Biomedical subjects

S Okada

Publications and source records attributed to S Okada.

At least 253 records · Page 14Linked to original sources

PubMed1999

The establishment of sublines with opposite chemosensitivity from a patient with pulmonary large cell carcinoma and the implementation of treatment based on tumor heterogeneity.

Two sublines were established from the primary tumor of a patient with pulmonary large cell carcinoma. These two sublines had different growth characteristics in vitro and different tumor tissue structure in nude mice, and opposite drug sensitivities. Subline 1 was sensitive to a number of drugs, while its sensitivity to cisplatin (CDDP) was not very strong. In contrast, subline 2 was resistant to many drugs, but showed very strong sensitivity to CDDP. When the patient developed recurrence, he was first treated with CDDP-based chemotherapy based on the sensitivity of subline 2, followed by methotrexate-based treatment on the basis of sensitivity for subline 1. Complete remission (CR) was achieved after this alternating chemotherapy. To our knowledge, this is the first report of sublines with opposite sensitivity being established from the same tumor, achieving CR by the treatment of each subline.

Aged↗

PubMed1999

Genetic alterations in the JAG1 gene in Japanese patients with Alagille syndrome.

Alagille syndrome (AGS) is a congenital anomaly syndrome that affects liver, heart, pulmonary artery, eyes, face, and skeleton. Recently, mutations of the JAG1 gene, which encodes a ligand for the Notch receptor, have been identified in AGS patients. We investigated the JAG1 gene for genetic alterations in eight Japanese AGS patients, using fluorescence in situ hybridization (FISH), single strand conformation polymorphism (SSCP) analysis, and direct sequencing. Subtle genetic alterations were identified in six of the eight patients, including three frameshift mutations, two splice donor mutations, and one nonsense mutation. All alleles with identified mutations can be expected to produce non-functional truncated proteins without a transmembrane domain. There was no apparent correlation between the genotypes of the patients and their affected organs, although the phenotypes of the patients with mutations at the splice donor site were found to be less severe.

Alagille Syndrome↗

PubMed1999

Mutation analysis of a Japanese patient with fucosidosis.

Fucosidosis is a rare autosomal recessive disorder resulting from a deficiency of alpha-L-fucosidase. Recently, various mutations have been reported in this disease, but it is difficult to elucidate the phenotype from the genetic mutations. We report a patient with chronic infantile type fucosidosis, with a compound heterozygote of a nonsense mutation (W148X, Trp at codon 148 to stop codon) and a large deletion, including all exons. This is the first report of a large deletion demonstrated in fucosidosis. It is interesting that this patient has a relatively mild clinical course despite the absence of the mRNA. This case also indicates the difficulty in determining the phenotype from the genotype in fucosidosis.

Adolescent↗

PubMed1999

Selectin on activated platelets enhances neutrophil endothelial adherence in myocardial reperfusion injury.

OBJECTIVES: The glycoprotein P-selectin is an adhesion molecule that is rapidly expressed on the surface of platelets and endothelium during the inflammatory process. P-selectin on endothelium has been reported to play an important role in reperfusion injury. However, little is known regarding P-selectin on platelets in contributing to the pathophysiology of myocardial reperfusion injury. In this study, we hypothesized that P-selectin on platelets may enhance neutrophil endothelial adherence and this may play a role in neutrophil-mediated reperfusion injury. METHODS: Endothelial cells, cardiomyocytes, platelets and neutrophils were isolated from adult rats. Endothelial cells and cardiomyocytes were cultivated in a co-culture system. After exposure to hypoxia and reoxygenation, neutrophil adherence and migration were examined. RESULTS: After exposure to 6 h of hypoxia, endothelial cells co-incubated with platelets showed significantly greater neutrophil adherence (63.1 +/- 4.0%) and migration (78.2 +/- 6.7%) than endothelial cells alone (adhesion: 44.2 +/- 2.8%, migration: 57.9 +/- 4.9%). These increases were significantly inhibited (adhesion: 42.1 +/- 3.5%, migration: 65.5 +/- 3.8%) by an anti-P-selectin monoclonal antibody. Moreover, the superoxide-anion production was significantly elevated when activated platelets were added to neutrophils. This enhanced production was also inhibited by anti-P-selectin antibody. CONCLUSION: The presence of activated platelets enhanced neutrophil adhesion and migration process after hypoxia reoxygenation. This process may occur following platelet-neutrophil interactions via P-selectin and subsequent neutrophil activation.

Animals↗

PubMed1999

Epithelioid trophoblastic tumor: morphological and immunohistochemical study of three lung lesions.

Epithelioid trophoblastic tumor (ETT) is a term proposed for an unusual variant of trophoblastic tumor that is closely related to choriocarcinoma but shows monomorphic growth of highly atypical trophoblastic cells instead of the typical dimorphic pattern of choriocarcinoma. We report here 3 cases of ETT, all of which were lung lesions probably originating from uterine trophoblastic disease. The antecedent pregnancies of the 3 cases were hydatidiform mole, invasive mole, and term pregnancy, respectively. The tumors were composed of highly atypical mononucleate cells, which mainly involved alveolar spaces, forming nests with central eosinophilic necrosis. Multinucleate giant cells were found within the nests, but they were fewer in number than in typical choriocarcinoma. The tumors were not associated with extensive hemorrhage or necrosis, except for 1 case, in which the ETT was combined with typical dimorphic choriocarcinoma. Immunohistochemically, multinucleate giant cells and occasional mononucleate tumor cells showed positivity for human chorionic gonadotropin. Staining for human placental lactogen was positive in rare multinucleate giant cells, and in 1 case, tumor cells showed diffuse positivity for placental alkaline phosphatase. Because ETT has a remarkably epithelioid appearance in cytological and architectural features, differentiation from the epithelial malignancies is problematic. Trophoblastic markers are frequently expressed in nontrophoblastic tumors, and reactivity for those markers alone is not sufficient for exclusion of other tumors. Rather, evidence of ETT comes from a combination of morphological features, immunohistochemical study, and clinical history.

Adult↗

PubMed1999

Lineage switch in childhood leukemia with monosomy 7 and reverse of lineage switch in severe combined immunodeficient mice.

Morphophenotypic lineage switches occur in a small percentage of those with acute leukemia, and the underlying mechanisms are not clear. In this study, we attempted to induce a lineage switch in acute myelocytic leukemia (AML) with monosomy 7, whose lineage had switched from acute T-lymphocytic leukemia (T-ALL) during chemotherapy, in severe combined immunodeficient (SCID) mice. Although the transplanted myeloid cells were engrafted in SCID mice without cytokine administration, T-ALL developed in SCID mice treated with recombinant human granulocyte-macrophage colony-stimulating factor or recombinant human interleukin 3. Analysis of the nucleotide sequences of the rearranged T-cell receptor gamma-chain (TCR-gamma) gene revealed that this lineage switch resulted from the selection of the T-lineage subclone in SCID mice, which had expanded at onset. In addition, we found that the T-lineage and myeloid cells belonged to the distinct subclones, which were different in TCR-gamma gene rearrangements, but were derived from a common clone with an identical N-ras gene mutation for both subclones. In in vitro cultures, only the myeloid subclone grew; the T-lineage subclone failed to grow even in the presence of recombinant human granulocyte-macrophage colony-stimulating factor or recombinant human interleukin 3. These results suggested that the initial diagnostic T-lymphoid subclone, whose growth was dependent on these cytokines and the hematopoietic microenvironment, emerged from a bipotential T-lymphoid/myeloid leukemic stem cell, and further genetic event(s) induced the myeloid subclone, which grew independently of these cytokines and the microenvironment.

Acute Disease↗

PubMed1999

109Cd transport in rat brain.

The brain distribution of 109CdCl2 following administration into either the tail vein, the lateral ventricle or the olfactory bulb was studied to clarify permeability of the brain barrier system to cadmium (Cd) and Cd movement in the cerebrospinal fluid (CSF) and the brain extracellular fluid. One hour after intravenous (i.v.) injection, 109Cd was largely concentrated in the choroid plexus, and 109Cd concentration in the major part of the brain parenchyma, except for the circumventricular organs such as the pineal gland and the regions around them, was low. Six days after i.v. injection, 109Cd concentration in the choroid plexus was still high, and 109Cd was also detected highly in the pineal gland and small part around the median eminence. 109Cd concentration in the major part of the brain parenchyma was decreased in parallel with that in the blood. In the case of injection of 109CdCl2 into the lateral ventricle, a large portion of 109Cd was detected in the ventricular system 6 days after injection, and 109Cd concentration in the major part of the brain parenchyma was less than the detection limit. These results suggest that Cd cannot easily get into the brain and is blocked not only by the blood- brain and the blood-CSF barriers, but also by the ependymal and pial surfaces. In the case of injection of 109CdCl2 into the olfactory bulb, a large portion of 109Cd was detected in the injected area 24 h after injection, and, the next 24 h later, 109Cd distribution in the brain was not changed appreciably. These results suggest that Cd cannot easily move in the brain extracelular space, and is taken up into the brain parenchyma.

Animals↗

PubMed1999

Remission of progressive multifocal leukoencephalopathy following highly active antiretroviral therapy in a patient with HIV infection.

Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease resulting from lytic infection of oligodendrocytes by the papovavirus JC (JCV). PML has also been recognized as an AIDS-defining illness. The incidence of PML has increased since 1987 and it occurs in up to 4% of patients with AIDS. To date, there is no treatment available for PML and it usually results in death within 3-6 months of diagnosis. However, there are some reports of remission of PML after antiretroviral therapy. We report a 12-year-old child with hemophilia B and developing AIDS with the onset of PML. With highly active antiretroviral therapy, PML subsided with an increase of CD4 count from 10 to 300/microl in spite of about 1.0 X 10(4) human immunodeficiency virus (HIV)-1-RNA copies. He has survived more than 1 year without specific therapy against JCV. Highly active antiretroviral therapy appears to have improved his prognosis in HIV-associated PML.

Acquired Immunodeficiency Syndrome↗

PubMed1999

Ring chromosome 14 complicated with complex partial seizures and hypoplastic corpus callosum.

A Japanese male with mosaicism of ring chromosome 14 and chromosome 14 monosomy is described. He demonstrated the characteristic morphologic features of ring chromosome 14, in addition to mental retardation and epileptic seizures. Clusters of complex partial seizures, one of which originated in the left frontocentral region on electroencephalographic monitoring, were evident. His seizures responded to phenobarbital, and his mental and motor development was only mildly retarded. Magnetic resonance imaging revealed a hypoplastic corpus callosum, previously unknown in association with this syndrome.

Agenesis of Corpus Callosum↗

PubMed1999

Cupric nitrilotriacetate-induced apoptosis in HL-60 cells association with lipid peroxidation, release of cytochrome C from mitochondria, and activation of caspase-3.

Oxidative stress may be a common mechanism underlying various forms of cell death, including necrosis and apoptosis. The authors have reported previously that the cupric nitrilotriacetate (Cu-NTA), a renal carcinogen, induces oxidative DNA damage and apoptosis in HL-60 human leukemia cells (Ma, Y., et al. Free Radic. Biol Med. 25:568-575; 1998). The focus of this investigation was to examine the possible pathway of the apoptosis induced by Cu-NTA. Results of the present study demonstrated that after exposure of HL-60 cells to Cu-NTA, an increase in lipid hydroperoxide and loss of mitochondrial membrane potential (deltaphim) were observed, followed by the increase in cytosolic cytochrome c that was released from the mitochondria. These events proceeded and triggered the activation of caspase-3 (CPP32/apopain/Yama), resulting in the degradation of poly (ADP-ribose) polymerase and DNA fragmentation. The antioxidants, N-acetylcysteine and glutathione, protected the loss of deltaphim and blocked the apoptosis induced by Cu-NTA. In addition, Ac-DEVD-CHO, a specific inhibitor of caspase-3, inhibited Cu-NTA-induced apoptosis. These results suggested that Cu-NTA-induced apoptosis in HL-60 cells was, at least in part, triggered by free radical-induced lipid peroxidation of membrane, which induced the release of cytochrome c from mitochondria and activation of caspase-3.

Acetylcysteine↗

PubMed1999

Synip: a novel insulin-regulated syntaxin 4-binding protein mediating GLUT4 translocation in adipocytes.

Insulin-stimulated glucose transport and GLUT4 translocation require regulated interactions between the v-SNARE, VAMP2, and the t-SNARE, syntaxin 4. We have isolated a novel syntaxin 4-binding protein, Synip, which specifically interacts with syntaxin 4. Insulin induces a dissociation of the Synip:syntaxin 4 complex due to an apparent decrease in the binding affinity of Synip for syntaxin 4. In contrast, the carboxyterminal domain of Synip does not dissociate from syntaxin 4 in response to insulin stimulation but inhibits glucose transport and GLUT4 translocation. These data implicate Synip as an insulin-regulated syntaxin 4-binding protein directly involved in the control of glucose transport and GLUT4 vesicle translocation.

Adipocytes↗

PubMed1999

Molecular heterogeneity of Krabbe disease.

Krabbe disease (globoid cell leukodystrophy) is an autosomal recessive neurodegenerative disorder that affects both the central and peripheral nervous system due to an enzymatic defect of galactocerebrosidase (GALC). Following its cloning, many mutations in the galactocerebrosidase gene have been reported, but the correlation between phenotype and genotype was not clear in many cases. In this study we further investigated the molecular defects in another 10 patients (6 Japanese and 4 non-Japanese), using cultured skin fibroblasts, and found 10 mutations, of which 8 were novel, including a nonsense mutation (W647X) and 7 missense mutations (G43R, S52F, T262I, Y319C. W410G, R515H, T652R) in the coding region. Some phenotype-specific mutations were found but the other mutations were private. Mutations reported so far have been distributed over the whole GALC gene and it is difficult to speculate on functional domains of the GALC protein and phenotypically specific regions.

Alanine↗

PubMed1999

Phase II study of docetaxel in patients with metastatic pancreatic cancer: a Japanese cooperative study. Cooperative Group of Docetaxel for Pancreatic Cancer in Japan.

Docetaxel has been reported to show promising anti-tumour activity in pancreatic ductal cancer (PC). This study was conducted to evaluate the activity and toxicity of moderate-dose (60 mg m(-2)) docetaxel in Japanese chemo-naive patients with measurable metastatic PC. The patients had a performance status of 0-2. They received docetaxel intravenously over a 1- to 2-h period without any premedication for hypersensitivity reactions. This treatment was repeated every 3-4 weeks with dose adjustments based on the toxic effects observed. Twenty-one patients were eligible and treated with docetaxel. The median number of courses was 2 (range, 1-4). None of the patients achieved an objective response; seven showed no change and 13 showed progressive disease. In one patient, the response was not assessable because of early death. The median survival time for all patients was 118 days. The main grade 3-4 toxicities by patient were leucocytopenia (67%) and neutropenia (86%). Other grade 3-4 toxicities included anaemia (10%), thrombocytopenia (5%), nausea/vomiting (29%), anorexia (29%), GOT/GPT increase (10%), alkaline phosphatase increase (14%), malaise/fatigue (33%) and alopecia (24%). In conclusion, docetaxel, administered on this schedule, did not show significant anti-tumour activity in patients with metastatic PC.

Adult↗

PubMed1999

Thrombotic microangiopathy associated with reactivation of human herpesvirus-6 following high-dose chemotherapy with autologous bone marrow transplantation in young children.

Thrombotic microangiopathy (TMA) is a serious complication of BMT. Several factors are important in the etiology of TMA, such as cyclosporin A, GVHD, irradiation, intensive conditioning chemotherapy and infection, which cause damage to vascular endothelial cells leading to activation of these cells. We describe two young children with TMA following high-dose chemotherapy with autologous BMT. Development of TMA was accompanied by reactivation of HHV-6, which was identified by both an increase in the copy number of HHV-6 DNA in the peripheral blood and a significant increase in antibody titers to HHV-6. Thus, it was suggested that reactivation of HHV-6 together with high-dose chemotherapy played an important role in the pathogenesis of TMA in these patients. Since HHV-6 is known to infect vascular endothelial cells, and CMV which is virologically closely related to HHV-6, has been reported to be a pathogen that causes TMA, infection with HHV-6 of vascular endothelial cells may induce TMA via damage and activation of these cells.

Bone Marrow Transplantation↗

PubMed1999

Enhanced expression of recombinant dystrophin following intramuscular injection of Epstein-Barr virus (EBV)-based mini-chromosome vectors in mdx mice.

Gene transfer by direct intramuscular injection of naked plasmid DNA has been shown to be a safe, simple but relatively inefficient method for gene delivery in vivo. Eukaryotic plasmid expression vectors incorporating the Epstein-Barr virus (EBV) origin of replication (oriP) and EBNA1 gene have been shown to act as autonomous episomally replicating gene transfer vectors which additionally provide nuclear matrix retention functions. Prolonged expression of a LacZ reporter gene and recombinant human dystrophin was shown using EBV-based plasmid vectors transfected into C2C12 mouse myoblast and myotube cultures. Intramuscular injection of EBV-based dystrophin expression plasmids into nude/mdx mice resulted in significant enhancement in the number of muscle fibres expressing recombinant dystrophin compared with a conventional vector. This effect was observed for over 10 weeks after a single administration. These results indicate the potential advantage of EBV-based expression vectors for focal plasmid-mediated gene augmentation therapy in Duchenne muscular dystrophy (DMD) and a range of other gene therapeutic applications.

Animals↗

PubMed1999

Regional cerebral blood flow abnormalities in chronic solvent abusers.

This study aimed to reveal regional abnormalities of cerebral blood flow (CBF) and their relation to amotivational syndrome which causes poor social prognosis in solvent abusers Sixteen chronic solvent abusers (12 males and four females) along with five normal subjects underwent single photon emission computed tomography with N-isopropyl-p[123I]iodoamphetamine. The patients received a clinical evaluation with the Scale for the Assessment of Negative Symptoms. Using a semiquantitative method (normalized by the parietal cortex count), patients showed a statistically significant decrease in regional cerebral blood flow (rCBF) in the bilateral prefrontal cortices (P<0.01). In addition, the severity of hypoperfusion in the bilateral prefrontal cortices was related to the degree of severity of the avolition-apathy scale on SANS (left; P<0.05, right; P<0.01) even after excluding the effect of antipsychotics. These results suggest that rCBF abnormalities, especially in the prefrontal cortex, develop in chronic solvent abusers, and that this frontal hypoperfusion may be a biological basis of amotivational syndrome.

Adolescent↗

PubMed1999

A retroperitoneal bronchogenic cyst with malignant change.

A unique case of adenocarcinoma arising in a retroperitoneal bronchogenic cyst is presented. A 55-year-old woman presented with lower abdominal discomfort. Computed tomography revealed a retroperitoneal cystic mass attached to the ascending colon. The resected cyst was unilocular and filled with milky white mucus and hemorrhagic debris. Histologically, most of the cyst wall was of well-differentiated papillary adenocarcinoma with no cyst wall invasion. Other small areas of the cyst were lined with variably atypical dysplastic/metaplastic cuboidal to pseudostratified columnar epithelium. The cyst wall was mostly hyalinized, but there was apparent thickened subepithelial basement membrane, elastosis, and a single layer of smooth muscle that suggested bronchial wall structures. A mucin staining study with O-acylated sialic acid, which is used for the demonstration of gastrointestinal, cholecystic and uterine cervical mucins, was negative for the mucin-producing epithelial cells of the cyst. Thus, to our knowledge, this is the first reported case of adenocarcinoma arising in a retroperitoneal bronchogenic cyst.

Adenocarcinoma↗

PubMed1999

Local ablation therapy for hepatocellular carcinoma.

Several local ablation methods, most of which can be performed percutaneously under imaging guidance, have recently been developed as minimally invasive therapy for hepatocellular carcinoma (HCC). Among these, percutaneous ethanol injection has been the most widely performed and is now accepted as an attractive alternative to surgery in patients with small HCC. Other local ablation therapeutic options to achieve more effective tumor necrosis with less invasiveness have also been developed. Some of these techniques, such as microwave coagulation therapy and radiofrequency ablation, have already been introduced clinically. However, the real role of these new ablation methods in the treatment of HCC remains to be determined because of the lack of randomization and the small number of patients in the published series. Therefore, further trials, possibly randomized trials to compare the results of different options, are mandatory. Moreover, the prevention of recurrence after local ablation therapy for HCC has become an urgent problem to be resolved.

Acetic Acid↗