Expression of leucine-rich repeats and immunoglobulin-like domains (LRIG) proteins in human ependymoma relates to tumor location, WHO grade, and patient age.

Three human leucine-rich repeats and immunoglobulin-like domains (LRIG1-3) genes and proteins have recently been characterized. LRIG1 has been shown to be a suppressor of tumor growth by counteracting the signaling of epidermal growth factor receptor (EGFR) family members, including EGFR (ERBB1). Expression of LRIG proteins seems to be of importance in the pathogenesis of astrocytic tumors. In this study, the expression of LRIG1-3 was evaluated in 51 human ependymomas by immunohistochemistry. LRIG proteins were detected in all ependymomas analyzed, however, with a pronounced heterogeneity in expression and subcellular localization. Higher cytoplasmic immunoreactivity of LRIG1 correlated with older patient age and higher LRIG1 nuclear immunoreactivity with lower WHO Grade. LRIG1 displayed a stronger immunoreactivity in the cytoplasm and nuclei in spinal ependymomas than in the posterior fossa or supratentorial ependymomas, while perinuclear LRIG3 was more highly expressed in supratentorial than in infratentorial ependymomas. The indications that expression and subcellular localization of LRIG proteins could be pathogenetically associated with specific clinicopathological features of ependymoma tumors might be of importance in the carcinogeneses and tumor progression of human ependymomas.

CSF biomarkers in the evaluation of idiopathic normal pressure hydrocephalus.

BACKGROUND - To evaluate cerebrospinal fluid (CSF) markers for neuronal degeneration and demyelination in idiopathic normal pressure hydrocephalus (INPH), subcortical arteriosclerotic encephalopathy (SAE), and neurologically healthy subjects. METHODS - Lumbar CSF concentrations of sulfatide, neurofilament protein light (NFL), total-tau (T-tau), hyperphosphorylated tau (P-tau), and beta-amyloid(1-42) (Abeta42) were analyzed in 62 INPH patients, 26 SAE patients, and 23 neurologically healthy controls. In INPH patients, samples before and after shunt surgery were analysed. RESULTS - The CSF concentration of NFL was elevated in INPH and SAE compared with the controls, and levels of T-tau, P-tau, and Abeta42 were lower in INPH compared with SAE and controls. No difference was seen for sulfatide. All markers except Abeta42 were significantly elevated after shunt surgery. CONCLUSIONS - The most striking finding was the power of the combined pattern of NFL, P-tau, and Abeta42 in distinguishing between the clinical diagnoses of INPH, SAE, and neurologically healthy elderly.

CSF pressure assessed by lumbar puncture agrees with intracranial pressure.

The accuracy of estimating intracranial pressure in brain tissue (ICP(BT)) via lumbar space was investigated using preset pressure levels in the interval 0 to 600 mm H(2)O in patients with communicating hydrocephalus. Lumbar space ICP correlated excellently to ICP(BT), demonstrated by a measured mean difference of 10 mm H(2)O (0.75 mm Hg) and a regression coefficient of 0.98. The concurrence supports the lumbar puncture as an accurate technique to determine ICP in patients with communicating CSF systems.

Protein expression in experimental malignant glioma varies over time and is altered by radiotherapy treatment.

Radiotherapy is one of the mainstays of glioblastoma (GBM) treatment. This study aims to investigate and characterise differences in protein expression patterns in brain tumour tissue following radiotherapy, in order to gain a more detailed understanding of the biological effects. Rat BT4C glioma cells were implanted into the brain of two groups of 12 BDIX-rats. One group received radiotherapy (12 Gy single fraction). Protein expression in normal and tumour brain tissue, collected at four different time points after irradiation, were analysed using surface enhanced laser desorption/ionisation - time of flight - mass spectrometry (SELDI-TOF-MS). Mass spectrometric data were analysed by principal component analysis (PCA) and partial least squares (PLS). Using these multivariate projection methods we detected differences between tumours and normal tissue, radiation treatment-induced changes and temporal effects. 77 peaks whose intensity significantly changed after radiotherapy were discovered. The prompt changes in the protein expression following irradiation might help elucidate biological events induced by radiation. The combination of SELDI-TOF-MS with PCA and PLS seems to be well suited for studying these changes. In a further perspective these findings may prove to be useful in the development of new GBM treatment approaches.

The Swedish Malignant Middle cerebral artery Infarction Study: long-term results from a prospective study of hemicraniectomy combined with standardized neurointensive care.

OBJECTIVES: Hemicraniectomy in patients with malignant middle cerebral artery (mMCA) infarct may be life-saving. The long-term prognosis is unknown. METHODS: Patients with mMCA infarct treated with hemicraniectomy between 1998 and 2002 at three hospitals were included. The criterion for surgical intervention was if the patients deteriorated from awake to being responding to painful stimuli only. All patients were followed for at least 1 year. Outcome was defined as alive/dead, walkers/non-walkers or modified Rankin Scale (mRS) score

Brain energy metabolism and intracranial pressure in idiopathic adult hydrocephalus syndrome.

BACKGROUND: The symptoms in idiopathic adult hydrocephalus syndrome (IAHS) are consistent with pathology involving the periventricular white matter, presumably reflecting ischaemia and CSF hydrodynamic disturbance. OBJECTIVE: To investigate whether a change in intracranial pressure (ICP) can affect energy metabolism in deep white matter. METHODS: A microdialysis catheter, a brain tissue oxygen tension probe, and an ICP transducer were inserted into the periventricular white matter 0-7 mm from the right frontal horn in 10 patients with IAHS. ICP and intracerebral Ptio2 were recorded continuously during lumbar CSF constant pressure infusion test. ICP was raised to pressure levels of 35 and 45 mm Hg for 10 minutes each, after which CSF drainage was undertaken. Microdialysis samples were collected every three minutes and analysed for glucose, lactate, pyruvate, and glutamate. RESULTS: When raising the ICP, a reversible drop in the extracellular concentrations of glucose, lactate, and pyruvate was found. Comparing the values during baseline to values at the highest pressure level, the fall in glucose, lactate, and pyruvate was significant (p < 0.05, Wilcoxon sign rank). There was no change in glutamate or the lactate to pyruvate ratio during ICP elevation. Ptio2 did not decrease during ICP elevation, but was significantly increased following CSF drainage. CONCLUSIONS: Raising intracranial pressure induces an immediate and reversible change in energy metabolism in periventricular white matter, without any sign of ischaemia. Theoretically, frequent ICP peaks (B waves) over a long period could eventually cause persisting axonal disturbance and subsequently the symptoms noted in IAHS.

Combined effects of embolization and hypofractionated conformal stereotactic radiotherapy in arteriovenous malformations of the brain.

SUMMARY: There are three major treatment options for cerebral AVMs; surgery, embolization and radiosurgery. Embolization may be effective to reduce the size and density but completely obliterates AVMs only in a minority of cases. Radiosurgery may be an alternative to resection, especially in smaller AVMs. Large AVMs have been considered difficult to treat safely and effectively with single fraction radiosurgery. Hypofractionated conformal stereotactic radiotherapy (HCSRT) alone or in combination with embolization may be an alternative treatment. Embolization may reduce the volume and density of AVMs, followed by HCSRT, allowing a safe delivery of a higher total dose of radiation than possible with a single fraction. Sixteen patients with AVMs were treated with embolization and HCSRT. Embolization was performed in 1-6 (median 2) sessions. HCSRT was delivered in 5 fractions with 6-7 Gy each to the total dose of 30-35 Gy. Cerebral angiographies before and after embolization were digitally compared for calculation of volume reduction and luminescence as a measure of AVM density. The mean AVM volume in 15 patients was reduced from 11.9 +/- 2.1 (1-29, median 10.0) ml to 6.5 +/- 2.0 (0.5-28, median 3) ml by embolization. The luminescence for all AVMs was significantly higher after than before embolization, indicating that all AVMs were less dense after embolization. Thirteen out of 16 patients (13/16, 81%) treated with embolization and HCSRT have so far shown obliteration of their AVMs 2-9 (median 4) years after HCSRT. Three patients experienced neurological sequele after embolization, and three patients developed radionecrosis after HCSRT. Using a new method to compare cerebral angiographies in AVMs we report reduction in density and volume after embolization. The obliteration rate of a combined treatment with embolization and HCSRT seems comparable with single fraction radiosurgery although the AVMs in our series are larger than reported in most series treated with single fraction radiosurgery.

The tyrosine kinase inhibitor ZD6474 inhibits tumour growth in an intracerebral rat glioma model.

Malignant glioma is characterised by extensive neovascularisation, principally influenced by vascular endothelial growth factor (VEGF). ZD6474 is a potent inhibitor of VEGF-R2 tyrosine kinase activity, but with additional inhibitory effects on other growth factors. In this study, we have investigated the effects of ZD6474 with regard to tumour growth, neovascularisation, proliferation and apoptosis in the intracerebral rat glioma model, BT4C. ZD6474 (50 and 100 mg kg(-1)) was given as a daily oral gavage. Animals were killed on day 19 and tumour volume was measured. Sections were stained for factor VIII, Ki-67 and for apoptosis. The ability of ZD6474 to inhibit cell growth directly was examined in vitro, using the glioma cell line BT4C and the transformed rat brain endothelial cell line RBE4. Cell growth was analysed with fluorometric microculture cytotoxicity assay to quantify the cytotoxic effects. ZD6474 significantly decreased tumour volume compared to controls. Microvascular density increased after treatment with ZD6474, and tumour cell proliferation index was reduced. There was also an increase in tumour cell apoptosis. In vitro, the growth of both cell lines was significantly reduced. The results reported justify further experimental investigations concerning the effects of ZD6474 in malignant glioma alone or in combination with other modalities.

Heterogeneity in the expression of markers for drug resistance in brain tumors.

Brain tumors, in general, display a multidrug-resistant phenotype. This study evaluated the immunohistochemical expression and distribution of P-glycoprotein (Pgp), multidrug resistance protein (MRP1), lung resistance protein (LRP) and O6 methylguanine-DNA methyltransferase (MGMT) in low- and high-grade astrocytoma, oligodendroglioma and in different subgroups of meningioma. The results revealed a marked heterogeneity in the expression and distribution among the analyzed tumors. In astrocytoma and oligodendroglioma, Pgp and MRP1 were observed in the capillary endothelium and in scattered tumor cells, whereas LRP occurred only in tumor cells. A pronounced expression of MGMT was found independent of the histopathological grade. An enhanced expression of MRP1 and LRP in astrocytoma and oligodendroglioma were more often evident in older patients (> 50 years). Survival analysis suggested a markedly decreased overall survival for patients suffering from low-grade glioma overexpressing Pgp. In meningioma, a heterogeneous expression of Pgp, MRP1, LRP and MGMT was seen with the most prominent staining localized to the capillary endothelium. Pgp was significantly more often overexpressed (p < 0.05) in transitional compared to meningothelial meningioma. The marked heterogeneity in the expression suggests that analysis of these factors can be of importance in the selection of individualized chemotherapy, regardless of tumor type.

Intracerebral microdialysis and CSF hydrodynamics in idiopathic adult hydrocephalus syndrome.

BACKGROUND: In idiopathic adult hydrocephalus syndrome (IAHS), a pathophysiological model of "chronic ischaemia" caused by an arteriosclerotic process in association with a CSF hydrodynamic disturbance has been proposed. OBJECTIVE: To investigate whether CSF hydrodynamic manipulation has an impact on biochemical markers related to ischaemia, brain tissue oxygen tension (PtiO(2)), and intracranial pressure. METHODS: A microdialysis catheter, a PtiO(2) probe, and an intracerebral pressure catheter were inserted into the periventricular white matter 0-7 mm from the right frontal horn in 10 patients with IAHS. A subcutaneous microdialysis probe was used as reference. Intracranial pressure and intracerebral PtiO(2) were recorded continuously. Samples were collected for analysis between 2 and 4 pm on day 1 (baseline) and at the same time on day 2, two to four hours after a lumbar CSF hydrodynamic manipulation. The concentrations of glucose, lactate, pyruvate, and glutamate on day 1 and 2 were compared. RESULTS: After CSF drainage, there was a significant rise in the intracerebral concentration of lactate and pyruvate. The lactate to pyruvate ratio was increased and remained unchanged after drainage. There was a trend towards a lowering of glucose and glutamate. Mean intracerebral PtiO(2) was higher on day 2 than on day 1 in six of eight patients. CONCLUSIONS: There is increased glucose metabolism after CSF drainage, as expected in a situation of postischaemic recovery. These new invasive techniques are promising tools in the future study of the pathophysiological processes in IAHS.

Rapid induction of long-lasting drug efflux activity in brain vascular endothelial cells but not malignant glioma following irradiation.

The influence of radiotherapy on malignant glioma multidrug resistance to chemotherapy was evaluated because patients with glioma often are treated with a combination of radiotherapy and chemotherapy. Multidrug resistance gene (MDR1, mdr1a, and mdr1b) transcripts were found in human and rat glioma cell lines. P-Glycoprotein (Pgp) was immunohistochemically detected in glioma cell lines and in the rat brain vascular endothelial cell line (RBE4). A multidrug resistance pump efflux activity assay demonstrated increased calcein efflux of RBE4 endothelial cells, but not glioma cells, 2 h after irradiation and still increased 14 d after irradiation. The increased efflux was equally inhibited by verapamil with or without irradiation. In the rat intracranial glioma model (BT4C), Pgp was demonstrated in capillary endothelial cells of the tumor tissue and surrounding normal brain, but not in tumor cells. The expression of gene transcripts or Pgp was not affected by irradiation. The results indicate that long-lasting verapamil-resistant drug efflux mechanisms are activated in brain endothelial cells after irradiation. The results might explain the poor efficacy of chemotherapy following radiotherapy and contribute to consideration of new treatment strategies in the management of malignant glioma.

Impact of thalamic deep brain stimulation on disability and health-related quality of life in patients with essential tremor.

OBJECTIVES: To evaluate the impact of thalamic deep brain stimulation (DBS) on disability and health-related quality of life in patients with essential tremor. METHODS: Twenty seven consecutive patients were evaluated prospectively, before surgery and at a mean of 12 months (range 6-26) after thalamic DBS. Assessment tools included the Fahn-Tolosa-Marìn tremor rating scale (TRS), activities of daily living (ADL) taxonomy, Nottingham health profile (NHP) and the visual analogue scale (VAS) for measuring impact of disease on life. Additional information on the side effects of, and expectations from surgery was obtained by interview. RESULTS: Thalamic DBS improved the ability of the patients in eating, drinking, writing, home maintenance, hobbies, and participation in society. Activities of daily life requiring bimanual skills were less improved. The emotional condition of the patients was positively affected and the negative impact of the disease on life as a whole, and on social life was decreased. Seventy per cent of the patients considered that the surgical treatment met their expectations. CONCLUSIONS: After thalamic DBS, health-related quality of life including disability in ADL and social life were improved in patients with essential tremor.

Distribution of estramustine-binding protein during postnatal development of rat brain.

Estramustine-binding protein (EMBP) is expressed in several types of brain tumors, such as astrocytoma, ependymoma, and meningioma. It binds the cytotoxic drug estramustine with high affinity and is suggested to cause accumulation of the drug in EMBP-expressing tumor cells. In this study, the spatial distribution of EMBP in normal rat brain was studied with immunohistochemistry. Brains from male and female rats of different ages were used. EMBP was found in the cytoplasm of ependymal cells, in the leptomeninges, mainly the arachnoid, and in scattered neurons. Moreover, staining was seen in nuclei of choroid plexus cells, in the granular cell layer in the cerebellum, and in a few scattered endothelial cells. The nuclear staining was more frequent in younger animals. No obvious difference in EMBP expression between male and female rats was observed. The expression of EMBP in rat brain was confirmed with nested RT-PCR. Future studies are justified to elucidate the role of EMBP-like proteins in CNS and in brain tumors.

A 10-year follow-up review of patients who underwent Leksell's posteroventral pallidotomy for Parkinson disease.

OBJECT: The clinical condition of patients with Parkinson disease (PD) who had undergone posteroventral pallidotomy (PVP) between 1985 and 1990 was evaluated at a mean of 10 years postsurgery. These patients were part of a larger series described in the first paper on Leksell's PVP that was published in 1992. METHODS: Thirteen consecutive patients who had undergone pallidotomy at the University Hospital of Northern Sweden were tracked. Hospital and clinic records that had been updated regularly by the patients' various neurologists, geriatricians, and other clinicians were reviewed. Emphasis was placed on assessing the evolution of PD symptoms after surgery, and changes in the general health and social condition of the patients. The mean follow-up duration was 10.5 years (range 3-13.5 years). Five patients underwent a total of seven subsequent surgeries for their PD, 4 months to 11 years after the initial pallidotomy. The mean Hoehn and Yahr stage was 3 at the first surgery and 3.7 at the last follow-up review (p < 0.005). Dosages of levodopa and dopamine agonists were increased in all patients, without recurrence or induction of dyskinesias contralateral to the pallidotomy. Contralateral tremor, if it was initially controlled by surgery, remained improved. However, most patients exhibited a gradual recurrence of akinesia and an increase in gait freezing. Cognitive decline and presentation with diseases unrelated to PD were not uncommon. CONCLUSIONS: The long-term effect of PVP on dyskinesias was not only curative but also appeared to be prophylactic. Contralateral tremor was improved in the majority of patients, although additional surgeries for PD were needed in some patients. Further progression of axial and akinetic symptoms, and an eventual decline in cognition together with other concomitant illnesses, contributed to increased disability in several patients.

Two computerized methods used to analyze intracranial pressure B waves: comparison with traditional visual interpretation.

OBJECT: Slow and rhythmic oscillations in intracranial pressure (ICP), also known as B waves, have been claimed to be one of the best preoperative predictive factors in idiopathic adult hydrocephalus syndrome (IAHS). Definitions of B waves vary widely, and previously reported results must be treated with caution. The aims of the present study were to develop a definition of B waves, to develop a method to estimate the B-wave content in an ICP recording by using computer algorithms, and to validate these procedures by comparison with the traditional visual interpretation. METHODS: In eight patients with IAHS, ICP was continuously monitored for approximately 20 hours. The ICP B-wave activity as a percentage of total monitoring time (B%) was estimated by using visual estimation according to the definition given by Lundberg, and also by using two computer algorithms (Methods I and II). In Method I each individual wave was classified as a B wave or not, whereas Method II was used to estimate the B-wave content by evaluating the B-wave power in 10-minute blocks of ICP recordings. CONCLUSIONS: The two computerized algorithms produced similar results. However, with the amplitude set to 1 mm Hg, Method I yielded the highest correlation with the visual analysis (r = 0.74). At least 5 hours of monitoring time was needed for an acceptable approximation of the B% in an overnight ICP recording. The advantages of using modern technology in the analysis of B-wave content of ICP are obvious and these methods should be used in future studies.

Dilated perivascular spaces in the putamen and pallidum in patients with Parkinson's disease scheduled for pallidotomy: a comparison between MRI findings and clinical symptoms and signs.

Forty patients with Parkinson's disease without mental deterioration who were scheduled for ventroposterolateral (VPL) pallidotomy were randomly selected for retrospective stereotactic magnetic resonance image (MRI) analysis. The preoperative MRI study was performed on a 1.0-T MRI machine with a three-dimensional gradient-echo sequence. The MRI analysis was focused on five consecutive 2 mm thick axial slices without gap and parallel to the intercommissural line, starting from the level of the foramen of Monro and continuing in a ventral direction. Lacunar cysts of varying sizes (4-424 mm3) were seen at least in one hemisphere of all patients. The cysts had a clear dominance in posteroventral regions of the lateral-most pallidal regions (GP) and posteroventral regions of the putamen (PUT). No statistical correlation was found between the number or volume of the cysts and the sex, age, or duration of illness of the patients. Patients with predominantly left-sided clinical symptoms had a concentration of the cysts in the left GP, whereas those with predominantly right-sided symptoms had cysts significantly larger and more frequent in the right than the left GP. The cysts did not seem to affect the clinical outcome of pallidotomy. The authors think striatopallidal cysts develop from dilated perivascular spaces of the lenticulostriate vessels in the posteroventral regions of the GP and PUT. They are not pathognomonic for PD, but they may play some role in lateralization of the clinical symptoms in this classically asymmetric condition.

Estramustine-binding protein in malignant glioma in rat.

Estramustine is a chemotherapeutic drug, used in the treatment of prostatic carcinoma. In the prostate, it binds specifically to a 46 kDa glycoprotein called estramustine-binding protein (EMBP), which consists of three polypeptide components; C1, C2, and C3, each coded for by a specific gene. Expression of EMBP and binding of estramustine has also been detected in malignant glioma in both rats and humans. Elevated levels of this protein in astrocytoma have proved to correlate with poor prognosis. In the present work, expression of all three polypeptide components of EMBP was confirmed in an orthotopic rat glioma model with nested reverse transcriptase PCR and Western blot (molecular weights of 8, 10, and 12 kDa). Specific binding of estramustine with a Kd of 40 for male and 50 for female rats, and a total number of binding sites of 0.7 and 0.4 pmol/mg proteins for male and female rats respectively, was demonstrated with Scatchard plot analysis. These binding characteristics are similar to those of prostatic EMBP. Further studies to elucidate how EMBP expression affects the effect of estramustine treatment, and its putative prognostic value is of special clinical interest. The confirmation of BMBP expression in BT4C rat glioma demonstrates its suitability as a model system for such studies.

Interleukin-2 and histamine in combination inhibit tumour growth and angiogenesis in malignant glioma.

Biotherapy including interleukin-2 (IL-2) treatment seems to be more effective outside the central nervous system when compared to the effects obtained when the same tumour is located intracerebrally. Recently published studies suggest that reduced activity of NK cells in tumour tissue can be increased by histamine. The present study was designed to determine whether IL-2 and histamine, alone or in combination, can induce anti-tumour effects in an orthotopic rat glioma model. One group of rats was treated with histamine alone (4 mg kg(-1)s.c. as daily injections from day 6 after intracranial tumour implantation), another group with IL-2 alone as a continuous subcutaneous infusion and a third group with both histamine and IL-2. The animals were sacrificed at day 24 after tumour implantation. IL-2 and histamine in combination significantly reduced tumour growth. The microvessel density was significantly reduced, an effect mainly affecting the small vessels. No obvious alteration in the pattern of VEGF mRNA expression was evident and no significant changes in apoptosis were observed. Neither IL-2 nor histamine alone caused any detectable effects on tumour growth. Histamine caused an early and pronounced decline in tumour blood flow compared to normal brain. The results indicate that the novel combination of IL-2 and histamine can be of value in reducing intracerebral tumour growth and, thus, it might be of interest to re-evaluate the therapeutic potential of biotherapy in malignant glioma.

How was life after treatment of a malignant brain tumour?

The malignant glioma is a severe disease with an unfavourable prognosis. Aside from a few case studies, the knowledge of the victimised patients' lives from diagnosis to death is mainly restricted to studies assessing functional status and rating quality of life by means of questionnaires. From a clinician's perspective this knowledge is not sufficient. By introducing the concepts 'time of everyday life' and 'time of disease', the purpose of this paper is to supplement with descriptive knowledge of clinical value. Twenty-eight patients with malignant gliomas and their spouses were followed during the course of the disease by repeated interviews. The time after treatment was then judged as representing, 'time of everyday life' or 'time of disease'. Life after treatment turned out to be quite varied. To slightly more than a third of the patients', life-continuity was lost, experiencing only 'time of disease'. Among the others who were judged to experience 'time of everyday life' and who were of working age, nearly two-thirds were able to resume work or studies on a part-time basis. In the total sample, the mean 'time of everyday life' turned out to be nearly equal to 'time of disease', 6.1 and 5.4 months, respectively. The findings are illustrated by case descriptions and the conceptualisation of time into 'everyday life' and 'disease' is proposed as meriting further study.

Expression of the proteolytic factors, tPA and uPA, PAI-1 and VEGF during malignant glioma progression.

Various proteases and their inhibitors have been shown to be important in tumor invasion. Angiogenesis is further a prerequisite for the growth and progression of solid tumors. Since these systems are functionally linked, in situ hybridization and in situ zymography were used to investigate the spatial and temporal expression of factors representative of the plasmin/plasminogen system and of an angiogenic factor in the BT4C glioma model. This tumor is invasive with a high grade of neovascularization. Tissue-type plasminogen activator urokinase-type plasminogen activator and plasminogen activator inhibitor-1 mRNA were expressed in glioma cells during the entire tumor growth. Early in the tumor development the expression was found throughout the small tumor (approximately 10 mm3) while later in the time course the expression was found predominantly in the invasive tumor border of the tumor. The in situ zymography demonstrated that the plasminogen activators were translated into functional proteins. Vascular endothelial growth factor mRNA was expressed following a similar spatial and temporal pattern with an early expression in the entire small tumor while later, in larger tumors, it was exclusively expressed in the invasive tumor edge. In normal brain, the ventricular ependyma, meninges, as well as scattered neurons expressed tissue-type plasminogen activator mRNA. Vascular endothelial growth factor mRNA was observed in the choroid plexus, and in scattered cells in normal brain tissue. Our finding may suggest a functional co-operation of tissue-type plasminogen activator, urokinase-type plasminogen activator, plasminogen activator inhibitor-1 and vascular endothelial growth factor during glioma progression. This model could be of value when evaluating different treatment modalities aimed at blocking the migrating capacity and growth of glial tumors.