We concluded that a considerable number of cases appeared to need craniotomy and resection of intrahematomal membrane for complete recovery in CSDH, and that T2*-weighted MR imaging could be used as a basis for selecting the operative procedure for CSDH.

Vascular endothelial growth factor (VEGF), a potent inducer of angiogenesis and vascular permeability in diverse physiological and pathological conditions, may be involved in the pathophysiology of chronic subdural hematoma (CSDH). The present study investigated the source and mechanisms for the induction of VEGF in CSDH by measuring the concentration of VEGF in the hematoma of 102 patients (122 hematomas) using the enzyme-linked immunosorbent assay technique. The relationship between the VEGF concentration in hematoma and the intrahematoma membranous structure confirmed by preoperative T 2 *-weighted magnetic resonance image was examined in 46 of these patients. VEGF and hypoxia-inducible factor-1a (HIF-1a) expression was immunohistochemically studied and microvessel density (MVD) in the outer membrane was identified using anti-CD31 antibody in 30 patients. VEGF and HIF-1a were positive in the outer membranes of all 30 patients. VEGF expression was significantly correlated to HIF-1a expression (r s ＝ 0.651, p ＝ 0.0084) and VEGF concentration in the hematoma (r s ＝ 0.654, p ＝ 0.0013). VEGF concentration in layered hematomas, which have intrahematoma membranous structure, was significantly higher than in non-layered hematomas (p º 0.01). Although MVDs of the outer membranes were comparable to those described in tumors, there was no significant relationship with VEGF expression. The present study suggests that VEGF in CSDH, which may be induced in the neomembrane by HIF-1 release, may give rise to the excessive development of fragile microvessels and hyperpermeability, resulting in the enlargement of CSDH.

Cyclopentenone prostaglandins (PGs) are known to arrest the cell cycle at the G 1 phase in vitro and to suppress tumor growth in vivo. However, their effects on neurons are unclear. Here, we report that some cyclopentenone PGs function as neurite outgrowth-promoting factors. They promoted neurite outgrowth from PC12 cells and from dorsal root ganglion explants but only in the presence of nerve growth factor (NGF). We refer to these PGs as neurite outgrowth-promoting PGs (NEPPs). Through study of the structure-function relationship of NEPP1-10 and related compounds, we found that the cross-conjugated dienone moiety of NEPPs was essential for promoting neurite outgrowth, and NEPP10 was concluded to be the best candidate for drug development. We also investigated the intracellular mechanism of the promotion by NEPPs and obtained evidence that immunoglobulin heavy chain binding protein/glucose-regulated protein 78 (BiP/GRP78) plays a role in the promotion, based on the following observations: Antisense nucleotides for BiP/GRP78 gene blocked the promotion of neurite outgrowth; BiP/GRP78 protein level increased in response to NEPPs; and overexpression of BiP/GRP78 protein by adenoviral gene transfer promoted the neurite outgrowth by NGF. Key Words: ⌬ 7 -Prostaglandin A 1 -Immunoglobulin heavy chain binding protein/glucose-regulated protein 78 -Neurite outgrowthNerve growth factor-PC12 cells-Dorsal root ganglion explants.

Although the cyclopentenone prostaglandin A 1 (PGA 1 ) is known to arrest the cell cycle at the G 1 phase in vitro and to suppress tumor growth in vivo, its relatively weak activity limits its usefulness in cancer chemotherapy. In an attempt to develop antitumor drugs of greater potency and conspicuous biological specificity, we synthesized novel analogs based on the structure of PGA 1 . Of the newly synthesized analogs, 15-epi-⌬ 7 -PGA 1 methyl ester (NAG-0092), 12-iso-⌬ 7 -PGA 1 methyl ester (NAG-0093), and ent-⌬ 7 -PGA 1 methyl ester (NAG-0022) possess a cross-conjugated dienone structure around the five-member ring with unnatural configurations at C(12) and/or C(15) and were found to be far more potent than native PGA 1 in inhibiting cell growth and causing G 1 arrest in A172 human glioma cells. These three analogs induced the expression of p21 at both RNA and protein levels in a time-and dose-dependent fashion. Kinase assays with A172 cells treated with these analogs revealed that both cyclin A-and E-dependent kinase activities were markedly reduced, although cyclin D1-dependent kinase activity was unaffected. Immunoprecipitation-Western blot analysis showed that the decrease in cyclin A-dependent kinase activity was due to an increased association of p21 with cyclin A-cyclin-dependent kinase 2 complexes, whereas the decrease in cyclin E-dependent activity was due to a combined mechanism involving reduction in cyclin E protein itself and increased association of p21. Thus, these newly synthesized PGA 1 analogs may prove to be powerful tools in cancer chemotherapy as well as in investigations of the structural basis of the antiproliferative activity of A series prostaglandins.

Patients harboring CSDHs with high TPA concentrations on sampling at the initial surgery have a relatively high probability of recurrence and require follow up with computerized tomography scanning. Angiogenic factors, such as HGF and VEGF, might be candidate markers of CSDH enlargement but are not useful as predictors of recurrence.