Biomedical subjects

A Hata

Publications and source records attributed to A Hata.

At least 55 records · Page 3Linked to original sources

PubMed1998

Five familial hypercholesterolemic kindreds in Japan with novel mutations of the LDL receptor gene.

In the course of investigations of familial coronary artery disease in Hokkaido, the northern island of Japan, we identified five families in which multiple members showed elevated plasma levels of low-density lipoprotein (LDL) cholesterol. To determine the genetic etiology of their lipoprotein abnormalities, we screened DNA samples from these families for mutations in all 18 exons and the exon-intron boundaries of the LDL receptor (LDLR) gene. Novel point mutations were identified in each family: (1) a C-to-A transversion at nucleotide 285, causing a nonsense mutation at codon 74, in eight members of family A; (2) a G-to-A transition at nucleotide 1136, causing substitution of Tyr for Cys at codon 358, in six members of family B; (3) a C-to-T transition at nucleotide 1822, causing substitution of Ser for Pro at codon 587, in five members of family C; (4) a one-base insertion of G to a five-G stretch at nucleotides 1774-1778 (codons 571-572), causing a frameshift, in six members of family D; and (5) a one-base deletion of T at nucleotide 1963-1964 (codon 634), causing a frameshift, in three members of family E. Through the molecular genetic approach a total of 28 individuals in these families were diagnosed unequivocally as heterozygous for the respective LDLR mutations. This method also helped us to diagnose familial hypercholesterolemia, or to exclude from carrier status, 11 children with borderline high cholesterol levels.

Adolescent↗

PubMed1998

Decreased plasma cortisol level during alprazolam treatment of panic disorder: a case report.

1. Changes in the plasma cortisol level were reported in a male patient with panic disorder during the period of low-dose alprazolam treatment (mean 0.62 +/- 0.15 mg/day) compared with during the period of high-dose period (mean 1.08 +/- 0.28 mg/day). 2. The plasma cortisol level was significantly higher in the low-dose period (mean 13.90 +/- 3.35 micrograms/ml) than in the high-dose period (mean 9.06 +/- 2.75 micrograms/ml) although, paradoxically, the panic attack frequency was significantly lower in the low-dose period (mean 1.35 +/- 0.29/day) than in the high-dose period (mean 2.09 +/- 0.66/day). 3. Thus, the decreased plasma cortisol level during alprazolam treatment of panic disorder was suggested to be caused not by symptom alleviation due to alprazolam but by alprazolam administration itself.

Adult↗

PubMed1998

TGF-beta signaling and cancer: structural and functional consequences of mutations in Smads.

Transforming growth factor-beta (TGF-beta) and related cytokines control the development and homeostasis of many tissues by regulating the expression of genes that determine cell phenotype. Recent progress has elucidated the way in which members of the TGF-beta family initiate their signal through transmembrane receptors and transmit it to target genes via the Smad family of signal-transducing proteins. This review describes TGF-beta signaling pathways as currently understood and mutations of the genes that encode Smads that disrupt the function of these proteins and cause various forms of cancer.

Animals↗

PubMed1998

Angiotensin II type 1 receptor gene polymorphisms in patients with cardiac hypertrophy.

Chronic mechanical stress of the heart secondary to arterial hypertension is a primary cause of left ventricular hypertrophy (LVH). The renin-angiotensin system (RAS) plays an important role in the cardiovascular system, regulating the expression of cardiac hypertrophy, in part, independent of the effects of systemic hypertension. A major component of RAS is angiotensin converting enzyme (ACE), which is upregulated in pressure overload-induced cardiac hypertrophy as well as heart failure. In a recent study, we found that the T allele of the M235T polymorphism of the angiotensinogen gene in sporadic hypertrophic cardiomyopathy (HCM) patients is associated with LVH. The present study was designed to assess the contribution of the polymorphisms of the angiotensin II type 1 receptor (AGT1R A1166C) genes on development of left ventricular hypertrophy. Patients with hypertensive LVH and relatives of HCM without manifesting the disease, showed higher C allele frequency compared to patients with HCM (11.3% vs 4.2%, chi 2 = 5.3, p < 0.05 and 10.5% vs 4.2%, chi 2 = 5.3, p < 0.05, respectively), but healthy controls did not (11.3% vs 7.5%, chi 2 = 1.42, NS and 10.5% vs 7.5%, chi 2 = 1.2, NS). The strong interaction between ACE I/D and AGT1R A1166C gene polymorphisms has been found in groups of relatives of HCM patients; odds ratio associated with ACE D allele was significant in subjects carrying the AGT1R C allele (OR = 7.3, 95% CI 1.6-33.1; chi 2 = 7.9, p < 0.02) compared with healthy subjects. We conclude that the molecular variant of the AGT1R A1166C gene is not contributing to the development of cardiac hypertrophy in hypertensive LVH and HCM patients, whereas carriers of both C and D alleles had a four-fold increase in the odds ratio for family history of HCM without manifesting the disease.

Aged↗

PubMed1998

[Small cell carcinoma of the prostate: a case report].

A 57-year-old man was admitted with the chief complaint of macrohematuria. Digital rectal examination showed a slightly enlarged, irregular prostate with stony consistency. Serum levels of prostate specific antigen (PSA), neuron-specific enolase (NSE) and progastrin-releasing peptide (ProGRP) were elevated. Transurethral resection (TUR)-biopsy of the prostate revealed small cell carcinoma with poorly differentiated adenocarcinoma. Various radiological examinations revealed metastases to pelvic lymph nodes and liver. He was treated with chemoendocrine therapy consisting of cisplatin, etoposide, flutamide and luleinizing hormone-releasing hormone (LH-RH) agonist. The primary tumor and metastatic lesion decreased and serum PSA, NSE and ProGRP levels were decreased to normal ranges after 5 cycles of chemotherapy. After the 5-cycle chemotherapy, TUR-biopsy proved viable tumor cells. During the additional chemotherapy, tumor markers increased and 4 months later liver metastasis progressed. He died 13 months after diagnosis of small cell carcinoma of the prostate.

Carcinoma, Small Cell↗

PubMed1997

Genetic evidence for a tyrosine kinase cascade preceding the mitogen-activated protein kinase cascade in vertebrate G protein signaling.

The signal transduction pathway from heterotrimeric G proteins to the mitogen-activated protein kinase (MAPK) cascade is best understood in the yeast mating pheromone response, in which a serine/threonine protein kinase (STE20) serves as the critical linking component. Little is known in metazoans on how G proteins and the MAPK cascade are coupled. Here we provide genetic and biochemical evidence that a tyrosine kinase cascade bridges G proteins and the MAPK pathway in vertebrate cells. Targeted deletion of tyrosine kinase Csk in avian B lymphoma cells blocks the stimulation of MAPK by Gq-, but not Gi-, coupled receptors. In cells deficient in Bruton's tyrosine kinase (Btk), Gi-coupled receptors failed to activate MAPK, while Gq-coupled receptor-mediated stimulation is unaffected. Taken together with our previous data on tyrosine kinases Lyn and Syk, the Gq-coupled pathway requires tyrosine kinases Csk, Lyn, and Syk, while the Gi-coupled pathway requires tyrosine kinases Btk and Syk to feed into the MAPK cascade in these cells. The central role of Syk is further strengthened by data showing that Syk can bind to purified Lyn, Csk, or Btk.

Agammaglobulinaemia Tyrosine Kinase↗

PubMed1997

Mutations increasing autoinhibition inactivate tumour suppressors Smad2 and Smad4.

Smad2 and Smad4 are related tumour-suppressor proteins, which, when stimulated by the growth factor TGF-beta, form a complex to inhibit growth. The effector function of Smad2 and Smad4 is located in the conserved carboxy-terminal domain (C domain) of these proteins and is inhibited by the presence of their amino-terminal domains (N domain). This inhibitory function of the N domain is shown here to involve an interaction with the C domain that prevents the association of Smad2 with Smad4. This inhibitory function is increased in tumour-derived forms of Smad2 and 4 that carry a missense mutation in a conserved N domain arginine residue. The mutant N domains have an increased affinity for their respective C domains, inhibit the Smad2-Smad4 interaction, and prevent TGF beta-induced Smad2-Smad4 association and signalling. Whereas mutations in the C domain disrupt the effector function of the Smad proteins, N-domain arginine mutations inhibit SMAD signalling through a gain of autoinhibitory function. Gain of autoinhibitory function is a new mechanism for inactivating tumour suppressors.

Animals↗

PubMed1997

A structural basis for mutational inactivation of the tumour suppressor Smad4.

The Smad4/DPC4 tumour suppressor is inactivated in nearly half of pancreatic carcinomas and to a lesser extent in a variety of other cancers. Smad4/DPC4, and the related tumour suppressor Smad2, belong to the SMAD family of proteins that mediate signalling by the TGF-beta/activin/BMP-2/4 cytokine superfamily from receptor Ser/Thr protein kinases at the cell surface to the nucleus. SMAD proteins, which are phosphorylated by the activated receptor, propagate the signal, in part, through homo- and hetero-oligomeric interactions. Smad4/DPC4 plays a central role as it is the shared hetero-oligomerization partner of the other SMADs. The conserved carboxy-terminal domains of SMADs are sufficient for inducing most of the ligand-specific effects, and are the primary targets of tumorigenic inactivation. We now describe the crystal structure of the C-terminal domain (CTD) of the Smad4/DPC4 tumour suppressor, determined at 2.5 A resolution. The structure reveals that the Smad4/DPC4 CTD forms a crystallographic trimer through a conserved protein-protein interface, to which the majority of the tumour-derived missense mutations map. These mutations disrupt homo-oligomerization in vitro and in vivo, indicating that the trimeric assembly of the Smad4/DPC4 CTD is critical for signalling and is disrupted by tumorigenic mutations.

Amino Acid Sequence↗

PubMed1997

Behavioral and P3 amplitude enhancement in schizophrenia following feedback training.

In order to clarify the remediability of behavioral and electrophysiological abnormalities in schizophrenia, hit rate, reaction time, and P3 amplitude from auditory event-related potentials were evaluated before and after feedback training of a task in 14 schizophrenics and 12 age-matched normal controls. Although mean changes in the three indices due to the training were nonsignificant in both schizophrenic and normal control groups as a whole, the changes in hit rate and reaction time correlated significantly with the P3 amplitude change in the schizophrenic (r = 0.60 and -0.58, respectively) but not in the normal control group. The P3 amplitude change also correlated with the P3 amplitude before the training only in the schizophrenic group (r = -0.68), suggesting that the training was more effective for the schizophrenic patients with marked P3 amplitude reduction. The observed P3 amplitude increase due to training may represent an electrophysiological correlate of a remediable aspect of behavioral deficits in schizophrenics, which may underlie the effectiveness of nonpharmacological treatments.

Adult↗

PubMed1997

The TGF-beta family mediator Smad1 is phosphorylated directly and activated functionally by the BMP receptor kinase.

Bone morphogenetic proteins (BMPs) are members of the TGF-beta family that regulate cell proliferation, apoptosis, and differentiation, and participate in the development of most tissues and organs in vertebrates. Smad proteins function downstream of TGF-beta receptor serine/threonine kinases and undergo serine phosphorylation in response to receptor activation. Smad1 is regulated in this fashion by BMP receptors, and Smad2 and Smad3 by TGF-beta and activin receptors. Here, we report that BMP receptors phosphorylate and activate Smad1 directly. Phosphorylation of Smad1 in vivo involves serines in the carboxy-terminal motif SSXS. These residues are phosphorylated directly by a BMP type I receptor in vitro. Mutation of these carboxy-terminal serines prevents several Smad1 activation events, namely, Smad1 association with the related protein DPC4, accumulation in the nucleus, and gain of transcriptional activity. Similar carboxy-terminal serines in Smad2 are required for its phosphorylation and association with DPC4 in response to TGF-beta, indicating the generality of this process of Smad activation. As a direct physiological substrate of BMP receptors, Smad1 provides a link between receptor serine/threonine kinases and the nucleus.

Activin Receptors↗

PubMed1997

A nucleotide substitution in the promoter of human angiotensinogen is associated with essential hypertension and affects basal transcription in vitro.

In earlier studies, we provided statistical evidence that individual differences in the angiotensinogen gene, the precursor of the vasoactive hormone angiotensin II, constitute inherited predispositions to essential hypertension in humans. We have now identified a common variant in the proximal promoter, the presence of an adenine, instead of a guanine, 6 bp upstream from the initiation site of transcription, in significant association with the disorder. Tests of promoter activity and DNA binding studies with nuclear proteins suggest that this nucleotide substitution affects the basal transcription rate of the gene. These observations provide some biological insight about the possible mechanism of a genetic predisposition to essential hypertension; they may also have important evolutionary implications.

Angiotensinogen↗

PubMed1997

Angiotensinogen gene polymorphism in Japanese patients with hypertrophic cardiomyopathy.

To examine the contribution of the renin-angiotensin system to hypertrophic cardiomyopathy (HCM), we studied 96 patients with HCM (mean age 50 years, 55% male), 105 of their unaffected siblings and offspring, and 160 healthy subjects without known hypertension and left ventricular hypertrophy (LVH) who were frequency matched to cases by age and sex. Patients were divided into familial or sporadic HCM (FHCM or SHCM) groups with or without affected members of their family. The region of interest in the angiotensinogen (AGT) gene, the missense mutation with methione-to-threonine amino acid substitution at codon 235 in angiotensinogen (M235T), was amplified by polymerase chain reaction with the use of allele-specific oligonucleotide primers flanking the polymorphic region of the AGT gene to amplify template deoxyribonucleic acid prepared from peripheral leukocytes. The T allele frequency was higher in the SHCM group than in unaffected siblings and offspring (88% vs 78%, X2 = 4.6, p < 0.05). The M allele frequency was higher in unaffected siblings and offspring than in patients with SHCM (23% vs 12%, X2 = 4.6, p < 0.05). The T allele frequency among unaffected siblings and offspring was similar to that observed in healthy subjects (78% vs 78%). We conclude that HCM, especially in sporadic cases, is partially determined by genetic disposition. The molecular variant of angiotensinogen T235 seems to be a predisposing factor for cardiac hypertrophy in HCM and carries an approximately twofold increased risk.

Adult↗

PubMed1997

Prevalence of hepatitis C virus infection in Nanjing, southern China.

There is little information on the prevalence of hepatitis C virus (HCV) infection in China. The prevalence of HCV infection was determined in 998 subjects (398 with liver disease and 600 without) in the city of Nanjing in southern China. Subjects were tested for anti-HCV antibodies by a second generation assay. We also determined serological HCV genotypes and HCV RNA sequences. Among the 600 subjects without liver disease, 3 (0.5%) were seroreactive for anti-HCV. All were less than 12 years of age and had a history of transfusion. Of the 398 liver disease patients, 20 (5.0%) were seroreactive for anti-HCV. Of 16 patients in whom serological HCV genotype was determined, 10 (62.5%) were infected with HCV type 1, 5 (31.3%) with type 2 and 1 (6.3%) undetermined. HCV genomes sequenced from 2 patients belonged to genotype 2 and were closely related to strains in Beijing and Japan by molecular evolutionary analysis. These results suggest that HCV infection is rare and not a major cause of liver disease in southern China.

Adult↗

PubMed1997

Haplotypes of angiotensinogen in essential hypertension.

The M235T polymorphism of the angiotensinogen gene (AGT) has been associated with essential and pregnancy-induced hypertension. Generation of haplotypes can help to resolve whether the T235 allele itself predisposes to the development of hypertension or acts as a marker of an unknown causal molecular variant. We identified 10 diallelic polymorphisms at the AGT locus and genotyped both a series of 477 probands of hypertensive families and 364 controls, all French Caucasians, as well as a series of 92 hypertensives and 122 controls from Japan. Despite a large ethnic difference in gene frequency, a significant association of T235 with hypertension was observed both in Cancasians (.46 vs. .38, P = .004) and in Japanese (.91 vs. .76, P = .002). In both groups, the G-->A substitution located at position -6 upstream of the initial transcription site occurred at the same frequency and in complete linkage disequilibrium with the T235 allele. No other polymorphism was found to be consistently associated with hypertension. Five informative haplotypes subdividing the T235 allele were generated. Whereas two of them were associated with hypertension in Caucasians, none of these two haplotypes (H3 and H4) reached statistical significance in Japanese. The analysis of the AGT-GT repeat revealed marked linkage disequilibriums between each of the diallelic polymorphisms and some (GT)n alleles, with similar patterns in the two populations. The strong disequilibrium between M235 and (GT)16 explained the increased frequency of that particular allele in French controls compared with hypertensives (.42 vs. .36, P < .01). The haplotype combining the M235T and G-6A polymorphisms appears as the ancestral allele of the human AGT gene and as the one associated with hypertension.

Age of Onset↗

PubMed1997

Antigenic analysis of human herpesvirus 7 (HHV-7) and HHV-6 using immune sera and monoclonal antibodies against HHV-7.

Using polyclonal and monoclonal (MAbs) antibodies to human herpesvirus 7 (HHV-7), we have studied HHV-7-specific polypeptides. Human sera were obtained during the convalescent phase from patients with exanthem subitum due to HHV-7, and at least 16 HHV-7-specific polypeptides with apparent molecular masses of 26-210 kDa were immuno-precipitated. Sera prepared in mice also precipitated at least 17 HHV-7-specific polypeptides with molecular masses of 26-210 kDa. Among them, the most commonly observed antigenic protein had an apparent molecular mass of 52 kDa. Forty-two clones secreting MAbs against HHV-7-specific proteins, as determined by immunofluorescence assays, were established from BALB/c mice immunized with HHV-7-infected cell extracts. Seven MAbs which immunoprecipitated HHV-7-specific polypeptides were further characterized. Two of these, MAbs 5E12 and 5F12, reacted predominantly with glyco-proteins of 78 kDa and 85 kDa, respectively, and possessed neutralizing activity. This suggests that there are at least two neutralization-inducing proteins in HHV-7. MAb 16B4 reacted with the major immunogenic protein of 52 kDa. Five of the 42 MAbs also reacted in immunofluorescence assays with HHV-6 antigens to the same degree as to HHV-7. Two other MAbs, 7C10 and 10F1, recognized an HHV-7 protein of 40 kDa, and only 7C10 cross-reacted with an HHV-6 protein of 45 kDa.

Animals↗

PubMed1997

Characterization of glycoprotein H and L of human herpesvirus 7.

The genes encoding the glycoproteins H (gH) and L (gL) of human herpesvirus 7 (HHV-7) have been identified. The gH open reading frame (ORF) was 2,070 base pairs in length and encoded a predicted 690 amino-acid protein. The gH contained characteristics of a transmembrane glycoprotein including 10 consensus N-linked glycosylation sites, 12 cysteine residues, a potential amino-terminal signal sequence and a predicted transmembrane segment located near the carboxyl terminus. The gL ORF was 738 base pairs in length and encoded a predicted 246 amino-acid protein. Four possible N-glycosylation sites and 6 cysteine residues existed within gL. The predicted amino-acid sequences of the HHV-7 gH and human herpesvirus 6 variant A (HHV-6A) gH gene products exhibited 23.6% identity to each other; and those of the gL gene products had 26.0% identity. Upon in vitro translation of the gL gene, the addition of microsomal membranes resulted in two modified products with molecular weights of 32 kDa and 35 kDa from the unmodified initial translation product of 26 kDa. An amino-terminal portion of gH and the full length of gL were expressed as glutathione S-transferase fusion proteins, and these proteins were used to raise immune sera in mice. Lysates of cells infected with HHV-7 were subjected to immunoprecipitation analysis. Approximate molecular weights of 33, 37, 80 and 90 kDa polypeptides were immunoprecipitated with antibodies against the gH protein. Antibodies against the gL protein polypeptides with the same molecular weights were also precipitated, and were observed with the antibodies against the gH protein. These results suggest that HHV-7 gH and gL may form a heterodimeric complex with each other in HHV-7 infected cells, as has been reported for other herpesviruses.

Animals↗

PubMed1996

Partnership between DPC4 and SMAD proteins in TGF-beta signalling pathways.

The TGF-beta/activin/BMP superfamily of growth factors signals through heteromeric receptor complexes of type I and type II serine/threonine kinase receptors. The signal originated by TGF-beta-like molecules appears to be transduced by a set of evolutionarily conserved proteins known as SMADs, which upon activation directly translocate to the nucleus where they may activate transcription. Five SMAD proteins have so far been characterized in vertebrates. These factors are related to the mediator of decapentaplegic (dpp) signalling, mothers against dpp (Mad), in Drosophila and to the Sma genes from Caenorhabditis elegans. Smad1 and Smad2 have been shown to mimic the effects of BMP and activin, respectively, both in Xenopus and in mammalian cells, whereas Smad3 (a close homologue of Smad2) and the related protein DPC4, a tumour-suppressor gene product, mediate TGF-beta actions. We report here that DPC4 is essential for the function of Smad1 and Smad2 in pathways that signal mesoderm induction and patterning in Xenopus embryos, as well as antimitogenic and transcriptional responses in breast epithelial cells. DPC4 associates with Smad1 in response to BMP and with Smad2 in response to activin or TGF-beta. DPC4 is therefore a regulated partner of SMADs that function in different signalling pathways of the TGF-beta family.

Activins↗

PubMed1996

Plasma vanillylmandelic acid level as an index of psychological stress response in normal subjects.

The relationships between psychological stress responses and plasma levels of vanillylmandelic acid (VMA), 3-methoxy-4-hydroxyphenylglycol (MHPG), homovanillic acid (HVA), and 5-hydroxyindolacetic acid (5-HIAA) were investigated in normal volunteers. Two questionnaires were used to measure stress: the Psychological Stress Response Scale (PSRS) and the State-Trait Anxiety Inventory (STAI). Plasma levels of VMA--but not MHPG, HVA, and 5-HIAA--showed significant positive correlations with PSRS emotional and cognitive-behavioral stress and STAI state anxiety. Significant positive correlations were also found between plasma levels of VMA and MHPG and psychological stress responses measured repeatedly in a longitudinal study of an Olympic swimmer. Plasma VMA measurements, which reflect the level of activity of the peripheral sympathetic nervous system, may provide a useful biochemical index of psychological stress responses in normal subjects.

Adult↗