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R Meyermann

Publications and source records attributed to R Meyermann.

At least 19 recordsLinked to original sources
PubMed2003

The allograft inflammatory factor-1 in Creutzfeldt-Jakob disease brains.

The allograft inflammatory factor-1 (AIF-1) is a 17-kDa IFN-gamma inducible Ca(2+)-binding EF-hand protein that is encoded within the HLA class III genomic region and is involved in immune dysfunction and smooth muscle cell activation. We used immunohistochemistry double labelling experiments to analyse the spatial distribution and cell-type-specific localization of AIF-1 in the brains of patients who died as a result of sporadic Creutzfeldt-Jakob disease (CJD) and neuropathologically unaltered controls. Significantly more AIF-1 immunoreactive macrophages/microglial cells and, interestingly, neurones were observed in CJD patients compared to controls. Western blotting confirmed more prominent AIF-1 immunoreactive bands of approximately 50 kDa in four CJD patients compared to three controls. Chaotropic SDS-PAGE of the recombinant AIF-1 resulted in almost complete reduction of the 50 kDa band and mass spectrometry revealed only AIF-1-specific tryptic protein fragments suggesting that trimerized AIF-1 is the predominant form in vivo. Finally, we analysed mechanisms of neuronal AIF-1 induction. Following H2O2 challenge, a model of general cell stress, we observed the gradual induction of AIF-1 and, more interestingly, release to the supernatant of SKNSH neurones. Parallel reverse transcriptase polymerase chain reaction and sequencing was used to confirm AIF-1 mRNA expression.

Adult↗
PubMed2002

Cortical neurons of Creutzfeldt-Jakob disease patients express the urokinase-type plasminogen activator receptor.

Plasminogen belongs to the plasminogen activator system of cell signaling proteins and has recently been identified to bind to pathological prion protein PrPSC, but not to its normal conformer, PrPC. Plasminogen binds specifically to the urokinase-type plasminogen activator receptor (uPAR) to promote pericellular proteolysis, regulate integrin function, and mediate cell signaling. By using immunohistochemistry, we observed that significantly more cortical neurons in eight postmortem brains of patients who died with sporadic Creutzfeldt-Jakob disease (CJD) are immunoreactive for uPAR compared with controls. These data provide the pathophysiological basis for detailed analyses of the role of the plasminogen activator system in CJD and related diseases.

Adult↗
PubMed2001

AMP deaminase in rat brain: localization in neurons and ependymal cells.

The purine nucleotide cycle enzyme AMP deaminase (AMPD) catalyzes the irreversible hydrolytic deamination of AMP. The physiological function of the purine nucleotide cycle in the brain is unknown. In situ hybridization and immunocytochemical studies were performed to identify the regional and cellular expression of AMPD in rat brain with the goal of elucidating the neural function of the purine nucleotide cycle. AMPD messenger RNA was detected in ventricular ependymal cells and cells of the choroid plexus and in neurons of distinct brain areas. Although only low antibody titers were obtained by immunization with the purified sheep brain AMPD, immunization of mice with synthetic lipopeptide vaccines containing oligopeptides derived from a known partial complementary DNA sequence of the enzyme yielded an antiserum suitable for immunocytochemistry. Immunostaining of cells in culture showed that neurons but not astroglial cells express appreciable amounts of the enzyme. Results of immunocytochemical staining performed on rat brain slices were in accord with the localization of AMPD messenger RNA, thus confirming the expression of AMPD in neurons of the brain stem, hippocampus, cerebellar nuclei and mesencephalic nuclei, as well as in ventricular ependymal cells and their cilia.

AMP Deaminase↗
PubMed2001

Cerebral localization and regulation of the cell volume-sensitive serum- and glucocorticoid-dependent kinase SGK1.

The serum- and glucocorticoid-dependent kinase SGK1 is regulated by alterations of cell volume, whereby cell shrinkage increases and cell swelling decreases the transcription, expression and activity of SGK1. The kinase is expressed in all human tissues studied including the brain. The present study was performed to localize the sites of SGK1 transcription in the brain, to elucidate the influence of the hydration status on SGK1 transcription and to explore the functional significance of altered SGK1 expression. Northern blot analysis of human brain showed SGK1 to be expressed in all cerebral structures examined: amygdala, caudate nucleus, corpus callosum, hippocampus, substantia nigra, subthalamic nucleus and thalamus. In situ hybridization and immunohistochemistry in the rat revealed increased expression of SGK1 in neurons of the hippocampal area CA3 after dehydration, compared with similar slices from brains of euvolaemic rats. Additionally, several oligodendrocytes, a few microglial cells, but no astrocytes, were positive for SGK1. The abundance of SGK1 mRNA in the temporal lobe, including hippocampus, was increased by dehydration and SGK1 transcription in neuroblastoma cells was stimulated by an increase of extracellular osmolarity. Co-expression studies in Xenopus laevis oocytes revealed that SGK1 markedly increased the activity of the neuronal K+ channel Kv1.3. As activation of K+ channels modifies excitation of neuronal cells, SGK1 may participate in the regulation of neuronal excitability.

Animals↗
PubMed2001

Human focal cerebral infarctions induce differential lesional interleukin-16 (IL-16) expression confined to infiltrating granulocytes, CD8+ T-lymphocytes and activated microglia/macrophages.

Focal cerebral ischemia elicits a strong inflammatory response which readily participates in lipid oxygenation, edema formation, apoptotic cell death and tissue remodeling. Within these conditions, cytokines are key players of cell activation and are crucial for delayed mechanisms of ischemic damage. Mature IL-16 is an immunomodulatory cytokine, exerting CD4 dependent and independent effects and is characterized by chemotactic activity, induction of early gene phosphorylation, stimulation of pro-inflammatory IL-1beta, IL-6, TNFalpha expression in monocytic cells and also modulates apoptosis. We have now analyzed expression of IL-16 in 20 brains of patients following focal cerebral infarctions (FCI, n=20). Compared to normal control brains (n=3), IL-16 was expressed by infiltrating immune cells such as neutrophils, CD8+ lymphocytes and activated CD68+ microglia/macrophages accumulating in lesion associated reactive zones and in peri-vascular regions. IL-16+ cells accumulated significantly (P<0.0001) in the necrotic lesion and at bordering peri-lesional areas at day 1-2 reaching maximum levels at day 3-4 (P<0.0001). Also, peri-vascular IL-16+ cells reached maximum levels at day 3-4 (P<0.0001) following infarction and decreased after several weeks. During the early microglial activation period, IL-16+ microglia/macrophages coexpress the activation antigen MRP-8. The accumulation of IL-16+ granulocytes, IL-16+, CD8+ lymphocytes and activated IL-16+, CD68+, CD4- microglia/macrophages, early after infarction suggest a CD4 independent, paracrine role of IL-16 in the postinjury inflammatory response, such as recruitment and activation of immune cells leading to microvessel clustering and blood-brain barrier disturbance resulting in secondary damage.

Aged↗
PubMed2001

Localization of endostatin in rat and human gliomas.

BACKGROUND: Endostatin is a potent inhibitor of endothelial cell proliferation, angiogenesis, and tumor growth. Its occurrence and localization has not yet been examined in human brain tumors. The authors report the production of a monoclonal antibody and detection of endostatin in rat and human gliomas by immunohistochemistry. METHODS: The authors analyzed localization and tissue distribution of endostatin in 41 paraffin embedded glioma samples (18 glioblastoma multiforme, 7 WHO Grade III astrocytomas, 13 fibrillary, and 3 protoplasmic WHO Grade II astrocytomas) of human origin and 21 rat C6 gliomas by immunohistochemistry. Double labeling experiments confirmed the origin of endostatin-labeled cells. RESULTS: Endostatin immunoreactivity was detected in tumor cells, endothelial cells, macrophages, and lymphocytes of both rat and human gliomas. The percentage of cells labeled with the endostatin antibody was significantly lower (P = 0.0126) in the tumor parenchyma of human glioblastomas than in WHO Grade II astrocytomas. CONCLUSIONS: Endostatin was present in various cell types in rat and human gliomas in vivo. Lower levels in glioblastomas than in WHO Grade II astrocytomas might have reflected the shift of a probable regulatory balance between promoters and inhibitors of angiogenesis towards facilitation of neovascularization.

Adult↗
PubMed2001

Preirradiation gemcitabine chemotherapy for newly diagnosed glioblastoma. A phase II study.

BACKGROUND: The median survival for patients with glioblastoma is reported to be 12 months. To improve the outcome for glioblastoma patients, the authors evaluated the therapeutic efficacy of preirradiation gemcitabine chemotherapy followed by standard radiotherapy. METHODS: Twenty-one patients with newly diagnosed glioblastoma were enrolled in a prospective unicenter trial of preirradiation gemcitabine chemotherapy. Chemotherapy included up to 4 monthly cycles of intravenous gemcitabine (Day 1, Day 8, and Day 15; 1000 mg/m2). Involved field radiotherapy was given after chemotherapy or earlier in the case of disease progression or gemcitabine intolerance. RESULTS: With gemcitabine chemotherapy alone, there was a median progression free survival of 11 weeks and a progression free survival rate at 4 months of 24%. In 18 of 21 patients who subsequently received a full course of radiotherapy, the median progression free survival from the time of diagnosis was 8 months and the progression free survival rate at 12 months was 17% (3 of 18 patients). The median overall survival was 11 months. There was no specific treatment-related neurotoxicity reported. Neither age nor extent of residual postoperative tumor predicted the duration of progression free survival in patients treated with gemcitabine chemotherapy alone or in those treated with gemcitabine plus radiotherapy. CONCLUSIONS: Gemcitabine followed by radiotherapy is a safe regimen for patients with newly diagnosed glioblastoma but the gemcitabine schedule used in the current study did not appear to confer any survival advantage compared with standard involved field radiotherapy alone.

Adult↗
PubMed2001

Heme oxygenase-1 in lesions of human cerebral malaria.

Human cerebral malaria is a life threatening complication of Plasmodium falciparum infection. The cascades of signaling events resulting in tissue trauma, lesion formation, coma or resolution of lesions are only slowly becoming unraveled. Understanding the generation of local tissue protective cellular reactions might pave the way for generation of novel drugs limiting the formation of cerebral malaria lesions. Heme oxygenase-1 (HO-1) is an inducible enzyme degrading heme into the gaseous mediator carbon monoxide (CO) and biliverdin, a local antioxidant. Expression of HO-1 is considered a protective reaction against inflammatory and other insults to the brain. We have localized HO-1 to Durck's granulomas, typical lesions of advanced cerebral malaria. Here, activated monocytic cells and ramified microglia in direct vicinity to the lesions express HO-1. The striking association of HO-1 expression with areas of bleedings suggests that released hemoglobin and heme-- known inducers of HO-1--are mainly responsible for induction of monocytic HO-1 expression. HO-1 is expressed rather late to play a protective role in lesion formation and appears to have only a major role in Durck's granulomas. Further, generation of the gaseous mediator CO might contribute to the neurological derangements of advanced cerebral malaria.

Antigens, CD↗
PubMed2001

Local distribution of microglia in the normal adult human central nervous system differs by up to one order of magnitude.

Although microglia are considered to be a sensitive sensor for pathological processes in the central nervous system, there are only a few studies about the distribution and density of microglia in the normal human brain. Therefore, a study of local density of microglial cells was conducted by investigating 20 normal human brains with no clinical neurological symptoms or diseases and no neuropathological alterations. Microglial cells were visualized by immunolabeling of proteins which are known to be expressed either constitutively or facultatively, such as CD68, major histocompatibility complex class II (MHC-II), leukocyte common antigen (LCA), leukocyte chemotactic factor (LCF), macrophage inhibitory factor-related protein (MRP) 8, MRP14, CD4 and allograft-inflammatory factor-1 (AIF-1). CD68, MHC-II and AIF-1 showed the highest densities with significant regional differences ranging from 0.5% to 16.6% of all cells in the brain parenchyma with significantly more microglia in white than in gray matter. LCF and LCA showed a similar pattern of distribution as the proteins described above, but with lower percentages of microglial cells. CD4 was not found in the brain parenchyma. We conclude that CD68, MHC-II and AIF-1 define the main microglial cell population, whereas LCF and LCA are expressed by a subpopulation of microglial cells. The brains showed no or a negligible vascular expression of MRP8 and MRP14. Information about the local microglia density in the normal human brain can serve as a reference for the evaluation of pathological microglial responses.

Adult↗
PubMed2001

Differential activation of microglial cells in local and remote areas of IRBP1169-1191-induced rat uveitis.

Using a Lewis rat model of interphotoreceptor retinoid binding protein (IRBP)-induced experimental autoimmune uveitis (EAU) we examined cellular reactions in the optic pathway (retina, choroid, optic nerve, optic tract, colliculus superior, and visual cortex). Two to six animals were studied at days 0, 7, 9, 11, 12, 13, 14, 18 and 22 after immunization by immunohistochemistry with monoclonal antibodies against ED , ED2, OX6, OX22, EMAP II, AIF-1 and W3/13. In the retina, choroid and distal optic nerve increased immunoreactivity to ED1, OX6, OX22, EMAP II, AIF-1 and W3/13 was initially observed at day 9, peaked at days 13-14 and diminished rapidly from day 18 onwards. No changes were seen in the density of ED2-positive resident macrophages. In the optic tract, ED1 and OX6 expression was induced in microglial cells beginning with day 11 and persisted until day 22. AIF-1, EMAP II and ED2 expression was not visibly up-regulated and no lymphocytic infiltrates (OX22-, W3/13-positive cells) were observed. In the central projection fields, no cellular reaction could be found. Thus, cellular response in IRBP-induced rat uveoretinitis is not restricted to the eye. Microglial activation is also seen in the distal optic nerve and optic tract. This remote microglial activation, however, differs in intensity, time course and expression of activation markers, thus indicating different activation cascades. The mild remote microglial activation is probably due to neuronal-microglial interactions resulting from neuronal damage in the retinal ganglion cell layer and nerve fiber layer with consecutive axonal degeneration and not from an inflammatory reaction as seen in the eye.

Animals↗
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

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↗