Comparing febrile children presenting on and off antibiotics to the emergency department: a retrospective cohort study.

BACKGROUND: It is not yet known how antibiotics may affect Serious Bacterial Infections (SBI). Our aim is to describe the presentation, management, and serious bacterial infections (SBI) of febrile children on or off antibiotics. METHODS: Retrospective, cohort study of febrile Emergency Department patients, 0-36 months of age, at a single institution, between 2009and 2012. RESULTS: Seven hundred fifty-three patients were included: 584 in the No-Antibiotics group and 169 (22%) in the Antibiotics group. Age and abnormal lung sounds were predictors for being on antibiotics (OR 2.00 [95% CI 1.23-3.25] and OR 1.04 [95% CI 1.02-1.06] respectively) while female gender, and lower temperatures were negative predictors (OR 0.68 [95%0.47-0.98] and OR 0.47 [95% CI 0.32-0.67] respectively). Antibiotics were prescribed by a physician 89% of the time; the most common one being Amoxicillin/Clavulanic Acid (39%). The antibiotic group got more blood tests (57% vs 45%) and Chest X-Rays (37% vs 25%). Overall, the percent of SBIs (and pneumonias) was statistically the same in both groups (6.5% in the No-antibiotic group VS 3.6%). CONCLUSIONS: Children presenting on antibiotics and off antibiotics were significantly different in their presentation and management, although the overall percentages of SBI were similar in each group. Further investigations into this subgroup of febrile children are needed.

Acute neurological visual loss in young adults: causes, diagnosis and management.

Visual loss in the young adult can be caused by demyelinating diseases, inflammatory and autoimmune processes, infections, ischaemic events, and compressive lesions of the optic nerve. Diagnosis of the aetiologies of visual loss is reached by combining data from radiological studies, electrophysiological tests, and blood and cerebrospinal fluid analysis. Treatment is primarily aimed at decreasing the insult on the optic nerve and eventually controlling the primary disorder. The literature discusses separately the different aetiologies of visual loss. We present a review of the clinical characteristics of visual loss in the young adult, the different diagnostic measures, and the latest therapeutic strategies. The aim of this work is to summarise this entity in a practical way to guide clinicians in the diagnosis and management of this disorder.

Combined activation of Ras and Akt in neural progenitors induces glioblastoma formation in mice.

Gliomas are the most common primary malignant brain tumours and are classified into four clinical grades, with the most aggressive tumours being grade 4 astrocytomas (also known as glioblastoma multiforme; GBM). Frequent genetic alterations in GBMs (refs 2-5) result in stimulation of common signal transduction pathways involving Ras, Akt and other proteins. It is not known which of these pathways, if any, are sufficient to induce GBM formation. Here we transfer, in a tissue-specific manner, genes encoding activated forms of Ras and Akt to astrocytes and neural progenitors in mice. We found that although neither activated Ras nor Akt alone is sufficient to induce GBM formation, the combination of activated Ras and Akt induces high-grade gliomas with the histological features of human GBMs. These tumours appear to arise after gene transfer to neural progenitors, but not after transfer to differentiated astrocytes. Increased activity of RAS is found in many human GBMs (ref. 11), and we show here that Akt activity is increased in most of these tumours, implying that combined activation of these two pathways accurately models the biology of this disease.

Use of the Montreal global definition as an assessment of quality of life in reflux disease.

According to the Montreal Consensus Group's classification, gastroesophageal reflux disease develops when the reflux of stomach contents causes troublesome symptoms and/or complications such as esophagitis. The characteristic gastroesophageal reflux disease symptoms included in this statement are retrosternal burning and regurgitation. Troublesome is meant to imply that these symptoms impact on the well-being of affected individuals; in essence, quality of life (QOL). Whether heartburn and regurgitation symptoms would be characterized as more troublesome in those with confirmed pathologic acid reflux was determined. A second purpose was to assess how well troublesome scores correlated with the results of a validated, disease-specific QOL instrument. Subjects who underwent esophagogastroduodenoscopy (EGD) with 48-hour wireless esophageal pH testing off proton pump inhibitor therapy were interviewed. Esophagitis on EGD or pH < 4.0 for ≥4.5% of time over the 2-day period was considered positive for acid reflux. Assessment of how troublesome their symptoms of heartburn and regurgitation were made using separate 0-100 visual analog scales (VAS). Subjects were then asked to complete the Quality of Life in Reflux and Dyspepsia (QOLRAD) 25-item questionnaire. Sixty-seven patients (21 males, 46 females) with mean age 47.8 ± 15.6 years were identified. Forty (59.7%) had an EGD or pH study positive for acid reflux. Overall 35/40 (87.5%) complained of either heartburn or regurgitation. There was no difference (P= 0.80) in heartburn VAS troublesome ratings for those with (54.0 ± 43.9) and without (56.7 ± 37.6) confirmed acid reflux. The same was true for regurgitation VAS troublesome ratings (P= 0.62). Likewise, mean QOLRAD scores did not differ between those with and without confirmed acid reflux by pH or EGD (4.5 ± 1.7 vs. 4.3 ± 1.7; P= 0.61). There was a moderately strong inverse correlation between patient self-rated VAS troublesome scores for both heartburn and regurgitation with each dimension (emotional distress, sleep disturbance, eating problems, physical/social functioning, and vitality) of the QOLRAD (P < 0.05 for all comparisons). In regression analysis, both heartburn and regurgitation troublesome ratings were associated with the overall QOLRAD score independent of pH data, frequency of reflux episodes, age, and gender. Use of the term troublesome in the Montreal Consensus Group classification is supported by our findings. It correlates well with the results of a validated disease-specific QOL instrument. Use of heartburn and regurgitation VAS may serve as accurate measures of the burden of reflux disease on patients. It is likely that these scales will not have sufficient discriminate value to identify individuals with pathologic acid reflux from those with negative studies.

Cellular Density in Adult Glioma, Estimated with MR Imaging Data and a Machine Learning Algorithm, Has Prognostic Power Approaching World Health Organization Histologic Grading in a Cohort of 1181 Patients.

BACKGROUND AND PURPOSE: Recent advances in machine learning have enabled image-based prediction of local tissue pathology in gliomas, but the clinical usefulness of these predictions is unknown. We aimed to evaluate the prognostic ability of imaging-based estimates of cellular density for patients with gliomas, with comparison to the gold standard reference of World Health Organization grading. MATERIALS AND METHODS: Data from 1181 (207 grade II, 246 grade III, 728 grade IV) previously untreated patients with gliomas from a single institution were analyzed. A pretrained random forest model estimated voxelwise tumor cellularity using MR imaging data. Maximum cellular density was correlated with the World Health Organization grade and actual survival, correcting for covariates of age and performance status. RESULTS: A maximum estimated cellular density of >7681 nuclei/mm2 was associated with a worse prognosis and a univariate hazard ratio of 4.21 (P < .001); the multivariate hazard ratio after adjusting for covariates of age and performance status was 2.91 (P < .001). The concordance index between maximum cellular density (adjusted for covariates) and survival was 0.734. The hazard ratio for a high World Health Organization grade (IV) was 7.57 univariate (P < .001) and 5.25 multivariate (P < .001). The concordance index for World Health Organization grading (adjusted for covariates) was 0.761. The maximum cellular density was an independent predictor of overall survival, and a Cox model using World Health Organization grade, maximum cellular density, age, and Karnofsky performance status had a higher concordance (C = 0.764; range 0.748-0.781) than the component predictors. CONCLUSIONS: Image-based estimation of glioma cellularity is a promising biomarker for predicting survival, approaching the prognostic power of World Health Organization grading, with added values of early availability, low risk, and low cost.

Acute quadriplegia in a young man secondary to prothrombin G20210A mutation.

STUDY DESIGN: We present the case of an 18-year-old man, previously healthy, who presented with acute quadriplegia and respiratory failure. Physical examination was compatible with a high cervical anterior spinal cord lesion. OBJECTIVE: We plan to evaluate the cause of such a neurological presentation in a healthy young man. SETTING: American University Medical Center, Beirut, Lebanon. METHODS: The patient underwent routine blood hematological and chemistry work-up, hypercoagulable profile studies, genetic profile for thrombophelias, radiographic studies of the brain and cervical cord, cerebrospinal analysis and extensive electrophyisological studies. RESULTS: Magnetic resonance imaging and magnetic resonance angiogram of the brain, carotid and intracranial vessels were normal. Cerebral angiography was normal. Magnetic resonance imaging of the cervical cord revealed lesion of the anterior segment of the cervical cord between C2 and C5 levels. Hypercoagulable profile studies were normal. Electrophysiological studies confirmed an isolated lesion of the descending cortico-spinal tracts. DNA analysis revealed the presence of a G20210A mutation-causing hyperprothrombinemia. CONCLUSION: We conclude that a G20210A mutation causing-hyperprothrombinemia can cause anterior spinal artery thrombosis and anterior spinal cord infarction with the resultant neurological deficits in otherwise healthy patients.

Aberrant FoxM1B expression increases matrix metalloproteinase-2 transcription and enhances the invasion of glioma cells.

We recently showed that FoxM1 is overexpressed in human glioblastomas and that forced FoxM1B expression in anaplastic astrocytoma cells leads to the formation of highly invasive glioblastoma multiforme (GBM) in nude mice. However, the molecular mechanisms by which FoxM1 enhances glioma invasion are unknown. In this study, we found that FoxM1 overexpression increased matrix metalloproteinase (MMP)-2 expression in glioma cells, whereas blockade of FoxM1 expression suppressed MMP-2 expression. Transfection of FoxM1 into glioma cells directly activated the MMP-2 promoter, whereas inhibition of FoxM1 expression by FoxM1-siRNA suppressed its activation. We identified a FoxM1-binding site in the MMP-2 promoter and demonstrated that FoxM1 protein bound directly to it. Mutation of this FoxM1-binding site significantly attenuated MMP-2 promoter activity. Furthermore, FoxM1 overexpression increased the invasiveness of glioma cells, whereas inhibition of FoxM1 expression suppressed the invasiveness of GBM cells. Inhibition of MMP-2 by a specific MMP-2 inhibitor reversed the invasive phenotype of glioma cells overexpressing FoxM1. Finally, immunohistochemical analysis of 45 human GBM specimens showed a significant correlation between FoxM1 overexpression and elevated MMP-2 expression. Collectively, these findings provide evidence that FoxM1 contributes to glioma progression by enhancing MMP-2 gene transcription and thus tumor-cell invasion.

A novel inhibitor of the STAT3 pathway induces apoptosis in malignant glioma cells both in vitro and in vivo.

Signal transducer and activator of transcription-3 (STAT3) is constitutively activated in a variety of cancer types, including malignant gliomas. STAT3 is activated by phosphorylation of a tyrosine residue, after which it dimerizes and translocates into the nucleus. There it regulates the expression of several genes responsible for proliferation and survival at the transcriptional level. A selective inhibitor of STAT3 phosphorylation, AG490, has been shown to inhibit growth and induce apoptosis in some cancer cell types. However, although AG490 routinely shows in vitro anticancer activity, it has not consistently demonstrated an in vivo anticancer effect in animal models. Here, we have tested WP1066, a novel inhibitor structurally related to AG490 but significantly more potent and active, against human malignant glioma U87-MG and U373-MG cells in vitro and in vivo. IC(50) values for WP1066 were 5.6 muM in U87-MG cells and 3.7 muM in U373-MG cells, which represents 18-fold and eightfold increases in potency, respectively, over that of AG490. WP1066 activated Bax, suppressed the expression of c-myc, Bcl-X(L) and Mcl-1, and induced apoptosis. Systemic intraperitoneal administration of WP1066 in mice significantly (P<0.001) inhibited the growth of subcutaneous malignant glioma xenografts during the 30-day follow-up period. Immunohistochemical analysis of the excised tumors revealed that phosphorylated STAT3 levels in the WP1066 treatment group remained inhibited at 3 weeks after the final WP1066 injection, whereas tumors from the control group expressed high levels of phosphorylated STAT3. We conclude that WP1066 holds promise as a therapeutic agent against malignant gliomas.

Autophagy-inducing agents augment the antitumor effect of telerase-selve oncolytic adenovirus OBP-405 on glioblastoma cells.

Oncolytic adenoviruses are a promising tool in cancer therapy. In this study, we characterized the role of autophagy in oncolytic adenovirus-induced therapeutic effects. OBP-405, an oncolytic adenovirus regulated by the human telomerase reverse transcriptase promoter (hTERT-Ad, OBP-301) with a tropism modification (RGD) exhibited a strong antitumor effect on glioblastoma cells. When autophagy was inhibited pharmacologically, the cytotoxicity of OBP-405 was attenuated. In addition, autophagy-deficient Atg5(-/-) mouse embryonic fibroblasts (MEFs) were less sensitive than wild-type MEFs to OBP-405. These findings indicate that OBP-405-induced autophagy is a cell killing effect. Moreover, autophagy-inducing therapies (temozolomide and rapamycin) synergistically sensitized tumor cells to OBP-405 by stimulating the autophagic pathway without altering OBP-405 replication. Mice harboring intracranial tumors treated with OBP-405 and temozolomide survived significantly longer than those treated with temozolomide alone, and mice treated with OBP-405 and the rapamycin analog RAD001 survived significantly longer than those treated with RAD001 alone. The observation that autophagy inducers increase OBP-405 antitumor activity suggests a novel strategy for treating patients with glioblastoma.

Early neurologic complications following coronary bypass surgery.

BACKGROUND: Coronary artery bypass surgery is associated with central and peripheral nervous system complications in the period following surgery. Recognising these complications may help in their prevention or early treatment. METHODS: We reviewed medical records of all the patients who underwent coronary artery bypass surgery at our institution over a period of two years. We studied their risk factors, reasons for surgery, operative variables, and post operative neurologic complications. RESULTS: Of the 587 coronary artery bypass surgeries performed at our centre over a two year period. We found that 2.04% of these patients developed neurologic complication in the two weeks following the surgery. Fifty percent of these patients suffered from cerebrovascular insults and 50% suffered from cognitive decline. No patients in this group developed seizures or peripheral nerve lesions. Patients with renal failure, carotid stenosis, history of cerebral strokes, and redo coronary bypass surgery were more predisposed to develop neurologic complications after bypass surgery. Furthermore, a longer stay in the coronary care unit and the development of arrhythmias predisposed patients to neurologic complications. Mortality for patients who developed neurologic complications post bypass surgery ranged between 16.7% and 33.4%. CONCLUSIONS: Around 2% of patients who undergo coronary artery bypass surgery develop neurologic complications in the period directly after the surgery. Patients with previous history of cerebral, coronary, or carotid disease are more predisposed for such complications, as well as patients who spend more time in the intensive units after the surgery.

Ionizing radiation induces apoptosis and inhibits neuronal differentiation in rat neural stem cells via the c-Jun NH2-terminal kinase (JNK) pathway.

A substantial number of neural stem cells (NSCs) continue to proliferate and generate neurons in the central nervous system throughout life. Ionizing radiation, an important adjuvant therapy for glioma patients, may damage NSCs and cause neuronal deficits, such as cognitive dysfunction and memory impairment. However, the precise mechanism of radiation effects on death and differentiation of NSCs remains largely unknown. Here, we found that radiation induced apoptosis in NSCs via the mitochondrial pathway, upregulating the ratio of Bax to Bcl-2 and releasing cytochrome c into the cytoplasm. Radiation also inhibited neuronal differentiation of NSCs by 50%. Of the three stress-associated mitogen-activated protein kinases (MAPKs), only c-Jun NH(2)-terminal kinase (JNK) was activated in NSCs after radiation. Interestingly, JNK inhibition by the specific inhibitor SP600125 rescued NSCs from apoptosis and improved neuronal differentiation. Furthermore, we examined whether radiation directly inhibits neuronal differentiation or not. Radiation did not affect the promoter activity of NeuroD, a basic helix-loop-helix transcription factor that regulates the expression of neuronal differentiation markers. Radiation induced more apoptosis in NeuroD-positive cells than NeuroD-negative cells. We concluded that radiation activates JNK and induces apoptosis, especially in neural progenitor cells, resulting in the inhibition of neurogenesis. Our findings raise the possibility that JNK inhibition has therapeutic potential in protecting NSCs from the adverse effects of radiation.

Hypercalcemia in glioblastoma multiforme.

Hypercalcemia is commonly associated with cancer, occurring in around 10-20% of cancer patients. Hypercalcemia is usually related to solid and non-solid malignancies specifically breast cancer, lung cancer and multiple myeloma. Hypercalcemia has been reported to occur in association with astrocytomas, and uncommonly in gliomas. We report a case of a previously healthy man presenting with glioblastoma multiforme . He was found to have persistently elevated serum calcium and calcitriol with normal parathyroid function. This is the first reported case of hypercalcemia associated with glioblastoma multiforme.

Elevated levels of M(r) 92,000 type IV collagenase in human brain tumors.

Local invasive growth is one of the key features of primary malignant brain tumors accompanied by remodeling of the vasculature and destruction of normal brain tissue. Tissue invasiveness is an essential biological function used by a tumor to overcome the various barriers to its progression. The expression of metalloproteases has been shown to play a critical role in the invasive process in a number of tumors; however, their expression in human brain tumors has not been previously reported. In this study we showed metalloprotease activities at M(r) 240,000, 123,000, 92,000, 72,000, and 67,000 in brain tumor extracts. These enzyme activities were inhibited by EDTA, an inhibitor of metalloproteases. Significant increases in levels of protease bands at M(r) 92,000, 123,000, and 240,000 were observed in glioblastoma and metastatic lung tumors. Enzymatic inhibition and Western blotting with M(r) 92,000 type IV collagenase antibody confirmed the presence of M(r) 92,000 type IV collagenase in all samples. Quantitative analysis by densitometry showed 8-10-fold and 6-8-fold increases in M(r) 92,000 type IV collagenase activity in glioblastoma and metastatic lung carcinoma samples, respectively, when compared with normal brain, meningioma, astrocytoma, metastatic colon, and breast carcinoma samples. These findings provide evidence for elevated levels of metalloproteases in glioblastomas and suggest a therapeutic target for minimizing the invasive propensity of gliomas using protease inhibitors.

Modulation of in vitro invasion of human glioblastoma cells by urokinase-type plasminogen activator receptor antibody.

Four human glioblastoma cell lines (U251, UWR1, UWR2, and UWR3) were tested for the expression of the cell surface receptor for urokinase-type plasminogen activator (uPA). To our knowledge there have been no previous reports about the uPA receptors (uPARs) in glioblastoma cell lines. All four glioblastoma cell lines we tested were found to bind recombinant Pro-uPA saturably and reversibly. Scatchard analysis of radioligand binding with acid-pretreated cells showed the presence of a single population of high-affinity uPARs on glioblastoma cells. Northern blot analysis confirmed that glioblastoma cells like other human cell lines express a 1.4-kilobase uPAR mRNA and 2.4-kilobase uPA mRNA. The significance of the uPAR in the invasive potential of the cells was examined by incubating uPAR antibody in an in vitro invasion assay. The anti-uPAR monoclonal antibody blocked the invasion effectively in a Matrigel assay, in which inhibition of invasion ranged between 20 and 57% for the cells studied. These data suggest that the uPARs contribute significantly to the invasive capacity of the cells, possibly by facilitating uPA activity.

Differential expression of membrane-type matrix metalloproteinase and its correlation with gelatinase A activation in human malignant brain tumors in vivo and in vitro.

In this study, we investigated the expression of activated gelatinase A and membrane-type metalloproteinase (MT-MMP) induced by concanavalin A (ConA) in four highly invasive glioma cell lines (UWR2, UWR3, U251MG, and SNB-19). We also examined gelatinase A and MT-MMP expression in human brain tumor tissues in vivo. Gelatin zymography showed that all four cell lines expressed latent progelatinase A (M(r) 66,000). Activated gelatinase A (M(r) 62,000) was induced by ConA in only UWR2 or UWR3 cells. MT-MMP mRNA was present in all four cell lines prior to ConA treatment, and the relative hybridization signals were 1, 0.80, 0.25, and 0.15 in UWR2, UWR3, U251MG, and SNB-19 cells, respectively. These mRNA signals were dramatically increased (2,8-, 5.4-, and 2.2-fold in UWR2, UWR3, and U251MG cells, respectively) following ConA treatment; however, MT-MMP mRNA expression was unchanged in SNB-19 cells. MT-MMP protein was detected in various amounts in the four cell lines, but only after ConA pretreatment. The amount of MT-MMP mRNA was unchanged in SNB-19 after ConA treatment, and the MT-MMP mRNA level in ConA-treated U251MG was lower than in UWR2 and UWR3 without ConA treatment. MT-MMP protein was detected in SNB-19 and U251 cell lines only after ConA treatment. Gelatin zymography of human brain tumor tissues revealed that almost all samples examined contained a latent form of gelatinase A, whereas the activated form of gelatinase A was only seen in metastatic lung adenocarcinomas and malignant astrocytomas, and especially in glioblastomas. MT-MMP mRNA levels were significantly higher in malignant astrocytomas than in low-grade gliomas and normal brain tissues. These results were confirmed by PCR analysis, which showed that MT-MMP mRNA was absent or barely detectable in normal brain white matter but was easily detectable in malignant astrocytomas. Immunohistochemistry of MT-MMP in frozen sections showed that MT-MMP was localized in neoplastic astrocytes of malignant astrocytomas but was undetectable in normal white brain matter. The data indicate that MT-MMP is present in malignant human glial tumors and that MT-MMP expression correlates with expression and activation of gelatinase A during malignant progression in vivo. A direct correlation between the levels of MT-MMP protein and its transcripts was not found in vitro, suggesting that MT-MMP expression in glioma cell lines might be regulated either at the level of transcription message stability or at posttranscription. Altered MT-MMP expression might contribute, in part, to gelatinase A activation, which in turn facilitates invasion of these tumors.

Expression and localization of urokinase-type plasminogen activator receptor in human gliomas.

Urokinase-type plasminogen activator receptors (uPARs) play an important role in tumor invasion by localizing degradative enzymes at the invasive zone. In the present study, we examined the presence and distribution of uPARs in human gliomas in vivo. The amounts of uPARs were measured by radioreceptor assays and Northern blotting and were significantly higher in anaplastic astrocytomas and glioblastomas than they were in normal brain tissues and low-grade gliomas. In situ hybridization was performed to investigate the cellular source of uPAR mRNA in various types of astrocytomas and normal brain tissues. uPAR mRNA was localized in astrocytoma cells and endothelial cells within tumor tissue, especially near sites of vascular proliferation and at the leading edges of tumors. uPAR mRNA was also expressed in tumor cells near necrotic areas. Expression was barely detectable in low-grade astrocytomas and normal brain tissues. These results suggest that expression of uPAR in the invading astrocytoma cells may play a significant role in the invasive behaviors of glioblastomas.

Expression and cellular localization of messenger RNA for plasminogen activator inhibitor type 1 in human astrocytomas in vivo.

We investigated the expression and cellular localization of plasminogen activator inhibitor type 1 (PAI-1) in human astrocytoma in vivo. Northern blot and densitometric quantitation of PAI-1 mRNA indicated that PAI-1 transcripts were significantly higher in human malignant astrocytomas and especially in glioblastomas than in low-grade gliomas and normal brain tissues in vivo. Using in situ hybridization with paraffin-embedded surgical specimens of human gliomas and normal brain tissues, PAI-1 mRNA was abundantly expressed in glioblastomas. PAI-1 mRNA was localized mainly in tumor cells and endothelial cells. The distribution of PAI-1 mRNA expression was particularly abundant around areas of vascular proliferation and in remnant tumor cells surrounding necrotic foci. PAI-1 mRNA was also expressed in both the tumor and endothelial cells of anaplastic astrocytomas, whereas it was not expressed or only weakly expressed in low-grade astrocytomas or normal brain tissues. These results suggest that high expression of PAI-1 is associated with the malignant progression of astrocytic tumors and that excessive PAI-1 expression might be associated with intratumoral necrosis in glioblastomas.

Expression and localization of urokinase-type plasminogen activator in human astrocytomas in vivo.

Plasminogen activators regulate a variety of processes involved in tissue morphogenesis, as well as cell differentiation, migration, and invasion. We examined the relative amounts of mRNA and protein and localization of urokinase-type plasminogen activator (uPA) in human astrocytomas in vivo. Using fibrin zymography and densitometric quantitation, we found that uPA activity was significantly higher in malignant astrocytomas, especially in glioblastomas, than it was in normal brain tissues or low-grade gliomas. The amounts of uPA mRNA, as determined by Northern blot analysis, were higher in anaplastic astrocytomas and glioblastomas than in normal brain tissues and low-grade gliomas, consistent with the amount of uPA activity. To investigate the cellular source of uPA in various tissues, we performed immunocytochemical localization of uPA protein and in situ hybridization of uPA mRNA with astrocytomas and normal brain tissues. Immunocytochemical staining for uPA showed strong immunoreactivity in the tumor cells and vasculature of glioblastomas and anaplastic astrocytomas but undetectable or very low immunoreactivity for uPA in low-grade gliomas and normal brain tissues. uPA mRNA was located in astrocytoma and endothelial cells and was heterogeneously distributed within glioblastoma, with preferential localization near vascular proliferation and at the leading edge of the tumor. uPA expression was dramatically higher in highly malignant astrocytomas, especially glioblastomas, and was correlated with malignant progression of astrocytomas.