Izumi Nagata

Bone regeneration by basic fibroblast growth factor complexed with biodegradable hydrogels

The objective of this study is to enhance the bone induction activity of basic fibroblast growth factor (bFGF) for reconstruction of skull bone defects which has been clinically recognized as almost impossible. For this purpose, we prepared biodegradable hydrogels from gelatin with an isoelectric point of 4.9 which is capable of polyionic complexing with basic bFGF. When implanted in rabbit skull defects of 6 mm in diameter (6 defects per experimental group), the gelatin hydrogels incorporating 100 microg of bFGF promoted bone regeneration at the defect in marked contrast to free bFGF of the same dose, finally closing the bone defects after 12 weeks of implantation as is apparent from histological examination. In dual energy X-ray absorptometry analysis, the bone mineral density at the skull defects enhanced by the hydrogels was significantly higher than that by free bFGF at doses ranging from 2 to 200 microg/defect (P < 0.05). The extent of bone regeneration induced by gelatin hydrogels incorporating 100 microg of bFGF increased with a decrease in their water content. Histological examination indicated that more slowly degrading hydrogels of lower water content prolonged the retention period of osteoblasts in the bone defects. This led to enhanced bone regeneration compared with faster degrading hydrogels of higher water content. It was concluded that this biodegradable hydrogel system was a promising surgical tool to assist self-reconstruction of the skull bone.

Prevention of Rat Cerebral Aneurysm Formation by Inhibition of Nitric Oxide Synthase

BACKGROUNDnCerebral saccular aneurysm is a major cause of subarachnoid hemorrhage, one of the cerebrovascular diseases with the highest mortality. The mechanisms underlying the development of aneurysms, however, still remain unclear. We have made a series of reports on an animal model of experimentally induced cerebral aneurysms that resemble human cerebral aneurysms in their location and morphology, suggesting that the arterial wall degeneration associated with aneurysm formation develops near the apex of arterial bifurcation as a result of an increase in wall shear stress. Using the animal model and human specimens, we examined the role of nitric oxide (NO) in the degenerative changes and cerebral aneurysm formation.nnnMETHODS AND RESULTSnInducible NO synthase (iNOS) was immunohistochemically located at the orifice of human and rat aneurysms. Nitrotyrosine distribution was also seen in the human aneurysm. Although no iNOS immunostaining was found in normal arteries, iNOS immunoreactivity was observed in parallel with the development of early aneurysmal changes in rats. In contrast, during the early development of aneurysm, endothelial NOS immunostaining in the endothelium was weakened compared with that in the control arteries. An NOS inhibitor, aminoguanidine, attenuated both early aneurysmal changes and the incidence of induced aneurysms. A defibrinogenic agent, batroxobin, which may diminish shear stress by reduction of blood viscosity, prevented iNOS induction as well as early aneurysmal changes.nnnCONCLUSIONSnThe evidence suggests that NO, particularly that derived from iNOS, is a key requirement for the development of cerebral aneurysm. The iNOS induction may be caused by an increase in shear stress near the apex.

Experiences of 120 microsurgical reconstructions of hepatic artery in living related liver transplantation

BACKGROUNDnWe reviewed 120 microsurgical reconstructions of a hepatic artery in living related liver transplantation and discussed the problems encountered.nnnMETHODSnFrom January 1991 to July 1994 we performed a series of 105 living related liver transplantations on children with end-stage liver disease. Arterial reconstruction was performed under the optical field of a continuous zoom magnification of approximately 10 times with an operating microscope.nnnRESULTSnTwenty-six percent of the graft arteries were less than 2 mm in diameter. The time required for an arterial reconstruction was 49.5 +/- 1.8 minutes. In 15 of the 31 cases in which there were two graft arteries, two arterial reconstructions were required. The caliber differences between the graft artery and the recipient artery in 30 instances was dealt with by cutting an undersized artery obliquely (17 instances), by fish-mouth method (10 instances), by end-to-side anastomosis (1 instance), or by funnelization method (2 instances). In one case we performed an intimal dissection of a recipient hepatic artery and substituted a splenic artery. Consequently, hepatic arterial thrombosis occurred in only two cases (1.7%).nnnCONCLUSIONSnMicrosurgical technique has overcome the high risk of hepatic arterial thrombosis in cases of fine graft arteries, enabled the reconstruction of arteries with caliber difference, and decreased arterial complications with its delicate manipulation.

Venous Congestion Is a Major Cause of Neurological Deterioration in Spinal Arteriovenous Malformations

OBJECTIVEAlthough venous congestion is considered to be a major cause of progressive myelopathy in patients with spinal dural arteriovenous fistulae (DAVFs), the neurological deterioration in patients with spinal intradural arteriovenous malformations (AVMs) has been attributed to hemorrhage or to vascular steal. To reexamine this theory, we analyzed our own cases of spinal vascular diseases. METHODSIn 24 patients with spinal vascular diseases, those who demonstrated progressive myelopathy with T2 hyperintensity in the spinal cord on magnetic resonance imaging (MRI) were diagnosed as patients with congestive myelopathy. We further examined the clinical courses, MRI findings, and reversibility of these cases. RESULTSVenous congestion was judged to be a cause of neurological deterioration in 13 patients (7 DAVFs, 6 intradural AVMs). The T2 signals on these patients’ MRI scans were located in the center and extended over several levels not corresponding to distribution of ischemia due to arterial steal. Of the patients who were diagnosed with congestive myelopathy, no differences between those with DAVFs and those with intradural AVMs were apparent in terms of clinical manifestations and reversibility. Eight (four DAVFs, four intradural AVMs) of 13 patients experienced neurological improvement after treatment. All patients with poor outcomes had intervals from onset of more than 3 years and showed contrast enhancement of the spinal cord on MRI studies. CONCLUSIONSpinal intradural AVMs as well as spinal DAVFs can be a cause of venous congestive myelopathy. Regardless of its etiology, congestive myelopathy is potentially reversible if properly diagnosed and treated.

Posttreatment sequelae of palliatively treated cerebral arteriovenous malformations.

OBJECTIVEnPosttreatment sequelae of palliatively treated cerebral arteriovenous malformations (AVMs) were studied to evaluate the significance of these nonradical treatments.nnnMETHODSnBetween 1987 and 1997, 46 patients with cerebral AVMs were managed with treatments such as partial embolization, radiosurgery, subtotal resection, or feeder ligation alone. Their AVMs were not radically resected because of difficulties in radical treatment, hesitance to treat eloquent area lesions, or residual nidi after subtotal obliteration. The patients posttreatment sequelae were evaluated. The duration of follow-up ranged from 0.5 to 169 months (mean, 49.4+/-39.8 mo).nnnRESULTSnTwenty-six bleeding episodes from AVMs were documented in 18 patients. The annual risk of bleeding in this palliatively treated group was 14.6%. Persistent progressive neurological deficit was observed in one patient. Major neurological deficits occurred in 10 patients (23.3%), and the mortality rate was 9.3%.nnnCONCLUSIONnPalliative treatments cannot prevent bleeding and may even worsen the posttreatment course compared with the natural history of cerebral AVMs. A more conservative indication is required in recommending palliative treatment alone.

Expression of Somatostatin Receptor (SSTR) Subtypes in Pituitary Adenomas: Quantitative Analysis of SSTR2 mRNA by Reverse Transcription-Polymerase Chain Reaction

The expression of somatostatin receptor (SSTR) subtypes and relative abundance of SSTR2 mRNA were examined in 18 pituitary adenomas using the reverse transcription‐polymerase chain reaction (RT‐PCR) method. SSTR1 and SSTR2 were expressed in all pituitary adenomas examined. Six of 9 somatotroph adenomas, 1 of 4 lactotroph adenomas and 1 of 2 thyrotroph adenomas also expressed SSTR5. SSTR3 and SSTR4 mRNAs were detected in 1 and 2 cases of somatotroph adenoma, respectively. SSTR2 mRNA expression was quantified by comparison with the PCR cycle‐dependent amplification of β‐actin or cyclophilin. The relative abundance of SSTR2 mRNA varied greatly among adenomas with more than a 1000‐fold difference. SSTR2 mRNAs in lactotroph adenomas were less abundant (P<0.01) than those in somatotroph adenomas. No significant correlation was found between the relative abundance of SSTR2 mRNA levels and GH sensitivity to octreotide administration. However, one of the thyrotroph adenomas exhibited marked shrinkage in tumor size after octreotide therapy, in which SSTR2 mRNA was the most abundant among the adenomas examined. GH sensitivity to octreotide was not significantly different between SSTR5 mRNA positive and negative adenomas. In conclusion, SSTR2 mRNA levels varied greatly among pituitary adenomas but were not correlated with GH sensitivity to octreotide. Further investigations of functional SSTR subtype proteins and of postreceptor signal transductions are required to clarify the molecular mechanisms of octreotide action.

Experimentally induced cerebral aneurysms in rats: VII. Scanning electron microscope study

The luminal surfaces of experimentally induced cerebral aneurysms and the branching sites in the circle of Willis in rats were investigated by scanning electron microscopy. Gap formation at the junctions of the endothelial cells was one of the most obvious changes on the endothelial surface of the aneurysms. Many leukocytes were observed adhering to these gaps. Regressive changes of endothelial cells, such as balloonlike protrusions and craterlike depressions, were also found in the aneurysms. At the branching site, where cerebral aneurysms often develop, endothelial cells were disarranged, rounded, and varied in size. A deep groove was also found adjacent to the apex. The role of endothelial cells and leukocytes in the development of cerebral aneurysms is discussed.

Intrasellar meningioma: case report and review of the literature.

BACKGROUNDnIntrasellar meningioma is a rare clinical entity, and surgical resection may be difficult when it is hypervascularized.nnnMETHODSnA case of subdiaphragmatic hypervascular intrasellar meningioma with attachment to the dura of the anterior wall of the sella turcica is described. Literature review of 18 cases with operatively confirmed intrasellar meningioma discloses unexpected intraoperative bleeding and relatively low resectability of the tumor are also described.nnnRESULTSnWe used preoperative endovascular embolization of feeding arteries, and resected a hypervascular intrasellar meningioma by a combined transsphenoidal-transcranial approach safely and without massive bleeding.nnnCONCLUSIONSnPreoperative endovascular embolization of feeding arteries and combined transsphenoidal-transcranial approach are useful for the surgical resection of hypervascular intrasellar meningiomas.

Prevention of Neointimal Formation by a Serine Protease Inhibitor, FUT-175, After Carotid Balloon Injury in Rats

BACKGROUND AND PURPOSEnIn vivo and vitro studies revealed the activation of thrombin and the complement system in vascular lesion formation during the process of atherosclerosis, along with pathological proliferation of smooth muscle cells. We examined the effect of the synthetic serine protease inhibitor FUT-175 (developed as a potent inhibitor of thrombin and the complement system) on vascular lesions using balloon dilatation-induced neointimal formation in the carotid artery of rats.nnnMETHODSnSprague-Dawley (SD) rats underwent balloon dilatation injury of the left carotid artery to induce neointimal formation. Three groups of these rats (n=8, each) were treated with daily intraperitoneal injections of 1 of the following doses of FUT-175: 0.5, 1.0, or 2.0 mg/d in 1 mL of saline for 7 consecutive days. The control group (n=8) was similarly treated with 1 mL of saline for 7 days. The injections were started immediately after balloon injury. Two weeks after the injury, the left carotid arteries were perfusion-fixed, and the areas of the neointimal and medial layer were analyzed under a microscope.nnnRESULTSnA morphometric analysis revealed that there were significant differences in the intima-media ratio between the 4 groups treated with vehicle (saline) or a low, medium, or high dose of FUT-175 (1.45+/-0.11, 1.08+/-0.06, 0.71+/-0.04, or 0.32+/-0.04, respectively). This suppression was achieved in a dose-dependent manner by the administration of FUT-175 after balloon injury. In the histological study, it was demonstrated that FUT-175 suppresses the production of platelet-derived growth factor (PDGF)-BB in the neointima and the medial smooth muscle cell layer.nnnCONCLUSIONSnAfter balloon injury activated proteases that were inhibited by FUT-175 were demonstrated to have an essential role in the development of the pathological thickening of the arterial wall.

Treatment of a giant aneurysm of the cavernous internal carotid artery associated with a persistent primitive trigeminal artery: case report

A case of an unruptured giant aneurysm of the cavernous portion of the left internal carotid artery associated with a persistent primitive trigeminal artery (PTA) is presented. The usual surgical approach to giant aneurysms at this site, including ligation of the ipsilateral internal carotid artery (ICA) and an extracranial-intracranial (EC-IC) bypass, was inadequate because of continued blood supply to the aneurysm via the PTA from the vertebrobasilar system. The patient was successfully treated with a combination of EC-IC bypass surgery, ICA ligation, and simultaneous intravascular balloon obliteration of the ICA just distal to the junction of the PTA and immediately proximal to the aneurysmal neck. Follow-up radiological investigations showed thrombosis of the aneurysm.