Biomedical subjects

Werner Paulus

Publications and source records attributed to Werner Paulus.

At least 55 records · Page 3Linked to original sources

PubMed2003

Cerebral c-jun expression mapping in sudden infant death syndrome.

Despite a decline in the overall rate of sudden infant death syndrome (SIDS), it remains the leading cause of postneonatal infant mortality. Research into underlying mechanisms of SIDS has still not yielded a morphological, histopathological correlate explaining aetiology and pathophysiology of an infant's sudden death. Of particular interest would be elucidating pathophysiological and molecular events immediately preceding the infant's sudden death. C-jun is an immediate early gene with a physiological role in orchestrating cellular responses following injury including a role in cell death. It is also one of the earliest and most consistent markers for neurons undergoing stress, degeneration and survival. We investigated the immunohistochemical expression of the acute phase protein c-jun within 47 separate cerebral regions of interest in the brains of 23 SIDS and 7 control cases for evidence of acute neuronal injury immediately preceding sudden death and to assess the distribution of cellular damage suggestive of pathophysiologically sensitive or critical cerebral regions. Dividing SIDS-cases and controls into subgroups with (1) no neuronal expression of c-jun at all or (2) some c-jun expression, a statistically significant higher c-jun expression for SIDS compared with control cases was established for the inferior colliculi ( P=0.008), the spinal trigeminal nuclei ( P=0.046) and the premotoric cortex layers II and IV ( P=0.029). The increased expression of c-jun in these areas might be directly related to the pathogenesis of sudden death, or may represent a secondary marker of neuronal injury with the primary event/injury being elsewhere in critical cardioventilatory circuits.

Cerebral Cortex↗

PubMed2003

A new neurophysiological/neuropathological ex vivo model localizes the origin of glioma-associated epileptogenesis in the invasion area.

Seizures commonly occur in glioma patients, but their pathogenesis is poorly understood, in part due to a lack of valid and versatile experimental models. We have established a new model that enables comprehensive neuropathological and neurophysiological analysis on identical tissue preparations. Rat C6 glioma cells stably transfected with a green fluorescence protein (GFP) gene are transplanted into rat neocortex, giving rise to diffusely invading gliomas histologically resembling human glioblastomas. After 2 weeks, 500- micro m-thick cerebral slices are prepared, stained with the voltage-sensitive dye RH795, and fluorescence changes associated with origin and spread of abnormal bioelectric activity upon washout of Mg(2+) are detected by a 464-element photodiode array at a rate of 785 frames/s. GFP fluorescence promotes identification of tumor cells during electrophysiological experiments and in neuropathological analyses using frozen and paraffin-embedded tissue sections. By performing subsequent histological analysis of the slices examined neurophysiologically, origin and spread of abnormal activity can be correlated with structural and molecular (immunohistochemical) features. Specifically, we found that ictaform activity was initiated in cortical areas diffusely invaded by single tumor cells. This model is useful for further elucidating the electrophysiological, molecular and structural basis of glioma-associated epileptogenesis.

Animals↗

PubMed2003

Sensitivity and specificity of epithelial membrane antigen staining patterns in ependymomas.

Pattern and extent of epithelial membrane antigen (EMA) immunoreactivity in ependymomas as compared to other glial tumors have only been investigated in small series. To determine sensitivity and specificity of EMA staining, 54 ependymomas were evaluated in comparison to 54 glioblastomas, 43 fibrillary astrocytomas and 21 oligodendrogliomas. Distinct punctate intracytoplasmic EMA immunoreactivity was observed in 48/54 ependymomas (89%), whereas ring-like EMA staining was observed in 17/54 ependymomas (31%). Apart from the absence in most myxopapillary ependymomas, neither staining pattern was related to tumor grade or localization. Dot-like EMA immunoreactivity was less frequently observed in glioblastomas [32/54 (59%), P<0.05 vs ependymomas], fibrillary astrocytomas [10/43 (23%), P<0.001 vs ependymomas] and oligodendrogliomas [2/21 (10%), P<0.001 vs ependymomas], whereas ring-like EMA staining was absent. Sensitivity and specificity of punctate EMA staining for the diagnosis of ependymoma as compared to other glial tumors were determined: A finding of 5 EMA dots/high-power field was associated with a sensitivity of 72% and a specificity of 81%. The presence of ring-like EMA positive structures was less sensitive (32%), but highly specific (100%). To conclude, distinct punctate and ring-like EMA staining might serve as sensitive and specific markers of ependymal differentiation in glial tumors and, thus, may aid the diagnosis of ependymoma.

Adolescent↗

PubMed2003

A new role for the cell adhesion molecule L1 in neural precursor cell proliferation, differentiation, and transmitter-specific subtype generation.

Adhesion molecules play important roles in the development and regeneration of the CNS and PNS. We found that the immunoglobulin superfamily recognition molecule L1 influences proliferation and differentiation of neural precursor cells. Substrate-coated L1 reduced proliferation of precursor cells in a dose-dependent manner and increased neuronal and decreased astrocytic differentiation when compared with poly-l-lysine or laminin substrates. Enhancement of neuronal differentiation was more effective if L1 was offered via the cell surface of transfected fibroblasts compared with substrate-coated purified L1. Furthermore, L1 decreased cholinergic-subtype differentiation and accelerated GABAergic differentiation of precursor cell-derived neurons in comparison with poly-l-lysine or laminin. Generation of dopaminergic neurons was not influenced by L1. Experiments with precursor cells generated from L1-deficient mice indicate that L1 acts via heterophilic interaction on proliferation and differentiation of L1-negative precursor cells and via a homophilic or L1 coreceptor-mediated interaction on maturation of precursor cell-derived L1-positive neurons. Clonal analysis revealed that L1 equally inhibits proliferation of monopotential, bipotential, and multipotential precursor cells, but selectively enhances neuronal differentiation of multipotential and bipotential neuron-astrocyte precursors. Our observations support a new role for L1 or L1 ligands in neural precursor cell proliferation and differentiation.

Animals↗

PubMed2003

Up-regulation of striatal adenosine A(2A) receptors in schizophrenia.

Adenosine A (2A) receptors have been implicated in the pathophysiology of schizophrenia by clinical, anatomical, biochemical and genetic studies. We hypothesized that a genetically determined low number of adenosine A (2A) receptors could be a vulnerability factor for the development of the disease. The density of adenosine A (2A) receptors was investigated in human postmortem striatum of patients with schizophrenia (n = 9) and matched controls ( n= 9) using [ H)CGS 21680 as a radioligand probe. The maximum number of binding sites (B) (max) was 70% higher in patients with schizophrenia than in matched controls (609.4 +/- 259.1 354.0 +/- 156.4 fmol/mg protein, p=0.04). No significant difference could be discerned for the affinity of caffeine for adenosine A receptors between patients and controls. The increase in receptor density correlated with the dose of antipsychotic medication in chlorpromazine equivalents (r =0.61, = 0.014). We failed to provide evidence for a genetically determined reduction of adenosine A 2(A) receptors in schizophrenia. Instead, consistent with findings from animal experiments, our observation supports a role of adenosine A (2A) receptors in the molecular effects of antipsychotic drugs.

Adenosine↗

PubMed2003

Microdysgenesis in mesial temporal lobe epilepsy: a clinicopathological study.

The interrelationship of mesial temporal lobe epilepsy (MTLE), hippocampal sclerosis, and febrile convulsions still remains an enigma. Additional microscopical cortical dysplasia or microdysgenesis has been suggested as pre-existent susceptibility factor rendering the affected brain vulnerable to the development of MTLE after initial precipitating injuries such as febrile convulsions. Twenty-four MTLE cases with histopathologically definite hippocampal sclerosis were examined for clearly defined features of microdysgenesis and further signs of neocortical dysplasia. Although unequivocal signs of dysplasia were absent, 29.2% of cases showed cortical neuronal clustering, 25.0% showed perivascular clustering, and 20.8% showed increased white matter neurons. The features of microdysgenesis studied here were not linked with each other and were not related to initial precipitating injuries, positive family history, or any other clinical parameter. Their suggested fundamental role as dysplastic factor within development of hippocampal sclerosis and MTLE is not confirmed.

Adult↗

PubMed2003

Primary anaplastic large cell lymphoma of the central nervous system: prognostic effect of ALK-1 expression.

Anaplastic large cell lymphoma (ALCL) rarely occurs in the central nervous system. Although defined by its composition of large, pleomorphic, CD30-positive lymphocytes, ALCL is heterogeneous. Most are T cell but some are null cell. Most but not all have a characteristic 2:5 translocation producing the fusion protein ALK-1, which is reliably detected by immunohistochemistry. In systemic ALCL, ALK-1 expression correlates with young patient age and a favorable prognosis. Herein we report four new cases of primary central nervous system ALCL from the Mayo Clinic and incorporate additional data from five previously published cases. ALK-1 expression was determined in all nine tumors. Patient age was 4-66 years (mean 29 years) with a bimodal distribution: 6 < or = 22 years, 3 > or = 50 years. Six were female. Tumors were mostly supratentorial, five were multifocal, and seven had involvement of dura or leptomeninges. Seven tumors were T cell, two were null cell, and five of nine were ALK-1 immunopositive. Total mortality was six of nine. Three patients, 4-18 years of age (mean 13 years), were alive at 4.8-6.1 years postdiagnosis; these tumors were all ALK positive. Five patients, 13-66 years of age (mean 43 years), died of tumor 4 days to 11 weeks postdiagnosis; four of five of these tumors were ALK negative. One 10-year-old child with an ALK-positive tumor died of sepsis, but in remission. Central nervous system ALCL is aggressive. Our study suggests that a better outcome may be associated with young age and ALK-1 positivity, prognostic parameters similar to systemic ALCL.

Activin Receptors, Type I↗

PubMed2003

Intracranial follicular dendritic cell sarcoma. Case report.

Intracranial occurrence of follicular dendritic cell (FDC) sarcoma, a rare tumor derived from dendritic cells of the lymphoid follicle, has not yet been described. Therefore, the case of a 53-year-old man presenting with an intracranial mass invading the clivus is reported. The diagnosis of FDC sarcoma was confirmed by immunohistochemical staining for dendritic cell markers, that is, CD21, CD23, and CD35. Due to some similarities with meningioma, intracranial FDC sarcoma might be an underdiagnosed disease.

Brain Neoplasms↗

PubMed2002

No chromosomal imbalances detected by comparative genomic hybridisation in a case of fetal immature teratoma.

CASE REPORT: We present the first application of comparative genomic hybridisation (CGH) in fetal brain tumours in the case of a fetal immature teratoma. The tumour was discovered in a female fetus at 22 weeks gestation after presentation with significant craniomegaly of such degree that the head size measured by sonography was found to correspond to a gestational age of 37 weeks, and the pregnancy was terminated. RESULTS: Neuropathological examination showed an immature teratoma measuring 1.7 x 1.6 x 0.5 cm and containing tissue from all three germinal layers. CGH was successfully performed and, in contrast to earlier results in both cerebral and extracerebral teratomas also investigated with the same technique, it revealed no chromosomal imbalances. CONCLUSION: This indicates that mono- or trisomies did not have a role in the pathogenesis in this particular case and that a fetal immature teratoma may contain aberrations smaller than the detection threshold of CGH. However, it remains to be seen in larger cohorts whether fetal teratomas follow a different pathogenetic pathway and may be triggered by different molecular events than teratomas occurring in later life.

Abortion, Eugenic↗

PubMed2002

No chromosomal imbalances detected by comparative genomic hybridisation in subependymal giant cell astrocytomas.

Eight subependymal giant cell astrocytomas (SEGA) were studied by comparative genomic hybridisation. These consisted of six primary SEGA and two recurrences gained from six paediatric patients suffering from tuberous sclerosis complex (TSC). No DNA copy number changes were found in any of the tumours. Our data show that chromosomal imbalances are absent or very rare events in primary and recurrent SEGA and that no aberrations were detected at the sites of the TSC-associated genes, thus indicating that mutational inactivation of one of the TSC genes is not followed by genomic instability.

Adolescent↗

PubMed2002

Use-related gene expression patterns of rat motor cortex.

Current evidence indicates reorganization of motor cortex in association with motor behavior. To investigate the molecular basis for these changes rats were fitted with limb-restricting vests which forced the use of one forelimb for 10 days. Using cDNA macroarrays, expression profiles of the corresponding motor cortices connected to the overused and immobilized limbs were analyzed. In the overused motor cortex up-regulations were observed exclusively, including genes coding for voltage-gated ion channels, trafficking and targeting proteins, and intracellular kinase network members (10 genes). In the contralateral immobilized cortex changes were restricted to down-regulation, mainly involving genes pertaining to DNA-binding, translation, neuronal signaling and metabolic pathways (9 genes). At least some of these changes are likely to represent the molecular substrate of use-dependent plasticity.

Animals↗

PubMed2002

L1 expressed by glioma cells promotes adhesion but not migration.

L1 is an adhesion molecule of the immunoglobulin superfamily expressed by several types of cancer, including gliomas. It has been shown that L1 can act as chemoattractant to glioma cells, while the effects of L1 expressed by glioma cells themselves are unknown to date. We established a C6 rat glioma clone, conditionally expressing murine L1 under control of a tetracycline responsive promoter. In vitro experiments revealed increased adhesion on matrigel as well as increased intercellular adhesion in the presence of L1, whereas no L1-dependent effects on proliferation or migration on either matrigel or myelin were observed. In vivo experiments using transplantation into nude mouse striatum, where L1 expression by glioma cells was regulated by tetracycline via drinking water, did not show effects of L1 on tumor size or brain invasion. Our data suggest that L1 expressed on the surface of glioma cells increases cell-matrix and intercellular adhesion, but has no apparent effects on proliferation and invasion.

Animals↗

PubMed2002

Genetic characterisation of granular cell tumours.

Seven granular cell tumours (GCT) were studied by comparative genomic hybridisation. These consisted of two cerebral and one pituitary GCT as well as four other central nervous system tumours predominantly composed of granular cells (one glioblastoma, meningioma, ganglioglioma and neurinoma each). DNA copy number changes were found in four of seven tumours. Overall, losses (mean: 1.0 per tumour) were more frequent than gains (mean: 0.6 per tumour) and no high-level gains were found. The only DNA copy number change found in two tumours (both cerebral GCT) was loss of 13q21, while the other nine aberrations were only encountered once each: the granular cells of one cerebral GCT additionally showed +1p32-pter, +9q33-qter, +20q, -4, and -18q, of the glioblastoma +7 and -10, and of the meningioma -1p and -22q, while the pituitary GCT, the ganglioglioma and the neurinoma showed no imbalances. Our data suggest that a variety of genetic changes are associated with granular cell formation and support the notion that GCT are not a distinct tumour entity characterised by specific chromosomal imbalances but rather a degenerative phenomenon of cells of various origin showing DNA copy number changes akin to the underlying tumour.

Adult↗

PubMed2002

Fetal ependymoma associated with Down's syndrome.

Down's syndrome (DS) is the most common multiple malformation syndrome occurring in humans and is associated with an increased risk of childhood malignancies, in particular leukemias. However, solid tumors seem to be underrepresented in DS patients and brain tumors occurring in association with DS have so far been limited to sporadic case reports, predominantly in children and young adults. We present the first case of an ependymoma associated with DS. This is also the youngest patient with DS suffering from a brain tumor as well as the first case in the English literature of a fetal ependymoma. The tumor was discovered incidentally at autopsy in a female fetus with DS after amniocentesis and termination of pregnancy in the 19th gestational week. Neuropathological examination revealed a tumor of 3x2x1 mm attached to the medulla oblongata rostrally of the floor of the fourth ventricle. Histologically, the ependymoma was moderately cellular and well demarcated with numerous perivascular pseudorosettes. Immunohistochemistry showed strong reactivity for GFAP, in particular of the fibrillary elements of the pseudorosettes, while the neuronal marker synaptophysin was not expressed. The Ki67/MIB-1 proliferation index was 0.5%.

Adult↗

PubMed2002

Chromosomal imbalances in choroid plexus tumors.

We studied 49 choroid plexus tumors by comparative genomic hybridization. Chromosomal imbalances were found in 32 of 34 choroid plexus papillomas and 15 of 15 choroid plexus carcinomas. Choroid plexus papillomas frequently showed +7q (65%), +5q (62%), +7p (59%), +5p (56%), +9p (50%), +9q (41%), +12p, +12q (38%), and +8q (35%) as well as -10q (56%), -10p, and -22q (47%); choroid plexus carcinomas mainly showed +12p, +12q, +20p (60%), +1, +4q, +20q (53%), +4p (47%), +8q, +14q (40%), +7q, +9p, +21 (33%) as well as -22q (73%), -5q (40%), -5p, and -18q (33%). Several chromosomal imbalance differences could be found that were characteristic for a tumor entity or age group. In choroid plexus papillomas +5q, +6q, +7q, +9q, +15q, +18q, and -21q were significantly more common whereas choroid plexus carcinomas were characterized by +1, +4q, +10, +14q, +20q, +21q, -5q, -9p, -11, -15q, and -18q. Among choroid plexus papillomas, children more often showed +8q, +14q, +12, and +20q; adults mainly presented with +5q, +6q, +15q, +18q, and -22q. Although the number of aberrations overall as well as of gains and losses on their own bore no significance on survival among choroid plexus tumors, a significantly longer survival among patients with choroid plexus carcinomas was associated with +9p and -10q. Our results show that aberrations differ between choroid plexus papillomas and choroid plexus carcinomas as well as between pediatric and adult choroid plexus papillomas, supporting the notion of different genetic pathways. Furthermore, gain of 9p and loss of 10q seem to be correlated with a more favorable prognosis in choroid plexus carcinomas.

Adult↗

PubMed2002

Suprasellar melanocytoma: a case of primary radiotherapy and review of the literature.

Meningeal melanocytoma is a rare benign neoplasm of the central nervous system. Approximately 50% of the tumors are located intracranially with a preference for posterior fossa. We report a new case of intracranial suprasellar melanocytoma in a 57-year-old male patient treated with primary high-dose conformal radiotherapy to 50.4 Gy. Fourty-two months subsequent to treatment the tumor is well under control without neither deterioration of clinical symptoms nor progression of gross tumor volume on MR imaging. No late sequelae of treatment have been observed. A review of the literature is presented indicating that resection of melanocytoma is the treatment of first choice hampered by a relapse rate of approximately 30% depending on resection status. The role of adjuvant radiotherapy in patiens with complete resection of melanocytoma has not yet been defined. These patients carry a risk of relapse of approximately 15%, and adjuvant irradiation is currently not recommended. Primary high-dose radiotherapy has been shown to be effective in long-term control of the neoplasm in patients where no resection of the tumor could be accomplished. In case of incomplete resection of melanocytoma, data of the literature indicate that adjuvant radiotherapy may in fact increase long-term local control of the tumor. Requirements for optimal treatment results of radiotherapy are sufficiently high doses of, at least, 50 Gy for intracranial lesions and three-dimensional treatment planning guaranting precise targeting of the tumor volume with only a low-risk of late sequalae to the surrounding tissues.

Humans↗

PubMed2002

Increased menin expression in sporadic pituitary adenomas.

BACKGROUND: Germline mutations of the multiple endocrine neoplasia type 1 (MEN1) tumour-suppressor gene are responsible for multiple endocrine neoplasia type 1, and menin, the MEN1 gene product, is usually downregulated or truncated in MEN1-associated adenomas. In contrast, exonic MEN1 mutations seem to be very rare in sporadic (MEN1-unrelated) pituitary adenomas, and it has been suggested that menin does not play a major role in these tumours. However, menin might be involved in sporadic adenoma tumorigenesis by downregulation through intronic mutations, epigenetic, posttranscriptional or posttranslational mechanisms. PATIENTS AND MEASUREMENTS: We screened MEN1 coding regions and flanking intronic sequences of 136 sporadic pituitary adenomas by temporal temperature gradient gel electrophoresis (TTGE) and studied menin expression by immunoblotting in 11 of these tumours. RESULTS: Sequencing of DNAs showing aberrant migration on TTGE revealed five somatic MEN1 mutations, including two missense mutations (F134L, E530K), a 2-bp deletion in exon 10 (c.1567-1568del) leading to a premature stop codon, and two 3-bp deletions in intron 5 (g.5236-5238del, g.5237-5239del). These mutations have not been reported previously in studies analysing the MEN1 gene. Immunoblotting showed menin upregulation in all adenomas examined (including one case with a missense mutation) from 1.7-fold to 10.4-fold (mean, 4.2-fold) compared to non-neoplastic adenohypophysis. CONCLUSIONS: Our data suggest that neither MEN1 mutations nor menin downregulation play a significant role in the development of sporadic pituitary adenomas.

Adenoma↗

PubMed2002

Gene expression profiling in perilesional and contralateral areas after ischemia in rat brain.

Structural and functional reorganization in the vicinity of damaged neocortex and other connected brain areas seems to be responsible for postlesional functional recovery. To better understand the molecular mechanisms underlying this type of plasticity, gene expression patterns were analyzed by using DNA macroarrays comprising 1176 genes. Circumscribed unilateral infarcts consistently affecting the forelimb area of the motor cortex were induced photochemically in adult rats. Ten days after lesioning, cortical gene expression fingerprints were evaluated from an area adjacent to the lesion as well as two contralateral areas of motor and somatosensory cortex. Discrete regions showed distinct expression patterns. Upregulation was observed of different members of transcription factors, immediate early genes, neuronal signaling as well as neuronal growth and structure-associated genes, ipsilaterally (six genes) and/or contralaterally (eight genes in the motor and seven in the somatosensory cortex). In contrast, downregulations were restricted to ipsilateral areas and included genes coding for ion channels, transport proteins, mediators of metabolic pathways, and intracellular transducers (14 genes). A subset of these regulations were further confirmed by real-time polymerase chain reaction (TaqMan assay). At least part of the detected regulations, in particular those of the contralateral hemisphere, are likely to underlie plasticity processes.

Animals↗