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Biomedical subjects

T Mimaki

Publications and source records attributed to T Mimaki.

At least 19 recordsLinked to original sources
PubMed2000

Compound heterozygous group A xeroderma pigmentosum patient with a novel mutation and an inherited reciprocal translocation.

The severity of neurological abnormalities in Japanese group A xeroderma pigmentosum (XP-A) patients correlates with the sites of non-sense mutation in the XP-A gene. We describe a patient who presented with a more severe photosensitivity and neurological abnormality than those in typical Japanese XP-A patients with a splicing mutation in intron 3. The patient was compound heterozygous for the splicing mutation in intron 3, which resulted in formation of a non-sense codon in exon 4, and a novel non-sense mutation at codon 208 in exon 5, a C to T transition creating a stop codon TAG. Although the combination of these mutations might have been thought to cause only mild neurological signs, the longer truncated XP-A proteins than those of typical XP-A patients may have resulted in severe neurological symptoms. This phenomenon may be explained by a translocation of chromosome (1;10)(q25.3;q22.3) inherited from his father.

Adult↗
PubMed1998

Clinical pharmacology and therapeutic drug monitoring of zonisamide.

Zonisamide (1,2-benzisoxazole-3-methanesulfonamide) is a new antiepileptic drug developed in Japan. This compound is insoluble in water, and it is available in tablet and powder form. In experimental animals, this compound has been found to have a strong inhibitory effect on convulsions of cortical origin because it suppresses focal spiking and the spread of secondary generalized seizures. In humans, a series of double-blind, placebo-controlled studies revealed the efficacy of zonisamide for patients with refractory partial seizures and for selected patients with infantile spasms. Its antiepileptic mechanism of action remains unclear, but it is likely to involve blockade of both sodium and T-type calcium channels. Oral bioavailability of zonisamide is excellent in healthy human volunteers. Zonisamide is slowly absorbed and has a mean tmax of 5 to 6 hours. Almost 100% of it is absorbed; there is no difference in bioavailability between tablets and powder. Zonisamide concentrations are highest in erythrocytes and then in whole blood and plasma. It is approximately 40% to 60% bound to plasma proteins, primarily albumin. Its volume distribution is 0.9 to 1.4 L/kg. In adults, the elimination half-life is between 50 and 62 hours, and it takes as long as 2 weeks to reach steady state. The dose-serum level correlation is linear up to doses of 10 to 15 mg/kg per day, and the therapeutic range is 10 to 40 microg/ml. However, the relationship between serum zonisamide levels, clinical response, and adverse effects appears weak. Concurrent enzyme-inducing anticonvulsants such as phenytoin, carbamazepine, or barbiturates stimulate zonisamide metabolism and decrease serum zonisamide levels at steady state. Although zonisamide has been reported to increase the serum levels of phenytoin and carbamazepine in some patients, the interactions of zonisamide with other antiepileptic drugs seem to be of minor clinical relevance. A pilot study of zonisamide suppositories revealed that it is beneficial for patients with neurologic disorders in whom antiepileptic drugs cannot be administered by mouth.

Animals↗
PubMed1996

Truncated XPA protein detected in atypical group A xeroderma pigmentosum.

XPA protein from a patient with typical group A xeroderma pigmentosum (XP) and three atypical group-A XP patients were analysed. Immunoblot analysis of XPA proteins revealed that a typical group-A XP patient showed no XPA protein band, while a smaller, truncated XPA protein, which appears to be responsible for mid skin lesions and minimal neurological abnormalities, was detected in cells from three atypical group-A XP patients. Furthermore, the difference in the amount of truncated XPA protein correlated with the mildness of neurological manifestations in these three atypical group-A XP patients. The results suggest a correlation between clinical manifestations and qualitative and quantitative abnormalities of XPA protein products.

Adolescent↗
PubMed1996

[Usefulness of MRA in an infant with cerebral infarction due to streptococcal meningitis].

We described a 4-month-old boy with cerebral infarction due to streptococcal meningitis. He complained of cough and high fever for 2 days. On the next day he admitted to our hospital because of bad humor, drowsiness, and vomiting associated with high fever, respiratory failure and loss of consciousness. On admission, he had opisthotonic posturing, anisocoria and elevated deep tendon reflexes with left side dominance. The cerebrospinal fluid showed increased cells (564/mm3), protein (295 mg/dl), and decreased sugar (1 mg/dl). Streptococcus pneumoniae was detected in the cerebrospinal fluid. Despite intensive treatment by antibiotics, glycerol, and dexamethasone, general condition was worsened, MRI showed a high intense area along the territory of bilateral anterior cerebral arteries and left middle cerebral artery 3-D time-of-flight MRA revealed a decreased signal of these arteries, confirming cerebral infarction. Recanalization of the arteries were observed 17 days after the first MRA examination. Since complication of cerebral infarction influences the prognosis of meningitis, repetitive MRA is very beneficial in patients with bacterial meningitis in order to evaluate the vascular lesion.

Cerebral Infarction↗
PubMed1995

Enhancement of damage-specific DNA binding of XPA by interaction with the ERCC1 DNA repair protein.

The human XPA and ERCC1 proteins, which are involved in early steps of nucleotide excision repair of DNA, specifically interacted in an in vitro binding assay and a yeast two-hybrid assay. A stretch of consecutive glutamic acid residues in XPA was needed for binding to ERCC1. Binding of XPA to damaged DNA was markedly increased by the interaction of the XPA and ERCC1 proteins. ERCC1 did not enhance binding to DNA when a truncated XPA protein, MF122, was used in place of the XPA protein. MF122 retains damaged DNA binding activity but lacks the region for protein-protein interaction including the E-cluster region. These results suggest that the XPA/ERCC1 interaction may participate in damage-recognition as well as in incision at the 5' site of damage during nucleotide excision repair.

Binding Sites↗
PubMed1994

Anticonvulsant tolerance to clonazepam in amygdala kindled rats: clonazepam concentrations and benzodiazepine receptor binding.

The relationship between anticonvulsant tolerance to clonazepam and benzodiazepine receptor changes was studied in amygdala kindled rats. Fully kindled rats were given 1 mg/kg clonazepam (clonazepam treated) or vehicle (kindled control) orally three times per day for 4 weeks. During chronic treatment, amygdala stimulation was given twice per week, 30 min after a single protective dose of clonazepam (0.5 mg/kg, i.p.) was injected to both groups of rats. As measured by seizure stage, clonazepam treated rats showed a greater degree of tolerance than kindled control rats; contingent tolerance to the anticonvulsant effects of clonazepam developed in kindled control rats, while clonazepam treated rats shows contingent plus pharmacologic tolerance. There were no significant differences between clonazepam treated and kindled control rats in "peak" plasma clonazepam concentrations 40 min after clonazepam injections. Benzodiazepine receptor assays showed no significant difference in maximal binding capacity (Bmax), dissociation constant (Kd) or gamma-aminobutyric acid (100 microM) enhancement of benzodiazepine receptor binding between clonazepam treated and kindled control rats. These data suggest that pharmacologic tolerance to anticonvulsant action of clonazepam is not related to either plasma clonazepam concentrations or benzodiazepine receptor changes.

Amygdala↗
PubMed1994

Regional distribution of 14C-zonisamide in rat brain.

Zonisamide (1,2-benzisoxazole-3-methane sulfonamide) is a new antiepileptic drug developed in Japan. This compound was proven to possess a strong inhibitory effect on convulsions of cortical origin, whether induced by electric or chemical stimuli. Regional distribution of 14C-zonisamide was investigated in rat brain using autoradiography. A high uptake of 14C activity was observed in the cerebral cortex and the midbrain. A pair-match analysis of primary motor cortex versus primary sensory cortex revealed a slightly higher uptake in primary motor cortex. In the cerebellum, a higher uptake was observed in the cortex than medulla. Sagittal section analyses revealed that a high uptake of 14C activity was observed in the cerebral cortex and colliculus, and a moderate uptake was seen in the cerebellum, thalamus, hypothalamus, and striatal body, thus suggesting the distribution of 14C-zonisamide is similar to that of flunitrazepam and phenytoin.

Animals↗
PubMed1994

Phenytoin age-dose-concentration relationship in children.

A list (n = 423) of phenytoin steady-state concentrations from children taking phenytoin alone or in combination with other drugs (n = 308) was obtained from our therapeutic drug monitoring database (1984-1990). Only 43% of concentrations were within the commonly accepted "therapeutic" or "reference" range (10-20 mg/L). Age-dose-concentration relationships showed that while occasional concentrations were above 20 mg/L, many patients receiving commonly recommended pediatric phenytoin doses (4-8 mg/kg/day) achieved concentrations below the reference range, especially children under 3 years of age. Michaelis-Menten pharmacokinetic parameters, maximal elimination rate (Vmax) and Michaelis constant (Km), were evaluated for patients with at least two steady-state concentrations measured for two or more different daily doses. Comedication with other drugs had no effect on either Vmax or Km for phenytoin. Vmax appeared to decrease significantly with age, but there was no age relationship for Km.

Adolescent↗
PubMed1994

A case of tetrasomy 9p.

A case of mosaic 9p tetrasomy (46,XX/47,XX, + dic[9] [q21]) is reported. Clinical manifestations of the patient were generalized hypotonia, severe mental retardation and characteristic dysmorphic features of 9p tetrasomy. A brief review of the literature is also included.

Chromosome Aberrations↗
PubMed1993

Mature teratoma arising from intra-abdominal contralateral undescended testis in an infant: a case report.

A 4-month-old male infant was seen because of an asymptomatic undescended left testis and a right sided abdominal mass. CT revealed a calcified retroperitoneal tumour. Histological examination of surgical specimens showed a mature primary teratoma of the contralateral undescended testis. While this is very rare, infants with undescended testis should be carefully examined to rule out intra-abdominal malignant tumours.

Cryptorchidism↗
PubMed1993

Intermittent clonazepam treatment prevents anticonvulsant tolerance in mice.

The influence of intermittent benzodiazepine treatment on anticonvulsant tolerance was studied by comparing mice treated either daily or on alternate days with clonazepam, 0.25 mg/kg, i.p., administered twice a day. Tolerance was assessed by the ability of clonazepam to prevent pentylenetetrazol (PTZ) induced clonic convulsions. In mice treated daily with clonazepam, significant tolerance was evident after 5 days of treatment but did not increase further after 10 or 20 days of treatment. However, mice treated with clonazepam only on alternate days for 10 or 20 days showed no tolerance. Our data indicate that intermittent treatment may prevent development of tolerance to the anticonvulsant action of benzodiazepines.

Animals↗
PubMed1993

[Neurological manifestations and molecular basis of group A xeroderma pigmentosum].

The molecular basis of group A xeroderma pigmentosum (XP) was investigated by Southern blot analysis of genomic DNA and Northern blot analysis of poly (A)+ RNA from patients with group A and atypical group A XP and normal controls. The clones of a patient with group A XP who had typical symptoms showed a G-->C substitution at the 3' splice acceptor site of intron 3, which is the most common mutation in Japanese group A XP patients. On the other hand, one typical group A patient and one atypical group A patient with mild skin lesions and minimal neurological abnormalities showed compound heterozygote for the splicing mutation of intron 3 and the nonsense mutation of exon 6. The other one atypical group A patient showed a homozygote of the nonsense mutation of exon 6, thus suggesting no direct correlationship between severity of neurological complication and DNA abnormality. Northern blot analysis of poly (A)+ RNA revealed that the XPAC mRNAs of group A XP cells were smaller than that of normal controls, and amounts were markedly reduced. Of three atypical group A XP patients, one showed almost normal size and amount of the XPAC mRNA, another showed as small size and reduced amount of the XPAC mRNA, while the third one showed an intermediate type between typical group A XP and normal controls.

Adolescent↗
PubMed1992

Three nonsense mutations responsible for group A xeroderma pigmentosum.

The molecular basis of xeroderma pigmentosum (XP) group A was studied and 3 nonsense mutations of the XP-A complementing gene (XPAC) were identified. One was a nucleotide transition altering the Arg-228 codon (CGA) to a nonsense codon (TGA). This transition creates a new cleavage site for the restriction endonuclease HphI. Of 21 unrelated Japanese XP-A patients examined, 1 (XP39OS) was a homozygote for this mutation and 3 were compound heterozygotes for this mutation and for the splicing mutation of intron 3 reported previously which is the most common mutation in Japanese patients and creates a new cleavage site for the restriction endonuclease AlwNI. The second mutation was a nucleotide transition altering the Arg-207 codon (CGA) to a nonsense codon (TGA). A Palestinian patient (XP12RO) who had severe symptoms of XP was homozygous for this mutation. The third mutation was a nucleotide transversion altering the Tyr-116 codon (TAT) to a nonsense codon (TAA). This transversion creates a new cleavage site for the restriction endonuclease MseI. Of the Japanese patients, 2 with severe clinical symptoms had this mutant allele. One was a compound heterozygote for this mutation and for the splicing mutation, and the other was heterozygous for this mutation and homozygous for the splicing mutation. Although most XP-A patients such as XP12RO have severe skin symptoms and neurological abnormalities of the de Sanctis-Cacchione syndrome, patient XP39OS was an atypical XP-A patient who had mild skin symptoms and minimal neurological abnormalities. Our results suggest that the clinical heterogeneity in XP-A is due to different mutations in the XPAC gene. Moreover, our data indicate that almost all Japanese cases of XP-A are caused by one or more of the 3 mutations, i.e., the splicing mutation of intron 3 and the 2 nonsense mutations of codons 116 and 228. Therefore, by restriction fragment length polymorphism analysis of PCR-amplified DNA sequences using the 3 restriction enzymes described above, rapid and reliable diagnosis of XP-A can be achieved in almost all Japanese subjects including prenatal cases and carriers.

Base Sequence↗
PubMed1992

Allelic heterogeneity in group A xeroderma pigmentosum.

The molecular basis of Group A xeroderma pigmentosum was investigated by restriction fragment length polymorphism analysis of PCR-amplified DNA sequences using the two restriction enzymes, endonucleases AlwN I and Hph I. The clones of a patient with Group A xeroderma pigmentosum who had typical symptoms showed a G-C substitution at the 3' splice acceptor site of intron 3. However, of the two atypical Group A xeroderma pigmentosum patients with mild skin lesions and minimal neurological abnormalities, the milder one showed homozygosity for the nonsense mutation of exon 6, while the other patient with slightly greater central nervous involvement was shown to be a compound heterozygote for the splicing mutation of intron 3 and the nonsense mutation of exon 6, thus indicating an allelic heterogeneity in group A xeroderma pigmentosum.

Adolescent↗
PubMed1991

Effect of gamma-vinyl gamma-aminobutyric acid on the gamma-aminobutyric acid receptor-coupled chloride ion channel in vesicles from the brain of the rat.

The effect of gamma-vinyl GABA on the gamma-aminobutyric acid (GABA) receptor-coupled chloride ion (Cl-) channel was studied using membrane vesicles from cerebral cortex of the rat. gamma-Vinyl GABA, an antiepileptic drug, had no effect on uptake of 36Cl-, without preincubation. However, preincubation of membrane vesicles with gamma-vinyl GABA (100-1000 microM) produced a concentration-dependent decrease in net uptake of 36Cl-. No alteration was observed in basal uptake of 36Cl-. This decrease in net uptake of 36Cl- was not related to desensitization induced by endogenous GABA, which might be increased by gamma-vinyl GABA through selective, irreversible inhibition of GABA-transaminase (GABA-T). Concentration-response curves for GABA showed that preincubation with gamma-vinyl GABA inhibited GABA-stimulated uptake of 36Cl- with no change in ED50. These results indicate that gamma-vinyl GABA may act directly at the GABA/benzodiazepine ionophore complex, as a non-competitive antagonist of GABA.

4-Aminobutyrate Transaminase↗