Biomedical subjects

Takao Ohta

Publications and source records attributed to Takao Ohta.

35 records · Page 2Linked to original sources

PubMed2004

Elevated expression of CCL5/RANTES in adult T-cell leukemia cells: possible transactivation of the CCL5 gene by human T-cell leukemia virus type I tax.

HTLV-I is the etiologic agent of ATL and of tropical spastic paraparesis/HTLV-I-associated myelopathy. Infiltration of various tissues by circulating leukemic cells and HTLV-I-infected T cells is a characteristic of ATL and HTLV-I-associated inflammatory diseases. Chemokines play important roles in migration and tissue localization of various lymphocyte subsets. Here, we report the highly frequent expression of CCL5 (RANTES) in ATL and HTLV-I-infected T-cell lines. Among various human T-cell lines, those infected with HTLV-I selectively expressed the CCL5 gene and secreted CCL5. Furthermore, CCL5 was expressed by leukemic cells in peripheral blood and lymph nodes from patients with ATL. Inducible expression of HTLV-I transcriptional activator Tax in a human T-cell line Jurkat, up-regulated CCL5 mRNA and induced CCL5 secretion. Analysis of the CCL5 promoter revealed that this gene is activated by Tax, via the activation of NF-kappaB, whose responsive element, R(A/B), is located at positions -71 to -43 relative to the putative transcription start site. Aberrant expression of CCL5 by HTLV-I-infected T cells may impact on the pathophysiology of HTLV-I-associated diseases.

Cell Line↗

PubMed2004

The influence of the acyl-CoA:cholesterol acyltransferase-1 gene (-77G-->A) polymorphisms on plasma lipid and apolipoprotein levels in normolipidemic and hyperlipidemic subjects.

BACKGROUND: Acyl-CoA:cholesterol acyltransferase (ACAT) plays important roles in cellular cholesterol homeostasis. Two isoforms of ACAT have been reported (ACAT-1 and ACAT-2). ACAT inhibitors cannot only prevent atherosclerosis formation, but may also induce its regression in animals. In humans, an ACAT inhibitor was shown to have a lipid-lowering effect. The present study was carried out to clarify the relationship between ACAT-1 gene variants and hyperlipidemia. METHODS AND RESULTS: To identify genetic variants, we screened 30 subjects with hyperlipidemia by direct sequencing. As a result, a missense variant (R526G) and a variant in the 5' untranslated region (-77G-->A) were identified. The genotype frequencies of each variant were determined in 178 unrelated normolipidemic and 441 unrelated hyperlipidemic subjects. The alleles frequencies of the R526G variant in normolipidemic and hyperlipidemic subjects were 0.676 and 0.633, respectively. The alleles frequencies of the -77G-->A variant in normolipidemic and hyperlipidemic subjects were 0.503 and 0.515, respectively. Differences in allele frequencies between normolipidemic and hyperlipidemic subjects were not significant in both variants. R526G variant did not affect plasma concentrations of lipids or apolipoproteins in subjects studied. However, among hyperlipidemic subjects, plasma concentrations of HDL-C and apoA-I in subjects with -77G-->A variant were significantly higher than those in subjects without variant. CONCLUSION: Two variants in ACAT-1 gene were identified in subjects with hyperlipidemia. -77G-->A variant affects plasma HDL concentrations only in hyperlipidemic subjects. These data suggest that the intracellular FC concentration might modulate plasma HDL concentrations.

Apolipoprotein A-I↗

PubMed2004

Childhood blastic NK cell leukemia successfully treated with L-asparagenase and allogeneic bone marrow transplantation.

Blastic NK cell lymphoma/leukemia is a rare and highly malignant neoplasia in both adults and children. It is characterized by lymphoblastoid morphology without cytoplasmic granules and immature NK cell immunophenotypes (CD56+, CD57-, CD16-). It has predilection for extranodal organ involvement, and the prognosis of affected patients is extremely poor under the current chemotherapy. We present a 14-year-old girl who was diagnosed as having blastic NK cell leukemia with mediastinal, pleural, and pericardial involvement. Immunophenotyping of her leukemic cells showed positive for CD2, CD5, CD7, CD34, CD56, HLA-DR, and cytoplasmic CD3. T cell receptor (TCR) and Immunoglobulin heavy chain genes were not rearranged. She received chemotherapy for acute lymphoblastic leukemia incorporating L-asparaginase (L-asp) which successfully induced complete remission. Bone marrow transplantation (BMT) from her HLA-identical sibling was conducted after two courses of consolidation therapy. Expression of aspargine synthetase (AS) protein in the leukemic cells at diagnosis was examined by an immunocytochemical method. She remains in hematological remission for over 36 months after BMT. The expression of AS protein was negative, suggesting that the leukemic cells were sensitive to L-asp. Induction and consolidation therapy incorporating L-asp followed by allo-BMT might be a promising treatment for child hood blastic NK cell leukemia, but more samples of the rare leukemia need to be studied before any definitive conclusions can be drawn.

Adolescent↗

PubMed2004

A case of X-linked agammaglobulinemia with progressive encephalitis.

This report describes a case of agammaglobulinemia with progressive encephalitis. The patient was a 6-year-old male who was diagnosed as having Bruton-type agammaglobulinemia at age 6 months. After the diagnosis was made, he received monthly intravenous immunoglobulin replacement with a residual immunoglobulin G level of more than 400 mg/dL. At 5 years of age, he presented with symptoms of mental deterioration and gait disturbance. He had no history of infection of the central nervous system. Brain biopsy revealed CD8-positive T-cell infiltration with cortical damage, but no infectious agents were observed by either immunohistochemistry or virus isolation. Treatment with subcutaneous interferon-alpha and high-dose intravenous immunoglobulin was begun, and clinical symptoms improved within a month. Hence, patients with agammaglobulinemia should be carefully monitored for complications of the central nervous system even if there is no history of infection.

Agammaglobulinaemia Tyrosine Kinase↗

PubMed2004

Apoptosis induced by the histone deacetylase inhibitor FR901228 in human T-cell leukemia virus type 1-infected T-cell lines and primary adult T-cell leukemia cells.

Inhibition of histone deacetylase (HDAC) activity induces growth arrest, differentiation, and, in certain cell types, apoptosis. FR901228, FK228, or depsipeptide, is an HDAC inhibitor effective in T-cell lymphomas. Adult T-cell leukemia (ATL) is caused by human T-cell leukemia virus type 1 (HTLV-1) and remains incurable. We examined whether FR901228 is effective for treatment of ATL by assessing its ability to induce apoptosis of HTLV-1-infected T-cell lines and primary leukemic cells from ATL patients. FR901228 induced apoptosis of Tax-expressing and -unexpressing HTLV-1-infected T-cell lines and selective apoptosis of primary ATL cells, especially those of patients with acute ATL. FR901228 also efficiently reduced the DNA binding of NF-kappaB and AP-1 in HTLV-1-infected T-cell lines and primary ATL cells and down-regulated the expression of Bcl-x(L) and cyclin D2, regulated by NF-kappaB. Although the viral protein Tax is an activator of NF-kappaB and AP-1, FR901228-induced apoptosis was not associated with reduced expression of Tax. In vivo use of FR901228 partly inhibited the growth of tumors of HTLV-1-infected T cells transplanted subcutaneously in SCID mice. Our results indicated that FR901228 could induce apoptosis of these cells and suppress the expression of NF-kappaB and AP-1 and suggest that FR901228 could be therapeutically effective in ATL.

Adult↗

PubMed2004

Low-density lipoprotein particle size and its regulatory factors in school children.

Small low-density lipoprotein (LDL) particles are more atherogenic than larger LDL particles. To help prevent atherosclerotic coronary heart diseases, it may be useful to understand risk factors during childhood. In the present study, we evaluated LDL size and its relationship to other risk factors for atherosclerotic coronary heart disease. LDL size was measured by 2-15% gradient gel electrophoresis in 586 Japanese children (316 boys and 270 girls). Plasma lipids, apolipoproteins (apo), glucose, and insulin were also determined by conventional methods. Pattern B (LDL size < 25.5 nm) was found in 10.8% of boys and 4.4% of girls. Children with pattern B had a higher body mass index (BMI) and insulin resistance and a more atherogenic lipoprotein profile [higher triglycerides, higher apoB, and lower high-density lipoprotein cholesterol (HDL-C)] than children with pattern A (LDL size > or = 25.5 nm). BMI, insulin resistance, and plasma concentrations of triglycerides, glucose, and insulin decreased and plasma concentrations of HDL-C and apoA-I increased as LDL size increased. HDL-C and insulin in boys, and BMI, HDL-C, and apoA-I in girls predicted 22.9 and 28.1% of the variability of LDL size, respectively. LDL size was correlated with BMI and plasma concentrations of HDL-C, apoA-I, and insulin. Although the contribution of these parameters to LDL size in children was less than that in adults, improvement of these parameters by changes in lifestyle might be important for preventing the development of atherosclerosis even in children.

Body Mass Index↗

PubMed2004

Novel mutations of the chloride channel Kb gene in two Japanese patients clinically diagnosed as Bartter syndrome with hypocalciuria.

Hypokalemic metabolic tubulopathy, such as in Bartter syndrome and Gitelman syndrome, is caused by the dysfunction of renal electrolyte transporters. Despite advances in molecular genetics with regard to hypokalemic metabolic tubulopathy, recent reports have suggested that the phenotype-genotype correlation is still confusing, especially in classic Bartter and Gitelman syndromes. We report here two Japanese patients who suffered from clinically diagnosed classic Bartter syndrome but who presented hypocalciuria. Hypocalciuria is generally believed to be a pathognomonic finding of NCCT malfunction. To better understand the genotype-phenotype correlation in these two cases, we screened four renal electrolyte transporter genes [Na-K-2Cl cotransporter (NKCC2), renal outer medullary K channel (ROMK), Cl channel Kb (ClC-Kb), and Na-Cl cotransporter (NCCT)] by the PCR direct sequencing method. We identified three ClC-Kb allelic variants, including two new mutations (L27R and W610X in patient 1 and a G to C substitution of a 3' splice site of intron 2 and W610X in patient 2). We did not find any mutations in the other three genes. Our present data suggest that some ClC-Kb mutations may affect calcium handling in renal tubular cells.

Adolescent↗

PubMed2003

Traveling waves in phase-separating reactive mixtures.

A model of phase separation of chemically reactive ternary mixtures is constructed. In this model, spatially periodic structures that coherently propagate at a constant speed emerge through a Hopf bifurcation at a finite wave number. It is shown by computer simulations that both lamellar and hexagonal structures undergo a coherent propagating motion in two dimensions, and there are two types of traveling hexagons depending on the relative direction between the traveling velocity and the lattice vectors of the hexagonal structure. Amplitude equations for the traveling waves are derived, and the stability of the traveling and standing waves is discussed.

Journal Article↗

PubMed2003

Molecular genetic study in Japanese patients with Alexander disease: a novel mutation, R79L.

Since the first report by Brenner et al. of mutations in the glial fibrillary acidic protein (GFAP) gene in patients with Alexander disease, several molecular genetic studies have been performed in different ethnic groups. We previously reported a Japanese patient with a mutation, R239C, which is identical to one commonly found in American patients. Here we have analyzed four additional Japanese patients by screening for known mutations or, if no known mutation was found, by sequencing of all exons of the GFAP gene. We detected three missense mutations; one was a novel mutation, R79L, and two were previously reported mutations, R239C and R79C. All of our patients were heterozygous for their mutations. Together with the novel mutation, R79L, four different nucleotide changes altering the R79 residue have been reported, implying that any alternation of this arginine residue can give the GFAP protein a dominant negative effect, leading to accumulation of GFAP as Rosenthal fibers. We conclude that molecular genetic analysis of the GFAP gene is feasible for antemortem diagnosis of Alexander disease in Japanese patients.

Alexander Disease↗

PubMed2003

Effect of Trp64Arg mutation of the beta3-adrenergic receptor gene and C161T substitution of the peroxisome proliferator activated receptor gamma gene on obesity in Japanese children.

OBJECTIVE: Obesity is a multifactorial syndrome influenced by both genetic and behavioral factors. Trp64Arg mutation of the beta3-adrenergic receptor (AR) gene and C161T substitution of the peroxisome proliferator-activated receptor (PPAR) gamma gene have been reported to be associated with obesity or lipid metabolism in adults. However, the effects of these mutations on children have not yet been clarified. For this reason, we studied the effects of Trp64Arg mutation of the beta3-AR gene and C161T substitution of the PPARgamma gene on obesity in Japanese children. SUBJECTS AND METHODS: In order to determine the effects of Trp64Arg mutation of the beta3-AR gene and C161T substitution of the PPARgamma gene on obesity in children, 105 obese Japanese children were screened by the polymerase chain reaction and restriction fragment-length polymorphism analysis. Plasma lipid, apolipo-protein (apo), glucose, insulin and leptin levels were also determined. RESULTS: Obese boys with Trp64Arg showed a higher obesity index and lower plasma levels of high-density lipoprotein cholesterol (HDL-C), apoA-I and apoA-II than those of them without the mutation. Obese boys with both mutations showed a higher plasma leptin level than those with only the beta3-AR gene mutation or PPARgamma gene mutation. No significant effect of these mutations was found in obese girls. CONCLUSION: All of these data suggest that Trp64Arg mutation of the beta3-AR gene might affect obesity and HDL metabolism in obese boys. In contrast, C161T mutation of the PPARgamma gene, by itself, is unlikely to influence obesity, lipid metabolism or plasma leptin levels.

Apolipoproteins↗

PubMed2003

Analysis of renal tubular electrolyte transporter genes in seven patients with hypokalemic metabolic alkalosis.

BACKGROUND: Disorders that manifest hypokalemic metabolic alkalosis, such as Bartter's syndrome and Gitelman's syndrome, are caused by the malfunction of renal tubular electrolyte transporters. Bartter's syndrome may be linked to dysfunction of Na-K-2Cl cotransporter (NKCC2), renal outer medullary K channel (ROMK), or Cl channel Kb (ClC-Kb), while Gitelman's syndrome may be linked to Na-Cl cotransporter (NCCT) dysfunction. However, previous genetic analyses in these syndromes have included many heterozygotes for each gene and there has been no further analysis of other genes. Thus, to clarify the interaction of these transporter genes, in the present study we investigated all 4 transporter genes in 7 patients with hypokalemic metabolic alkalosis. METHODS: Seven patients from 5 families (patients A-G) were collected, and a mutation analysis of the 4 renal electrolyte transporter genes was performed by direct sequencing. RESULTS: We identified 12 mutations in these 7 patients. Three mutations (del245Y in NKCC2, R1009X in NCCT, V524I in ClC-Kb) have not been reported previously. In NKCC2 gene screening, patient A was homozygous for del245Y. In ClC-Kb gene screening, L27R was detected in patients B, D, and E. V524I was detected in patient C. Both T562M and E578K were observed in patients B and E. In NCCT gene screening, patients B-G shared a common novel mutation, R1009X, and patients D, E, F, and G carried this mutation in both alleles. Patients B and C carried R1009X in one allele, and a 6-amino acid insertion in exon 6 and L849H in another allele, respectively. The 4 other mutations did not result in any amino acid exchange. Despite the NCCT gene mutation, patients C and E showed normomagnesemia. CONCLUSION: Our findings demonstrate that in Bartter's and Gitelman's syndromes, it may not be uncommon to see mutations in several causative transporter genes.

Alkalosis↗

PubMed2003

Effects of a new single-nucleotide polymorphism in the Acyl-CoA:cholesterol acyltransferase-2 gene on plasma lipids and apolipoproteins in patients with hyperlipidemia.

Acyl-CoA:cholesterol acyltransferase (ACAT) catalyzes cholesterol esterification in mammalian cells. Two isoforms of ACAT have been reported to date (ACAT-1 and ACAT-2). ACAT-1 protein is ubiquitously expressed in tissues, including macrophages, hepatocytes, adrenal glands, and intestines. In contrast, ACAT-2 is expressed mainly in the intestine in humans. However, the roles of ACAT-1 and ACAT-2 in lipoprotein metabolism in humans have not yet been reported. This study was carried out to clarify the relationship between ACAT-2 gene mutations and hyperlipidemia in humans. To identify gene mutations, we screened 30 subjects with hyperlipidemia (TC > 220 mg/dl or TG >150 mg/dl) by direct sequencing. As a result, we found a new single-nucleotide polymorphism (SNP; a point mutation in intron 1, IVS1 -8 G-->C) in the ACAT-2 gene. To investigate the relationship between this SNP and both plasma lipids and apolipoproteins, 91 unrelated hyperlipidemic subjects (40 males and 51 females), and 92 unrelated normolipidemic subjects (46 males and 46 females) were screened by direct sequencing. The frequencies of the IVS1 - 8G-->C allele in normolipidemic and hyperlipidemic subjects were 0.131 and 0.125, respectively. IVS1 -8 G-->C did not affect plasma concentrations of lipids or apolipoproteins in either normolipidemic or hyperlipidemic subjects. Although further studies are needed, our data suggest that the ACAT-2 gene may not affect lipid levels in humans.

Acyl Coenzyme A↗

PubMed2002

Time-modulated oscillatory structures in phase-separating reactive mixtures.

We investigate the effect of temporal modulation on the spatiotemporal patterns produced by phase separation in chemically reactive ternary mixtures. The temporal modulation is introduced by making one of the reaction rates periodic in time. Our main concern is the stability of traveling waves, which appear above a Hopf-type bifurcation at a finite wave number and are stable in the absence of external modulation. It is shown by computer simulations in two dimensions that when the external modulation is present, various types of coherent standing waves emerge near the special point in the parameter space, where the Turing-type bifurcation line and the Hopf-type bifurcation line meet each other. We carry out a theoretical analysis to understand the phase diagram of the synchronized oscillatory structures obtained numerically.

Journal Article↗

PubMed2002

Self-replication of a pulse in excitable reaction-diffusion systems.

We investigate self-replication of a pulse in Bonhoffer-van der Pol type reaction-diffusion systems in one dimension. The interface dynamics of front and back of a pulse developed for a bistable system is extended to a monostable case, which is useful to clarify the mechanism of the self-replication. We shall show that the threshold parameter for excitability plays the central role for self-replication. The present theory can be applied not only to a symmetric pulse, but also to a propagating asymmetric pulse.

Journal Article↗

PubMed2002

A 7-year-old boy with mycoplasmal infection requiring extracorporeal membrane oxygenation.

UNLABELLED: A 7-year-old boy with Down syndrome developed severe acute respiratory distress syndrome after a respiratory infection with Mycoplasma pneumoniae with an unusually high agglutination titre (1:10240). Initially, mechanical ventilation and nitric oxide inhalation were used, but these did not improve the alveolar-arterial oxygen gradient. Extracorporeal membrane oxygenation for 152 h improved the lung condition. CONCLUSION: our case suggests that Mycoplasma pneumoniae should be considered as an aetiological agent in acute respiratory distress syndrome. Extracorporeal membrane oxygenation might have a valuable role in the management.

Acute Disease↗

PubMed2002

Two newly identified genomic mutations in a Japanese female patient with fructose-1,6-bisphosphatase (FBPase) deficiency.

Fructose-1,6-bisphosphatase (FBPase) (EC 3.1.3.11) catalyzes the splitting of fructose-1,6-bisphosphate into fructose 6-phosphate and inorganic phosphate. FBPase deficiency is an autosomal recessive inherited disorder caused by distraction of the fructose-1,6-bisphosphatase 1 gene (FBP1) and features severely impaired gluconeogenesis. We studied a female patient with typical FBPase deficiency symptoms. The FBPase activity of her peripheral white blood cells was undetectable. Genetic analyses of FBP1 revealed her to be a compound-heterozygote of two new mutations F194S and P284R. Gene tracking in the family revealed the mother to be a heterozygote of F194S, and the father and a sister to be heterozygotes of P284R. As both Phe194 and Pro284 of FBPase are highly conserved in many species and close to crucial amino acid residues to FBPase functions, these mutations could be responsible for the loss of FBPase activities.

Base Sequence↗

PubMed2002

Dyslipidemia in young Japanese children: its relation to familial hypercholesterolemia and familial combined hyperlipidemia.

BACKGROUND: Most cases of dyslipidemia found in adults are non-familial. However, in children, especially young children, dyslipidemias other than familial hypercholesterolemia (FH) have not yet been characterized. METHODS: From April 1990 to March 1999, 56 181 children were screened, and 1380 showed abnormal levels of apolipoprotein B (more than 2.5 standard deviations above the mean). Among these, 1198 were re-examined and further characterized by measuring lipids and apolipoproteins, and by their familial histories. RESULTS: Seventy-seven percent of the children (928 of 1198) recalled were diagnosed as being dyslipidemic. Ninety-one children were FH, 423 were type IIa, 128 were type IIb, 98 were type IV, and 188 were hypoalphalipoproteinemia. The presumed incidence of FH was 0.19%, IIa 0.87%, IIb 0.26%, IV 0.20%, and hypoalphalipoproteinemia 0.39%, taking into account the percentage of subjects who refused recall. At regular follow-ups, in many children with type IIb, the phenotypic expression changes from type IIb to IIa or IV. Thus, lipid and apolipoprotein levels were determined in 77 family members in 34 families of children with type IIb. Forty-five family members were dyslipidemic (type IIa 18, type IIb 11, type IV 16). As a result, 27 children (79%) with type IIb met the criteria for familial combined hyperlipidemia. CONCLUSIONS: Children with dyslipidemia had more family or genetic background than adults. Unexpectedly, children with type IIb were mostly familial combined hyperlipidemia. Thus, setting appropriate eating patterns during childhood might be important for normalizing risk factors for atherosclerotic coronary heart disease, especially in children with FH or type IIb.

Analysis of Variance↗