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Biomedical subjects

I Nagata

Publications and source records attributed to I Nagata.

At least 91 records · Page 5Linked to original sources
PubMed1999

Gene transfer of human prostacyclin synthase prevents neointimal formation after carotid balloon injury in rats.

BACKGROUND AND PURPOSE: A disordered proliferative process in the vascular wall is thought to underlie the pathogenesis of restenosis after percutaneous transluminal angioplasty and carotid endarterectomy. A growth inhibitory property of overexpressed prostacyclin (PGI2) synthase (PGIS) was recently implicated in the pathological proliferation of vascular smooth muscle cells (VSMC) in vitro. Here, we investigated the effects of increased PGI2 synthesis on the pathological proliferation of VSMCs. METHODS: The cDNA encoding human PGIS was transfected into endothelium-denuded rat carotid arteries after arterial balloon injury with the use of hemagglutinating virus Japan (HVJ). HVJ liposome vector complex without PGIS cDNA was used for vehicle control. The level of 6-keto PGF1alpha, a stable hydrolyzed metabolite of PGI2, the histological distribution of the immunoreactivity for human PGIS and the ratio of neointimal/medial area were analyzed. RESULTS: In the analyses of 6-keto PGF1alpha, the level in the carotid arteries was significantly elevated 3 days after PGIS expression-vector transfection compared with that in the arteries after vehicle transfection. Seven days after human PGIS expression-vector transfection, the PGIS cDNA-transfected neointimal cells were strongly positive for human PGIS immunoreactivity in 81% sections examined. Fourteen days after the injury, the ratio of neointimal/medial area was 1.2+/-0.4 in the PGIS expression-vector transfected group, which was significantly smaller than that of the vehicle control group, 1.7+/-0.5; P<0.01. CONCLUSIONS: It was thus demonstrated that the gene transfer of human PGIS expression-vector into rat carotid arteries resulted in the increased production of human PGI2 in the vascular wall, the expression of human PGIS in the developing neointima and significantly inhibited the neointimal formation generated after balloon injury.

6-Ketoprostaglandin F1 alpha↗
PubMed1999

Prevention of neointimal formation by a serine protease inhibitor, FUT-175, after carotid balloon injury in rats.

BACKGROUND AND PURPOSE: In 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. METHODS: Sprague-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. RESULTS: A 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. CONCLUSIONS: After 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.

Animals↗
PubMed1999

Moyamoya disease showing atypical angiographic findings--two case reports.

A 7-year-old boy and a 10-year-old girl presented with moyamoya disease showing atypical angiographic findings. In these cases, the internal carotid artery (ICA) had a tapering occlusion just distal to the origin of the ophthalmic artery, whereas the top of the ICA was not occluded and was retrogradely supplied through the posterior communicating artery from the posterior circulation. Surgical treatment resolved the symptoms in both patients. Moyamoya disease may include a number of variant types not showing all the characteristic angiographic findings of moyamoya disease.

Carotid Artery, Internal↗
PubMed1999

Gains of 1q21-q22 and 13q12-q14 are potential indicators for resistance to cisplatin-based chemotherapy in ovarian cancer patients.

The mechanism of drug resistance in ovarian cancer is multifactorial, and accumulation of multiple genetic changes may lead to the drug-resistant phenotype. In our attempt to find characteristic genetic changes in drug-resistant tumors, we screened the whole genome for gene aberrations in 28 primary ovarian cancers using the comparative genomic hybridization method. These cancers included 14 tumors from patients who did not respond to cisplatin-based combination chemotherapy and 14 tumors from patients who had complete response to the chemotherapy. We found gains in chromosomal regions 1q21-q22 and 13q12-q14 to be related to the drug-resistant phenotype in ovarian cancer patients. Several genes encoding transcription factors, oncogenes, cell cycle regulators, and regulators of the apoptotic pathway are located on these regions of the chromosomes, and these genes are potential modulators for toxic insults in cancer cells. This is the first report that shows the relationship between certain genomic aberrations and clinical resistance to cisplatin-based chemotherapy in ovarian cancer patients based on the comparative genomic hybridization analysis. Present findings suggest that these chromosomal gains may be potential indicators for prediction of resistance in ovarian cancer patients before cisplatin-based chemotherapy.

Antineoplastic Agents↗
PubMed1999

[Remission due to CYVADIC chemotherapy of primary leiomyosarcoma derived from mesentelium of the sigmoid colon: a case report].

We report a case of leiomyosarcoma of mesenthelium origin, which was successfully treated with a combination of cyclophosphamide, vincristine, adriamycin and dacarbazine (CYVADIC). A 56-year-old woman received three courses of adjuvant CYVADIC chemotherapy after initial surgery consisting of tumorectomy, sigmoidectomy, descending colostomy, cystectomy and ureterostomy. A six-month disease-free period was attained obtained. A recurrent tumor showed remarkable reduction after three courses of CYVADIC chemotherapy. This case may be the first report of successful chemotherapy against a leiomyosarcoma of mesenthelium origin in Japan.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1999

[Endovascular surgery for untreated ruptured aneurysm with symptomatic vasospasm].

It is difficult to treat ruptured aneurysms with symptomatic vasospasm. Although direct surgery for such cases is associated with poor outcomes, conservative therapy has the risk of both rerupture and infarction. In two cases of ruptured aneurysms with symptomatic vasospasm, we performed aneurysmal coil embolization with Guglielmi electrodetatchable coils (GDC). At the same time we performed percutaneous transluminal angioplasty (PTA) with papaverine infusion. In both cases, rerupture did not occur and PTA was effective angiographically. A good outcome was achieved in case 1. However, broad cerebral infarction occurred in case 2, in which the patient had shown severe symptomatic vasospasm on admission. In advanced cases, such as in case 2, the outcome is poor. The aneurysm may not be able to be approached before PTA because of severe vasospasm. In such cases, PTA must be performed carefully to avoid aneurysmal rerupture. Intraarterial papaverine infusion is safer than PTA for severe spasm in distal vessels. However the efficacy of papaverine is known to be transient in many cases. It is often difficult to determine the exact relationship between branches and the aneurysm in the presence of vasospasm. In such cases, we recommend that the rupture point be packed and that the aneurysmal neck remain unpacked. After vasospasm is cured and good general condition has been recovered, direct surgery can be performed. In summary, endovascular surgery is an effective option for treatment of ruptured aneurysm with symptomatic vasospasm.

Aged↗
PubMed1998

Long-term outcome after STA-MCA anastomosis for moyamoya disease.

A long-term assessment was performed to determine the posttreatment clinical course of 113 patients with moyamoya disease. All patients sustained cerebral ischemic attacks and underwent superficial temporal artery-middle cerebral artery anastomosis with or without temporal muscle grafting. The follow-up duration was 3 to 24 years (mean 14.4 +/- 5.8 [standard deviation]). Complete cessation of the ischemic episodes was obtained in 110 of 113 patients. One hundred patients were able to return to independent acitvities of daily living. Intellectual delays prevented 24 patients from engaging in an independent social life . Although intracranial bleeding is one of the common manifestations in moyamoya disease, hemorrhage was not detected in the 113 patients who underwent cerebral revascularization.

Journal Article↗
PubMed1998

Infarct tolerance against temporary focal ischemia following spreading depression in rat brain.

A rat model of ischemic tolerance is useful for studying the intrinsic cellular mechanism of resistance to cerebral ischemia. Many types of preconditioning in the brain have been reported to induce ischemic tolerance; however, evaluation of their neuroprotective effect is primarily limited to differences in counts of surviving cells. A lesser but still large number of neurons die in the neocortex after global ischemia following ischemic tolerance. This study addressed the issue of whether any type of preconditioning could elicit a tolerance that limited the size of cerebral infarct against temporary focal ischemia. Cortical spreading depression was induced for a prolonged period and, after various intervals, the stress of temporary focal ischemia was evaluated in rats. Ten groups of male rats (n=8 each) were studied. In the first group, temporary focal ischemia was induced by occlusion of three vessels (bilateral carotid arteries and left middle cerebral artery, MCA) for 2 h (control). In the second to seventh groups, cortical spreading depression was generated by continuously infusing 4 M potassium chloride (KCl)(1.0 microliter l/h for 2 days) into the left neocortex via an osmotic pump. On days 6, 9, 12, 15, 21 and 24 (day 0=day of pump removal), temporary focal ischemia was induced in one of these groups. In the other three groups, saline was infused instead of KCl, and on day 6, 12 or 21, temporary focal ischemia was induced. All rats were sacrificed 2 days after the ischemia and the infarct volume was analyzed using TTC staining of brain slices. In a separate group of animals, regional cerebral blood flow (rCBF) at the periinfarct area (penumbra) was monitored before and during the ischemia with a laser-Doppler flowmetry (LDF) system on day 12 following saline (n=5) or KCl infusion (n=5) for 48 h. To obtain the absolute rCBF value before ischemia following saline (n=5) or KCl infusion (n=5), hydrogen clearance was examined in the same cortex under the same anesthesia. The cerebral infarct volume was gradually reduced as the interval between the induction of the spreading depression and the induction of temporary focal ischemia was extended. There was a significant reduction in infarct size between the control and the groups in which ischemia was induced on day 12 or 15. There was no significant difference in the preischemic or intraischemic rCBF between the saline and KCl-infused groups. The preconditioning method was demonstrated to limit the size of cerebral infarct after temporary focal cerebral ischemia; tolerance for cerebral infarct developed after an extended interval following a long period of spreading depression.

Animals↗
PubMed1998

In vitro growth suppression of vascular smooth muscle cells using adenovirus-mediated gene transfer of a truncated form of fibroblast growth factor receptor.

Vascular smooth muscle cell (VSMC) proliferation associated with arterial injury causes restenosis, which remains to be resolved in cardiovascular and ischemic cerebrovascular disease, especially after balloon angioplasty. Fibroblast growth factor (FGF) is a potent mitogen and a trophic factor for a variety of cells, including VSMCs. We constructed a replication-deficient adenovirus vector, designated AxCA delta FR, coding a truncated form of fibroblast growth factor receptor-1 (FGFR-1) gene lacking the intracellular domain to interrupt receptor-mediated FGF signaling, and examined its effect on the proliferation of primary-cultured rat VSMCs. We transferred the truncated form of the FGFR-1 gene to the VSMCs and confirmed its expression and localization in infected cells by Western blotting and immunofluorescence study. The VSMCs infected with AxCA delta FR degenerated and the proliferation of these cells was suppressed markedly by the infection with this virus in vitro. Our results suggest that the receptor-mediated signal of FGFs has an important role in VSMC proliferation and gene transfer of a truncated form of FGFR using adenoviral vector may be useful for the treatment of the diseases caused by excessive proliferation of VSMCs like restenosis after percutaneous transluminal angioplasty or carotid endoarterectomy.

Adenoviridae↗
PubMed1998

Three-vessel occlusion using a micro-clip for the proximal left middle cerebral artery produces a reliable neocortical infarct in rats.

We demonstrate a new three-vessel occlusion model of temporary focal ischemia in Sprague-Dawley rats (n=13). Under a surgical microscope, bilateral carotid arteries and the left middle cerebral artery (MCA) were occluded for 2 h using a snare for the neck and a micro-clip for the MCA. The reduction of regional cerebral blood flow (rCBF) monitored by laser Doppler flowmetry was 28% on average compared to the preischemic control value (100%) during ischemia. At that level of CBF reduction, there was no thrombus formation in the proximal MCA trunk, and a full recovery of rCBF was confirmed in the ischemic core within 5 min of reflow. Two days later, the cerebral infarct was limited to the neocortex, and the size and variability of the infarct are considered feasible for the assessment of any therapeutic challenge against the ischemic damage due to temporary focal ischemia in this model.

Animals↗
PubMed1998

Migration behavior of rodent granule neurons in the presence of antibody to the 4C5 antigen.

We have reported the production of monoclonal antibody 4C5, which recognizes a cell surface antigen, the 4C5 antigen, involved in granule cell migration processes. In the present study, we investigated in a more precise manner the role of the 4C5 antigen in the different types of granule cell migrations that take place during cerebellar development. When cerebellar explant cultures derived from 10-day-old rats were performed for 2 days in the presence of monoclonal antibody 4C5, vertical granule cell migration, occurring in the presence of glia, was not significantly inhibited. In contrast, when monoclonal antibody 4C5 was included in the medium of microexplant cultures derived from 4-day-old mice and maintained for 4 days in vitro, granule cell migrations that occurred both parallel and perpendicular to the neurite bundles that were free of glia were inhibited. Moreover, a stronger inhibitory effect of the antibody was observed on migration perpendicular to the neurite bundles compared with the parallel type of migration. Our results indicate that the 4C5 antigen differentially affects the different developmental stages and types of granule cell migration during rodent cerebellar development.

Animals↗
PubMed1998

Nitric oxide synthase immunoreactivity related to cold-induced brain edema.

To determine the relationship between brain edema and the expression of nitric oxide synthase (NOS), we immunohistochemically studied the distribution and level of NOS in rat brain cold injury model. Vasogenic brain edema was produced by cortical freezing lesion. NOS immunohistochemical studies were performed 4 and 8 h, 1, 3, 5, 7, 14 and 21 days after injury. In control normotensive rats, immunoreactivity for NOS was observed in scattered neuronal cells as reported previously, but there was no reactivity in glial cells. In the present study in the cold injury model, however, fibrinogen staining showed extravasated plasma fluid extending to the white matter contralateral to the site of cold injury. NOS immunoreactivity was observed in most reactive astrocytes and a proportion of the microglial cells and macrophages in the white matter not only just beneath the area of cold injury but also in the contralateral side. The nerve cells in the edematous region scarcely showed additional immunoreactivity for NOS. The distribution of increased NOS relatively corresponded with the sites of extravasated plasma fluid demonstrated by fibrinogen staining. Electron microscopically, NOS was observed in astrocytes along the rough endoplasmic reticulum suggesting that NOS was produced in the cells and not taken up from the surroundings. Based on these findings, we postulate that brain edema and the simultaneously generated free radicals or some extravasated plasma components may induce expression of NOS in the reactive cells, and that the NO thus generated may be involved in the development of diffuse degeneration of the white matter which accompanies brain edema.

Animals↗
PubMed1998

Inhibitory effects of ginsenoside Rh2 on tumor growth in nude mice bearing human ovarian cancer cells.

Ginsenoside Rh2 (Rh2), isolated from an ethanol extract of the processed root of Panax ginseng CA Meyer, inhibits the growth of B16 melanoma cells. This study was designed to evaluate the ability of Rh2 to inhibit growth of human ovarian cancer cells (HRA) in vitro and in nude mouse. Rh2 inhibited proliferations of various established human ovarian cancer cell lines in a dose-dependent manner between 10 and 60 microM in vitro and induced apoptosis at around the IC50 dose. When HRA cells were inoculated s.c. into the right flank of nude mice, all mice formed a palpable tumor within 14 days. Although i.p. administration of Rh2 alone hardly inhibited the tumor growth, when Rh2 was combined with cis-diamminedichloroplatinum(II) (CDDP) the tumor growth was significantly inhibited, compared to treatment with CDDP alone. When mice were treated p.o. with Rh2 daily (but not weekly), the tumor growth was significantly (P<0.01) inhibited, compared to CDDP treatment alone. When Rh2 was combined with CDDP, the degree of tumor growth retardation was not potentiated. The survival time was significantly (P<0.05) longer than that of medium alone-treated controls or the group treated with CDDP alone. Then, we examined whether p.o. administration of Rh2 has a dose-dependent inhibitory effect on the tumor growth. I.p. and weekly administration of CDDP had more potent antitumor activity in the order of 1 mg/kg, 2 mg/kg and 4 mg/kg, whereas p.o. and daily administration of Rh, (0.4 to 1.6 mg/kg) not only had antitumor activity comparable to that of 4 mg/kg CDDP, but also resulted in a significant increase of the survival. Doses of Rh2 used in this study did not result in any adverse side-effects as confirmed by monitoring hematocrit values and body weight, unlike 4 mg/kg CDDP, which had severe side-effects. It is noteworthy that p.o. but not i.p. treatment with Rh2 resulted in induction of apoptotic cells in the tumor in addition to augmentation of the natural killer activity in spleen cells from tumor-hearing nude mice. Thus, particularly in view of the toxicity of CDDP, Rh2 alone would seem to warrant further evaluation for treatment of recurrent or refractory ovarian tumor.

Animals↗
PubMed1998

Apoptosis of medial smooth muscle cells in the development of saccular cerebral aneurysms in rats.

BACKGROUND AND PURPOSE: Using an animal model, we examined the role of apoptosis in the disappearance of medial smooth muscle cells (SMCs) during the development and growth of cerebral aneurysms. METHODS: Various degrees of cerebral aneurysms were induced in the right anterior cerebral artery-olfactory artery bifurcations in 65 Sprague-Dawley rats with ligation of the left common carotid artery and renal hypertension. We performed in situ end labeling of fragmented DNA with the lesions in 45 rats and electron microscopic study in the other 20 rats. RESULTS: With in situ end labeling of fragmented DNA, 4+/-3 apoptotic medial SMCs were detected in 35 of the 45 bifurcations. Apoptotic SMCs appeared in the medial layer in the "preaneurysm" group, the site speculated to show an aneurysmal change in the near future (6+/-3), and in the media in the "early aneurysm" group, which showed characteristics such as a small depression (5+/-3). In the "progressive aneurysm" group, they appeared more frequently at the aneurysmal neck (3+/-2) than the dome (1+/-1). By electron microscopic study, shrunken medial SMCs exhibiting morphological apoptotic changes such as chromatin condensation and fragmentation of the cytoplasm and nucleus were observed in the preaneurysm and early aneurysm groups and at the neck portion in the progressive aneurysm group. In the aneurysmal dome, SMCs showed late characteristics of apoptosis such as more advanced nuclear and cytoplasmic condensation and formation of apoptotic bodies. CONCLUSIONS: The present findings indicate that there is an association between apoptosis of medial SMCs and the formation of saccular cerebral aneurysms.

Aneurysm↗
PubMed1998

Direct anastomotic bypass for cerebrovascular moyamoya disease.

Therapeutic result and pitfalls in the surgical treatment of cerebrovascular moyamoya disease are evaluated. During the recent 15 years, 268 patients with moyamoya disease have been treated in our clinic. Among them, 238 patients showed ischemic symptoms. Superficial temporal artery to middle cerebral artery anastomoses combined with temporal muscle grafting (encephalo-myo-synangiosis) were performed for most of the cases. Complete remission and clinical improvement were obtained in 34.0% and 64.2% of the patients, respectively. Symptomatic aggravation due to ischemic complication followed the operation in five patients (1.9%). Normocapnic control during general anesthesia with sufficient hydration is essential to avoid perioperative ischemic complications. Omental graft was performed in 16 patients. In 13 patients, omental graft was performed for the progressing ischemia in the posterior cerebral artery or anterior cerebral artery distribution. In the other three patients, omental graft was used for marked brain atrophy.

Anastomosis, Surgical↗
PubMed1998

Role of transforming growth factor-beta1 in the pathogenesis of moyamoya disease.

OBJECT: Prominent features of moyamoya disease are intimal thickening of the cerebral arterial trunks and abundant angiogenesis for collateral blood supplies, but its pathogenesis is still unknown. The aim of this study was to test the possibility that transforming growth factor-beta1 (TGFbeta1) may play a role in the pathogenesis of moyamoya disease. METHODS: The authors used reverse transcription-polymerase chain reaction to analyze the expression level of TGFbeta1 in smooth-muscle cells cultured from the superficial temporal arteries (STAs) and measured the serum level of TGFbeta1 by using enzyme-linked immunosorbent assay. Although the STA is not predominantly involved with moyamoya disease, it has been used in studies of the pathogenesis of this disease. In this report, the STAs from six patients with moyamoya disease and four with arteriosclerotic cerebrovascular disease, along with sera from 14 patients with moyamoya disease and 10 normal healthy volunteers, were studied. The expression of TGFbeta1 was significantly higher in cultured smooth-muscle cells derived from the STAs of patients with moyamoya disease than in those derived from the STAs of patients with arteriosclerotic cerebrovascular disease (p < 0.05). The serum level of TGFbeta1 was also significantly higher in patients with moyamoya disease than in controls (p < 0.0005). CONCLUSIONS: Taking into account the functional roles of TGFbeta1 in the expression of connective tissue genes and angiogenesis, these investigators suggest that TGFbeta1 is associated with the pathogenesis of moyamoya disease, including abundant neovascularization, although their findings do not necessarily mean that TGFbeta1 is a causative factor in this disease.

Adolescent↗
PubMed1997

Adenovirus-mediated gene transfer of basic fibroblast growth factor induces in vitro angiogenesis.

To investigate the possibility of adenovirus-mediated gene transfer in the treatment of vascular occlusive diseases, we constructed a replication-deficient recombinant adenovirus vector coding for human basic fibroblast growth factor (bFGF) and examined its effect on the proliferation and differentiation of vascular endothelial cells in vitro. Human umbilical vein endothelial cells (HUVECs) were successfully infected with high efficiency and expressed 18 kD protein which is immunoreactive to anti-bFGF monoclonal antibody. This protein was accumulated mainly in the nuclei of the cells, but was also detected in the culture medium although the complimentary DNA (cDNA) did not contain the classical secreting signal sequence. The proliferation assay of HUVECs infected with bFGF-expressing adenovirus revealed a significant increase in cell number over control. Infection with this virus also enhanced tubular formation of HUVECs on reconstituted basement membrane. Neovascularization and the formation of collateral vessels play important roles in minimizing tissue damage in ischemic disorders. These results imply that the use of bFGF-expressing recombinant adenovirus may be a suitable in vivo gene therapy for ischemic diseases.

Adenoviridae↗