Almuth Brandis

Immunohistochemical detection of female sex hormone receptors in meningiomas: correlation with clinical and histological features.

Sixty-one meningiomas from 60 patients were screened for estrogen receptors and progesterone receptors (PgR) with monoclonal antibodies in an immunohistochemical assay. In addition, 43 of the cases were evaluated for tumor size and peritumoral edema, as seen on computed tomographic scans and magnetic resonance images. Sixty-one percent of the tumors contained significant amounts of PgR, whereas no estrogen receptor-positive tumor was observed. Thirteen percent of all tumors were classified as nonbenign variants (atypical and anaplastic meningiomas) and were more frequently found in male patients (P < 0.05). Nonbenign tumors more frequently showed an absence of PgR (P < 0.05), and there was a tendency for PgR-negative tumors to be larger than PgR-positive ones. No correlation was found between PgR status and edema. It is concluded that PgR status in meningiomas is related to tumor differentiation and may be of prognostic value with regard to biological behavior and clinical outcome.

Chordoid Glioma of the Third Ventricle: Immunohistochemical and Molecular Genetic Characterization of a Novel Tumor Entity

Chordoid glioma of the third ventricle was recently reported as a novel tumor entity of the central nervous system with characteristic clinical and histopathological features (Brat et al., J Neuropathol Exp Neurol 57: 283–290, 1998). Here, we report on a histopathological, immunohistochemical and molecular genetic analysis of five cases of this rare neoplasm. All tumors were immunohistochemically investigated for the expression of various differentiation antigens, the proliferation marker Ki‐67, and a panel of selected proto‐oncogene and tumor suppressor gene products. These studies revealed a strong expression of GFAP, vimentin, and CD34. In addition, most tumors contained small fractions of neoplastic cells immunoreactive for epithelial membrane antigen, S‐100 protein, or cytokeratins. The percentage of Ki‐67 positive cells was generally low (< 5%). All tumors showed immunoreactivity for the epidermal growth factor receptor and schwan‐nomin/merlin. There was no nuclear accumulation of the p53, p21 (Waf‐1) and Mdm2 proteins. To examine genomic alterations associated with the development of chordoid gliomas, we screened 4 tumors by comparative genomic hybridization (CGH) analysis. No chromosomal imbalances were detected. More focussed molecular genetic analyses revealed neither aberrations of the TP53 and CDKN2A tumor suppressor genes nor amplification of the EGFR, CDK4, and M DM2 proto‐oncogenes. Our data strongly support the hypothesis that chordoid glioma of the third ventricle constitutes a novel tumor entity characterized by distinct morphological and immunohistochemical features, as well as a lack of chromosomal and genetic alterations commonly found in other types of gliomas or in meningiomas.

Comparison of unilateral and bilateral intrastriatal 6-hydroxydopamine-induced axon terminal lesions: Evidence for interhemispheric functional coupling of the two nigrostriatal pathways

Partial lesions of the nigrostriatal dopamine system can be induced reliably by the intrastriatal injection of 6‐hydroxydopamine (6‐OHDA) and are considered to be analogous to the early stages of human Parkinsons disease. Previous studies have established a clear correlation between different doses and placements of the 6‐OHDA toxin and the degree of neurodegenerative changes and behavioral impairments. In the present study, the influence of the interdependence between the two nigrostriatal systems in both hemispheres on the effects on sensorimotor behavioral performances after terminal 6‐OHDA lesions was investigated. The behavioral effects were correlated to the extent of nigral dopamine neuron cell and striatal tyrosine‐hydroxylase (TH)‐positive fiber loss. Sprague‐Dawley rats receiving unilateral intrastriatal 6‐OHDA injections (4 × 5 μg) exhibited a 30–70% reduction in striatal TH‐positive fiber density along an anterior‐posterior gradient, an 80% loss of nigral dopamine neurons and a mild degree of behavioral impairments as revealed by amphetamine‐induced rotational asymmetry, and a reduced performance in the stepping and postural balance tests. When the same amount of toxin was injected twice into both hemispheres (2 × 4 × 5 μg), additional behavioral deficits were observed, consisting of a significant, but temporary, weight loss, a stable reduction in general locomotor activity and explorational behavior, and a long‐term deficit in skilled forelimb use. This is interesting in light of the morphological findings, in which uni‐ and bilaterally lesioned animals did not differ significantly in the extent of TH‐immunoreactive fiber and dopamine neuron loss within the nigrostriatal system in each lesioned hemisphere. These results indicate that the interdependent regulation of the two nigrostriatal systems may provide some compensatory support for the function and behavioral performance of the lesioned side via the normal unlesioned side, which is lost in animals with bilateral lesions of the nigrostriatal system. Therefore, this model of uni‐ and bilateral partial lesions of the nigrostriatal system, as characterized in the present study, may foster further exploration of compensatory functional mechanisms active in the early stages of Parkinsons disease and promote development of novel neuroprotective and restorative strategies. J. Comp. Neurol. 432:217–229, 2001.

Immunohistochemical characterization of axonal sprouting and reactive tissue changes after long-term implantation of a polyimide sieve electrode to the transected adult rat sciatic nerve.

The development of artificial microstructures suited for interfacing of peripheral nerves is not only relevant for basic neurophysiological research but also for future prosthetic approaches. Aim of the present study was to provide a detailed analysis of axonal sprouting and reactive tissue changes after implantation of a flexible sieve electrode to the proximal stump of the adult rat sciatic nerve. We report here that massive neurite growth after implantation, steadily increasing over a period of 11 months, was observed. Parallel to this increase was the expression of myelin markers like Po, whereas non-myelin-forming Schwann cells did not change. Compared to five weeks post-implantation. where both Schwann-cell phenotypes were intermingled with each other, non-myelin-forming Schwann cells occupied a peripheral position in each microfascicle after 11 months. After an initial increase, hematogenous macrophages were down-regulated in number but maintained close contact with the implant. However, at no time were signs of its degradation observed. It is concluded that the introduced flexible polyimide electrode is suitable for contacting peripheral nerves since it permits substantial neurite growth and offers excellent long-term stability.

Microtransplantation of dopaminergic cell suspensions: further characterization and optimization of grafting parameters.

Intracerebral transplantation of dopaminergic (DA) cells is currently further explored as a potential restorative therapy for Parkinsons disease (PD). However, before they can be considered for a more widespread clinical use a number of critical issues have to be resolved, including an optimized transplantation protocol. This study has been performed in a rat 6-hydroxydopamine model of PD and is based on the microtransplantation approach. The results demonstrate a reduced survival (threefold) for a single cell suspension of E14 rat ventral mesencephalon compared to a fragment suspension when a metal cannula is used for implantation. However, fragment suspensions result in a more variable graft survival and ectopically placed cells along the implantation tract. When a glass capillary is used for implantation, the survival of the single cell suspension (so-called “micrograft”) improved by fourfold (vs. single cells/metal cannula) and is superior to the combination of the metal cannula and fragment suspension (+40%). The micrografts show a reduced variability in DA neuron survival as well as fewer ectopically placed cells. Moreover, the implantation time can significantly be reduced from 19 to 7 min in micrografted animals without a compromise in DA graft survival and functional behavioral outcome. Using the microtransplantation approach graft size can be tailored effectively by varying the density of the final cell suspension at least between 11,000 and 320,000 cells/μl, resulting in comparable survival of tyrosine hydroxylase (TH)-positive neurons in the range of 2–4%. With this approach no more than 100 surviving TH-positive neurons are necessary to produce functional effects in the amphetamine-induced rotation test. Interestingly, we found that DA micrografts into lesion striatum present 20% higher survival rates of TH neurons in comparison to the intact striatum. In summary, these results provide further evidence for the usefulness of the microtransplantation approach and allow for a more precise and tailored adaptation of the implantation parameters for further studies on DA, and possibly also other neural-, glial-, and stem cell-derived grafts.

Meningeal melanocytoma of the C8 nerve root: case report.

A case of a meningeal melanocytoma involving the C8 nerve root is presented. The clinical symptoms and the radiological investigations resembled a neurinoma of the spinal nerve root. Intraoperatively the tumor was seen to be firmly attached to the dural covering of the dorsal nerve root. By using microsurgical technique, complete removal of the tumor with preservation of the ventral nerve root was accomplished. Histological examination revealed a typical meningeal melanocytoma as described by Limas and Tio in 1972. Ten additional cases of previously reported spinal meningeal melanocytomas are reviewed. The importance of differentiating this benign lesion from meningeal malignant pigmented tumors is stressed.

Familial hypertrophic cardiomyopathy: Functional effects of myosin mutation R723G in cardiomyocytes

Familial Hypertrophic Cardiomyopathy (FHC) is frequently caused by mutations in the β-cardiac myosin heavy chain (β-MyHC). To identify changes in sarcomeric function triggered by such mutations, distinguishing mutation effects from other functional alterations of the myocardium is essential. We previously identified a direct effect of mutation R723G (MyHC723) on myosin function in slow Musculus soleus fibers. Here we investigate contractile features of left ventricular cardiomyocytes of FHC-patients with the same MyHC723-mutation and compare these to the soleus data. In mechanically isolated, triton-permeabilized MyHC723-cardiomyocytes, maximum force was significantly lower but calcium-sensitivity was unchanged compared to donor. Conversely, MyHC723-soleus fibers showed significantly higher maximum force and reduced calcium-sensitivity compared to controls. Protein phosphorylation, a potential myocardium specific modifying mechanism, might account for differences compared to soleus fibers. Analysis revealed reduced phosphorylation of troponin I and T, myosin-binding-protein C, and myosin-light-chain 2 in MyHC723-myocardium compared to donor. Saturation of protein-kinaseA phospho-sites led to comparable, i.e., reduced MyHC723-calcium-sensitivity in cardiomyocytes as in M. soleus fibers, while maximum force remained reduced. Myofibrillar disarray and lower density of myofibrils, however, largely account for reduced maximum force in MyHC723-cardiomyocytes. The changes seen when phosphorylation of sarcomeric proteins in myocardium of affected patients is matched to control tissue suggest that the R723G mutation causes reduced Ca(++)-sensitivity in both cardiomyocytes and M. soleus fibers. In MyHC723-myocardium, however, hypophosphorylation can compensate for the reduced calcium-sensitivity, while maximum force generation, lowered by myofibrillar deficiency and disarray, remains impaired, and may only be compensated by hypertrophy.

Ectopic Choroid Plexus within a Juvenile Arachnoid Cyst of the Cerebellopontine Angle: Cause of Cyst Formation or Reason of Cyst Growth

The unusual and rare case of a 6-year-old boy is reported who presented with an arachnoid cyst located in the cerebellopontine angle incorporating an ectopic piece of choroid plexus tissue. A microneurosurgical cyst wall resection was performed and the plexus tissue identified and removed. The rare occurrence of ectopic choroid plexus tissue within cysts of the CNS is discussed.

Meningeal Melanocytoma of the C8 Nerve Root

A case of a meningeal melanocytoma involving the C8 nerve root is presented. The clinical symptoms and the radiological investigations resembled a neurinoma of the spinal nerve root. Intraoperatively the tumor was seen to be firmly attached to the dural covering of the dorsal nerve root. By using microsurgical technique, complete removal of the tumor with preservation of the ventral nerve root was accomplished. Histological examination revealed a typical meningeal melanocytoma as described by Limas and Tio in 1972. Ten additional cases of previously reported spinal meningeal melanocytomas are reviewed. The importance of differentiating this benign lesion from meningeal malignant pigmented tumors is stressed.

Mitogen-Activated Protein Kinase-Activated Protein Kinases 2 and 3 Regulate SERCA2a Expression and Fiber Type Composition To Modulate Skeletal Muscle and Cardiomyocyte Function

ABSTRACT The mitogen-activated protein kinase (MAPK)-activated protein kinases 2 and 3 (MK2/3) represent protein kinases downstream of the p38 MAPK. Using MK2/3 double-knockout (MK2/3−/−) mice, we analyzed the role of MK2/3 in cross-striated muscle by transcriptome and proteome analyses and by histology. We demonstrated enhanced expression of the slow oxidative skeletal muscle myofiber gene program, including the peroxisome proliferator-activated receptor gamma (PPARγ) coactivator 1α (PGC-1α). Using reporter gene and electrophoretic gel mobility shift assays, we demonstrated that MK2 catalytic activity directly regulated the promoters of the fast fiber-specific myosin heavy-chain IId/x and the slow fiber-specific sarco/endoplasmic reticulum Ca2+-ATPase 2 (SERCA2) gene. Elevated SERCA2a gene expression caused by a decreased ratio of transcription factor Egr-1 to Sp1 was associated with accelerated relaxation and enhanced contractility in MK2/3−/− cardiomyocytes, concomitant with improved force parameters in MK2/3−/− soleus muscle. These results link MK2/3 to the regulation of calcium dynamics and identify enzymatic activity of MK2/3 as a critical factor for modulating cross-striated muscle function by generating a unique muscle phenotype exhibiting both reduced fatigability and enhanced force in MK2/3−/− mice. Hence, the p38-MK2/3 axis may represent a novel target for the design of therapeutic strategies for diseases related to fiber type changes or impaired SERCA2 function.