Atsuya Akabane

Regulatory role of CD38 (ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase) in insulin secretion by glucose in pancreatic beta cells. Enhanced insulin secretion in CD38-expressing transgenic mice.

Cyclic ADP-ribose (cADPR) serves as a second messenger for Ca2+ mobilization in insulin secretion, and CD38 has both ADP-ribosyl cyclase and cADPR hydrolase activities (Takasawa, S., Tohgo, A., Noguchi, N., Koguma, T., Nata, K., Sugimoto, T., Yonekura, H., and Okamoto, H.(1993) J. Biol. Chem. 268, 26052-26054). Here, we produced transgenic mice overexpressing human CD38 in pancreatic β cells. The enzymatic activity of CD38 in transgenic islets was greatly increased, and ATP efficiently inhibited the cADPR hydrolase activity. The Ca2+ mobilizing activity of cell extracts from transgenic islets incubated in high glucose was 3-fold higher than that of the control, suggesting that ATP produced by glucose metabolism increased cADPR accumulation in transgenic islets. Glucose- and ketoisocaproate-induced but not tolbutamide- nor KCl-induced insulin secretions from transgenic islets were 1.7-2.3-fold higher than that of control. In glucose-tolerance tests, the transgenic serum insulin level was higher than that of control. The present study provides the first evidence that CD38 has a regulatory role in insulin secretion by glucose in β cells, suggesting that the Ca2+ release from intracellular cADPR-sensitive Ca2+ stores as well as the Ca2+ influx from extracellular sources play important roles in insulin secretion.

Induction of brain-derived neurotrophic factor (BDNF) and the receptor trk B mRNA following middle cerebral artery occlusion in rat

Middle cerebral artery (MCA) occlusion in halothane-anesthetized rats induced brain-derived neurotrophic factor (BDNF) and the receptor, trk B mRNA, in brain. In situ hybridization studies showed that BDNF and trk B mRNAs were induced in a widespread region of the ipsilateral cortex outside the infarct at 4 h following MCA occlusion. They were also induced in the bilateral hippocampi which are remote from the ischemic MCA region. These data show that changes in neurotrophic factor and receptor gene expressions can occur in the areas outside the infarct which could survive.

Inducible nitric oxide synthase following hypoxia in rat cultured glial cells.

Nitric oxide (NO) produced by inducible nitric oxide (iNOS) exerts inhibitory and cytotoxic effects on various cells including neuronal cells. In the present study, we examined the ability of rat glial cells to produce NO following hypoxia/reoxygenation in vitro by measuring nitrite. The levels of nitrite produced in the cultured media of glial cells significantly increased after 12-h hypoxia but not after 0- and 6-h hypoxia. The NOS inhibitor, NG-monomethyl-L-arginine, decreased hypoxia-induced nitrite formation. In glial cells after hypoxia/reoxygenation, the iNOS and mRNA and protein expressions were detected by reverse-transcription polymerase chain reaction and by immunocytochemical analysis, respectively. The present study provides the first evidence that hypoxia induces NO production from glial cells. This hypoxia-induced, glial cell-derived NO may play a critical role in the pathogenesis of cerebral ischemia in vivo.

Value of constructive interference in steady-state three-dimensional, Fourier transformation magnetic resonance imaging for the neuroendoscopic treatment of hydrocephalus and intracranial cysts.

OBJECTIVETo assess the value of constructive interference in steady-state, three-dimensional, Fourier transformation (CISS) magnetic resonance imaging in the endoscopic management of hydrocephalus and intracranial cysts. METHODSCISS imaging and T2-weighted imaging were performed for 14 consecutive patients before and after fenestration procedures, using a flexible endoscope, to treat loculated or multiloculated hydrocephalus (4 patients), aqueductal stenosis or obstruction (4 patients), arachnoid cysts (4 patients), a cyst of the velum interpositum (1 patient), or an ependymal cyst (1 patient). Fifteen fenestration procedures were performed, including one reoperation. RESULTSPreoperative CISS imaging demonstrated intracystic intraventricular septa not observed with conventional T2-weighted imaging for 11 of 15 procedures and provided better brain tissue/cerebrospinal fluid contrast, allowing better understanding of the cause of hydrocephalus and the nature of the cysts. CISS imaging and T2-weighted imaging were equally useful for monitoring postoperative changes in the sizes of ventricles or cysts and the presence of flow voids after third ventriculostomies. However, only CISS imaging clearly demonstrated the site of fenestration for six of the nine patients who underwent fenestration procedures. CONCLUSIONCISS imaging provides excellent cerebrospinal fluid/brain tissue contrast, allowing detailed study of the anatomic features of the ventricular system and cystic lesions. CISS imaging is valuable for both preoperative decision-making and postoperative evaluation.

Gamma Knife radiosurgery for hemangiomas of the cavernous sinus: a seven-institute study in Japan

OBJECT Gamma Knife radiosurgery (GKS) is currently used for primary or postoperative management of cavernous sinus (CS) hemangiomas. The authors describe their experience with 30 cases of CS hemangioma successfully managed with GKS. METHODS Thirty patients with CS hemangiomas, including 19 female and 11 male patients with a mean age of 53 years (range 19-78 years) underwent GKS at 7 facilities in Japan. Pathological entity was confirmed using surgical specimens in 17 patients, and neuroimaging diagnosis only in 13. Eight patients were asymptomatic before GKS, while 22 had ocular movement disturbances and/or optic nerve impairments. The mean tumor volume was 11.5 cm(3) (range 1.5-51.4 cm(3)). The mean dose to the tumor periphery was 13.8 Gy (range 10.0-17.0 Gy). RESULTS The mean follow-up period was 53 months (range 12-138 months). Among the 22 patients with symptoms prior to GKS, complete remission was achieved in 2, improvement in 13, and no change in 7. Hemifacial sensory disturbance developed following GKS in 1 patient. The most recent MR images showed remarkable shrinkage in 18, shrinkage in 11, and no change in 1 patient. CONCLUSIONS Gamma Knife radiosurgery proved to be an effective treatment strategy for managing CS hemangiomas. Given the diagnostic accuracy of recently developed neuroimaging techniques and the potentially serious bleeding associated with biopsy sampling or attempted surgical removal, the authors recommend that GKS be the primary treatment in most patients who have a clear neuroimaging diagnosis of this condition.

Enhancement of Glucose‐induced Insulin Secretion in Transgenic Mice Overexpressing Human VIP Gene in Pancreatic β Cells1

Using transgenic mice technology, it has now become possible to test directly whether VIP and PHM-27 can enhance glucose-induced insulin secretion and reduce blood glucose in vivo. By microinjecting the entire human VIP gene ligated to the rat insulin II promoter, we have established a mouse model that overproduces VIP and PHM-27 in pancreatic beta cells. VIP was secreted from transgenic islets in a glucose-dependent manner. Analyses of these VIP-transgenic mice indicated that the transgene efficiently enhances glucose-induced insulin secretion and significantly reduces blood glucose as compared with control mice. The transgene also ameliorated glucose intolerance of 70% depancreatized mice. The present results suggest that somatic cell gene therapy directed to diabetic islets by human VIP/PHM-27 gene introduction may provide a means to improve the secretory function of the diabetic islets.

Gamma knife radiosurgery for arteriovenous malformations: the Furukawa experience.

The Furukawa experience treating 534 patients with cerebral arteriovenous malformations using gamma knife radiosurgery (GKRS) is summarized. By repeating radiosurgery for any residual nidus after the first GKRS, the rates of cumulative complete obliteration 7 years after this initial GKRS, according to four volume categories (< or =1, 4 > or = >1, 10 > or = > 4, > 10cm3), were 92, 89, 68 and 43%, respectively. Bleeding after GKRS was observed in 8.1% of the patients and was more frequently seen in patients with a large nidus and history of bleeding two or more times before GKRS. Cyst formation was recognized in 4.7% of patients, two thirds of which required some form of surgical intervention. Refinement of the total GKRS system contributed to earlier and more effective nidus obliteration.

Gamma knife radiosurgery for pituitary adenomas

Although surgical extirpation by transsphenoidal microsurgery is a major remedy for pituitary adenomas, adjuvant therapy also plays an important role in achieving tumor growth control and endocrine normalization in hormone-secreting tumors. Historically, the treatment options for pituitary adenomas included microsurgery, medical management, and fractionated radiotherapy, but radiosurgery has recently emerged as a practical treatment option. In this paper, we will describe the indications, radiosurgical procedure, results, histological change, and complications of gamma knife radiosurgery (GKS) for pituitary adenomas based on our experience since 1991 and a review of the literature.

Gamma Knife radiosurgery for brain metastases from pulmonary large cell neuroendocrine carcinoma: a Japanese multi-institutional cooperative study (JLGK1401)

OBJECTIVE In 1999, the World Health Organization categorized large cell neuroendocrine carcinoma (LCNEC) of the lung as a variant of large cell carcinoma, and LCNEC now accounts for 3% of all lung cancers. Although LCNEC is categorized among the non-small cell lung cancers, its biological behavior has recently been suggested to be very similar to that of a small cell pulmonary malignancy. The clinical outcome for patients with LCNEC is generally poor, and the optimal treatment for this malignancy has not yet been established. Little information is available regarding management of LCNEC patients with brain metastases (METs). This study aimed to evaluate the efficacy of Gamma Knife radiosurgery (GKRS) for patients with brain METs from LCNEC. METHODS The Japanese Leksell Gamma Knife Society planned this retrospective study in which 21 Gamma Knife centers in Japan participated. Data from 101 patients were reviewed for this study. Most of the patients with LCNEC were men (80%), and the mean age was 67 years (range 39-84 years). Primary lung tumors were reported as well controlled in one-third of the patients. More than half of the patients had extracranial METs. Brain metastasis and lung cancer had been detected simultaneously in 25% of the patients. Before GKRS, brain METs had manifested with neurological symptoms in 37 patients. Additionally, prior to GKRS, resection was performed in 17 patients and radiation therapy in 10. A small cell lung carcinoma-based chemotherapy regimen was chosen for 48 patients. The median lesion number was 3 (range 1-33). The median cumulative tumor volume was 3.5 cm3, and the median radiation dose was 20.0 Gy. For statistical analysis, the standard Kaplan-Meier method was used to determine post-GKRS survival. Competing risk analysis was applied to estimate GKRS cumulative incidences of maintenance of neurological function and death, local recurrence, appearance of new lesions, and complications. RESULTS The overall median survival time (MST) was 9.6 months. MSTs for patients classified according to the modified recursive partitioning analysis (RPA) system were 25.7, 11.0, and 5.9 months for Class 1+2a (20 patients), Class 2b (28), and Class 3 (46), respectively. At 12 months after GKRS, neurological death-free and deterioration-free survival rates were 93% and 87%, respectively. Follow-up imaging studies were available in 78 patients. The tumor control rate was 86% at 12 months after GKRS. CONCLUSIONS The present study suggests that GKRS is an effective treatment for LCNEC patients with brain METs, particularly in terms of maintaining neurological status.