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1. Neuropsychopharmacotherapy in Children and Adolescents

Author

Riederer, Peter, Laux, Gerd, Nagatsu, Toshiharu, Le, Weidong, Riederer, Christian, Riederer, P ( Peter ), Laux, G ( Gerd ), Nagatsu, T ( Toshiharu ), Le, W ( Weidong ), Riederer, C ( Christian ), Walitza, Susanne; https://orcid.org/0000-0002-8161-8683, Berger, Gregor; https://orcid.org/0000-0003-2030-141X, Geller, Daniel, Smigielski, Lukasz; https://orcid.org/0000-0002-7428-7644, Riederer, Peter, Laux, Gerd, Nagatsu, Toshiharu, Le, Weidong, Riederer, Christian, Riederer, P ( Peter ), Laux, G ( Gerd ), Nagatsu, T ( Toshiharu ), Le, W ( Weidong ), Riederer, C ( Christian ), Walitza, Susanne; https://orcid.org/0000-0002-8161-8683, Berger, Gregor; https://orcid.org/0000-0003-2030-141X, Geller, Daniel, and Smigielski, Lukasz; https://orcid.org/0000-0002-7428-7644

Abstract

The high prevalence of mental health dysfunction in childhood and adolescence, together with the fact that many mental disorders in adulthood emerge and consolidate in this period, underlines the importance of effective and safe treatments. The present chapter on neuropsychopharmacotherapy summarizes and discusses the critical issues of efficacy, tolerability, and acceptability in the application of the major medication groups, i.e., psychostimulants, antidepressants, and antipsychotics, prescribed to children and adolescents. Relevant questions and evidence-based knowledge are presented, complemented by descriptions of expert experience in the context of the most prevalent indications for these medications. Treatment strategies for attention-deficit-hyperactivity disorder, anxiety, depression, obsessive-compulsive disorder, and psychosis are outlined. This chapter focuses particularly on age-specific aspects, such as consent, patient participation, and off-label use, but it also includes a discussion of the current evidence and guideline recommendations in treating young patients.

Published
2022

2. Neopterin and Cytokines in Hereditary Dystonia and Parkinson's Disease

Author

Nagatsu T., Ichinose H., Mogi M., and Togari A.

Subjects
neopterin, cytokines, cerebrospinal fluid, striatum, parkinson's disease, Crystallography, QD901-999
Abstract

Both neopterin and biopterin concentrations in cerebrospinal fluid from patients with Parkinson's disease, in which the nigrostriatal dopamine neurons degenerate, were lower than those from age-matched older control subjects. However, the decrease in biopterin was more marked than that in neopterin, resulting in the increase in the neopterin/ biopterin ratio in Parkinson's disease. These results suggests that neopterin in cerebrospinal fluid in Parkinson's disease may partly be derived from immunoactivated glial cells, besides catecholamine or serotonin n eurons including nigrostriatal dopamine neurons. In accordance to this hypothesis, cytokines (TNF-α, IL-1, IL-2 , IL-6, EGF, TGF-α, TGF-β1) were found to be increased in the striatum and/or in cerebrospinal fluid. The increment of cytokines in the brain in Parkinson's disease may be related to the mechanism of neurodegeneration of dopaminergic neurons in Parkinson's disease . In contrast to Parkinson's disease, in hereditary progressive dystonia/ dopa-responsive dystonia, which is a dopamine deficiency caused by mutations in GTP cyclohydrolase I without neuronal cell death (Segawa's disease), neopterin and biopterin in cerebrospinal fluid decreases in parallel owing to the decreased activity in GTP cyclohydrolase I .

Published
1999
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3. Pharmacotherapy for Cocaine Use Disorders

Author

Riederer, Peter, Nagatsu, Toshiharu, Riederer, P ( Peter ), Nagatsu, T ( Toshiharu ), Quednow, Boris B; https://orcid.org/0000-0001-7933-2865, Engeli, Etna J E; https://orcid.org/0000-0001-7176-8728, Herdener, Marcus; https://orcid.org/0000-0001-5830-1971, Riederer, Peter, Nagatsu, Toshiharu, Riederer, P ( Peter ), Nagatsu, T ( Toshiharu ), Quednow, Boris B; https://orcid.org/0000-0001-7933-2865, Engeli, Etna J E; https://orcid.org/0000-0001-7176-8728, and Herdener, Marcus; https://orcid.org/0000-0001-5830-1971

Abstract

Cocaine is one of the most commonly used substances worldwide. It has a strong addictive potential, which often leads to excessive consumption causing pronounced physical and psychological harm to users. There is currently no approved or effective medication to treat cocaine use disorders. However, in the last decades, significant efforts have been made to identify medications that could increase the effectiveness of treatments, with several drugs showing some promise. Although current evidence to either support or reject their ultimate efficacy is insufficient, encouraging indications have been found in studies testing dopamine agonists to reduce cocaine use or prevent relapse. Particularly, positive signals have been identified for long-acting amphetamine formulations and for modafinil, each under specific conditions such as comorbid psychiatric disorders. Medications addressing cocaine-related glutamate disturbances, such as N-acetylcysteine and ketamine, have also shown some beneficial effects on cocaine craving and other withdrawal symptoms as well as on the severity of cocaine use. However, it remains unclear whether these drugs can consistently achieve therapeutic benefits in the longer term and in heterogeneous clinical populations. In sum, conclusive statements about the clinical efficacy of the tested medications cannot yet be made. While renewed emphasis on the discovery of novel drug targets for the treatment of cocaine use disorders is needed, there is also a clear necessity for further investigation of the most promising existing medications, such as ketamine, N-acetylcysteine, modafinil, and extended-release amphetamines, in longitudinal study designs with large patient samples to establish their potential long-term therapeutic value.

Published
2021

7. Somatic instability of CAG repeat occurs in the HD gene knock-in mouse

Author

Ishiguro, H., Yamada, K., Sawada, H., Nishii, K., Ichino, N., Sawada, M., Kurosawa, Y., Matsushita, N., Kobayashi, K., Goto, J., Kanazawa, I., and Nagatsu, T.

Subjects
Genetic research -- Analysis, Human genetics -- Research, Genetic disorders -- Research, Huntington's chorea -- Genetic aspects, Biological sciences
Published
2000

9. cGMP Inhibits GTP Cyclohydrolase I Activity and Biosynthesis of Tetrahydrobiopterin in Human Umbilical Vein Endothelial Cells

Author

Shiraishi, H., Kato, T., Atsuta, K., Sumi-Ichinose, C., Ohtsuki, M., Itoh, M., Hishida, H., Tada, S., Udagawa, Y., Nagatsu, T., Hagino, Y., Ichinose, Hiroshi, and Nomura, T.

Subjects
Umbilical Veins, medicine.medical_specialty, GTP', GTP cyclohydrolase I, Cycloheximide, Umbilical vein, Nitric oxide, chemistry.chemical_compound, Internal medicine, medicine, Humans, Enzyme Inhibitors, GTP Cyclohydrolase, Cyclic GMP, Pharmacology, Dose-Response Relationship, Drug, biology, lcsh:RM1-950, Endothelial Cells, Tetrahydrobiopterin, Biopterin, Enzyme Activation, Endothelial stem cell, lcsh:Therapeutics. Pharmacology, Endocrinology, chemistry, biology.protein, Molecular Medicine, Sodium nitroprusside, medicine.drug
Abstract

Tetrahydrobiopterin (BH4) acts as an essential cofactor for the enzymatic activity of nitric oxide (NO) synthases. Biosynthesis of the cofactor BH4 starts from GTP and requires 3 enzymatic steps, which include GTP cyclohydrolase I (GCH I) catalysis of the first and rate-limiting step. In this study we examined the effects of cGMP on GCH I activity in human umbilical vein endothelial cells under inflammatory conditions. Exogenous application of the cGMP analogue 8-bromo-cGMP markedly inhibited GCH I activity in the short term, whereas an cAMP analogue had no effect on GCH I activity under the same condition. NO donors, NOR3 and sodium nitroprusside, elevated the intracellular cGMP level and reduced GCH I activity in the short term. This inhibition of GCH I activity was obliterated in the presence of an NO trapper carboxy-PTIO. NO donors had no effect on GCH I mRNA expression in the short term. Moreover, cycloheximide did not alter the inhibition by NO donors of GCH I activity. These findings suggest that stimulation of the cGMP signaling cascade down-regulates GCH I activity through post translational modification of the GCH I enzyme.

Published
2003

10. Behavioral Recovery in a Primate Model of Parkinson's Disease by Triple Transduction of Striatal Cells with Adeno-Associated Viral Vectors Expressing Dopamine-Synthesizing Enzymes

Author

Muramatsu, S.-I., Kume, A., Matsumura, M., Nagatsu, I., Urano, F., Ichinose, Hiroshi, Nagatsu, T., Terao, K., Nakano, I., Ozawa, K., Fujimoto, K.-I., Ikeguchi, K., Shizuma, N., Kawasaki, K., Ono, F., Shen, Y., Wang, L., and Mizukami, H.

Subjects
Parkinson's disease, Tyrosine 3-Monooxygenase, Dopamine, GTP cyclohydrolase I, Genetic Vectors, Striatum, Motor Activity, Pharmacology, Biology, Transduction, Genetic, Genetics, medicine, Animals, GTP Cyclohydrolase, Molecular Biology, Aromatic L-amino acid decarboxylase, Tyrosine hydroxylase, Putamen, Genetic transfer, Parkinson Disease, Genetic Therapy, Dependovirus, medicine.disease, Virology, Disease Models, Animal, Macaca fascicularis, 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine, Aromatic-L-Amino-Acid Decarboxylases, biology.protein, Molecular Medicine, Female, medicine.drug
Abstract

One potential strategy for gene therapy of Parkinson's disease (PD) is the local production of dopamine (DA) in the striatum induced by restoring DA-synthesizing enzymes. In addition to tyrosine hydroxylase (TH) and aromatic-L-amino-acid decarboxylase (AADC), GTP cyclohydrolase I (GCH) is necessary for efficient DA production. Using adeno-associated virus (AAV) vectors, we previously demonstrated that expression of these three enzymes in the striatum resulted in long-term behavioral recovery in rat models of PD. We here extend the preclinical exploration to primate models of PD. Mixtures of three separate AAV vectors expressing TH, AADC, and GCH, respectively, were stereotaxically injected into the unilateral putamen of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated monkeys. Coexpression of the enzymes in the unilateral putamen resulted in remarkable improvement in manual dexterity on the contralateral to the AAV-TH/-AADC/-GCH-injected side. Behavioral recovery persisted during the observation period (four monkeys: 48 days, 65 days, 50 days, and >10 months, each). TH-immunoreactive (TH-IR), AADC-IR, and GCH-IR cells were present in a large region of the putamen. Microdialysis demonstrated that concentrations of DA in the AAV-TH/-AADC/-GCH-injected putamen were increased compared with the control side. Our results show that AAV vectors efficiently introduce DA-synthesizing enzyme genes into the striatum of primates with restoration of motor functions. This triple transduction method may offer a potential therapeutic strategy for PD.

Published
2002

11. Characterization of wild-type and mutants of recombinant human GTP cyclohydrolase I: Relationship to etiology of dopa-responsive dystonia

Author

Suzuki, T., Ohye, T., Inagaki, H., Nagatsu, T., and Ichinose, Hiroshi

Subjects
medicine.medical_specialty, Phenylalanine, Recombinant Fusion Proteins, GTP cyclohydrolase I, DNA Mutational Analysis, Molecular Sequence Data, Mutant, Genes, Recessive, Biology, Biochemistry, Frameshift mutation, Neuroblastoma, Cellular and Molecular Neuroscience, Internal medicine, Tumor Cells, Cultured, medicine, Humans, Point Mutation, Missense mutation, Amino Acid Sequence, Frameshift Mutation, GTP Cyclohydrolase, Genes, Dominant, Wild type, Tetrahydrobiopterin, Biopterin, Fusion protein, Endocrinology, Gene Expression Regulation, Dystonic Disorders, biology.protein, Dystonic disorder, medicine.drug
Abstract

To explore the molecular etiology of two disorders caused by a defect in GTP cyclohydrolase I--hereditary progressive dystonia with marked diurnal fluctuation (HPD), also known as dopa-responsive dystonia (DRD), and autosomal recessive GTP cyclohydrolase I deficiency--we purified and analyzed recombinant human wild-type and mutant GTP cyclohydrolase I proteins expressed in Escherichia coli. Mutant proteins showed very low enzyme activities, and some mutants were eluted at a delayed volume on gel filtration compared with the recombinant wild-type. Next, we examined the GTP cyclohydrolase I protein amount by western blot analysis in phytohemagglutinin-stimulated mononuclear blood cells from HPD/DRD patients. We found a great reduction in the amount of the enzyme protein not only in one patient who had a frameshift mutation, but also in an HPD/DRD patient who had a missense mutation. These results suggest that a dominant-negative effect of chimeric protein composed of wild-type and mutant subunits is unlikely as a cause of the reduced enzyme activity in HPD/DRD patients. We suggest that reduction of the amount of the enzyme protein, which is independent of the mutation type, could be a reason for the dominant inheritance in HPD/DRD.

Published
2002

12. Triple Transduction with Adeno-Associated Virus Vectors Expressing Tyrosine Hydroxylase, Aromatic-L-Amino-Acid Decarboxylase, and GTP Cyclohydrolase I for Gene Therapy of Parkinson's Disease

Author

Shen, Y., Nagatsu, I., Urano, F., Suzuki, T., Ichinose, Hiroshi, Nagatsu, T., Monahan, J., Nakano, I., Ozawa, K., Muramatsu, S.-I., Ikeguchi, K., Fujimoto, K.-I., Fan, D.-S., Ogawa, M., Mizukami, H., Urabe, M., and Kume, A.

Subjects
Male, medicine.medical_specialty, Time Factors, Tyrosine 3-Monooxygenase, Dopamine, GTP cyclohydrolase I, Genetic Vectors, Striatum, Motor Activity, Pharmacology, medicine.disease_cause, Cell Line, Injections, Transduction (genetics), Transformation, Genetic, Internal medicine, Genetics, medicine, Animals, Humans, Transgenes, Rats, Wistar, GTP Cyclohydrolase, Oxidopamine, Molecular Biology, Adeno-associated virus, Aromatic L-amino acid decarboxylase, biology, Tyrosine hydroxylase, Gene Expression Profiling, Gene Transfer Techniques, Parkinson Disease, Genetic Therapy, Tetrahydrobiopterin, Dependovirus, Biopterin, Corpus Striatum, Rats, Endocrinology, Aromatic-L-Amino-Acid Decarboxylases, biology.protein, Molecular Medicine, medicine.drug
Abstract

Parkinson's disease (PD), a neurological disease suited to gene therapy, is biochemically characterized by a severe decrease in the dopamine content of the striatum. One current strategy for gene therapy of PD involves local production of dopamine in the striatum achieved by inducing the expression of enzymes involved in the biosynthetic pathway for dopamine. We previously showed that the coexpression of tyrosine hydroxylase (TH) and aromatic-L-amino-acid decarboxylase (AADC), using two separate adeno-associated virus (AAV) vectors, resulted in more effective dopamine production and more remarkable behavioral recovery in 6-hydroxydopamine-lesioned parkinsonian rats, compared with the expression of TH alone. Not only levels of TH and AADC but also levels of tetrahydrobiopterin (BH4), a cofactor of TH, and GTP cyclohydrolase I (GCH), a rate-limiting enzymes for BH4 biosynthesis, are reduced in parkinsonian striatum. In the present study, we investigated whether transduction with separate AAV vectors expressing TH, AADC, and GCH was effective for gene therapy of PD. In vitro experiments showed that triple transduction with AAV-TH, AAV-AADC, and AAV-GCH resulted in greater dopamine production than double transduction with AAV-TH and AAV-AADC in 293 cells. Furthermore, triple transduction enhanced BH4 and dopamine production in denervated striatum of parkinsonian rats and improved the rotational behavior of the rats more efficiently than did double transduction. Behavioral recovery persisted for at least 12 months after stereotaxic intrastriatal injection. These results suggest that GCH, in addition to TH and AADC, is important for effective gene therapy of PD.

Published
2000

13. Behavioral Recovery in 6-Hydroxydopamine-Lesioned Rats by Cotransduction of Striatum with Tyrosine Hydroxylase and Aromatic <scp>l</scp>-Amino Acid Decarboxylase Genes Using Two Separate Adeno-Associated Virus Vectors

Author

Fan, D.-S., Ogawa, M., Fujimoto, K.-I., Ikeguchi, K., Ogasawara, Y., Urabe, M., Nishizawa, M., Nakano, I., Yoshida, M., Nagatsu, I., Ichinose, Hiroshi, Nagatsu, T., Kurtzman, G.J., and Ozawa, K.

Subjects
Male, Tyrosine 3-Monooxygenase, Genetic Vectors, Substantia nigra, Striatum, Biology, medicine.disease_cause, Cell Line, Stereotaxic Techniques, Transduction, Genetic, Dopamine, Genetics, medicine, Animals, Humans, Rats, Wistar, Oxidopamine, Molecular Biology, Adeno-associated virus, Aromatic L-amino acid decarboxylase, Hydroxydopamine, Tyrosine hydroxylase, Dopaminergic, Dependovirus, beta-Galactosidase, Molecular biology, Corpus Striatum, Rats, nervous system, Aromatic-L-Amino-Acid Decarboxylases, Molecular Medicine, medicine.drug
Abstract

Parkinson's disease (PD) is characterized by the progressive loss of the dopaminergic neurons in the substantia nigra and a severe decrease in dopamine in the striatum. A promising approach to the gene therapy of PD is intrastriatal expression of enzymes in the biosynthetic pathway for dopamine. Tyrosine hydroxylase (TH) catalyzes the synthesis of L-dopa, which must be converted to dopamine by aromatic L-amino acid decarboxylase (AADC). Since the endogenous AADC activity in the striatum is considered to be low, coexpression of both TH and AADC in the same striatal cells would increase the dopamine production and thereby augment the therapeutic effects. In the present study, the TH gene and also the AADC gene were simultaneously transduced into rat striatal cells, using two separate adeno-associated virus (AAV) vectors, AAV-TH and AAV-AADC. Immunostaining showed that TH and AADC were coexpressed efficiently in the same striatal cells in vitro and in vivo. Moreover, cotransduction with these two AAV vectors resulted in more effective dopamine production and more remarkable behavioral recovery in 6-hydroxydopamine (6-OHDA)-lesioned rats, compared with rats receiving AAV-TH alone (p0.01). These findings suggest an alternative strategy for gene therapy of PD and indicate that the simultaneous transduction with two AAV vectors can extend their utility for potential gene therapy applications.

Published
1998

14. DRD2 allele frequencies and linkage disequilibria, including the - 141CIns/Del promoter polymorphism, in European-American, African-American, and Japanese subjects

Author

Gelernter, J., Kranzler, H., Cubells, J.F., Ichinose, Hiroshi, and Nagatsu, T.

Subjects
Linkage disequilibrium, Black People, Biology, Population stratification, Linkage Disequilibrium, White People, Asian People, Gene Frequency, Japan, Polymorphism (computer science), Genetics, Humans, Allele, Promoter Regions, Genetic, Gene, Allele frequency, Alleles, Linkage (software), Polymorphism, Genetic, Receptors, Dopamine D2, Mental Disorders, Haplotype, Racial Groups, Europe, Connecticut
Abstract

Although many studies have addressed the possible association of D2 dopamine receptor (DRD2) alleles—particularly in the Taq I “A” system (with the DRD2*A1 allele)—with positive results for a range of behavioral phenotypes in populations of European origin, the interpretation of those results remains controversial; they could reflect physiological relationships between gene and phenotype, population stratification, or random variation. Since mutational analysis studies of the DRD2 gene have thus far failed to reveal a mutation that could provide a physiological basis for these results, functional meaning for them depends on linkage disequilibrium with a functional variant. A recently described functional variant in the DRD2 promoter (-141C Ins/Del ), which is about 250 kb 5′ to the variants studied in psychiatric illness, could conceivably provide an explanation for the positive findings, if it were in linkage disequilibrium with DRD2*A1 in populations similar to those for which an association has been reported. We studied linkage disequilibrium (LD) and frequencies of haplotypes containing the DRD2*A, DRD2*D, and -141C Ins/Del systems in European-Americans, African-Americans, and Japanese subjects. Although we found evidence for LD across the 250-kb first intron in both American populations, we did not find significant LD between the DRD2*A system and the -141C Ins/Del system in the European-Americans. This newly described functional variant therefore does not provide a straightforward physiological explanation for previously reported genetic associations with DRD2*A1 in European-American subjects.

Published
1998

15. Brain aging and Parkinson's disease

Author

Nagatsu T

Subjects
Aging, Parkinson's disease, business.industry, Brain, Parkinson Disease, medicine.disease, 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine, Humans, Medicine, Geriatrics and Gerontology, business, Brain aging, Neuroscience, Aged
Published
1990

16. Delayed delivery of AAV-GDNF prevents nigral neurodegeneration and promotes functional recovery in a rat model of Parkinson's disease

Author

Wang, L., Muramatsu, S., Lu, Y., Ikeguchi, K., Fujimoto, K., Okada, T., Mizukami, H., Hanazono, Y., Kume, A., Urano, F., Ichinose, Hiroshi, Nagatsu, T., Nakano, I., and Ozawa, K.

Subjects
Male, medicine.medical_specialty, Time Factors, viruses, Dopamine, Genetic Vectors, Nigrostriatal pathway, Gene Expression, Substantia nigra, Nerve Tissue Proteins, Striatum, Pharmacology, Injections, Neurotrophic factors, Genetics, Glial cell line-derived neurotrophic factor, medicine, Animals, Glial Cell Line-Derived Neurotrophic Factor, Nerve Growth Factors, Rats, Wistar, Oxidopamine, Molecular Biology, biology, Tyrosine hydroxylase, Neurodegeneration, Parkinson Disease, Genetic Therapy, Dependovirus, medicine.disease, Surgery, Rats, Substantia Nigra, medicine.anatomical_structure, nervous system, Models, Animal, biology.protein, Disease Progression, Molecular Medicine, medicine.drug
Abstract

Glial cell line-derived neurotrophic factor (GDNF) is a strong candidate agent in the neuroprotective treatment of Parkinson's disease (PD). We investigated whether adeno-associated viral (AAV) vector-mediated delivery of a GDNF gene in a delayed manner could prevent progressive degeneration of dopaminergic (DA) neurons, while preserving a functional nigrostriatal pathway. Four weeks after a unilateral intrastriatal injection of 6-hydroxydopamine (6-OHDA), rats received injection of AAV vectors expressing GDNF tagged with FLAG peptide (AAV-GDNFflag) or beta-galactosidase (AAV-LacZ) into the lesioned striatum. Immunostaining for FLAG demonstrated retrograde transport of GDNFflag to the substantia nigra (SN). The density of tyrosine hydroxylase (TH)-positive DA fibers in the striatum and the number of TH-positive or cholera toxin subunit B (CTB, neuronal tracer)-labeled neurons in the SN were significantly greater in the AAV-GDNFflag group than in the AAV-LacZ group. Dopamine levels and those of its metabolites in the striatum were remarkably higher in the AAV-GDNFflag group compared with the control group. Consistent with anatomical and biochemical changes, significant behavioral recovery was observed from 4-20 weeks following AAV-GDNFflag injection. These data indicate that a delayed delivery of GDNF gene using AAV vector is efficacious even 4 weeks after the onset of progressive degeneration in a rat model of PD.

Published
2001

17. Synaptic integration mediated by striatal cholinergic interneurons in basal ganglia function

Author

Kaneko, S., Hikida, T., Watanabe, D., Ichinose, Hiroshi, Nagatsu, T., Kreitman, R.J., Pastan, I., and Nakanishi, S.

Subjects
medicine.medical_specialty, Interneuron, Apomorphine, Dopamine, Central nervous system, Posture, Down-Regulation, Mice, Transgenic, Biology, Motor Activity, Substance P, Basal Ganglia, Choline O-Acetyltransferase, Mice, Interneurons, Internal medicine, Basal ganglia, medicine, Animals, Cholinergic neuron, Oxidopamine, Multidisciplinary, Receptors, Dopamine D2, Immunotoxins, Receptors, Dopamine D1, Enkephalins, Acetylcholine, Corpus Striatum, medicine.anatomical_structure, Endocrinology, Receptors, Glutamate, Dopamine receptor, Dopamine Agonists, Synapses, Cholinergic, Neuroscience, medicine.drug
Abstract

The physiological role of striatal cholinergic interneurons was investigated with immunotoxin-mediated cell targeting (IMCT). Unilateral cholinergic cell ablation caused an acute abnormal turning behavior. These mice showed gradual recovery but displayed abnormal turning by both excess stimulation and inhibition of dopamine actions. In the acute phase, basal ganglia function was shifted to a hyperactive state by stimulation and suppression of striatonigral and striatopallidal neurons, respectively. D1 and D2 dopamine receptors were then down-regulated, relieving dopamine-predominant synaptic perturbation but leaving a defect in controlling dopamine responses. The acetylcholine-dopamine interaction is concertedly and adaptively regulated for basal ganglia synaptic integration.

Published
2000

18. Molecular cloning of the human Nurr1 gene: characterization of the human gene and cDNAs

Author

Ichinose, Hiroshi, Ohye, T., Suzuki, T., Sumi-Ichinose, C., Nomura, T., Hagino, Y., and Nagatsu, T.

Subjects
DNA, Complementary, Molecular Sequence Data, Restriction Mapping, Nerve Tissue Proteins, Biology, Exon, Sequence Homology, Nucleic Acid, Nuclear Receptor Subfamily 4, Group A, Member 2, Genetics, Humans, Cloning, Molecular, Gene, Binding Sites, Base Sequence, Alternative splicing, Intron, Brain, Parkinson Disease, General Medicine, Exons, HNF1B, Introns, DNA-Binding Proteins, Alternative Splicing, Regulatory sequence, RNA splicing, Schizophrenia, Human genome, Transcription Factors
Abstract

Nurr1 is a member of the nuclear receptor superfamily of transcription factors that is expressed predominantly in the central nervous system, including developing dopaminergic neurons. Recently, it was demonstrated that Nurr1 is critical for midbrain dopaminergic cell differentiation. In order to investigate a possible relation of Nurr1 with the pathogenesis of Parkinson's disease or other neuropsychiatric disorders, we have cloned and characterized the human Nurr1 gene. The gene exists as a single copy in the human genome and comprises eight exons spanning 8kb. We determined the complete nucleotide sequence and flanking regions of the gene. Potential regulatory regions included consensus binding sites for NF-kappaB, CREB, and Sp1. Isolation of human Nurr1 cDNAs from fetal brain suggested the presence of a new splicing variant of Nurr1 in the human brain.

Published
1999

19. Establishment of a human small cell lung cancer cell line producing a large amount of anti-diuretic hormone

Author

Terasaki, T., Matsuno, Y., Shimosato, Y., Yamaguchi, K., Ichinose, Hiroshi, Nagatsu, T., and Kato, K.

Subjects
Male, Cancer Research, medicine.medical_specialty, Cytoplasm, Lung Neoplasms, G protein, Vasopressins, Microgram, medicine.medical_treatment, Mice, Nude, Biology, Article, Mice, Internal medicine, medicine, Tumor Cells, Cultured, Animals, Humans, Secretion, Carcinoma, Small Cell, Cell Nucleus, Small cell lung cancer, Respiratory disease, Cancer, Anti‐diuretic hormone, Middle Aged, medicine.disease, Microscopy, Electron, Endocrinology, Oncology, Cell culture, Cancer research, Diuretic, Cell line, Cell Division, Neoplasm Transplantation, Hormone
Abstract

A new cancer cell line (Lu-165) producing a large amount of anti-diuretic hormone (ADH, 2.8 micrograms/g protein) was established from a 50-year-old small cell lung cancer patient presenting with a syndrome of inappropriate anti-diuretic hormone secretion. These cells grew well in serum-supplemented medium and during more than 100 passages they continued producing a large amount of this hormone. This cell line will be a useful tool for studies of the biochemistry and pathology of ADH-producing cancer.

Published
1994

20. A branch site mutation leading to aberrant splicing of the human tyrosine hydroxylase gene in a child with a severe extrapyramidal movement disorder.

Author

Janssen, R.J.R.J., Wevers, R.A., Häussler, M., Luyten, J.A.F.M., Steenbergen-Spanjers, G.C.H., Hoffmann, G.F., Nagatsu, T., Heuvel, L.P.W.J. van den, Janssen, R.J.R.J., Wevers, R.A., Häussler, M., Luyten, J.A.F.M., Steenbergen-Spanjers, G.C.H., Hoffmann, G.F., Nagatsu, T., and Heuvel, L.P.W.J. van den

Abstract

Item does not contain fulltext

Published
2000

32. A quantitative-trait analysis of human plasma-dopamine β-hydroxylase activity: Evidence for a major functional polymorphism at the DBH locus

Author

Zabetian, C.P., Anderson, G.M., Buxbaum, S.G., Elston, R.C., Ichinose, Hiroshi, Nagatsu, T., Kim, K.-S., Kim, C.-H., Malison, R.T., Gelernter, J., and Cubells, J.F.

Subjects
Genotype, Population, DNA Mutational Analysis, Molecular Sequence Data, Locus (genetics), Dopamine beta-Hydroxylase, Quantitative trait locus, Biology, Polymorphism, Single Nucleotide, 03 medical and health sciences, 0302 clinical medicine, Quantitative Trait, Heritable, Gene Frequency, Report, Genetics, Humans, Point Mutation, Genetics(clinical), Allele, education, Gene, Genetics (clinical), 030304 developmental biology, 0303 health sciences, education.field_of_study, Analysis of Variance, Heterozygote advantage, DNA, Phenotype, Amino Acid Substitution, Genetic marker, 030217 neurology & neurosurgery, Polymorphism, Restriction Fragment Length
Abstract

Dopamine-beta-hydroxylase (D beta H) catalyzes the conversion of dopamine to norepinephrine and is released from sympathetic neurons into the circulation. Plasma-D beta H activity varies widely between individuals, and a subgroup of the population has very low activity levels. Mounting evidence suggests that the DBH structural gene is itself the major quantitative-trait locus (QTL) for plasma-D beta H activity, and a single unidentified polymorphism may account for a majority of the variation in activity levels. Through use of both sequencing-based mutational analysis of extreme phenotypes and genotype/phenotype correlations in samples from African American, European American (EA), and Japanese populations, we have identified a novel polymorphism (--1021C--T), in the 5' flanking region of the DBH gene, that accounts for 35%--52% of the variation in plasma-D beta H activity in these populations. In EAs, homozygosity at the T allele predicted the very low D beta H-activity trait, and activity values in heterozygotes formed an intermediate distribution, indicating codominant inheritance. Our findings demonstrate that --1021C--T is a major genetic marker for plasma-D beta H activity and provide new tools for investigation of the role of both D beta H and the DBH gene in human disease.

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34. Molecular cloning of cDNA and chromosomal assignment of the gene for human phenylethanolamine N-methyltransferase, the enzyme for epinephrine biosynthesis.

Author

Kaneda, N, Ichinose, H, Kobayashi, K, Oka, K, Kishi, F, Nakazawa, A, Kurosawa, Y, Fujita, K, and Nagatsu, T

Abstract

Phenylethanolamine N-methyltransferase (PNMT; EC 2.1.1.28) catalyzes the synthesis of epinephrine from norepinephrine, the last step of catecholamine biosynthesis. To isolate a cDNA clone for human PNMT, we first isolated a cDNA clone for bovine adrenal medulla PNMT using mixed oligodeoxyribonucleotide probes whose synthesis was based on the partial amino acid sequence of tryptic peptides from the bovine enzyme. By screening a bovine adrenal medulla cDNA library, a cDNA clone with an insert of about 200 base pairs (bp) was isolated. This clone consisted of 84 bp of carboxyl-terminal coding region, which contained amino acid sequences corresponding to two tryptic peptides, and about 100 bp of 3'-untranslated region. Using this cDNA fragment as the probe, we screened a human pheochromocytoma cDNA library and isolated a cDNA clone with an insert of about 1.0 kilobase pairs, which contained the complete coding region of the enzyme. Northern blot analysis of human pheochromocytoma poly(A)+ RNA using this cDNA insert as the probe showed a single RNA species of about 1,000 nucleotides, suggesting that this clone is a full-length cDNA. Determination of the nucleotide sequence revealed that human PNMT consists of 282-amino acid residues with a predicted molecular weight of 30,853, including initial methionine. The amino acid sequence of the human PNMT was highly homologous (88%) to that of the bovine enzyme. Chromosomal assignment of the gene for human PNMT was carried out using mouse-human somatic cell hybrids. The PNMT gene was assigned to chromosome 17.

Published
1988
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37. Characterization of mouse and human GTP cyclohydrolase I genes. Mutations in patients with GTP cyclohydrolase I deficiency.

Author

Ichinose, H, Ohye, T, Matsuda, Y, Hori, T, Blau, N, Burlina, A, Rouse, B, Matalon, R, Fujita, K, and Nagatsu, T

Abstract

GTP cyclohydrolase I is the first and rate-limiting enzyme for the biosynthesis of tetrahydrobiopterin in mammals. Previously, we reported three species of human GTP cyclohydrolase I cDNA in a human liver cDNA library (Togari, A., Ichinose, H., Matsumoto, S., Fujita, K., and Nagatsu, T. (1992) Biochem. Biophys. Res. Commun. 187, 359-365). Furthermore, very recently, we found that the GTP cyclohydrolase I gene is causative for hereditary progressive dystonia with marked diurnal fluctuation, also known as DOPA-responsive dystonia (Ichinose, H., Ohye, T., Takahashi, E., Seki, N., Hori, T., Segawa, M., Nomura, Y., Endo, K., Tanaka, H., Tsuji, S., Fujita, K., and Nagatsu, T. (1994) Nature Genetics 8, 236-242). To clarify the mechanisms that regulate transcription of the GTP cyclohydrolase I gene and to generate multiple species of mRNA, we isolated genomic DNA clones for the human and mouse GTP cyclohydrolase I genes. Structural analysis of the isolated clones revealed that the GTP cyclohydrolase I gene is encoded by a single copy gene and is composed of six exons spanning approximately 30 kilobases. We sequenced all exon/intron boundaries of the human and mouse genes. Structural analysis also demonstrated that the heterogeneity of GTP cyclohydrolase I mRNA is caused by an alternative usage of the splicing acceptor site at the sixth exon. The transcription start site of the mouse GTP cyclohydrolase I gene and the 5'-flanking sequences of the mouse and human genes were determined. We performed regional mapping of the mouse gene by fluorescence in situ hybridization, and the mouse GTP cyclohydrolase I gene was assigned to region C2-3 of mouse chromosome 14. We identified missense mutations in patients with GTP cyclohydrolase I deficiency and expressed mutated enzymes in Escherichia coli to confirm alterations in the enzyme activity.

Published
1995

38. Targeted disruption of the tyrosine hydroxylase locus results in severe catecholamine depletion and perinatal lethality in mice.

Author

Kobayashi, K, Morita, S, Sawada, H, Mizuguchi, T, Yamada, K, Nagatsu, I, Hata, T, Watanabe, Y, Fujita, K, and Nagatsu, T

Abstract

Tyrosine 3-hydroxylase (TH, EC 1.14.16.2) catalyzes the first and rate-limiting step of the catecholamine biosynthetic pathway in the nervous and endocrine systems. The TH locus was disrupted in mouse embryonic stem cells by homologous recombination. Mice heterozygous for the TH mutation were apparently normal. In these mice, TH activity in the embryos and adult tissues was less than 50% of the wild-type values, but the catecholamine level was decreased only moderately in the developing animals and was maintained normally at adulthood, suggesting the presence of a regulatory mechanism for ensuring the proper catecholamine level during animal development. In contrast, the homozygous mutant mice died at a late stage of embryonic development or shortly after birth. Both TH mRNA and enzyme activity were lacking in the homozygous mutants, which thus explained the severe depletion of catecholamines. These changes, however, did not affect gross morphological development of the cells that normally express high catecholamine levels. Analysis of electrocardiograms of surviving newborn mutants showed bradycardia, suggesting an alteration of cardiac functions in the homozygous mice that may lead to the lethality of this mutation. In addition, transfer of a human TH transgene into the homozygous mice corrected the mutant phenotype, showing recovery of TH activity by expression of the human enzyme. These results indicate that TH is essential for survival of the animals during the late gestational development and after birth.

Published
1995

39. Identification and characterization of a novel phorbol ester-responsive DNA sequence in the 5'-flanking region of the human dopamine beta-hydroxylase gene.

Author

Ishiguro, H, Yamada, K, Ichino, N, and Nagatsu, T

Abstract

The phorbol ester, 12-O-tetradecanoylphorbol-13-acetate (TPA), enhances transcription of many eukaryotic genes, including that for dopamine beta-hydroxylase (DBH). In the present study, we report identification and characterization of a novel sequence motif residing in the 5'-flanking region of the human DBH gene, which mediates transcriptional induction by TPA. Deletional analyses indicated the promoter region between -223 and -187 base pairs to be critical. Whereas this region does not contain any putative regulatory motifs with significant sequence homology to the AP-1 motif, extensive deletional and site-directed mutational analyses indicated that a sequence between -210 and -199 base pairs, 5'-ATCCGCCTGTCT-3', may represent a novel TPA-response element (TRE). In addition, alteration of the YY1-binding site decreased TPA-mediated induction of the DBH promoter activity, suggesting that contiguous cis-regulatory element(s) cooperate with this novel sequence motif. Furthermore, insertional mutation analyses between the YY1-binding site and the cyclic AMP-responsive element indicated that the stereospecificity of these motifs is important for intact transcriptional induction by TPA. Taken together, these data suggest that transcriptional up-regulation of the human DBH gene in response to TPA requires coordination of a novel TRE (human DBH TRE, hDTRE), cyclic AMP-responsive element, and the YY1-binding site.

Published
1998

40. Isolation of a full-length cDNA clone encoding human tyrosine hydroxylase type 3

Author

Kobayashi, K., Kaneda, N., Ichinose, Hiroshi, Kishi, F., Nakazawa, A., Kurosawa, Y., Fujita, K., and Nagatsu, T.

Subjects
Tyrosine hydroxylase, Base Sequence, Tyrosine 3-Monooxygenase, Clone (cell biology), Protein primary structure, DNA, Recombinant, DNA, Molecular cloning, Biology, Molecular biology, Genes, Complementary DNA, Genetics, Humans, Amino Acid Sequence, Peptide sequence, Gene
Published
1987

41. GENERAL SESSION

Author

TANAKA, Akio, primary, SUGIMURA, Kimiya, additional, MIZUTANI, Akira, additional, Baba, Masayuki, additional, Koya, Goyo, additional, AMEMIYA, Tsugio, additional, YOSHIDA, Hidehiko, additional, YOSHIDA, Masako, additional, Sasaki, Fumie, additional, KAKUTA, Sachiko, additional, MORIMOTO, Kouhei, additional, NAGATO, Yasukazu, additional, SUZUKI, Toshio, additional, TSUCHIHASHI, Yasunari, additional, KITAMURA, Tadahisa, additional, FUJITA, Setsuya, additional, Fujimura, Masaki, additional, Chen, S.T., additional, Tobe, Takayoshi, additional, Yajima, Haruaki, additional, NAGATSU, I., additional, INAGAKI, S., additional, KONDO, Y., additional, KATO, T., additional, NAGATSU, T., additional, KAMI, Koji, additional, MITSUI, Tadao, additional, KAWAOI, Akira, additional, OKANO, Tadao, additional, SHIKATA, Toshio, additional, DOBASHI, Kazuyoshi, additional, TAKAGI, Shigeo, additional, WATANABE, Kenji, additional, KUBO, Seiichi, additional, IBATA, Yasuhiko, additional, SANO, Yutaka, additional, Osamura, R.Y., additional, Nakahashi, E., additional, Watanabe, K., additional, ONO, Tetsuro, additional, SAKAI, Yasuhiro, additional, YAMAMOTO, Noboru, additional, YASUDA, Kenjiro, additional, MARUO, Naoyuki, additional, ISEMURA, Takuji, additional, FUKUDA, Masaru, additional, NOJYO, Yoshiaki, additional, MIZUKAWA, Kiminao, additional, MATSUURA, Tadao, additional, YAMAMOTO, Keizo, additional, TAKAKUSU, Akira, additional, YAMADA, Masakazu, additional, MATSUBARA, Hiroshi, additional, YAMADA, Masaoki, additional, MURATA, Fusayoshi, additional, YOSHIDA, Keizo, additional, MOMOSE, Yuriko, additional, OHNO, Shinichi, additional, NAGATA, Tetsuji, additional, OKADA, Akiko, additional, NOKUBI, Kazuto, additional, KATO, Morio, additional, Mizuhira, Vinci, additional, Shiihashi, Michiko, additional, Yokoyama, Masao, additional, Nishiyama, Fumiaki, additional, Hirano, Hiroshi, additional, Kawai, Norio, additional, SUGIURA, Hajime, additional, WATANABE, Hideki, additional, USHIKI, Kazuyo, additional, SUZUKI, Takuro, additional, NISHIMURA, Tamio, additional, OHKURA, Takuji, additional, IWATSUKI, Hirohiko, additional, SHIBA, Yoshiki, additional, KANNO, Yoshinobu, additional, KATSUYAMA, Tsutomu, additional, NASU, Tsuyoshi, additional, TSUKAHARA, Masanori, additional, NUMANO, Fujio, additional, MAEZAWA, Hidenori, additional, ISOMURA, Genzoh, additional, HIDA, Takehiko, additional, SHIMIZU, Nobuo, additional, KAIYA, Hisanobu, additional, IWATA, Tsuyoshi, additional, NAMBA, Masuyuki, additional, KASHIBA, Akira, additional, HASHIMOTO, Hisashi, additional, KIMURA, Hiroshi, additional, MAEDA, Toshihiro, additional, AMANO, Shigetoyo, additional, IMAMOTO, Kikuko, additional, KINOSHITA, Haruo, additional, YAMAMOTO, K., additional, SAKUMOTO, T., additional, SATOH, K., additional, KIMOTO, Y., additional, TAKAHASHI, Y., additional, TOHYAMA, M., additional, SHIMIZU, N., additional, AWAI, Michiyasu, additional, NARASAKI, Mikio, additional, YAMANOI, Yasuhiro, additional, SENO, Satimaru, additional, KISHINO, Yasuo, additional, MORIGUCHI, Satoru, additional, ISHII, Tetsuo, additional, KATAOKA, Katsuko, additional, SHIMIZU, Keisuke, additional, OCHI, Junzo, additional, KAJIHARA, Hiroki, additional, IIJIMA, Soichi, additional, SUEMATSU, Chiharu, additional, KUMAMOTO, Tetsuzo, additional, SAITO, Mitsunori, additional, TOMONAGA, Masanori, additional, UCHIDA, Yoko, additional, FUJIMOTO, Kazushi, additional, MAKITA, Takashi, additional, SAKURADA, Hiromi, additional, KANDA, Shigeto, additional, OTSUKA, Nagayasu, additional, Daimon, T., additional, Uchida, K., additional, Mizuhira, V., additional, HAMADA, Tetsuo, additional, Tsuru, Takeshi, additional, SATO, Kazuko, additional, IWAMASA, Teruo, additional, TAKEUCHI, Tadao, additional, IMAI, Harumichi, additional, NAKAI, Kunio, additional, ITAKURA, Tohru, additional, HIRAI, Kei-ichi, additional, YAMAUCHI, Mitsuaki, additional, WITSCHI, Hanspeter, additional, COTE, Michel G., additional, Nishi, Reiko, additional, Sawada, Shinji, additional, Midorikawa, Osamu, additional, NOZAWA, S., additional, IZUMI, S., additional, OHTA, H., additional, HAYASHI, S., additional, NAGAI, S., additional, KURIHARA, S., additional, KOMATSU, N., additional, WATANABE, K., additional, Izumi, Shinichi, additional, Komatsu, Nobuhiko, additional, Ozawa, Atsushi, additional, Onishi, Nobuhiko, additional, Nakahashi, Etsuko, additional, Watanabe, Keiichi, additional, TOMINAGA, Akio, additional, TAKASHIMA, Yoichiro, additional, FUKUNAGA, Hidetoshi, additional, OSAME, Mitsuhiro, additional, KAWABUCHI, Masaru, additional, IGATA, Akihiro, additional, Fujimori, Ken, additional, Yamada, Masa-oki, additional, Yamamoto, Keizo, additional, YAMASHINA, Shohei, additional, KAWAI, Kazuhiro, additional, KUSUMOTO, Takeo, additional, HARADA, Hisatoshi, additional, KUMAZAWA, Tadami, additional, MORII, Sotokichi, additional, KAMEI, I., additional, Tateiwa, Jiro, additional, Toki, Junko, additional, Osawa, Kotaro, additional, NAKANISHI, Kazuo, additional, OHNO, S., additional, MURATA, F., additional, YOSHIDA, K., additional, FURUTA, S., additional, NAGATA, T., additional, SENDA, R., additional, AKAGI, Y., additional, SANO, Y., additional, Sasaki, F., additional, KATSUYAMA, Tutomu, additional, Hamada, Tetsuo, additional, Iwamasa, Teruo, additional, Takeuchi, Tadao, additional, Komatsu, Noriyuki, additional, Yoshimura, Shinichi, additional, KIMURA, M., additional, NOKUBI, K., additional, KATO, M., additional, KISO, M., additional, OTSUKA, S., additional, TAKIGAMI, Shigeru, additional, MACHINAKA, Emiyo, additional, YOSHITOKI, Katsuhiko, additional, Osnwa, Votaro, additional, Haeda, Ryuei, additional, Iirime, Isao, additional, Ogawa, Ryokei, additional, and Hori, Hasuta, additional

Published
1978
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43. GENERAL SESSION

Author

YASUDA, Kenjiro, primary, IDE, Chizuka, additional, SAITO, Takuma, additional, MATSUSHITA, Masaya, additional, ARAKI, Nasasuke, additional, Murata, F., additional, Yoshida, K., additional, Ohno, S., additional, Nagata, T., additional, YOSHIDA, Keizo, additional, OHNO, Shinichi, additional, MURATA, Fusayoshi, additional, YAMAMOTO, Noboru, additional, YASUDA, Kenjiro, additional, YAMASHITA, Shuji, additional, SAKAI, Yasuhiro, additional, KIMOTO, HIROO, additional, ODA, TOMIO, additional, MAYAHARA, Hiroshi, additional, AGO, Yasuhiro, additional, FUJIMOTO, Toyoshi, additional, ANDO, Takao, additional, SHIMIZU, Satoru, additional, YAMADA, Kazuyori, additional, OHKURA, Takuji, additional, OHKURA, Minoru, additional, OHKURA, Motohiko, additional, HIRAI, Kei-ichi, additional, Ishii, Tetsuo, additional, Shiota, Toshiro, additional, WATANABE, Kensuke, additional, YAMASHINA, Shohei, additional, KAWAI, Kazuhiro, additional, IIDA, Futoshi, additional, KOMIYAMA, Kiyohiro, additional, SATO, Akira, additional, KATSUYAMA, Tsutomu, additional, SUGANUMA, Tatsuo, additional, NASU, Tsuyoshi, additional, NAGASE, Katsuro, additional, FUJIWARA, Masayuki, additional, TAKAHASHI, Michihito, additional, TATEMATSU, Masae, additional, HASHIMOTO, Yoshinori, additional, UCHIDA, Yuzo, additional, KOTAKE, Yasunori, additional, TSUJI, Yasukuni, additional, KAWAI, Kioko, additional, SUGIHARA, Hajime, additional, Tsuchiyama, Hideo, additional, HARADA, Tomoyuki, additional, SUGIMOTO, Akitoshi, additional, AMEMIYA, Tsugio, additional, YOSHIDA, Hidehiko, additional, TSURU, Takeshi, additional, MAENO, Masanobu, additional, SHIRAISHI, Yukiharu, additional, AKAGI, Masanobu, additional, TSUSU, Takeshi, additional, MIYAYAMA, Haruhiko, additional, TAKEMIYA, Masataka, additional, KITAJIMA, Kiyoaki, additional, SATOU, Yasuo, additional, OGAWA, Narumi, additional, OKADA, Kiyoki, additional, KISHIMOTO, Takashi, additional, KAWAOI, Akira, additional, OKANO, Tadao, additional, SHIKATA, Toshio, additional, YAMAGUCHI, Takahiro, additional, HOSHINO, Tadahiko, additional, TAMATE, Hideo, additional, OSAMURA, R. Yoshiyuki, additional, NAKAHASHI, Etsuko, additional, TANAKA, Minoru, additional, YANAIHARA, Noboru, additional, KAMEYA, Yuzuru, additional, HOSHINO, Munemitsu, additional, WATARI, Nakazo, additional, KAMEYA, Toru, additional, DOBASEI, Kazuyoshi, additional, OKUMURA, Hajime, additional, NISHIYAMA, Fumiaki, additional, KAWAI, Norio, additional, SAMPEI, Kiyoe, additional, OHSATO, Yukihiro, additional, HIRANO, Hiroshi, additional, KAMEDA, Yoko, additional, IKEDA, Akira, additional, HARADA, Tanekazu, additional, ITO, Kunihiko, additional, ASO, Yoshio, additional, OHTAWARA, Yoshihisa, additional, SUZUKI, Kazuo, additional, TAJIMA, Atsushi, additional, FUJITA, Kimio, additional, AIHA, Motohiko, additional, SUZUKI, Hiroshi, additional, Izumi, Shinichi, additional, Mitani, Fumiko, additional, Ishimura, Yuzuru, additional, NAGATSU, I., additional, KARASAWA, N., additional, KONDO, Y., additional, INAGAKI, S., additional, MURAKOSHI, MASANORI, additional, YAMAMOTO, ICHIRO, additional, Ogura, Motohiro, additional, Nishikawa, Kiyohisa, additional, Maeda, Ryuei, additional, Toki, Junko, additional, YANAGISAWA, Takaaki, additional, TAKUMA, Shosaburo, additional, SASAKI, Daizo, additional, SIMAZAKI, Masayoshi, additional, MITSUHASHI, Takehiro, additional, HASEGAWA, Kiyoshi, additional, SUMI, Yawara, additional, TANAKA, Ayako, additional, MURAKI, Takeshi, additional, MURAKI, Takuro, additional, Yamasaki, Yuichiro, additional, Kuramochi, Shigeru, additional, Yoshimura, Shinichi, additional, ANDOH, Takao, additional, MIYAJIMA, Hiroaki, additional, NOMURA, Masaji, additional, NUMANO, Fujio, additional, WATANABE, Yoshinori, additional, YAJIMA, Michiyoshi, additional, WATABIRI, Sadakiyo, additional, TAKENO, Kyoko, additional, YOSHIDA, Nobuyoshi, additional, TANIYAMA, Kohtaro, additional, TANAKA, Chikako, additional, NAGASHIMA, Toshiko, additional, BEPPU, Hirokuni, additional, UONO, Masanori, additional, YAMADA, Hiroshi, additional, MIZUKAWA, Kiminao, additional, IMAI, H., additional, NAKAI, K., additional, ITAKURA, T., additional, KOMAI, N., additional, NAGAI, T., additional, KIMURA, H., additional, IMAMOTO, K., additional, MAEDA, K., additional, IMAMOTO, Kikuko, additional, NAGAI, Toshisaburo, additional, KATAOKA, Katsuko, additional, SHIMIZU, Keisuke, additional, YAMAMOTO, Toshiharu, additional, OCHI, Junzo, additional, NAKAMURA, Toshio, additional, IBATA, Yasuhiko, additional, KOJIMA, H., additional, NAGATSU, T., additional, Kojima, Hideki, additional, Anraku, Shigemi, additional, Toshima, Nobuo, additional, Yoshida, Masami, additional, Kotorii, Ken, additional, TAKAHASHI, Y., additional, SAKUMOTO, T., additional, TOHYAMA, M., additional, KIMOTO, Y., additional, YAMAMOTO, K., additional, KASHIBA, A., additional, SHIMIZU, N., additional, SAKAI, K., additional, SALVERT, D., additional, JOUVET, M., additional, KISHIDA, Takenobu, additional, KITO, Shozo, additional, ITOGA, Eiko, additional, KITOI, Shozo, additional, WAKABAYASHI, Ichizi, additional, OGAWA, Norio, additional, KAIYA, Hisanobu, additional, IWATA, Tsuyoshi, additional, NAMBA, Masuyuki, additional, TSUCHIHASHI, Yasunari, additional, FUKUDA, Masaru, additional, FUJITA, Setsuya, additional, NAKANISHI, Kazuo, additional, Kagawa, K., additional, Tomimasu, H., additional, Kamachi, M., additional, Kitamura, O., additional, Ashihara, T., additional, Takeoka, O., additional, Hidaka, T., additional, NISHIKAWA, Akiyoshi, additional, MORI, Hideki, additional, TAKAHASHI, Masayoshi, additional, MAEDA, Osami, additional, Onogi, K., additional, Ito, R., additional, KAITA, Hisanobu, additional, KATO, Kazuo, additional, Shiihashi, Michiko, additional, SAKUMOTO, Tetsuro, additional, NAGATO, Yasukazu, additional, TADANO, Yanagi, additional, TADANO, Masashi, additional, OSHIMA, Kiyoshi, additional, OKADA, Akiko, additional, KIMURA, Maseru, additional, NOKUBI, Kazuto, additional, KATHO, Mario, additional, KASHIBA, Akira, additional, HASHIMOTO, Hisashi, additional, TAKIGAMI, Shigeru, additional, MORII, Sotokichi, additional, NAKAO, Iezo, additional, SASAKI, Fumie, additional, WATANABE, Kyozo, additional, Daimon, T., additional, MUKUDAI, Tatsuhiko, additional, WADA, Tetsushi, additional, IKADO, Shinsuke, additional, Yamagami, Takahiro, additional, Gamou, Atsushi, additional, Mori, Masahiko, additional, SASAKI, Junzo, additional, NAKAMOTO, Shu, additional, MORI, Masaharu, additional, Asada-Kubota, Mari, additional, Kanamura, Shinsuke, additional, MORIGUCHI, Satoru, additional, KISHINO, Yasuo, additional, KITAMURA, Osamu, additional, HIDAKA, Takashi, additional, ASHIHARA, Tsukasa, additional, TAKEOKA, Osamu, additional, INOMATA, Kenichirou, additional, OKADA, Shintaro, additional, YABUUCHI, Hyakuji, additional, NAKAGAWA, Shiro, additional, SUEMATSU, Chiharu, additional, KANAGAWA, Ryuichi, additional, KUMAMOTO, TETSUZO, additional, OGAWA, Kazuo, additional, OGAWA, Hiroshi, additional, KAMI, Koji, additional, MITSUI, Tadao, additional, MIZUHIRA, Vinci, additional, KIMURA, Hiroshi, additional, MAEDA, Toshihiro, additional, SATOH, K., additional, KANDA, Shigeto, additional, OTSUKA, Nagayasu, additional, SUZUKI, Toshio, additional, HAMADA, Tetsuo, additional, IWAMASA, Teruo, additional, TAKEUCHI, Tadao, additional, WATANABE, Keiichi, additional, KOMATSU, Noriyuki, additional, WATANABE, Kenji, additional, OBATA, Hiroko, additional, SANO, Yutaka, additional, NAGATA, Tetsuji, additional, KINOSHITA, Haruo, additional, and KUBO, Seiichi, additional

Published
1979
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46. Parkinson's Disease: Cells Succumbing to Lifelong Dopamine-Related Oxidative Stress and Other Bioenergetic Challenges.

Author

Watanabe H, Dijkstra JM, and Nagatsu T

Subjects
Humans, Dopamine metabolism, Substantia Nigra metabolism, Dopaminergic Neurons metabolism, Oxidative Stress physiology, Energy Metabolism, Parkinson Disease metabolism
Abstract

The core pathological event in Parkinson's disease (PD) is the specific dying of dopamine (DA) neurons of the substantia nigra pars compacta (SNc). The reasons why SNc DA neurons are especially vulnerable and why idiopathic PD has only been found in humans are still puzzling. The two main underlying factors of SNc DA neuron vulnerability appear related to high DA production, namely (i) the toxic effects of cytoplasmic DA metabolism and (ii) continuous cytosolic Ca 2+ oscillations in the absence of the Ca 2+ -buffer protein calbindin. Both factors cause oxidative stress by producing highly reactive quinones and increasing intra-mitochondrial Ca 2+ concentrations, respectively. High DA expression in human SNc DA neuron cell bodies is suggested by the abundant presence of the DA-derived pigment neuromelanin, which is not found in such abundance in other species and has been associated with toxicity at higher levels. The oxidative stress created by their DA production system, despite the fact that the SN does not use unusually high amounts of energy, explains why SNc DA neurons are sensitive to various genetic and environmental factors that create mitochondrial damage and thereby promote PD. Aging increases multiple risk factors for PD, and, to a large extent, PD is accelerated aging. To prevent PD neurodegeneration, possible approaches that are discussed here are (1) reducing cytoplasmic DA accumulation, (2) blocking cytoplasmic Ca 2+ oscillations, and (3) providing bioenergetic support.

Published
2024
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47. The Life and Science of Professor Tsuneko Okazaki, and her time at Fujita Health University.

Author

Dijkstra JM and Nagatsu T

Abstract

Distinguished Professor Emeritus Tsuneko Okazaki is a hero of science. Together with her late husband, Professor Reiji Okazaki, she discovered that DNA replication involves the discontinuous synthesis of the DNA lagging strand by intermediates of, what is now called, "Okazaki fragments." She has been a pioneer for women in science and, in 1983, became the first female full Professor at Nagoya University. From 1997 to 2012, she was a full Professor and later a Visiting Professor at Fujita Health University, and this review zooms in on that period. Besides a summary of her career, this article also includes personal memories of researchers who worked with Professor Okazaki., Competing Interests: None.

Published
2024
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48. Refusal of Subsequent Treatment in Patients With EGFR-mutant Non-small-cell Lung Cancer After Response to EGFR-TKIs.

Author

Hashimoto S, Fujii Y, Ujiie M, Miyazaki K, Sato S, Kodama T, Nagatsu T, Kayauchi N, and Satoh H

Abstract

Background/aim: During the course of effective and long-term treatment with epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI), some elderly patients might decline further treatment after EGFR-TKI. We conducted a study to try and understand the reasons for this treatment decision., Patients and Methods: We analyzed the medical records of all patients diagnosed with non-small-cell lung cancer with EGFR mutations between 2016 and 2021., Results: There were 108 patients who received EGFR-TKIs. Of these, 67 patients responded to TKI. These responding patients were divided into two groups according to whether they received subsequent TKI treatment. At their request, 24 patients (group A) did not receive further anticancer treatment following TKI. The other 43 patients (group B) received anticancer therapy following TKI. Progression-free survival in group A patients was significantly longer (median=18 months, range=1-67 months) than in group B patients. The reasons for not wanting subsequent treatment after TKI were older age, reduced general condition, deterioration of physical comorbid disease and dementia. Dementia was the most common reason for patients over 75 years of age., Conclusion: Some elderly patients with well-controlled disease might express their refusal of all subsequent anticancer therapy after TKIs. Medical staff should respond seriously to these requests., Competing Interests: None declared., (Copyright 2023, International Institute of Anticancer Research.)

Published
2023
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49. INTER-PROFESSIONAL 360-DEGREE EVALUATION OF THE PERFORMANCE OF INTENSIVE CARE UNIT NURSES.

Author

Nagatsu T, Kayauchi N, and Satoh H

Subjects
Humans, Surveys and Questionnaires, Intensive Care Units, Nurses
Abstract

A 360-degree evaluation is an objective evaluation method for people to be surveyed by evaluators from various positions and perspectives. The purpose of this study to create an objective method of 'comprehensive' verification of the entire survey using Spearman rank correlation coefficient and Wilcoxon signed rank test. With these statistical methods, a detailed correlation and comparison between the self-evaluation of intensive care unit nurses and their evaluation by staff of other medical occupations could be assessed. Detailed correlations and differences were clarified for each survey item and surveyees. By a scoring method that takes into account the correlation and comparison results of the evaluation scores in evaluators and surveyees, and the total evaluation scores were visualized as radar charts. Our results could highlight agreement and discrepancies between the evaluations performed by the surveyees and those by the evaluators. This time, the survey was conducted with a small number of surveyors, surveyees, and survey items, but the possibility of responding to a larger scale survey was indicated. It might be meaningful to make full use of statistical methods to comprehensively evaluate the overall survey results and clearly show them in visual methods such as radar charts.

Published
2022

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