Biomedical subjects
Publications and source records attributed to S Okazaki.
Investigation of the relationship between visual search (eye movement) and walking (head and body movement) during way-finding through a maze by each of 6 subject pedestrians who wore an eye camera showed patterns of sight lin, head movement, body movement, and changes of coordination between eye-head-body movement during the process of comprehension of the pathways were revealed.
In order to elucidate the underlying mechanisms of a discordant case with HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) in monozygotic twins, we investigated HTLV-I tax sequences of 10 - 18 polymerase chain reaction-based clones each derived from peripheral blood mononuclear cells of the twins as well as their infected mother and an elder brother who also suffered from HAM/TSP. Sequence comparison revealed that three of the infected individuals including a twin with HAM/TSP shared the consensus tax sequence identical to the reference, ATK-1, but that of another healthy twin was different at five nucleotide positions including three nonsynonymous changes from ATK-1. This finding strongly suggested that different HTLV-I strains infected the monozygotic twins and the difference in infected proviral sequences determined the discordant clinical outcomes. Transfection and subsequent reporter assays failed to show a significant difference in transactivation activity on HTLV-I LTR and NF-kappaB elements between the products of the two sequences. Two HAM/TSP patients (a twin and elder brother) among three members infected with the ATK-1 type virus shared a paternal HLA allele which was absent in the healthy individual (mother). Genetic analysis of sequence variation in the tax sequences of the discordant twins showed that the Dn/Ds ratio was high in the healthy twin but low in the twin with HAM/TSP, implying the presence of more intense selection forces in the carrier. Our findings strongly suggested that a particular combination of HTLV-I strains with an HLA genotype would be a risk for HAM/TSP.
We have experienced massive blood loss (> 80,000 g) during living-related donor liver transplantation (LRDLT) of a 14-year old girl with biliary atresia. As available homologous blood was not sufficient, we transfused autologous blood (13,400 ml) during operation. Although immunosuppressant was administered to the patient, severe infection did not occur for 10 days after the operation. Cold ischemia time of the graft liver was about 16 hr, but her postoperative liver function was well-maintained. The case suggests that intraoperative autologus blood transfusion is effective if homologous blood is insufficient during LRDLT.
An 11-month-old boy presented with recurrent wheezing and atelectasis in the right upper lobe of the lung. Bronchoscopy and bronchography confirmed an ectopic bronchus arising from the right main bronchus. The diagnosis of VATER association was made on the basis of multiple vertebral and rib anomalies, imperforate anus with a perineal fistula, unilateral hydronephrosis, atrial septal defect, and a preauricular tag, he did not have tracheo-esophageal fistula. We emphasize the importance of recognizing tracheobronchial anomalies in VATER association.
Several investigators have reported patients with acute pure red cell aplasia (PRCA) caused by anticonvulsants, antibiotics, or antithyroid agents. Allopurinol is known to be a causative agent of aplastic anemia, but there have been few reports of acute PRCA induced by allopurinol. We describe here a 15-year-old boy who suffered from anemia 6 weeks after initiation of allopurinol therapy; his anemia immediately improved after cessation of the drug. His bone marrow showed severe erythroid hypoplasia with a myeloid/erythroid ratio of 18.6 and low expression of glycophorin A detected on cell-surface antigen analysis. No morphological abnormalities were observed in myeloid series and megakaryocytes. The prolonged plasma iron disappearance rate and the decreased plasma iron turnover rate also indicated erythroid hypoplasia. He had been free from any infections, including parvovirus B19, before manifestation of PRCA. Taken together, these results suggest a diagnosis of acute PRCA. This side effect of allopurinol should be taken into consideration.
We studied the histories of eight patients who lacked clear evidence of cardiac abnormalities other than marked bilateral atrial dilatation and atrial fibrillation, which have rarely been discussed in the literature. From the time of their first visit to our hospital, the patients' chest radiographs and electrocardiograms showed markedly enlarged cardiac silhouettes and atrial fibrillation, respectively. Each patient's echocardiogram showed a marked bilateral atrial dilatation with almost normal wall motion of both ventricles. In one patient, inflammatory change was demonstrated by cardiac catheterization and endomyocardial biopsy from the right ventricle. Seven of our eight cases were elderly women. Over a long period after the diagnosis of cardiomegaly or arrhythmia, diuretics or digitalis offered good results in the treatment of edema and congestion in these patients. In view of the clinical courses included in the present study, we conclude that this disorder has a good prognosis.
We have previously reported that the non-transforming jun D (wild type) gene can acquire transforming activity through spontaneous mutations when it is replicated through avian replication-competent retrovirus vectors in chicken embryo fibroblasts. In two of these spontaneous mutants, T1 and T2, which were isolated from proviral DNA in the same transformed cell clone, a specific 48 bp polynucleotide segment of the jun D coding sequence was tandemly repeated three and five times, respectively. We report here that the number of direct repeats in these mutants rapidly changes (mostly decreases) in the context of either RSV-based replication-competent or MLV-based replication-defective retroviruses, most likely during the process of reverse transcription, while these mutations are stable in the cellular chromosome. We also show that the growth conditions of the infected culture modulate the proportions of polymorphic proviral populations in the infected culture. We finally discuss the possible molecular mechanisms that generate genetic diversity in these amplification mutants.
The junD gene encodes one component of the transcription factor, AP-1. Since two forms of JunD protein have been reported, we analyzed here the molecular mechanisms involved in the isoform production. Immunochemical analysis indicated that the longer and shorter forms of mouse JunD (JunD-L and JunD-S, with apparent molecular weights of 44 and 39 kDa, respectively) differ in their content of an N-terminal peptide. Mutational analysis further indicated that JunD-S is the translational product initiated at the third AUG located 144 bp from the first AUG, at which JunD-L translation starts. Such production of two junD isoforms from a single mRNA using the same reading frame seems to be conserved in human, rat, and chicken. To examine the functional differences between the isoforms, each type of JunD was exclusively expressed by the use of retrovirus vectors harboring the mutated junD gene. The exogenous expression of either one of these forms did not cause cellular transformation of NIH3T3, but suppressed the anchorage-independent growth of NIH3T3 transfor-bold by the activated K-ras or v-src gene. These two isoforms were expressed in all the mouse tissues examined and in various cell lines established from human tumors, though the expression ratio between JunD-L and JunD-S varied, suggesting that some factor(s) modulate the alternative usage of the initiation codon of the junD gene.
We report here that, upon UV irradiation or growth stimulation, endogenous c-Jun (40 kDa) in chicken embryo fibroblasts (CEF) is converted into several forms with apparently higher molecular weights in SDS-polyacrylamide gel electrophoresis (45, 44, 42 kDa). Two of the bands (44 and 45 kDa) were transient after growth stimulation, but were much more persistent after UV irradiation. In both cases, the drastic mobility shifts were accompanied with the activation of endogenous JNK activity but not of MAPK activity, and the bands were shown to represent different phosphorylation states of c-Jun rather than ubiquitinated c-Jun. Biochemical analysis indicated that phosphorylation at Ser63 and Ser73 was not sufficient to produce these drastic mobility shifts, which additionally required phosphorylation at Thr91 and Thr93. Substitution of both Ser63 and Ser73 with either Ala or Asp had no significant effect on the transforming activity of c-Jun, but the mutants failed to show drastic mobility shifts even after UV irradiation. These results indicate that Ser63 and Ser73 are essential for the drastic mobility shifts and further suggest that the highly phosphorylated forms of c-Jun are not directly involved in cellular transformation.
The present study assessed fidelity to the behavioral family management (BFM) model for treating bipolar disorder patients and their families. The BFM Therapist Competency/Adherence Scale (BFM-TCAS) was developed to evaluate clinicians' competency and adherence to BFM, as outlined by Miklowitz' (1989) BFM Manual for use with bipolar patients. Therapist competency and treatment adherence was also evaluated with regard to two family characteristics: overall level of family difficulty and family expressed emotion (EE) status. The BFM-TCAS was used to code 78 videotaped sessions of 26 families with a bipolar member, selected from a larger treatment study of bipolar disorder patients. The findings suggest that, overall, clinicians adhered closely to the BFM manual. Specific areas in which there was high competency and treatment adherence were (a) skill in conveying factual information about bipolar illness, (b) establishment of a therapeutic environment, and (c) ability to take command of therapy sessions. The one area in which there was less competency and relatively weak adherence to the manual was the use of between-session homework assignments to assist families in mastering the BFM exercises. Results of this study also suggest that, for the most part, therapist competency and adherence ratings were not related to overall level of difficulty or to family EE status.
During the past 17 years, 1,722 of 4,832 consecutive patients investigated with endoscopic retrograde cholangiopancreatography (ERCP) were assessed by the radiological criteria of the Japanese Study Group of Pancreaticobiliary Maljunction (PBM). Out of these 1,722 patients, PBM was found in a total of 52, representing 3.0%, of which gallbladder carcinoma was associated with 14. These 14 with gallbladder carcinoma consisted of 10 (62.5%) of the 16 with PBM without association of congenital bile duct dilatation (CBDD) and 4 (11.1%) of the 36 PBM with CBDD. The relationship between PBM and gallbladder carcinoma was closely examined; PBM was noted in 14 (32.6%) of a total of 43 patients with gallbladder carcinoma compared to 38 (2.3%) among the 1,679 patients with various diseases excluding gallbladder carcinoma. Similarly, it was revealed that gallbladder carcinoma was predominantly noted in the 14 (26.5%) of the 52 patients with PBM in contrast to an incidence of 1.7% (29) among the 1,670 patients without PBM. As we studied the characteristic clinical features of the 14 gallbladder carcinoma patients with PBM when compared with 29 of those without PBM, the following was disclosed: on average, the patients with PBM were 10 years younger (49.4 vs 61.4 years in mean age); there was a preponderance of women (0/14 vs 12/17, male-female ratio); there existed a significantly lower incidence of associated gallstone disease (7.1% vs 72.4%). These figures were shown to be statistically significant. We concluded that the results prove a link between the crucial features of gallbladder carcinoma and PBM, and also suggest the promotive role of PBM in carcinogenesis of the gallbladder.
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The Finkel-Biskis-Jinkins murine sarcoma virus, which carries v-fos, induces osteosarcomas, whereas high-level expression of exogenous c-fos in transgenic and chimeric mice leads to postnatal development of osteogenic and chondrogenic tumors, respectively. To test whether such target cell specificity of an oncogene can be detected even in early development, we induced ectopic expression of fos in chicken limb buds by microinjecting replication-competent retrovirus into the presumptive leg field of stage 10 embryos. This caused cartilage truncation of all the long bones of the injected leg, which was mainly attributable to chondrodysplasia due to severe retardation of differentiation of the proliferating chondrocytes into mature or hypertrophic chondrocytes, as well as a slight delay in precartilagenous condensation. Expression of genes for all the other known members of chicken AP-1, which include such transforming genes as c-jun and fra-2, however, caused no macroscopic abnormalities in limb formation, indicating a specific function of Fos proteins in embryonic endochondral bone differentiation. The extent of truncation was stronger with v-Fos than with c-Fos, and comparative analysis of these proteins, as well as v-Fos mutants, revealed that strong transforming activity of Fos protein is necessary to cause dysplasia, suggesting that common molecular mechanisms are involved in both embryonic chondrodysplasia and bone tumor formation in postnatal mice.
The telomeres of the silkworm, Bombyx mori, consist of pentanucleotide repeats (TTAGG)n . We previously characterized the non-LTR element TRAS1, which terminates with oligo (A) in a head to tail orientation at the exact position (between A and C) of the (CCTAA) n repeats. Here we characterized another family of telomere-specific non-LTR retrotransposon named SART1. The SART1 family was inserted at another site of the (TTAGG) n in a reverse orientation from that of TRAS1. The complete unit of SART1, 6.7 kb in length with a poly (A) stretch, contains two open reading frames encoding putative gag and pol products, overlapping by 54 bp in the -1 reading frame. Most of the 600 SART1 copies in the silkworm haploid genome are completely conserved in structure without 5'truncation. All SART1 sequences analyzed were inserted at the same position (between T and A) within the (TTAGG) n repeats. Fluorescence in situ hybridization showed that many of the SART1 copies were localized in the chromosomal ends. A phylogenetic tree showed that the SART1, TRAS1 and two other site-specific elements, R1 and RT, which insert into 28S ribosomal RNA genes in insects, belong to the same group. Based on the orientation for the chromosomal insertion and structural similarities, these elements could be further classified into two subgroups, R1/TRAS1 and RT/SART1, suggesting that the target specificity of the two telomere-associated elements was changed independently.
This study tested an affect-specific explanation for the Asian and White American differences in depression and social anxiety. Construal of the self as independent or interdependent in relation to others (H. R. Markus & S. Kitayama, 1991) was hypothesized to be 1 possible way in which culture may be expressed in individuals' psychological functioning, which in turn was hypothesized to be linked specifically to social anxiety. College students (N = 348; 183 White Americans and 165 Asian Americans) completed self-report measures of depression, social anxiety, and self-construals. Asian Americans scored significantly higher than White Americans on measures of depression and social anxiety. When the covariance between depression and social anxiety was statistically controlled, ethnicity and self-construal variables were found, as predicted, to be associated with measures of social anxiety but not depression. These findings suggest a more differentiated perspective on the relations between culture, ethnicity, and emotional distress.
A novel quinoline derivative, TAS-103 (6-[[2-(dimethylamino)ethyl]amino]-3-hydroxy-7H-indeno[2,1-c]quinolin -7-one dihydrochloride), was developed as an anticancer agent targeting topoisomerases (topo) I and II, with marked efficacy in solid tumors. TAS-103 inhibited topo I and II (IC50: 2 microM, 6.5 microM) at a concentration similar to or lower than those of previous agents, and had a strong cytotoxic effect on P388 and KB cells (IC50: 0.0011 microM, 0.0096 microM). TAS-103 stabilized topo I and II-DNA cleavable complexes in KB cells, generating a similar amount of topo II-DNA complex to that induced by etoposide (VP-16) but a smaller amount of topo I-DNA complex than that produced by camptothecin (CPT). In the in vivo study, intermittent i.v. administration was markedly effective against s.c.-implanted murine tumors. Furthermore, TAS-103 had marked efficacy against various lung metastatic tumors, and a broad antitumor spectrum in human tumor xenografts (derived from lung, colon, stomach, breast, and pancreatic cancer). The efficacy of TAS-103 was generally greater than that of irinotecan (CPT-11), VP-16, or cis-diamminedichloroplatinum (CDDP).
Single and repeated intravenous toxicity studies of Pamiteplase (genetical recombination) YM866, a novel recombinant human tissue-type plasminogen activator, were conducted. No animal died from toxic effects of YM866 after single administration to F344 rats, squirrel monkeys and cynomolgus monkeys. Male and female F344 rats were given YM866 intravenously for 4 weeks at doses of 0 (vehicle), 0.1, 0.3 and 1 mg/kg/day. An increase in platelet count, slight decreases in hemoglobin and hematocrit, increases in plasma phospholipids, total cholesterol and total protein, and liver weight were observed at 1.0 mg/kg. Histopathology revealed no changes in any organ except for hemorrhage at the injection sites. These changes recovered after 4 weeks of withdrawal. Male and female squirrel monkeys were given YM866 intravenously for 4 weeks at doses of 0 (saline), 0 (vehicle), 0.1, 0.3 and 1 mg/kg/day. Prolongation of coagulation time at the injection site was observed at 0.3 mg/kg or more. Subcutaneous hemorrhage and a transient decrease in locomotor activity were observed at 1 mg/kg. Prolongation of coagulation time at the injection site was considered to be related to the pharmacological action of YM866. The results show that the approximate single lethal dose of YM866 is more than 60 mg/kg in rats, and more than 10 mg/kg in squirrel monkeys and cynomolgus monkeys. The no-toxic-effect level of YM866 after repeated administration for 4 weeks in rats and squirrel monkeys is considered to be 0.3 mg/kg.
We examined the effect of the glutamate uptake inhibitor L-trans-pyrrolidine-2,4-dicarboxylic acid (PDC) on the neurotoxicity of L-glutamate in organotypic cultures of rat spinal cord. Eighteen-day-old cultures were incubated with 500 microM L-glutamate, 1 mM PDC, or both. After 72 hours, the tissues were stained for acetylcholinesterase (AChE), and the ventral horn AChE-positive neurons (VHANs) analyzed using morphometry. Neither L-glutamate nor PDC affected AChE staining, but in combination they produced markedly reduced AChE staining in the dorsal horn and a significant decrease in the number of VHANs (especially the smaller VHANs) as compared with the control. Moreover, treatment with 200 microM PDC for 2 weeks preferentially affected the smaller VHANs. The neurotoxicity of L-glutamate plus PDC was blocked by the N-methyl-D-aspartate (NMDA) antagonist 3-((RS)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP). Results suggest that glutamate uptake system has an important protective function in the aggravation of acute neuronal damage.