Biomedical subjects

S Nagao

Publications and source records attributed to S Nagao.

At least 73 records · Page 4Linked to original sources

PubMed2000

Effect of probucol in a murine model of slowly progressive polycystic kidney disease.

Epithelial proliferation, extracellular matrix remodeling, and interstitial inflammation are central elements in the pathogenesis of slowly progressive polycystic kidney disorders. Probucol, an antioxidant that lowers plasma cholesterol, has been shown to decrease smooth muscle cell proliferation and macrophage accumulation in blood vessels and to prevent restenosis after coronary angioplasty. We determined in 30-day-old male BDF1-pcy hybrid mice (derived from mating DBA/2FG-pcy and C57BL/6FG-pcy) the effect of probucol administered in the diet (1%) for 200 days on kidney weight relative to body weight (KW/BW), cyst expansion, renal interstitial fibrosis, and serum urea nitrogen (SUN) concentration. Animals were fed a moderately high-protein diet (HPD, 36%) to accentuate the development of renal cysts and to promote interstitial fibrosis. Probucol decreased serum cholesterol from 68 to 16 mg/dL but had no effect on food intake or body weight. Probucol decreased relative kidney size from 4.16% +/- 0.55% to 2.64% +/- 0.12% KW/BW (P < 0.01), SUN from 30.5 +/- 1.8 to 25.9 +/- 1.0 mg/dL (P < 0.05), cystic index from 2.45 +/- 0.11 to 1.36 +/- 0.10 (P < 0.01), and fibrosis index from 2.40 +/- 0.11 to 1.82 +/- 0.08 (P < 0.01). We conclude that probucol ameliorates the progressive deterioration in renal function and structure in pcy mice ingesting a relatively high level of dietary protein.

Animals↗

PubMed2000

Appearance and alteration of TUNEL positive cells through epileptogenesis in amygdaloid kindled rat.

To evaluate the role of neural cell death during and after kindling epileptogenesis, apoptotic cells were analyzed in amygdaloid kindled rat using TUNEL staining as a marker of programmed cell death. TUNEL positive cells (TPC) were stained and counted as apoptotic cells in hippocampus, white matter, diencephalon, and cortex at three stages; C0 (before kindling), C3 (during kindling) and C5 (fully kindled). The animals were studied 2 h after the last stimulation. In all regions except cortex, apoptotic cells in stage C3 were significantly increased as compared to those in stage C0. Especially, in white matter significantly more apoptotic cells in stage C3 were detected than in stage C5. The present data showed that in the course of getting the epileptogenesis, apoptosis had already occurred and this type of cell death may play a significant role in reaching stage C5 through kindling.

Amygdala↗

PubMed2000

Progressive renal fibrosis in murine polycystic kidney disease: an immunohistochemical observation.

BACKGROUND: The appearance of interstitial fibrosis in polycystic kidneys is emblematic of progressive disease. Matrix forming this scar tissue is derived from local renal cells in response to cystogenesis. We investigated the phenotype of collagen-producing cells in the cystic kidneys of DBA/2-pcy mice to better characterize the spectrum of interstitial cells associated with renal fibrogenesis. METHODS: The extent of interstitial fibrosis and the number of fibroblasts in cystic kidneys were first quantitated over time using computer-assisted image analysis. Subsequently, antisera to four cell protein markers were studied by coexpression immunohistochemistry during progression of fibrosis using confocal microscopy. The antisera included fibroblast-specific protein 1 (FSP1) for fibroblast phenotype, alpha-smooth muscle actin (alpha-SMA) for contractile phenotype, vimentin (VIM) for mesenchymal phenotype, and heat shock protein 47 (HSP47) for interstitial collagen-producing phenotype. RESULTS: Interstitial fibrosis in cystic kidneys gradually increased throughout the 30-week observation period of our study. With progression of cystogenesis, most of the tubules in pcy mice either dilated or disappeared with time. FSP1+ fibroblasts were distributed sparsely throughout the renal interstitium of young pcy and wild-type mice. Their number increased in the widening fibrotic septa by 18 weeks of age and persisted through 30 weeks of the study interval. Some epithelia among remnant tubules trapped within fibrotic septa around adjacent cysts also acquired the phenotype of FSP1+, HSP47+ collagen-producing fibroblasts, suggesting a possible role for epithelial-mesenchymal transformation (EMT) in this process. Most FSP1+ fibroblasts were alpha-SMA-, but HSP47+, suggesting they were producing collagen proteins for the extracellular matrix. alpha-SMA+, FSP1-, HSP47+ or HSP47- cells were also observed, and the latter tended to distribute independently in a linear pattern, reminiscent of vasculature adjacent to forming cysts. VIM+ expression was not observed in alpha-SMA+ cells. CONCLUSIONS: Many nonoverlapping as well as fewer overlapping populations of FSP1+ and alpha-SMA+ cells shared in the collagen expression associated with progressive fibrogenesis in pcy mice undergoing cystogenesis. Some FSP1+ fibroblasts are likely derived from tubular epithelium undergoing EMT, while alphaSMA+, VIM- cells probably represent vascular smooth muscle cells or pericytes surviving vessel attenuation during the chaos of fibrogenesis. Importantly, not all interstitial cells producing collagens are alpha-SMA+.

Actins↗

PubMed2000

cAMP stimulates the in vitro proliferation of renal cyst epithelial cells by activating the extracellular signal-regulated kinase pathway.

BACKGROUND: : Cellular proliferation is a key factor in the enlargement of renal cysts in autosomal dominant polycystic kidney disease (ADPKD). We determined the extent to which adenosine 3':5'-cyclic monophosphate (cAMP) may regulate the in vitro proliferation of cyst epithelial cells derived from human ADPKD cysts. METHODS: : Epithelial cells from cysts of individuals with ADPKD and from normal human kidney cortex (HKC) of individuals without ADPKD were cultured. The effects of agonists and inhibitors on the rate of cellular proliferation and the activation of extracellular signal-regulated kinase (ERK1/2) were determined. RESULTS: : 8-Br-cAMP (100 micromol/L) stimulated the proliferation of cells from eight different ADPKD subjects to 99.0% above baseline; proliferation was inhibited by protein kinase A (PKA) antagonists H-89 (97%) and Rp-cAMP (90%). Forskolin (10 micromol/L), which activates adenylyl cyclase, increased proliferation 124%, and receptor-mediated agonists arginine vasopressin, desmopressin, secretin, vasoactive intestinal polypeptide, and prostaglandin E2 stimulated proliferation 54.2, 56.3, 46.7, 37.1, and 48.3%, respectively. The mitogen extracellular kinase (MEK) inhibitor PD98059 completely inhibited ADPKD cell proliferation in response to cAMP agonists, but genistein, a receptor tyrosine kinase inhibitor, did not block cAMP-dependent proliferation. cAMP agonists increased the activity of ERK above control levels within five minutes. In contrast to ADPKD, proliferation and ERK activity of cells derived from normal HKC were not stimulated by cAMP agonists, although electrogenic Cl- secretion was increased by these agonists in both ADPKD and HKC cell monolayers. CONCLUSIONS: : We conclude that cAMP agonists stimulate the proliferation of ADPKD but not HKC epithelial cells through PKA activation of the ERK pathway at a locus distal to receptor tyrosine kinase. We suggest that the adenylyl cyclase signaling pathway may have a unique role in determining the rate of cyst enlargement in ADPKD through its actions to stimulate cellular proliferation and transepithelial solute and fluid secretion.

Cell Division↗

PubMed2000

Treatment of arteriovenous malformation of the brain--preliminary experience.

With the availability of new techniques, such as intravascular embolisation and radiosurgery, the therapeutic approach to arteriovenous malformations (AVMs) of the brain has recently been modified. The present study reports the authors, experiences in treating AVMs over the past 13 years. Spetzler-Martin grading of AVMs was I and II in 19 cases, III in 12, IV in 5 and V in 1 case. Four therapeutic regimens were utilised: surgical resection alone, embolisation and resection, and radiosurgery alone or after surgical resection. Generally, for low-grade AVMs (Spetzler-Martin grades I, II and III), the therapeutic choice was surgical resection in 27 cases, in combination with pre-operative embolisation in two of these patients. Two cases received radiotherapy only and one case received radiosurgery after embolisation, while one case was treated conservatively. Of the five cases of grade IV, four required surgical treatment, whereas the fifth case was treated conservatively. Favourable results (good recovery and moderate disability) were obtained in 96% of the low-grade AVMs as compared with the high-grade AVMs (66%) that had a poor outcome (due to primary brain damage resulting from haemorrhage at the onset in three cases and due to postoperative re-bleeding in one case). This report summarises preliminary experience in treating intracranial AVMs by surgical resection, intravascular embolisation and radiotherapy. Good therapeutic results can be expected by combining these therapeutic modalities.

Adult↗

PubMed2000

Effects of hypothermia on intracranial pressure and brain edema formation: studies in a rat acute subdural hematoma model.

Acute subdural hematoma (SDH) is the most common mass lesion in severe head injury, and brain ischemia is the leading pathophysiological mechanism in the development of secondary brain damage following SDH. Hypothermia has been employed as an effective neuroprotective procedure in clinical and laboratory studies on cerebral ischemic and contusional injuries. In the present study, we used a rat acute SDH model to assess the effect of hypothermia on the intracranial pressure (ICP) and also on the brain edema formation at 4 h after hematoma induction. Mild (34 degrees C) and moderate (32 degrees C) hypothermia did not significantly affect the ICP or cerebral perfusion pressure, but they were associated with a significant lower cortical brain edema formation beneath the hematoma (81.09 +/- 0.49%, p<0.05; and 80.88 +/- 0.17%, p<0.01) when compared with the normothermic control group (81.65 +/- 0.52%). This reduction in brain edema formation was comparable to the results of MK-801 treatment (80.95 +/- 0.35%, p<0.01). The present findings indicate that hypothermia represents a potent neuroprotective strategy. The possible protective mechanisms of hypothermic protection afforded in this rat acute SDH model are discussed.

Animals↗

PubMed2000

Transforming growth factor-beta1 stimulates contraction of human glioblastoma cell-mediated collagen lattice through enhanced alpha2 integrin expression.

Rapid invasiveness is a feature of the highly malignant glioblastoma tumor and is closely related to patient prognosis. The interaction between extracellular matrix (ECM) and cell surface receptors such as integrin heterodimers play a key role in the process of tumor invasion. We investigated the effects of transforming growth factor-beta1 (TGF-beta1), which is a mitogenic factor for glial cells, on integrin expression in T98G human glioblastoma cells using an in vitro model 3-dimensional collagen lattice. Exogenously applied TGF-beta1 dose-dependently enhanced collagen lattice contraction. Among the inhibitory antibodies tested against alpha integrin subunits, the anti-alpha2 antibody, P1-E6, alone prevented the enhanced contractile response by TGF-beta1, whereas any alpha integrin antibody (including P1-E6) had little effect on lattice contraction when cultured without TGF-beta1. RT-PCR analysis revealed that TGF-beta1 strongly increased alpha2 integrin transcript level. Furthermore, pretreatment with antisense phosphorothioate oligodeoxynucleotides against human alpha2 integrin using hemagglutinating virus of Japan (HVJ) liposome-mediated transfer prevented the effects of TGF-beta1 and also reduced the lattice contraction even in the absence of TGF-beta1. This data indicates that increased expression of alpha2 integrin is responsive to enhanced collagen lattice contraction by TGF-beta1. We suggest that TGF-beta1 exerts its effects on the invasive property of glioblastoma cells via upregulation of the alpha2 integrin subunit expression.

Antigens, CD↗

PubMed2000

Assessment of efficiency and safety of adenovirus mediated gene transfer into normal and damaged murine livers.

BACKGROUND: When recombinant adenoviruses are infused directly into the circulation, transgene expression is almost completely restricted to the liver. AIMS: Efficiency and safety of adenovirus mediated gene transfer into damaged livers were examined in mice with liver cirrhosis or fulminant hepatitis. METHODS: Liver cirrhosis and fulminant hepatitis were induced by intraperitoneal administration of thioacetamide and D-galactosamine followed by lipopolysaccharide, respectively. Mice were infused with adenoviruses carrying the Escherichia coli beta-galactosidase gene, lacZ gene, into the tail vein. Transduction efficiency of the lacZ gene was estimated histochemically by X-gal staining and quantitatively using a chemiluminescent assay. Activation of adenovirus specific T cells and development of neutralising antibodies against adenovirus were also examined. RESULTS: Histochemical evaluation revealed that approximately 40%, 80%, and 40% of cells in normal, cirrhotic, and fulminant hepatitis livers, respectively, were stained blue using X-gal staining. Quantitative analyses revealed that levels of lacZ expression in cirrhotic livers were approximately 2.5-fold and sixfold greater than those in normal and fulminant hepatitis livers, respectively. Although transgene expression in fulminant hepatitis livers was significantly lower than that in normal livers, marked levels of transgene expression were achieved even in fulminant hepatitis livers. Significant adverse effects of adenoviruses were not observed in damaged livers. There were no significant differences in cellular or humoral immune responses to adenoviruses among animals with normal, cirrhotic, and fulminant hepatitis livers. CONCLUSIONS: Our results suggest that gene therapy with adenoviruses may be used efficiently and safely, even in patients with severe liver disease.

Adenoviridae↗

PubMed2000

Effects of delayed intraischemic and postischemic hypothermia on a focal model of transient cerebral ischemia in rats.

BACKGROUND AND PURPOSE: Intraischemic mild hypothermia has been shown to be neuroprotective in reducing cerebral infarction in transient focal ischemia. As a more clinical relevant issue, we investigated the effect of delayed intraischemic and postischemic hypothermia on cerebral infarction in a rat model of reversible focal ischemia. We also examined the effect of hypothermia on the inflammatory response after ischemia-reperfusion to assess the neuroprotective mechanism of brain hypothermia. METHODS: Rats were subjected to 2 hours of middle cerebral artery occlusion followed by 22 hours of reperfusion under the following protocols: (1) rats were treated with normothermia (37.0 degrees C, 4 hours) and then housed in room temperature (25 degrees C, 18 hours) and (2) rats were treated with hypothermia (33.0 degrees C, 4 hours, brain temperature modulation was started 30 minutes before the reperfusion) and then housed in cold temperature (5 degrees C, 18 hours). Animals were killed 24 hours after the onset of ischemia. The infarct volume was examined with 2,3,5-triphenyl-tetrazolium chloride staining. The accumulation of polymorphonuclear leukocytes (PMNLs) and the expression of intercellular adhesion molecule-1 mRNA were evaluated in both groups. RESULTS: A significant reduction (P<0.05) in infarct volume was found in the hypothermia group compared with the normothermia group. Compared with the normothermia group, hypothermic treatment also significantly reduced the accumulation of PMNLs (P<0.01) and inhibited the overexpression of intercellular adhesion molecule-1 mRNA at 22 hours of reperfusion after 2 hours of ischemia. CONCLUSIONS: Ischemic brain damage can be reduced with delayed intraischemic and prolonged postischemic hypothermia in a focal model of transient cerebral ischemia in rats. The neuroprotective mechanism of hypothermia may be mediated by suppression of PMNL-mediated inflammatory response after ischemia-reperfusion in this model.

Animals↗

PubMed2000

Endovascular treatment of basilar tip aneurysm associated with moyamoya disease--case report.

A 58-year-old female was admitted unconscious to a local hospital. Computed tomography demonstrated subarachnoid hemorrhage. Cerebral angiography revealed evidence of moyamoya disease and a saccular aneurysm at the tip of the basilar artery. The patient was transferred to our hospital for embolization of the basilar tip aneurysm. Endovascular embolization was performed using Guglielmi detachable coils (GDCs), and the aneurysm was completely occluded with preservation of the parent artery. No change in the patient's neurological status was seen during and after the procedure. Endovascular treatment using GDCs appears to be particularly suitable for ruptured cerebral saccular aneurysms in patients with moyamoya disease.

Basilar Artery↗

PubMed2000

Balloon-assisted coil placement in wide-necked cerebral aneurysms: preliminary clinical experience.

Endovascular treatment of wide-necked cerebral aneurysms with Guglielmi detachable coils (GDCs) has been limited due to coil protrusion into the artery. Seven patients with wide-necked cerebral aneurysms were treated with GDCs with temporary balloon inflation for mechanical protection during coil placement. Transarterial embolization of the aneurysm with GDCs had failed due to coil protrusion into the parent artery. The use of simultaneous temporary balloon protection achieved more dense intra-aneurysmal coil packing, especially in the neck, without compromising the parent artery.

Aged↗

PubMed2000

Alteration of the CDKN2/p16 gene is not required for HPV-positive uterine cervical cancer cell lines.

To determine whether alterations of the CDKN2/p16 might be involved in HPV-positive cervical cancers, we examined for alterations of this gene and function of the protein p16 to interact with CDK4 in 5 cervical cancer cell lines. No alteration of this gene was detected. Proteins for p16 and CDK4 were normally expressed and function of p16 to interact with CDK4 was not abrogated in these cell lines. These cell lines were human papillomavirus (HPV)-positive and carried wild-type p53. These findings suggest that phosphorylation of pRb by CDK4 is not critical in the carcinogenesis or in the establishment of HPV-positive cervical cancer cell lines, since HPV E6 or E7 viral-transforming proteins inactivate p53 and pRb tumor suppressor protein function, resulting in deregulated progression of the cell cycle.

Cyclin-Dependent Kinase 4↗

PubMed2000

Electrochemotherapy can eradicate established colorectal carcinoma and leaves a systemic protective memory in mice.

Mice bearing subcutaneously established colorectal carcinoma (CRC) were given intratumoral, intravenous or intraperitoneal injection of various doses of bleomycin (BLM), followed by the delivery of direct current, square wave electric pulses to the tumor. Approximately 50% of animals treated with electrochemotherapy with BLM had completely eradicated established CRC tumors. Importantly, it was shown that CRC-specific cytotoxic T lymphocytes were elicited in the spleens of cured animals, resulting in the protection of the rechallenge with CRC. These results indicate that electrochemotherapy with BLM is promising for the treatment of metastatic CRC as well as the original lesion.

Animals↗

PubMed2000

Amelioration of murine experimental colitis by inhibition of mucosal addressin cell adhesion molecule-1.

Mucosal addressin cell adhesion molecule-1 (MAdCAM-1) is an adhesion molecule that mediates recruitment of lymphocytes into the gut mucosa. Attenuation of excessive expression of MAdCAM-1 in the inflamed mucosa could be useful for treatment of inflammatory bowel diseases. The aim of this study was to investigate whether anti-MAdCAM-1 antibody has a prophylactic effect on experimental colitis induced by dextran sulfate sodium (DSS). Colitis was induced by orally feeding BALB/c mice 5% DSS (mol. wt. 5000). Mice were sacrificed at intervals up to 21 days after administration to evaluate the changes over time in intestinal damage. The infiltrating lymphocytes and their subpopulations, and the expression of cell adhesion molecules were determined by immunohistochemistry. In another set of experiments, the attenuating effect of i.p.-injected anti-MAdCAM-1 antibody on colonic lesions was evaluated on day 14. Significant histological damage with shortening of crypts was observed on day 14 in colonic mucosa of DSS-treated mice. Before mucosal inflammation had become significant, expression of MAdCAM-1 was already increased in the microvessels of lamina propria on day 7. Significant infiltration of beta7-integrin-positive T and B cells in the mucosa was then noted on day 14. Administration of anti-MAdCAM-1 antibody significantly reduced colonic injury as well as the infiltration of beta7-integrin-positive lymphocytes in the colonic mucosa. This antibody also was effective when given 7 days after the start of DSS treatment. In the present study, we demonstrated that anti-MAdCAM-1 antibody significantly ameliorates DSS-induced colitis, suggesting that MAdCAM-1 may be useful for control of inflammatory bowel diseases.

Animals↗

PubMed1999

Re-evaluation of sexual dimorphism in human corpus callosum.

To study the sexual dimorphism of human corpus cauosum (CC), we analyzed the midsaggital magnetic resonance imaging (MRI) morphometry in 67 adults aged (mean+/-s.d.) 36.82+/-9.35 years. Four specific angles of the CC were determined. All four angles in 34 females and 33 age-matched males showed a significant difference between females and males. These morphometric findings confirm a gender difference in the orientation of corpus callosum.

Adult↗

PubMed1999

Differences in mossy and climbing afferent sources between flocculus and ventral and dorsal paraflocculus in the rat.

Sources of mossy and climbing fiber inputs to the flocculus (FL), ventral paraflocculus (VP) and/or dorsal paraflocculus (DP) were identified in the vestibular ganglion, medulla oblongata and pons of 19 Wistar rats after 26 local injections of horseradish peroxidase, wheat-germ agglutinin-conjugated horseradish peroxidase, fast blue or diamidino yellow into the FL, VP and/or DP. There were large differences in the sources of mossy fibers to the FL and VP/DP. Labeled neurons after injections into the FL were observed mainly in the ipsilateral vestibular ganglion, bilaterally in the vestibular and prepositus hypoglossal nuclei, and in the caudal part of the nucleus reticularis tegmenti pontis. Labeled neurons were rarely observed in the pontine nuclei after localized injections into the FL. By contrast, after injections into the VP and/or DP, numerous labeled neurons were observed in the pontine nuclei with a contralateral predominance and in the rostral part of the nucleus reticularis tegmenti pontis bilaterally, but not in the vestibular nuclei in either side. Sources of climbing fibers to the FL and paraflocculus were completely contralateral to the injection side. After injection into the FL, labeled neurons were observed in the caudal dorsal cap and ventrolateral outgrowth of the inferior olivary nucleus. After injections into the VP, labeled neurons were observed mainly in the rostral dorsal cap, ventral medial accessory olivary nucleus (MAO) and caudal half of the ventral leaf of the principal olivary nucleus. After injections into the DP, labeled neurons were observed in the ventral MAO and caudal half of the ventral leaf of the principal olivary nucleus. These differences in the sources of mossy and climbing fiber inputs may suggest functional differences between the FL and VP/DP. The present results are consistent with our previous observations in monkey that the FL and VP/DP exhibit quite different mossy fiber input organizations.

Amidines↗

PubMed1999

Two cases of inflammatory bowel disease with multiple myeloma.

A significant increase has been reported in reticuloendothelial neoplasms in patients with inflammatory bowel diseases. We present two rare cases of multiple myeloma in patients with inflammatory bowel diseases. One was in a 58-year-old woman with ulcerative colitis, and the other was in a 59-year old woman with Crohn's disease. In both patients, multiple myeloma occurred during long-term observation of inflammatory bowel disease and during the inactive stage of intestinal inflammation. The multiple myeloma appeared to have resulted from monoclonal gammopathy of undertermined significance in both patients, and was diagnosed by characteristic serum and bone marrow findings. Our findings suggested that multiple myeloma should be particularly considered in women of middle or advanced age with ulcerative colitis or Crohn's colitis and serum monoclonal gammopathy.

Female↗

PubMed1999

The chronic cell death with DNA fragmentation after post-ischaemic hypothermia in the gerbil hippocampus.

The long-term effects of post-ischaemic hypothermia are controversial. The purpose of this study was to examine the long-term effects of post-ischaemic hypothermia on neuronal survival in gerbils in terms of morphology and function. Hypothermia was induced at 32 degrees C for 4 h immediately after ischaemia. Examination was performed at 1 week and at 1 month after ischaemia. Post-ischaemic hypothermia prevented CA1 neuronal damage 1 week after ischaemia. At 1 month after ischaemic insult, however, the degree of the protective effect of post-ischaemic hypothermia was reduced in the lateral and medial CA1 areas. DNA fragmentation was also observed at 1 month. The errors in the 8-arm radial maze trial were increased at 1 month. These data may indicate that cells in the CA1 area are very vulnerable to ischaemia and die after post-ischaemic hypothermia, and that their death is associated with apoptosis.

Analysis of Variance↗