Biomedical subjects

T Ashizawa

Publications and source records attributed to T Ashizawa.

At least 91 records · Page 5Linked to original sources

PubMed1996

Myotonic dystrophy phenotype without expansion of (CTG)n repeat: an entity distinct from proximal myotonic myopathy (PROMM)?

Myotonic dystrophy (DM) is associated with an expansion of an unstable (CTG)n repeat in the 3' untranslated region of the DM protein kinase (DMPK) gene on chromosome 19q13.3. We studied six patients from two families who showed no expansions of the repeat, in spite of their clinical diagnosis of DM. These patients had multi-systemic manifestations that were distinguishable from those seen in other myotonic disorders, including proximal myotonic myopathy (PROMM). In one additional family, two symptomatic members showed no expanded (CTG)n repeats, while their affected relatives had the expanded repeats. DM haplotype analysis failed to exclude the DMPK locus as a possible site of mutation in each family; however, DMPK mRNA levels were normal. We conclude that a mutation(s) other than the expanded (CTG)n repeat can cause the DM phenotype. The mutation(s) in these families remain(s) to be mapped and characterized.

Adolescent↗

PubMed1996

Effects of ceruletide on perioral movements and the dopamine receptor-adenylate cyclase system in rats chronically treated with fluphenazine.

The effects of repeated administration of ceruletide (100 micrograms/kg/perday, i.p. for 3 days) on perioral movements and the striatal dopamine receptor adenylate cyclase system were examined in rats chronically treated with fluphenazine enanthate (FPZ) (25 mg/kg i.m. every 3 weeks for 30 weeks) and sesame oil-treated (control) rats. After the tenth injection of fluphenazine, the rats started to display five types of perioral movements (teeth chattering, chewing, tongue protrusion, mouth opening and perioral tremors). Moreover, increases in SCH23390 binding and spiperone binding to striatal membranes, were found in the FPZ-treated rats. Furthermore, dopamine receptor-coupled adenylate cyclase activity was potentiated in striatal membranes. High amplitude EMG discharges (8-10 Hz), recorded from the masseter in the FPZ-treated rats occurred concurrently with perioral tremors. Repeated ceruletide (CLT) injections abolished perioral movements, and reversed both the elevated SCH23390 binding and the dopamine stimulated adenylate cyclase (AC) activity to the control level. The effect of CLT on perioral movements, D1 receptors and dopamine-stimulated AC activity continued for 6 days after the final CLT injection. These findings suggest that systemically administered CLT affects the D1 receptor adenylate cyclase system and that an increase of the D1 receptor mechanism may play an important role in the pathogenesis of tardive dyskinesia.

Adenylyl Cyclases↗

PubMed1996

[A case of amotivational syndrome as a residual symptom after methamphetamine abuse].

We had a case of psychiatric evidence who was homeless and exhibited severe abulia and autism on detention for assault and battery. It was thought that his past history of chronic methamphetamine abuse and his familial history played some part in his showing such symptoms. His mother was alcohol dependent. He was an ACOA (adult child of alcoholics), which might have led to his chronic abuse of methamphetamine. On the other hand, it is well-known fact that the amotivational syndrome induced by marijuana abuse is typified by a diminution of ambition, productivity, and motivation. However, it has been contended that amotivational syndrome is induced not only by marijuana but also by amphetamine and its analogs, cocaine and volatile solvents. Since we positively support this view, we diagnosed the case as amotivational syndrome after long-term methamphetamine abuse. This was also a rare criminal case of amotivational state without hallucinations and delusions after methamphetamine abuse. We suggested that the crime committed in this case was closely related to crime induced by economic problems in residual states of schizophrenic offenders. This could be a case of both ACOA and methamphetamine dependence. There were unresolved alcohol- and drug-related problems in this case. Therefore, careful early intervention in a crisis, cooperation with the authorities and the institutions concerned, and comprehensive rehabilitation should be employed to resolve such alcohol- and drug-related problems.

Adult↗

PubMed1996

[A case report of volatile solvent psychosis].

A case (male, 27 years old) with chronic thinner intoxication, whose mental condition was reexamined in accord with a court order, is reported. He had been sniffing thinner from age 12 to 27. Since the age of 17, he experienced visual and auditory hallucinations without sniffing thinner. He had no family history of schizophrenia. The psychiatric examination revealed that he had positive symptoms of schizophrenia, especially the first rank symptoms, such as auditory hallucinations (i.e. voices commenting and voices arguing), experience of influence (withdrawal of thought, thought insertion and influence of thought) and delusional perception, but did not show negative symptoms (i.e. blunting thought). Furthermore, he could maintain good emotional contact with others. Hallucinations, which appeared in acute intoxication with thinner, were second rank symptoms, different from those observed in the sober period when he was not under the influence of the thinner. Judging from above facts it was difficult to diagnose this case as schizophrenia or the flashback phenomenon of thinner dependence. Although the disease concept of volatile solvent psychosis has not been clearly established, this case may suggest that the first rank symptoms are important manifestations of volatile solvent psychosis.

Adult↗

PubMed1995

Cardiac involvement in a large kindred with myotonic dystrophy. Quantitative assessment and relation to size of CTG repeat expansion.

OBJECTIVE: To evaluate and quantitate cardiac involvement in myotonic dystrophy and assess whether the size of the trinucleotide (cytosine-thymine-guanine [CTG]) repeat expansion is a significant predictor of cardiac abnormalities. DESIGN: Case-control study of a large kindred with myotonic dystrophy. PATIENTS: Ninety-one bloodline members of the kindred underwent clinical and cardiac evaluation with electrocardiograms, echocardiography (with Doppler in the majority of cases), and genetic and neurologic evaluations. Affected individuals were age-matched to normal family members. MAIN OUTCOME MEASURES: Electrocardiographic conduction abnormalities, wall motion abnormalities, mitral valve prolapse, and global parameters of systolic and diastolic function were determined by an observer blinded to all clinical data and genetic analysis. RESULTS: Compared with age-matched normals, patients with myotonic dystrophy (n = 25) were more likely to have conduction abnormality (52% vs 9%), mitral valve prolapse (32% vs 9%), and wall motion abnormality (28% vs 0%) (all P < .05). Left ventricular ejection fraction and stroke volume were reduced compared with normals matched for age and heart rate (P < .05), whereas Doppler indexes of diastolic function were only marginally altered. Using multivariate analysis, the number of CTG repeats (range, 69 to 1367; normal, < or = 37) was the strongest predictor of abnormalities in wall motion and electrocardiographic conduction (odds ratio of 16.5 and 5.07 per 500 repeats, respectively). The relation of mitral valve prolapse to the size of the CTG repeat was of borderline significance. Patients with more extensive neurologic findings (n = 12) had a higher incidence of wall motion and/or electrocardiographic conduction abnormalities (83% vs 43%; P = .04). CONCLUSIONS: Cardiac involvement in myotonic dystrophy affects predominantly the conduction system and myocardial function. Alterations in myocardial relaxation and diastolic properties, in contrast to skeletal muscle myotonia, are minor. In this kindred, the number of CTG repeats was a significant predictor of cardiac dysfunction in myotonic dystrophy.

Adolescent↗

PubMed1995

Synthesis and antitumor activity of various 6-demethylmitomycins and 6-demethyl-6-halomitomycins.

A series of 6-demethylmitomycins and 6-demethyl-6-halomitomycins having various mitomycin skeletons were synthesized, taking into account the electronic effect toward the quinone moiety and the partition coefficients. Treatment of enones 15 and 16 with selenenamide or N-halosuccinimide-Et2NH afforded the 6-demethyl intermediates 17, 18, and 21-24 via the tandem Michael addition/retro-Mannich reaction sequence. Subsequent conversions into the mitomycin skeletons resulted in the formation of the desired derivatives 7a-c, 8a-c, 11a-c, and 12a,b. These mitomycin derivatives including 3a-c and 4a-c were evaluated for their anticellular activity against HeLa S3 cells and antitumor activity against Sarcoma 180 in mice. The anticellular activity of 1 and 3a-c depends on the substituent at the C-6 position and the order of increasing activity is H < CH3 < Br < Cl. A similar tendency was observed in their antitumor potency (ED50). The activities of 9 and 11a-c also follow a pattern similar to that of 1 and 3a-c. Compounds 4b,c, 8b,c, and 12b having both a halogen at the C-6 position and a methoxy group at the C-7 position did not show the activities because of the instability of the compounds. Interestingly, a correlation between the anticellular activity (IC50) and the partition coefficients (log kappa') determined by HPLC was observed within the compounds studied except the unstable compounds, while their antitumor activity (ED50 or T/C) did not correlate with the quinone reduction potential (E1/2). These results would indicate the importance of the C-6 substituents and the mitomycin skeletons for exhibiting both anticellular and antitumor activities.

Animals↗

PubMed1995

Effect of myotonic dystrophy trinucleotide repeat expansion on DMPK transcription and processing.

The myotonic dystrophy (DM) mutation has been identified as an unstable, expanded (CTG)n repeat in the 3' untranslated region of a gene designated DM protein kinase (DMPK). Both decreased and increased levels of mutant DMPK mRNA as well as decreased levels of protein have been variously reported and invoked to explain disparate molecular bases of this dominantly inherited disease. Most recently, increased nucleosome binding to such expanded repeats has been interpreted as support for transcriptional repression. A quantitative allele-specific RT-PCR procedure was developed and applied to a spectrum of patient tissue samples and cell lines. Equal levels of unprocessed pre-mRNA were produced by the wildtype (+) and disease (DM) alleles in skeletal muscle and cell lines of heterozygous DM patients. Thus, any increased nucleosome binding had no effect at the level of transcriptional initiation and transcription of the mutant DMPK locus. In contrast, processed mRNA levels from the DM allele were reduced relative to the+allele as the size of the expansion increased. The unstable repeat, therefore, impairs post-transcriptional processing of DM allele transcripts. This phenomenon has profound effects on overall DMPK locus steady-state transcript levels in cells missing a wildtype allele and does not appear to be mediated by imprinting, decreased mRNA stability, generation of aberrant splice forms, or absence of polyadenylation of the mutant allele.

Adolescent↗

PubMed1995

Tourettism associated with Huntington's disease.

The identification of the gene for Huntington's disease (HD) has made it possible to diagnose patients with HD who present with unusual or atypical features. We describe a 41-year-old man whose initial manifestation of HD was dominated by the presence of motor and vocal tics and other features of Tourette's syndrome. This case illustrates the broad range of clinical manifestation of HD and the usefulness of testing for the HD mutation in selected cases with familial movement disorders.

Adult↗

PubMed1995

Somatic mosaicism, germline expansions, germline reversions and intergenerational reductions in myotonic dystrophy males: small pool PCR analyses.

In order to characterize the dynamics of CTG repeat instability in somatic and germline tissue from myotonic dystrophy (DM) males we have used small pool polymerase chain reaction (PCR) in a detailed quantitative analysis of repeat length variation. We demonstrate that the heterogeneous smear of CTG repeats observed in DM patients using standard analyses is comprised of multiple unresolved bands that may be dissected into discrete length alleles derived from single cells using single molecule PCR techniques. Analysis of somatic tissues demonstrates a bias toward increasing allele length and a lower boundary below which variant alleles are rare, consistent with a highly directional expansion pathway in the soma. Two sperm samples show extensive variation and a size increase bias, concordant with the phenomenon of anticipation. In addition, sperm analysis shows that large contractions, including reversions into the normal size range, are restricted to the germline. Detailed analysis of intergenerational 'reductions' paternally transmitted to two offspring suggests that some apparent reductions may be artifacts of somatic expansion in the parent. Our data indicate that in addition to germline variation, substantial somatic expansion can also contribute to the intergenerational differences usually observed in DM.

Adult↗

PubMed1995

Characteristics of the antitumor activity of M-16 and M-18, major metabolites of a new mitomycin C derivative KW-2149, in mice.

The cell growth inhibitory activity, antitumor activity and toxicity of M-16 and M-18, the major metabolites of a new mitomycin C (MMC) derivative KW-2149, in mouse and human were compared with those of KW-2149 or MMC in vitro and in vivo. The growth inhibitory activity of M-18, a symmetrical disulfide dimer, against human uterine cervix carcinoma HeLa S3 cells was almost equivalent to that of KW-2149 and their IC50 values were about 10-fold smaller than that of MMC. The activity of M-16, a methyl sulfide form, was almost equivalent to that of MMC. The cell-killing activity of MMC and M-16 was augmented in the hypoxic condition, whereas that of KW-2149 and M-18 was reduced. M-16 also exhibited almost equivalent activities to MMC in vivo in terms of many biological profiles, i.e., antitumor activity against murine P388 leukemia, ascitic or solid B16 melanoma or human lung carcinoma xenograft L-27, and bone marrow toxicity in mice. These in vitro and in vivo results indicate that the antitumor activity and toxicity of KW-2149 might not be mediated by M-16 in mice. On the other hand, M-18 exhibited almost equivalent activities to KW-2149 in these regards, suggesting the involvement of M-18 in the biological activities of KW-2149. However, the small values of the area under the curve of M-18 in mice make this unlikely. Thus the biological activities of KW-2149 in mice are not explained by the M-16 or M-18 concentration in plasma and are postulated to be manifested by KW-2149 itself.

Animals↗

PubMed1995

Emotional and functional impact of DNA testing on patients with symptoms of Huntington's disease.

The potential impact of DNA testing on asymptomatic subjects at risk for Huntington's disease (HD) has been addressed by numerous studies, but the effect of revealing the genetic results to patients with a clinically established diagnosis of HD has not been previously evaluated. We studied 36 patients, with equal distribution of men and women, mean age 53.9 (SD 12.3) years (range 25-76) and mean duration of symptoms of 11.2 (SD 7.7) years (range 2-33), whose clinical diagnosis of HD was confirmed by expanded CAG repeats (> 40). Coping strategies and depression levels were assessed before the results of DNA testing were imparted. The assessments were repeated two weeks and three months after the results were explained to the patients and their relatives and were compared to the baseline assessments. This group of HD patients was compared with 10 patients who had similar symptoms but the diagnosis of HD was excluded by normal CAG repeats (< 30). Although some patients with HD expressed a subjective reaction to the positive result (four were "surprised", one was "frustrated", and one "devastated"), there were no differences in any psychological scores including Beck Depression Inventory, functional capacity, symptom interference, independence scale, and other measures of mood and behaviour two weeks and three months later. Similarly, no change was noted in any of these measures in the non-HD group. These results suggest that mood and coping strategies are unaffected by DNA confirmation of diagnosis in symptomatic patients with HD.

Adaptation, Psychological↗

PubMed1995

De novo myotonic dystrophy mutation in a Nigerian kindred.

An expansion of an unstable (CTG)n trinucleotide repeat in the 3' UTR of a gene encoding a putative serine/threonine protein kinase (DMPK) on human chromosome 19q13.3 has been shown to be specific for the myotonic dystrophy (DM) disease phenotype. In addition, a single haplotype composed of nine alleles within and flanking DMPK over a physical distance of 30 kb has been shown to be in complete linkage disequilibrium with DM. This has led to two hypotheses: (1) predisposition for (CTG)n instability results from a founder effect that occurred only once or a few times in human evolution; and (2) elements within the disease haplotype may predispose the (CTG)n repeat to instability. A detailed haplotype analysis of the DM region was conducted on a Nigerian (Yoruba) DM family, the only indigenous sub-Saharan DM case reported to date. Each affected member of this family had an expanded (CTG)n repeat in one of his or her DMPK alleles. However, unlike all other DM populations studied thus far, disassociation of the (CTG)n repeat expansion from other alleles of the putative predisposing haplotype was found. We conclude that the expanded (CTG)n repeat in this family is the result of an independent mutational event. Consequently, the origin of DM is unlikely to be a single mutational event, and the hypothesis that a single ancestral haplotype predisposes to repeat expansion is not compelling.

Adult↗

PubMed1995

Somatic heterogeneity of the CTG repeat in myotonic dystrophy is age and size dependent.

The most common form of adult muscular dystrophy, myotonic dystrophy (DM), is caused by the abnormal expansion of the CTG repeat, located in the 3' UTR of the DM gene. The expanded-CTG allele often presents as a diffused band on Southern blot analysis, suggesting somatic mosaicism. In order to study the somatic instability of the CTG repeat, we have investigated the dynamics of the size heterogeneity of the CTG expansion. Size heterogeneity is shown as a smear on Southern blot and is measured by the midpeak-width ratio of the expanded allele to the normal sized allele. The ratio is also corrected for compression in the higher-molecular-weight region. It is found that the size heterogeneity of the expanded-CTG repeats, of 173 DM patients, correlates well with the age of the patient (r = .81, P << .001). The older patients show larger size variation. This correlation is independent of the sex of either the patient or the transmitting parent. The size heterogeneity of the expansion, based on age groups, is also dependent on the size of the expanded trinucleotide repeat. However, obvious size heterogeneity is not observed in congenital cases, regardless of the size of expansion. Comparison of individual patient samples collected at two different times has confirmed that the degree of size heterogeneity increases with age and has revealed a subtle but definite upward shift in the size of the expanded-CTG allele. The progression of the CTG repeat toward larger expansion with age is further confirmed by small-pool PCR assay that resolved the heterogeneous fragments into discrete bands.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

PubMed1994

Synthesis and antitumor activity of novel mitomycin derivatives containing functional groups at the C-6-methyl position.

A series of C-6-substituted methyl mitomycins was synthesized and evaluated for anticellular and antitumor activities. These novel compounds were prepared by Michael addition of various alcohols or thiols to 6-demethyl-7,7-(ethylenedioxy)-6,7-dihydro-6-methylidenemitosanes followed by treatment with NH3 or MeOH/K2CO3. Most compounds were potent against HeLa S3, and some of them showed superior activity to that of mitomycin C (MMC) against P388 leukemia and sarcoma 180 in mice. In addition, some compounds exhibited remarkable activity against MMC-resistant P388 in mice. FAB-MS spectra of these mitomycin derivatives showed the elimination of the C-6-methyl substituents from the mitomycin skeletons to form quinonemethides. Interestingly, treatment of 6-demethyl-6-[[(2-pyrimidinyl)thio]methyl ]mitomycin C (12v) with diethylamine afforded 6-demethyl-6-[(diethylamino)methyl]mitomycin C (31) in good yield. These results suggested that the C-6-substituted methyl mitomycins would have different biological character from that of MMC.

Animals↗

PubMed1994

Synthesis and antitumor activity of novel 6-alkyl-6-demethylmitomycins.

A series of 6-alkyl-6-demethylmitomycins (1-5) was synthesized and evaluated for anticellular and antitumor activities. These novel compounds were prepared by Michael addition of various carbanion species to 6-demethyl-7, 7-(ethylenedioxy)-6, 7-dihydro-6-methylidenemitosane (6 and 9) followed by treatment with NH3 or MeOH/K2CO3. Alkylation at the C-6 position of 6-demethyl-6-selenide (7) was also useful for the alternative synthesis of 6-alkyl-6-demethylmitomycins. The antitumor activity of these derivatives was evaluated, and 6-demethyl-6-ethylmitomycin A (2a) was found to exhibit excellent activity against S-180 solid tumor in mice. The structure-activity relationship is also discussed.

Animals↗

PubMed1994

6H-pyrazolo[4,5,1-de]acridin-6-ones as a novel class of antitumor agents. Synthesis and biological activity.

The 7-substituted 6H-pyrazolo[4,5,1-de]acridin-6-ones with (aminoalkyl)amino and/or (hydroxyalkyl)amino groups in the side chains were synthesized by bromination using N-bromosuccinimide and the subsequent reaction with amines from the 7-substituted 5-bromo-2-methyl-6H-pyrazolo-[4,5,1-de]acridin-6-one. The substitution reaction of the amines with alkyl bromide (the C2 position) and aryl bromide (the C5 position) was accomplished by choosing the proper reaction conditions. These compounds show DNA intercalating ability in ethidium fluorescence assay and antiproliferative activity against Hela S3 cells. Impressive antitumor activity in vivo against murine P388 leukemia and murine sarcoma 180 solid tumor in mice was demonstrated for the 7-hydroxy analogs. In addition, some of these showed excellent antitumor activity against adriamycin-resistant murine P388 leukemia (P388/ADM) in mice.

Aminoacridines↗

PubMed1994

Mapping of the polypeptide chain organization of the main extracellular domain of the alpha-subunit in membrane-bound acetylcholine receptor by antipeptide antibodies spanning the entire domain.

To study the organization of the polypeptide chain of the main extracellular domain of the nicotinic acetylcholine receptor (AChR) alpha-subunit, we examined the ability of the native membrane-bound AChR of Torpedo californica (T-AChR) to bind a panel of antibodies against overlapping synthetic peptides which collectively encompassed this entire domain. Antibodies against the alpha-chain peptides alpha 1-16, alpha 89-104 and alpha 158-174 were able to bind to membrane-bound T-AChR. Other anti-peptide antibodies showed little or no binding to T-AChR in the membrane. It is concluded that regions alpha 1-16, alpha 89-104 and alpha 158-174 are highly exposed on the surface of the alpha subunit of membrane-bound AChR.

Amino Acid Sequence↗

PubMed1994

Analysis of exposed regions on the main extracellular domain of mouse acetylcholine receptor alpha subunit in live muscle cells by binding profiles of antipeptide antibodies.

To study the structural organization of the main extracellular domain of the nicotinic acetylcholine receptor (AChR) alpha subunit in live muscle cells, we examined the native membrane-bound receptors in cultured mouse skeletal muscle cells for their ability to bind a panel of antibodies against uniform-sized overlapping synthetic peptides which collectively represent this entire domain. The binding profile indicated that the regions alpha 23-49, alpha 78-126, alpha 146-174, and alpha 182-210 are accessible to binding with antibody. Residues alpha 23-49, alpha 78-126, and alpha 194-210 contain binding regions for alpha-neurotoxin and some myasthenia gravis autoantibodies. A comparison of this binding profile with the profile obtained for membrane-bound Torpedo californica AChR in isolated membrane fractions showed some similarities as well as significant differences between the subunit organization in the isolated membrane fraction and that in the membrane of live muscle cells. Regions alpha 89-104 and alpha 158-174, which are exposed in the isolated membrane fraction, are also exposed in the live cell. On the other hand, regions alpha 23-49, and alpha 182-210, which are exposed in the live cell, are not accessible in the isolated membrane and, furthermore, the region alpha 1-16, which has marginal accessibility in the cell, becomes highly accessible in the membrane isolates. The exposed regions defined by this study may be the primary targets for the initial autoimmune attack on the receptors in experimental autoimmune myasthenia gravis.

Amino Acid Sequence↗