerase chain reaction was used to demonstrate HO-1 gene expression. HO-1 immunoreactivity was predominantly observed in macrophages/microglial cells. The number of HO-1 expressing macrophages/microglial cells was significantly lower in primary oligodendrogliomas than in their matched relapses (P<0.0001) and lower in primary anaplastic oligodendrogliomas than in their relapses (P=0.0006). Prominent accumulation of HO-1 expressing macrophages/microglial cells was observed in perinecrotic areas of both experimental rat and human glioblastoma relapses. HO-1 expressing neurons, macrophages/microglial cells and astrocytes were scattered in areas of infiltrative tumor growth. Surprisingly, HO-1 mRNA was detected in only one glioblastoma multiforme relapse. We conclude from these data that HO-1 expressing macrophages/microglial cells accumulate during oligodendroglioma progression in areas of focal necrosis. However, overall biological function of this phenomenon remains to be determined.

Adult↗

PubMed2000

Lesion associated expression of urokinase-type plasminogen activator receptor (uPAR, CD87) in human cerebral malaria.

Blood-brain barrier disintegration and inflammatory cell recruitment are key processes in the pathogenesis of cerebral malaria (CM). Recent data provide convincing evidence that the serine protease urokinase-type plasminogen activator receptor (uPAR) is a key molecule in promoting cell adhesion and spreading. We have now analyzed expression of urokinase-type plasminogen activator receptor (uPAR, CD87), which is part of a cell surface associated proteolytic system, in brains of eight CM patients and seven neuropathologically unaltered and diseased controls by immunohistochemistry. Double labeling experiments with antibodies directed against CD68 (macrophages/microglial cells), myeloid-related protein (MRP8), and glial fibrillary acid protein (GFAP) confirmed the nature of uPAR expressing cells. We observed focal accumulation of uPAR expressing macrophages/microglial cells in Dürck's granulomas and adjacent to petechial hemorrhages, in astrocytes, and in endothelial cells. In contrast, focal uPAR expression in macrophages/microglial cells but not in astrocytes was found in microglial nodules of toxoplasmic encephalitis and in the cellular infiltrate of bacterial meningitis. Normal brains showed only faint uPAR expression in endothelial cells. We conclude from these data that lesion-associated uPAR expression at least in part contributes to blood-brain barrier alteration and immunologic dysfunction in CM patients.

Adult↗

PubMed2000

Glutathione S-transferase and drug sensitivity in malignant glioma.

Malignant gliomas are largely resistant to current approaches of adjuvant chemotherapy. Gluthatione S-transferases (GST) have been attributed a role in the resistance of cancer cells, e.g., to nitrosoureas. Here, we assessed the expression levels of GST-pi and GST-mu RNA and protein as well as total GST activity in a panel of 12 human glioma cell lines and correlated these data with p53 status, BCL-2 family protein expression and drug sensitivity in these cells. Neither GST protein levels nor GST activity correlated with genetic or functional p53 status or with the expression of various BCL-2 family proteins. No evidence for GST-mediated protection from chemotherapeutic drugs became apparent. In contrast, high levels of GST-pi protein, probably the major source of GST activity in glioma cells, and of total GST activity correlated with enhanced sensitivity to vincristine-induced clonogenic cell death. Expression of GST-pi in human glioblastomas in vivo was confirmed by immunohistochemistry. Neither total, nor cytoplasmic or nuclear, GST-pi immunoreactivity correlated with the response to adjuvant radiotherapy or radiochemotherapy. A comparative analysis of primary and recurrent tumors showed that GST expression was not enhanced by radiochemotherapy in vivo. We conclude that GST does not account for the differential chemosensitivity of glioma cell lines in vitro and does not accumulate in glioma subpopulations that form recurrent tumors after radiochemotherapy in vivo.

Adult↗

PubMed2000

"Allograft-inflammatory-factor-1 is upregulated in microglial cells in human cerebral infarctions".

Allograft inflammatory factor-1 (AIF-1) is a 17-kDa-peptide identified in rat cardiac allografts undergoing chronic rejection and in activated microglial cells in inflammatory autoimune disease of the CNS. We have investigated the expression of AIF-1 in 18 autopsy cases of human focal cerebral infarction. AIF-1-positive cells show the morphology of microglia and are CD68- but not GFAP-positive. The peptide is expressed at a low level in normal brain. In infarctions, activated microglial cells in the area of glial reaction show strongly enhanced cytoplasmic immunoreactivity. The density of AIF-1-expressing cells increases during the first three days post infarction and remains elevated until chronic cystic stages. The upregulation of AIF-1-immunoreactivity precedes the rise in expression of the S-100-protein MRP-8. We conclude that AIF-1 is a sensitive marker of human microglial activation not only in inflammation but also in non-inflammatory lesions of the CNS.

Aged↗

PubMed2000

Focal accumulation of cyclooxygenase-1 (COX-1) and COX-2 expressing cells in cerebral malaria.

Intravascular sequestration and altered cytokine expression patterns are key determinators of CNS lesion formation in patients with cerebral malaria (CM). Among others, altered prostaglandin concentrations were revealed by clinical trials in peripheral blood of CM patients. Prostaglandin synthesis is controlled by cyclooxygenases (COX, prostaglandin endoperoxide synthase, PGG/H synthase) and COX expression has been attributed a key role in immunomodulation, hemostasis and inflammation in a wide variety of pathologically altered brain tissues. We have now analyzed expression of COX-1 and COX-2 in brains of patients with CM by immunohistochemistry. Double labeling experiments were used to verify the cellular identity of COX-1 and COX-2 expressing cells. Compared to healthy controls, significant (P=0.0006) accumulation of COX-1 expressing macrophages/microglial cells was detected in Dürck's granulomas. Accumulations of COX-2 expressing endothelial cells (P=0.0006) and COX-2 expressing astrocytes (P=0.0012) were detected in CM brain parenchyma. The restricted expression and accumulation of COX-1 and COX-2 in CM brains adds convincing evidence for the participation of cyclooxygenases in the formation of fever, inflammation and granuloma in these patients.

Brain↗

PubMed2000

Differential cellular accumulation of transforming growth factor-beta1, -beta2, and -beta3 in brains of patients who died with cerebral malaria.

In cerebral malaria (CM), pathologic cytokine expression patterns are thought to contribute to disruption of the blood-brain barrier, inflammation, and astrocytic scar formation. Expression of transforming growth factor (TGF)-beta1, -beta2, and -beta3 was analyzed in the brains of 7 patients who died with CM and in 8 control patients. In the brains of patients with CM, there were significantly (P=.0003) more TGF-beta1-immunoreactive astrocytes adjacent to brain vessels with deposition of malarial pigment, significantly (P=.0081) more TGF-beta2-expressing macrophages/microglial cells in glioses of ring hemorrhages and Dürck's granulomas, and significantly (P=.0022) more TGF-beta3-expressing smooth-muscle cells and endothelial cells of brain vessels with sequestration. It is concluded that focal accumulation of TGF-beta1, -beta2, and -beta3 provides evidence for their involvement in the reorganization process of the brain parenchyma, immunologic dysfunction, and endothelial cell activation in patients with CM.

Alzheimer Disease↗

PubMed2000

Allograft-inflammatory-factor-1 is upregulated in microglial cells in human cerebral infarctions.

Aged↗

PubMed2000

Expression and functional activity of heat shock proteins in human glioblastoma multiforme.

OBJECTIVE: To assess the expression of heat shock proteins (HSP) in glioma cells in vitro and in vivo and to examine their role in resistance to apoptosis. BACKGROUND: HSP are expressed in response to various forms of stress. Constitutive HSP expression may confer resistance to cytotoxic stimuli in human cancers. METHODS: HSP expression was assessed by immunoblot analysis in glioma cells in vitro and by immunocytochemistry in human glioblastomas in vivo. Modulation of apoptosis by hyperthermia-mediated HSP induction was examined in glioma cell lines in vitro. RESULTS: Immunoblot analysis revealed constitutive expression of HSP27, HSP72, HSP73, and HSP90 in all 12 human glioma cell lines. B-crystallin (alphaBC) was expressed in 3 of 12 cell lines. High levels of alphaBC and HSP72 correlated with drug resistance and high p53 levels in vitro. Transient hyperthermia (43 degrees C/2 hours) induced HSP27 and HSP72 expression but had no effect on the levels of alphaBC, HSP73, or HSP90. HSP induction provided no survival advantage against subsequent cytotoxic challenges, including cytotoxic cytokines and radiochemotherapy. Immunohistochemistry showed strong expression of all HSP in vivo. The comparative analysis of HSP27, alphaBC, HSP72, HSP73, and HSP90 expression in 24 paired samples of first resections and recurrences of human glioblastoma multiforme revealed no impact of HSP expression on response to adjuvant radiochemotherapy and no modulation of HSP expression by radiochemotherapy. CONCLUSIONS: High constitutive, as opposed to inducible, expression of HSP may play a role in the primary resistance of human malignant gliomas to cytotoxic radiochemotherapy. Superinduction of HSP levels by hyperthermia in vitro provided no further survival advantage.

Adult↗

PubMed2000

Long-term expression of heme oxygenase-1 (HO-1, HSP-32) following focal cerebral infarctions and traumatic brain injury in humans.

Extracellular heme derived from hemoglobin following hemorrhage or released from dying cells induces the expression of heme oxygenase-1 (HO-1, HSP-32) which metabolizes heme to the gaseous mediator carbon monoxide (CO), iron (Fe) and biliverdin. Biliverdin and its product bilirubin are powerful antioxidants. Thus, expression of HO-1 is considered to be a protective mechanism against oxidative stress and has been described in microglia, astrocytes and neurons following distinct experimental models of pathological alterations to the brain such as subarachnoidal hemorrhage, ischemia and traumatic brain injury (TBI) and in human neurodegenerative diseases. We have now analyzed the expression of HO-1 in human brains following TBI (n = 28; survival times: few minutes up to 6 months) and focal cerebral infarctions (FCI; n = 17; survival time: < 1 day up to months) by immunohistochemistry. Follwing TBI, accumulation of HO-1+ microglia/macrophages at the hemorrhagic lesion was detected as early as 6 h post trauma and was still pronounced after 6 months. In contrast, after FCI HO-1+ microglia/macrophages accumulated within focal hemorrhages only and were absent in non-hemorrhagic regions. Further, HO-1 was weakly expressed in astrocytes in the perifocal penumbra. In contrast to experimental data derived from rat focal ischemia, these results indicate a prolonged HO-1 expression in humans after brain injury.

Adolescent↗