Potential therapeutic effect of glycogen synthase kinase 3beta inhibition against human glioblastoma.

PURPOSE: Glioblastoma represents the malignant brain tumor that is most refractory to treatment and in which the identification of molecular target(s) is urgently required. We investigated the expression, activity, and putative pathologic role of glycogen synthase kinase 3beta (GSK3beta), an emerging therapeutic target for neurodegenerative diseases, in human glioblastoma. EXPERIMENTAL DESIGN: The active fraction of GSK3beta that is phosphorylated at the tyrosine 216 residue (pGSK3betaY216) was identified in glioblastoma cell lines. GSK3beta activity for phosphorylating its substrate was detected in these cells by nonradioisotopic in vitro kinase assay. RESULTS: Higher expression levels of GSK3beta and pGSK3betaY216 were frequently detected in glioblastomas compared with nonneoplastic brain tissues. Inhibition of GSK3beta activity by escalating doses of a small-molecule inhibitor (AR-A014418) or inhibition of its expression by RNA interference induced the apoptosis and attenuated the survival and proliferation of glioblastoma cells in vitro. Inhibition of GSK3beta was associated with increased expression of p53 and p21 in glioblastoma cells with wild-type p53 and with decreased Rb phosphorylation and expression of cyclin-dependent kinase 6 in all glioblastoma cell lines. Administration of AR-A014418 at a low dose significantly sensitized glioblastoma cells to temozolomide and 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea, chemotherapeutic agents used in the clinical setting, as well as to ionizing radiation. CONCLUSION: These results indicate that GSK3beta exerts a pathologic role by promoting the survival and proliferation of glioblastoma cells and by protecting them from apoptosis via the inactivation of p53- and/or Rb-mediated pathways. Consequently, we propose that GSK3beta provides a potential therapeutic target in glioblastoma.

Treatment of cavernous sinus dural arteriovenous fistulae by external manual carotid compression.

OBJECTIVE: External manual carotid compression is a noninvasive method to treat cavernous sinus (CS) dural arteriovenous fistulae (DAVF). We studied a group of patients with CS-DAVF to identify what factors made complete resolution of their clinical symptoms and closure of the DAVF on magnetic resonance angiography (MRA) by compression therapy possible. METHODS: We treated 23 patients with CS-DAVF without cortical venous drainage or a recent decline in visual acuity by compression therapy. All were followed up by magnetic resonance angiography at 1, 3, 6, and 12 months after treatment and the characteristics of the imaging findings, their neurological symptoms, and the patterns of symptom improvement were examined. RESULTS: In Group A (n = 8), complete resolution was achieved by manual carotid compression. In the other 15 patients (Group B), complete resolution was not obtained. Group B manifested significantly higher ocular pressure and a significantly longer interval between symptom onset and compression treatment. In Group A, venous drainage was via the superior orbital vein with or without involvement of the inferior petrosal sinus. Closure of the CS-DAVF occurred within 4.1 months after the start of treatment. In three patients, symptom improvement progressed steadily and gradually. The other five patients with complete resolution experienced transient worsening of their symptoms at 2 to 4 months after the start of treatment and symptom resolution occurred within 4 to 7 months. CONCLUSION: We identified lower ocular pressure, a shorter interval between symptom onset and compression treatment, and venous drainage solely via the superior orbital vein without involvement of the inferior petrosal sinus as the factors in our CS-DAVF patients that made complete resolution by manual carotid compression possible.

Uremic tumoral calcinosis in hemodialysis patients: clinicopathological findings and identification of calcific deposits.

OBJECTIVE: Extraskeletal calcifications generally develop in uremic patients. Periarticular massive calcifications, referred to as uremic tumoral calcinosis (UTC), represent solitary or multifocal calcium phosphate deposits. Our objectives were to clinically analyze a series of 8 patients with UTC undergoing hemodialysis, and to characterize calcium deposits in UTC. METHODS: The clinical, radiological, and pathological features of 8 consecutive patients (4 men and 4 women, mean age 49 yrs) with UTC were analyzed, and treatment and outcome were evaluated. Calcific specimens from the 8 patients were analyzed by x-ray diffraction, Raman spectroscopy, and infrared spectroscopy. RESULTS: Unifocal UTC was observed in 5 patients, whereas multifocal lesions occurred in 3 patients. The most common sites of UTC were the shoulders, elbows, and hands. Elevated serum calcium and phosphorus and intact parathyroid hormone were detected in 63% (n = 5), 100% (n = 8), and 63% (n = 5) of the patients, respectively. An increased calcium-phosphorus (Ca P) product was observed in 6 patients. Medical intervention to decrease the Ca P product achieved complete remission in 3 of 5 patients with solitary UTC, whereas this treatment was ineffective for multiple UTC. The 8 calcium deposits were identified as carbonate apatite. CONCLUSION: The most important pathogenic factors in UTC are an increased Ca P product and hyperphosphoremia, which is not necessarily related to hyperparathyroidism. Medical intervention is effective for solitary UTC, but combined treatment (surgery and medical therapy) is required for multiple UTC. Calcium deposits in UTC are composed of carbonate apatite.

The Kabuto, or the Japanese helmet: evolution from war implement to status symbol.

WARRIORS THROUGHOUT THE AGES have considered the unprotected head to be particularly vulnerable. The traditional Japanese helmet, the Kabuto, was the part of a protective suit of armor that reflected the wearer's character and personality. Over time, it changed from a primarily protective device to a vehicle for the expression of a distinctly Japanese sense of magnificent artistry. Each Kabuto was custom-made, and these helmets remain without peer in the world. They were designed and crafted to answer the demands of their era, and thus they provide historical evidence not only of the state of Japanese warfare, but also of social organization, metallurgical knowledge, artisanship, and aesthetic sensibility. Even now, during the national Golden Week Festival in early May, Kabuto are displayed in the alcoves of Japanese homes as a petition that the boys in the house be granted courage and good health. Thus, even in modern Japan, the Kabuto represents a talisman. We present an overview of the evolution of the Kabuto, with special reference to the Japanese sword and the warrior tradition.