Clinico-pathological study of meningiomas with haemorrhagic onset.

BACKGROUND: Haemorrhage from meningiomas is rare and the underlying pathophysiological mechanisms remain to be determined. We sought to identify these mechanisms by studying clinical and histological records of 6 meningioma patients treated at our institution. PATIENTS AND METHODS: We retrospectively studied 6 patients with meningiomas whose acute onset was due to haemorrhage. We evaluated clinical features and imaging studies. The vascularity and proliferative nature of these tumours were examined immunohistochemically and tissue factor (TF) immunoreactivity was assessed. For comparison we evaluated 25 non-haemorrhagic meningiomas. FINDINGS: At onset, the haemorrhages mimicked stroke in all 6 patients. On imaging studies, 3 of the haemorrhages were intra- and extratumoural, the other 3 were extratumoural only. Hyperintensity on T2-weighted MRI was a characteristic of these meningiomas. Histologically, they were of 3 subtypes, meningothelial (n=3), transitional (n=2), and anaplastic (n=1). The MIB-1 labelling index of the 5 WHO Grade I meningiomas was 5.8+/-2.2. The mean number of CD31-positive blood vessels did not differ in haemorrhagic and non-haemorrhagic meningiomas. The TF-positivity rate of haemorrhagic meningiomas was higher than of non-haemorrhagic meningiomas. INTERPRETATION: The proliferative nature of the meningiomas and TF expression in tumour cells may have contributed to the eventual haemorrhage of the meningiomas in our series.

Phosphorylation of neurofibromin by cAMP-dependent protein kinase is regulated via a cellular association of N(G),N(G)-dimethylarginine dimethylaminohydrolase.

The neurofibromatosis type 1 (NF1) tumor suppressor (neurofibromin) is thought to play crucial roles in cellular Ras- and cAMP-dependent kinase (PKA)-associated signals. In this study, we identified a cellular neurofibromin-associating protein, N(G),N(G)-dimethylarginine dimethylaminohydrolase (DDAH) that is known as a cellular NO/NOS regulator. The interaction of DDAH was mainly directed to the C-terminal domain (CTD) and to the cysteine/serine-rich domain (CSRD) of neurofibromin, coinciding with the regions containing specific PKA phosphorylation sites. DDAH increased PKA phosphorylation of native neurofibromin in a dose-dependent manner, especially affecting the phosphorylation of CSRD. These findings suggest that the PKA accessibility of neurofibromin was regulated via DDAH interaction, and this regulation may modulate the cellular function of neurofibromin that is implicated in NF1-related pathogenesis.

Comparative analysis of brain proteins from p53-deficient mice by two-dimensional electrophoresis.

p53 is a tumor suppressor protein that regulates many cellular processes including the cell cycle, DNA repair, and apoptosis. It also serves as a critical regulator of neuronal apoptosis in the central nervous system (CNS). To elucidate the role of p53 in the CNS, brain proteins of p53 knock-out mice (p53-/-) were analyzed by two-dimensional gel electrophoresis (2-DE) and compared with those from p53 wild type (p53+/+) mice. Six types of brain tissue (temporal cortex, cerebellum, hippocampus, striatum, olfactory bulb, and cervical spinal cord) and other control tissues (lung and blood) from 18-week-old non-stress-induced mice were analyzed. The morphology of brains from p53-/- mice appeared to be normal and identical to that of p53+/+ mice, although lungs showed diffuse tumors that may have been caused by p53 deficiency. Comparative 2-D gel analysis showed that, on average, 7 of 886 spots from brain tissue were p53-/- specific, whereas 12 of 1008 spots from lung tissue were p53-/- specific. N-terminal amino acid sequence was determined for p53-/- specific proteins. In all brain tissues from p53-/- mice, a newly identified mouse mitochondrial NADH-ubiquinone oxidoreductase 24 kDa subunit showed decreased expression, and apolipoprotein A1 acidic forms showed increased expression. In addition, brain-type creatine kinase B chain and tubulin beta-5 N-terminal fragment were increased in the p53-/- cerebellum, and a new protein in mouse, hydroxyacylglutathione hydrolase (glyoxalase II) was decreased in the temporal cortex of p53-/- mice. The alterations in protein expression identified in this study may imply a p53-related brain function. This is the first proteomic analysis on the p53-/- mouse brain, and further information based on this study will provide new insights into the p53 function in the CNS.