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Y Niho

Publications and source records attributed to Y Niho.

At least 109 records · Page 6Linked to original sources
PubMed1998

Genetic basis of human complement C8 alpha-gamma deficiency.

Deficiency of the alpha-gamma subunit of the eighth component of complement (C8alpha-gammaD) is frequently associated with recurrent neisserial infections, especially meningitis caused by Neisseria meningitidis. We here report the molecular basis of C8alpha-gammaD in two unrelated Japanese subjects. Screening all 11 exons of the C8alpha gene and all 7 exons of the C8gamma gene and their boundaries by exon-specific PCR/single-strand conformation polymorphism demonstrated aberrant single-stranded DNA fragments in exon 2 of C8alpha gene in case 1 and in exons 2 and 9 of C8alpha gene in case 2. Nucleotide sequencing of the amplified DNA fragments in case 1 revealed a homozygous single-point mutation at the second exon-intron boundary, inactivating the universally conserved 5' splice site consensus sequence of the second intron (IVS2+1G-->T). Case 2 was a compound heterozygote for the splice junction mutation, IVS2+1G-->T, and a nonsense mutation at Arg394 (R394X). R394X was caused by a C to T transition at nucleotide 1407, the first nucleotide of the codon CGA for Arg394, leading to a stop codon TGA. No mutations were detected in the C8gamma gene by our method. Our results indicate that the pathogenesis of C8alpha-gammaD might be caused by heterogeneous molecular defects in the C8alpha gene.

Adult↗
PubMed1998

MAP kinase pathways as a route for regulatory mechanisms of IL-10 and IL-4 which inhibit COX-2 expression in human monocytes.

Mitogen-activated protein kinases (MAPKs) are activated by various extracellular stimuli and play an important role in regulating the expression of proinflammatory molecules in monocytes/macrophages. We first questioned whether MAPK activation in involved in cyclooxygenase (COX)-2 expression in lipopolysaccharide (LPS)-stimulated human monocytes. LPS induced the expression of COX-2 protein and COX-2 mRNA as well as the phosphorylation and activation of extracellular signal-regulated protein kinase (ERK)2 and p38 MAPK in monocytes. The induction of COX-2 mRNA, COX-2 protein, and prostaglandin (PG)E2 by LPS was inhibited by the specific inhibitors of ERK and p38 MAPK, suggesting that the activation of ERK2 and p38 MAPK is involved in COX-2 expression in LPS-stimulated monocytes. Since we previously showed that interleukin (IL)-10 and IL-4 similarly inhibited COX-2 expression in LPS-stimulated monocytes, we next questioned whether these cytokines regulate the phosphorylation and activation of ERK2 and p38 MAPK in LPS-stimulated monocytes. Interestingly, LPS-induced phosphorylation and activation of ERK2 was significantly inhibited by IL-4 and IL-10, while that of p38 MAPK was inhibited by IL-10, but not IL-4. These results suggest that the mechanisms of inhibition by IL-10 and IL-4 of the LPS-induced expression of proinflammatory molecules could be ascribed to the regulatory effects of both cytokines on MAPK activation.

Calcium-Calmodulin-Dependent Protein Kinases↗
PubMed1998

Interferon-alpha and -gamma inhibit the growth and neoplastic potential of v-src-transformed human epithelial cells by reducing Src tyrosine kinase activity.

To investigate whether interferons (IFNs) selectively suppress the growth of solid tumor cells with elevated protein tyrosine kinase (PTK) activity, we evaluated the effect of recombinant IFN-alpha2a and IFN-gamma on the proliferative and neoplastic potentials triggered by p60v-src using v-src-transformed HAG-1 human epithelial cells. When compared with control cells harboring the pSV2neo gene, the monolayer growth of v-src-transformed cell lines was inhibited by both recombinant IFNs, in a dose-dependent manner, whereas growth of ras-transfected cell lines was not affected. Moreover, IFNs markedly reduced the clonogenic growth of v-src-transformed cells in soft-agar rather than monolayer growth, suggesting the preferential activity of IFNs on anchorage-independent growth. Pretreatment of cells with Src or the Src-like PTK inhibitor herbimycin A or radicicol, alleviated dose-dependently the growth-inhibitory activity of IFN-alpha2a against v-src-transformed cells, suggesting that IFNs may share a common inhibitory pathway with Src PTK inhibitors. Accordingly, like herbimycin A, IFNs were found to reduce tyrosine phosphorylation of p60v-src and suppressed in vitro p60v-src kinase activity in v-src-transformed cells. Our data, together with the fact that IFNs inhibit the growth potential driven by Src but not by activated Ras, suggest that inhibition of signal transduction pathway through Src to downstream transduction events may be a primary mechanism of IFN-induced anti-prolifeative and anti-tumoral activity.

Adenocarcinoma↗
PubMed1998

A common genetic polymorphism (46 C to T substitution) in the 5'-untranslated region of the coagulation factor XII gene is associated with low translation efficiency and decrease in plasma factor XII level.

We studied the Hga I polymorphism (46 C/T) in the 5'-untranslated region of the coagulation factor XII (FXII) gene corresponding to four bases upstream from the ATG translation initiation codon. By using allele-specific restriction analysis with restriction endonuclease Hga I, the allele frequency of 46C/T was estimated to be 0.27/0.73 in Orientals (allele number =152), and conversely, 0.8/0.2 in Caucasians (allele number =40). Because it has been reported that plasma levels of FXII were lower in Orientals than in Caucasians, we investigated the relationship between this polymorphism and plasma levels of FXII. As a result, there were significant differences in plasma FXII levels between these three allele types: C/C,170+/-38% (178+/-27%); C/T, 141+/-29% (123+/-34%); and T/T, 82+/-19% (61+/-11%) [FXII activity (FXII antigen levels)]. In heterozygotes of 46 C/T both alleles were equally transcribed in hepatocytes, as determined by reverse transcription polymerase chain reaction (RT-PCR), suggesting little influence of the polymorphism at the level of transcription or on the stability of mRNA. In in vitro transcription/translation analysis, less FXII was produced from cDNA containing 46 T than from that containing 46 C. Therefore, it is highly likely that the 46 T polymorphism in the FXII gene decreased the translation efficiency and led to low plasma levels of FXII activity and antigen, probably due to the creation of another ATG codon and/or impairment of the consensus sequence for the translation initiation scanning model.

Adolescent↗
PubMed1998

Lyn-mediated down-regulation of B cell antigen receptor signaling: inhibition of protein kinase C activation by Lyn in a kinase-independent fashion.

Stimulation of the B cell Ag receptor (BCR) induces activation of tyrosine kinases such as Lyn and Syk, phosphorylation and activation of multiple signaling components, and eventually, the expression of several genes including c-myc. Syk is required for activation of phospholipase C-gamma 2 and the subsequent phosphatidylinositol hydrolysis, leading to protein kinase C (PKC) activation and intracellular Ca2+ increase. In contrast, the function of Lyn remains obscure. Here, we report that BCR-mediated induction of c-myc promoter activity and of PKC activity, but not the expression level of functional PKC, was markedly augmented in Lyn-deficient chicken B cells. This enhancement was reversed to the level of wild-type cells by the expression of exogenous Lyn of kinase-inactive form. These results indicate that Lyn inhibits BCR-mediated activation of a large portion of PKC isozymes in a kinase-independent fashion. This finding reveals a novel role of Lyn in negative regulation of BCR signaling.

Animals↗
PubMed1998

A non-sense mutation at Arg95 is predominant in complement 9 deficiency in Japanese.

Deficiency of the ninth component of complement (C9D) is one of the most common genetic abnormalities in Japan, with an incidence of one homozygote in 1000. Although C9D individuals are usually healthy, it has been shown that they have an significantly increased risk of developing meningococcal meningitis. In the present study we report the molecular bases for C9D in 10 unrelated Japanese subjects. As a screening step for mutations, exons 2 to 11 of the C9 gene were analyzed using exon-specific PCR/single-strand conformation polymorphism analysis, which demonstrated aberrantly migrating DNA bands in exon 4 in all the C9D subjects. Subsequent direct sequencing of exon 4 of the C9D subjects revealed that eight of the 10 C9D subjects were homozygous for a C to T transition at nucleotide 343, the first nucleotide of the codon CGA for Arg95, leading to a TGA stop codon (R95X). R95X is a novel mutation different from those recently identified in a Swiss family with C9D. Cases 6 and 7 were heterozygous for the R95X mutation. Family study in case 10 confirmed the genetic nature of the defect. In case 6, the second mutation for C9D of the C9 gene was identified to be the substitution of Cys to Tyr at amino acid residue 507 (C507Y), while the genetic defect(s) in the other allele in case 7 remains unknown. Our results indicate that a novel mutation, R95X, is present in most cases of C9D in Japan.

Adult↗
PubMed1998

Activation of STAT5 by lipopolysaccharide through granulocyte-macrophage colony-stimulating factor production in human monocytes.

LPS is a potent stimulator of monocytes, inducing many of their functions. Although the details of how LPS exerts such functions remain largely unknown, transcription factors such as nuclear factor-kappaB, nuclear factor-IL-6, and activator protein-1 have been shown to be involved in this process. However, to date it has been thought that no known STAT molecule plays a role in the activation of monocytes by LPS. In this study we examined whether some known STAT molecule is stimulated by LPS, based on the finding that a GAS motif sequence is conserved in the promoter regions of human, mouse, and rat cyclo-oxygenase-2 (COX-2) genes. Consequently, LPS induced activation of STAT5 in human monocytes, and this STAT5 activation occurred in an indirect way via granulocyte-macrophage CSF (GM-CSF) secreted by LPS-stimulated monocytes. Expression of COX-2 protein was partially reduced by treatment of anti-human GM-CSF Ab. Activation of STAT5 was inhibited by either IL-10 or dexamethasone (Dex), but not by aspirin. IL-10 blocked activation of STAT5 indirectly by suppressing GM-CSF production, while Dex inhibited this activation both directly and indirectly. Taken together, these results suggest that in addition to other transcription factors, STAT5 plays an important role in activation of monocytes by LPS, and that STAT5 is another target for IL-10 and Dex to inhibit COX-2 expression in activated monocytes.

Cyclooxygenase 2↗
PubMed1998

Constitutive activation of Jak-2 and Tyk-2 in a v-Src-transformed human gallbladder adenocarcinoma cell line.

It is well known that v-Src phosphorylates various substrates on tyrosine residue and associates with tyrosine-phosphorylated proteins as well as proline-rich ligands through its SH2 and SH3 domains, respectively, thereby inducing oncogenic transformation. A signal pathway from the cell surface to genes in the nucleus, the Jak/STAT (signal transducers and activators of transcription) pathway, has been shown to be involved in the signal transduction mechanism mediated by many cytokines and growth factors. Although a member of the STAT family, STAT3 has been reported to be constitutively activated in several v-Src-transformed cells, and it still remains unknown whether Jak molecules, which act upstream of STATs, are involved in the v-Src-induced activation mechanism of STAT3. In this study, we analyzed activations of both Jak and STAT molecules using v-Src-transformed HAG-1 cells derived from a human gallbladder adenocarcinoma. STAT3 was found to be constitutively activated in v-Src-transformed HAG-1 cells, but not in either non-transformed mock-transfected or activated c-H-ras-transfected HAG-1 cells, even though the other known STAT molecules are expressed. Furthermore, both Jak-2 and Tyk-2 were constitutively activated only in v-Src-transformed HAG-1 cells. Association of v-Src with either STAT3 or the Jak molecules was not observed. No change of this activation was detected by either interferon (IFN)-alpha2a or IFN-gamma, which had shown inhibitory effects on the growth of v-Src-transformed HAG-1 cells. These results raise the possibility that Jak-2 and Tyk-2 are both activated by v-Src, thereby contributing to the constitutive activation of STAT3 in the v-Src-transformed cells.

DNA-Binding Proteins↗
PubMed1998

Intradermal administration of viral vaccines.

Intradermal administration maybe useful in lowering the cost of vaccination against hepatitis B significantly, and may also be helpful for the rapid induction of antibodies, reversing non-responsiveness, improving postexposure prophylaxis and immunising immunocompromised people. In addition, delayed type hypersensitivity skin reaction to the vaccine could serve as a useful marker for the acquisition of T helper type 1 immunoreactivity in vivo. However, there are some disadvantages when using intradermal vaccinations, including the requirement for skilful administration, the absence of approval from licensing authorities, the development of local skin reactions and a lower antibody response when 1/10 of the standard vaccine dose is used. This requires that appropriate vaccination regimens, including the correct vaccine dosage, and vaccination schedule are followed. In the future, a similar vaccination strategy might also be applied for the prevention and control of other infectious diseases. Copyright 1998 John Wiley & Sons, Ltd.

Journal Article↗
PubMed1998

Propylthiouracil-induced severe hepatitis: a case report and review of the literature.

A 21-year-old woman was diagnosed as having Graves' disease in April, 1995. Thiamazole was administered; about a month later the patient had a skin rash and propylthiouracil (PTU) was given instead. Two months after commencing PTU, she rapidly developed jaundice, accompanied by severe liver damage. The drug-induced lymphocyte stimulating test was positive for PTU and she was diagnosed as having severe hepatitis induced by PTU. After pulse therapy with 500 mg of methylprednisolone was given for 3 days, liver function test results were gradually improved, and became normalized 1 1/2 months after admission. The pathology findings of the liver biopsy sample taken before administration of corticosteroid showed necrosis of hepatocytes predominantly around the central veins (i.e., zone 3 necrosis), and moderate to severe infiltration of lymphocytes and neutrophils in portal areas and lobules. Severe hepatic damage due to PTU is rare; 25 cases have been reported so far in the English-language literature. When we use PTU for patients with hyperthyroidism, we should keep in mind that severe liver damage induced by PTU can be fatal, and we should therefore diagnose it earlier by liver biopsy and lymphocyte stimulating test.

Adult↗
PubMed1998

Growth inhibition of leukemic cells by (-)-epigallocatechin gallate, the main constituent of green tea.

In this report, we presented the results that EGCG, the main constituent of the polyphenols present in Japanese green tea inhibited growth of leukemic cell lines of both human and mice. The proliferation of human leukemic cell lines and mouse NFS60 cell line was inhibited by EGCG. Sensitivity of each line to EGCG was different, and more than 50% of DNA synthesis was reduced in all the cell lines in the presence of 50 microM EGCG. On the other hand, normal hematopoietic progenitor cells retained their natural function of supplying mature cells of various lineages in the presence of less than 10 microM EGCG in vitro. Even in the presence of 100 microM EGCG, half the colonies containing all the lineages of cells were developed. All the dead cells of each line showed characteristics of apoptosis, which might be due to inhibition by EGCG of growth factors' signaling. Besides anticarcinogenic activity, EGCG is expected to have a new function for leukemia therapy without side effects.

Animals↗
PubMed1998

Interferon-alpha treatment of acute lymphoblastic leukemia relapse after unrelated bone marrow transplantation.

A 32-year-old Japanese male in his second remission of acute lymphoblastic leukemia (ALL) received a matched unrelated donor bone marrow transplant (BMT) from the Japan Marrow Donor Program. On day +83, a bone marrow examination revealed 5.2% leukemic cells. Despite the cessation of cyclosporine, leukemic cells in the bone marrow increased to 18.4% on day +91. Treatment was started with interferon (IFN)-alpha-2b 3 x 10(6) U/body s.c. daily on day +92 and leukemic cells in the bone marrow disappeared completely. The toxicity of IFN-alpha treatment included leukoencephalopathy consisting of somnolence, disorientation, short-term memory loss, lack of coordination and ataxia, myelotoxicity requiring multiple platelet transfusions and exacerbation of graft-versus-host disease (GVHD) of oral cavity, skin and lung. Because of progressive GVHD, IFN-alpha was discontinued on day +124. On day +132, a bone marrow aspirate showed 6.4% leukemic cells. The patient died of progressive ALL on day +178. IFN-alpha may be useful for the treatment of leukemic relapse following BMT, although its toxicity is marked.

Adult↗
PubMed1998

A patient with a hemoglobin variant (Hb JLome) unexpectedly detected by HPLC for glycated hemoglobin (Hb A1c).

A rare hemoglobin variant, Hb JLome, was identified by chance in a male patient with diabetes mellitus (DM). The patient had no evidence of anemia or hemolysis. However, when his glycated hemoglobin (Hb A1c) was examined by high-performance liquid chromatography (HPLC) to assess the state of his DM, an abnormal Hb was unexpectedly detected on the chromatogram. The morphology of the red blood cells was normal. A fast-moving band as well as a normally moving Hb band, of roughly equal intensities, were observed by cellulose acetate membrane electrophoresis. The oxygen equilibrium curve was essentially normal (P50 = 3.59 kPa). In other words, the ability of the patient's Hb to carry oxygen was nearly the same as that of typical Hb A. The stability of his Hb in isopropanol was normal, and all the functions of his Hb that were tested were essentially normal. The identity of the abnormal Hb was finally determined, by sequencing the globin gene, to be Hb JLome, which is produced by a point mutation changing AAG to AAC at the 59th codon in exon 2 of the Hb beta chain. As previously reported, replacing the beta 59 lysine with asparagine does not affect the function of Hb or the red blood cells. There have been only five documented cases of Hb JLome in Japan. Interestingly, all these cases are from Kyushu Island. When an abnormal chromatogram for Hb A1c is unexpectedly obtained, it is worthwhile searching for an abnormal Hb, even if there are no signs that suggest its existence, such as anemia, hemolysis, erythrocytosis, or cyanosis.

Aged↗
PubMed1998

Fatal cytomegalovirus interstitial pneumonia following autologous peripheral blood stem cell transplantation. Fukuoka Bone Marrow Transplantation Group.

A 52-year-old Japanese woman suffering from AML (FAB classification M4) in her first remission received an autologous peripheral blood stem cell transplant (APBSCT). She was seropositive for CMV prior to APBSCT. Her post-APBSCT course was complicated with CMV-associated disease and hemophagocytic syndrome. Finally, CMV interstitial pneumonia developed and death ensued. Even after APBSCT, there can be a short period of immune deficiency resembling that occurring following allogeneic or autologous BMT. CMV infection must be considered in the differential diagnosis in cases of unexplained fever or pneumonia following APBSCT.

Cytomegalovirus Infections↗
PubMed1998

Donor lymphocyte transfusion for the treatment of Epstein-Barr virus-associated lymphoproliferative disorder of the brain.

EBV-associated lymphoproliferative disorder (LPD) is a rare but serious complication in marrow transplant recipients. A 31-year-old Japanese woman in the second chronic phase of CML received an allogeneic BMT from her HLA 2-locus-incompatible 62-year-old father. Around day +200, she developed EBV-LPD of the right parieto-temporal lobe which caused slowly progressive left hemiparesis. Two courses of donor lymphocyte transfusions (DLT) of 10(6)CD3+ T cells/kg of body weight failed to suppress her central nervous system (CNS) EBV-LPD. The patient died of recurrent blastic crisis of CML. This case suggests that DLT may be ineffective for the treatment of CNS EBV-LPD.

Adult↗
PubMed1998

Autoreactive antibodies following autologous peripheral blood stem cell transplantation.

A 35-year-old woman diagnosed with multiple myeloma (IgG, lambda type, stage IIIA) received an autologous peripheral blood stem cell transplant (PBSCT). She was euthyroid without autoreactive antibodies prior to the transplant. The patient complained of malaise, weight loss and low grade fever 1 month after transplant, despite rapid haematopoietic recovery. Thyroid function tests on day 34 revealed hyperthyroidism associated with anti-thyroid peroxidase antibody. Antinuclear antibody was also detected, and platelet-associated immunoglobulin was increased. These findings disappeared spontaneously by day 62 without treatment. Autoimmune diseases may occur transiently after autologous PBSCT.

Adult↗