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Biomedical subjects

M Shoji

Publications and source records attributed to M Shoji.

At least 109 records · Page 6Linked to original sources
PubMed1999

Effects of AH-1058, a new antiarrhythmic drug, on experimental arrhythmias and cardiac membrane currents.

AH-1058 is a newly synthesized antiarrhythmic agent. We investigated the antiarrhythmic and electrophysiological effects of AH-1058 in experimental arrhythmia models and isolated cardiomyocytes. In the ouabain-induced arrhythmia model of the guinea pig, pretreatment with AH-1058 (0.1-0.3 mg/kg, i.v.) delayed the appearance of premature ventricular complex (PVC) and ventricular fibrillation (VF) induced by intravenous infusion of ouabain. However, disopyramide (10 mg/kg, i.v.) delayed only that of PVC, and verapamil (1 mg/kg, i.v.) failed to affect the ouabain-induced ventricular arrhythmias. In the reperfusion-induced arrhythmia model of the rat, in which 5-min coronary occlusion and 10-min reperfusion were produced, AH-1058 (0.1-0.3 mg/kg, i.v.) inhibited the incidence of both ventricular tachycardia (VT) and VF, whereas disopyramide (5 mg/kg, i.v.) inhibited only reperfusion-induced VF. On the other hand, a higher dose of AH-1058 (1 mg/kg, i.v.) did not affect the aconitine-induced arrhythmias in rats, which were inhibited by disopyramide (5 mg/kg, i.v.). We also confirmed oral activity of AH-1058 in the reperfusion-induced arrhythmia model of the rat. AH-1058, at doses of 2-4 mg/kg, dose-dependently inhibited VT and VF. Electrophysiological experiments with patch-clamp techniques revealed that AH-1058 potently suppressed the L-type Ca2+ currents in isolated cardiomyocytes of the guinea pig. These results suggest that AH-1058 is a potent antiarrhythmic drug having a Ca2+ channel-blocking action. The antiarrhythmic profile of AH-1058 is different from that of disopyramide and verapamil.

Aconitine↗
PubMed1999

Glucocorticoidal regulation of pituitary vasopressin content in rats.

Although glucocorticoids are known to attenuate vasopressin (AVP) secretion, it is still controversial whether glucocorticoids act on the hypothalamo-neurohypophysial system. We report here glucocorticoidal regulation of pituitary AVP content, which is a specific indicator for the system. The hypothalamic AVP mRNA content and the pituitary AVP content were measured in rats given dexamethasone (2 mg/kg, 2 times over the course of 5 d) or the glucocorticoid receptor antagonist RU-38486 (20 mg/kg, 3 times over the course of 3 d) during euhydration or dehydration. In dexamethasone-treated rats, both the hypothalamic AVP mRNA content and pituitary AVP content decreased after dehydration. In contrast, in the RU-38486 group the hypothalamic AVP mRNA content and pituitary AVP content increased in both euhydrated and dehydrated rats. These results suggest that glucocorticoids may act on hypothalamo-neurohypophysial vasopressinergic system and attenuate its activity under both basal and dehydrated states.

Actins↗
PubMed1999

Analysis of aldehyde dehydrogenase 2 gene polymorphism and ethanol patch test as a screening method for alcohol sensitivity.

To assess clinical availability of the aldehyde dehydrogenase (ALDH) 2 gene polymorphism to detect alcohol sensitivity among a Japanese population, we determined the ALDH 2 genotypes and also compared to an ethanol patch test in 119 young Japanese. Their alcohol sensitivity was evaluated by a questionnaire on the frequency of alcohol-associated symptoms when they drink. Genomic DNA was extracted from blood samples and amplified by polymerase chain reaction (PCR). PCR primers were flanking the polymorphic region in exon 12 of the ALDH 2 gene. The distribution of the typical homozygote, the heterozygote and the atypical homozygote was 63.9, 31.9 and 4.2%, respectively. Gene frequencies of the typical and atypical alleles calculated from the genotype frequencies were 0.80 and 0.20. The atypical genotypic homozygotes were positively associated with facial flushing symptom, but not with positive response for ethanol patch test. These results indicate that ALDH 2 genotypes determination is essential to detect alcohol sensitivity whereas the ethanol patch test has some limitations.

Adolescent↗
PubMed1999

Deletion and nonsense mutations of the connexin 32 gene associated with Charcot-Marie-Tooth disease.

Two patients with a mild to moderate phenotype of Charcot-Marie-Tooth disease were identified to carry the mutations of the connexin (Cx) 32 gene. One of the patient had a novel nonsense mutation of tryptophan at amino acid 132 and the other had a deletion of the Cx 32 gene. Our study indicated that a loss of Cx 32 function contributes to a major pathogenesis of X-linked Charcot-Marie-Tooth disease.

Adult↗
PubMed1999

Analysis of spinocerebellar ataxia type 2 gene and haplotype analysis: (CCG)1-2 polymorphism and contribution to founder effect.

Spinocerebellar ataxia type 2 is a familial spinocerebellar ataxia with autosomal dominant inheritance. The gene responsible was recently cloned and this disorder was found to be the result of a CAG expansion in its open reading frame. We analysed 13 SCA2 patients in seven unrelated families in Gunma Prefecture, Japan. In four of the seven families, we detected CCG or CCGCCG interruptions in only the expanded alleles. Cosegregation of these polymorphisms with SCA2 patients was established within each family. Together with the results of haplotype analyses, we considered that at least two founders were present in our area and that these (CCG)1-2 polymorphisms may make analysis of founder effects easier. By sequencing analysis we found that although the number of the long CAG repeat varied in each subclone of expanded alleles, these polymorphisms did not change their configuration. This finding suggests that CCG or CCGCCG sequences are stable when surrounded by the long CAG repeat and a single CAG. Moreover, the presence of these polymorphisms may lead to miscounting the repeat size by conventional estimation using a size marker such as an M13 sequencing ladder. Therefore we should consider these polymorphisms and accurately determine the repeat size by sequencing.

Alleles↗
PubMed1999

Lipoprotein-free amyloidogenic peptides in plasma are elevated in patients with sporadic Alzheimer's disease and Down's syndrome.

About 90% of the soluble amyloid beta (sA beta) that circulates in normal human plasma is associated with lipoprotein particles. In sporadic Alzheimer's disease patients, free sA beta42 but not sA beta40 is increased approximately 2.3-fold compared with age-matched controls, although a more marked elevation (approximately 8-fold for free sA beta40 and about 20-fold for sA beta42) is found in Down's syndrome patients. The data suggest that lipoprotein-sA beta dissociation may contribute to the influx of sA beta into the brain as a result of decreased plasma clearance.

Adult↗
PubMed1999

[Water metabolism and its disturbances].

The central and peripheral mechanisms regulate body water balance near an ideal set point. Osmosensitive neurons in the organum vasculosum lamina terminalis (OVLT) in the anterior hypothalamus play a key role in regulating vasopressin release and drinking behaviour. Patients with OVLT lesions are known to have osmostat fluctuations. Although the brain water channel is suggested to participate in osmoreception, the precise molecular mechanisms of osmoreception and thirst appreciation remain to be clarified. Vasopressin gene mutation is responsible for hereditary central diabetes insipidus. Mutant vasopressin precursors have been reported to impair the secretion of wild-type proteins or cause cellular toxicity. Despite the intact production and secretion of vasopressin, the kidney is unable to concentrate urine in nephrogenic diabetes insipidus (NDI). Most congenital NDI patients have mutations in the G protein-coupled vasopressin V2 receptor gene. V2 receptor mutants are shown not to reach the plasma membrane, not to bind AVP, and not to trigger an intracellular cyclic adenosine-monophosphate signal. Congenital NDI with an autosomal recessive inheritance has mutations of Aquaporin-2 gene, a vasopressin-sensitive water channel in the renal inner medullary collecting duct (IMCD). Aquaporin-2 mutant proteins cannot be expressed at the luminal membrane. The corticopapillary osmotic gradient is necessary for renal sensitivity to vasopressin. The vasopressin-regulated urea transporter in IMCD and the chloride channel (CLC-K1) in the ascending loop of the Henle contribute to the formation of the osmotic gradient. NDI has been shown in mice lacking the CLC-K1. The pathophysiological significance of urea transporter and CLC-K1 has yet to be demonstrated in patients with NDI.

Animals↗
PubMed1998

CDK4, a possible critical regulator of apoptosis in rat pheochromocytoma PC12 cells.

The function of cell cycle regulator molecules during apoptosis induced by serum withdrawal was examined in rat pheochromocytoma PC12 cells. When human cDNAs encoding cyclins, cyclin-dependent kinase 2 (CDK2), CDK4, and cell-division cycle 2 (CDC2), were introduced, only CDK4-overexpressing cells were more prone to apoptosis compared with parental cells. In the parental cells, serum withdrawal resulted in the upregulation of CDK4 protein expression 6.6-fold for the first 12 h after serum withdrawal. In contrast, CDK4 protein levels in CDK4-overexpressing cells remained constant for the first 12 h followed by a gradual decline. Expression of cyclin D1 was upregulated in both cell lines. The change in CDK4 kinase activity almost paralleled that of CDK4 protein expression. These results suggest that CDK4 kinase activity is one of the critical regulators in the apoptotic cascade in PC12 cells.

Animals↗
PubMed1998

Mutagenicities of 2,4- and 2,6-dinitrotoluenes and their reduced products in Salmonella typhimurium nitroreductase- and O-acetyltransferase-overproducing Ames test strains.

Mutagenicities of 2,4- and 2,6-dinitrotoluene (2,4-and 2,6-DNT), and reduced metabolites formed by the incubation of 2,4- and 2,6-DNT with Salmonella typhimurium TA98, were tested using S. typhimurium YG strains possessing high level of nitroreductase (NR) and/or O-acetyltransferase (OAT) activities. All compounds tested showed greatest mutagenic activities toward strains YG1041 and YG1042, which possess high levels of NR and OAT activities. The relative mutagenic activities of 2,4-DNT and its related compounds toward YG1041 and YG1042 were aminonitrotoluenes<2,4-DNT<2,2'-dimethyl-5, 5'-dinitroazoxybenzene (2,2'-DM-5, 5'-DNAOB)4-hydroxylamino-2-nitrotoluene (4HA2NT)<<4, 4'-dimethyl-3,3'-dinitroazoxybenzene (4,4'-DM-3,3'-DNAOB), and aminonitrotoluenes (2A4AT, 4A2NT)<2,4-DNT<4HA2NT4,4'-dimethyl-3, 3'-dinitroazoxybenzene (4,4'-DM-3,3'-DNAOB)<2HA4NT, respectively. In addition, the relative mutagenic activities of 2,6-DNT and its related compounds toward YG1041 and YG1042 were 2, 6-DNT<2-hydroxylamino-6-nitrotoluene (2HA6NT)<2,2'-dimethyl-3, 3'-dinitroazoxybenzene (2,2'-DM-3,3'-DNAOB), and 2-amino-6-nitrotoluene (2A6NT)<2,6-DNT<2HA6NT, respectively. These results, together with previous findings, suggested that aminohydroxylamino dimethylazoxybenzenes or aminohydroxylamino dimethylazobenzenes produced either by the reduction of hydroxylaminonitrotoluenes or by the reduction of dimethyl dinitroazoxybenzenes are active metabolites responsible for the mutagenic activities of 2,4- and 2,6-DNT.

Acetyltransferases↗
PubMed1998

Molecular analysis of a de novo mutation for spinocerebellar ataxia type 6 and (CAG)n repeat units in normal elder controls.

Spinocerebellar ataxia type 6 (SCA6) is an autosomal dominant spinocerebellar degenerative disease caused by CAG repeat expansions in the human alpha1A voltage-dependent calcium channel subunit gene (CACNL1A4). We analyzed 15 SCA6 patients in 14 unrelated Japanese families and 52 healthy Japanese aged over 74 years. Sequence analysis was performed to determine the correct number of CAG repeats. The expanded CAG repeat number was 23.6+/-2.1 (mean+/-S.D., n=15) with a range of 20-29, and the shortest expanded allele was 20 repeats. Moreover, the analysis of normal subjects revealed that the CAG repeat number of normal alleles was 12.3+/-1.9 (n=104) with a range of 7-18. We concluded that the normal range of CAG repeats in the CACNL1A4 gene is 18 or less, and that the disease range is 20 or more. Of 15 SCA6 patients, three sporadic cases were observed. In one male patient with 26 CAG repeats, the CAG repeat numbers of his parents were within normal range. His expanded allele was considered to be caused by an expansion of a normal allele from his mother (14 or 17 repeats). This is the first SCA6 case which was genetically proven to occur due to a de novo mechanism, suggesting that larger CAG repeats of normal alleles in the CACNL1A4 gene may be unstable and result in full expansion.

Aged↗
PubMed1998

A Japanese family with adrenoleukodystrophy with a codon 291 deletion: a clinical, biochemical, pathological, and genetic report.

We report a Japanese family with adrenoleukodystrophy (ALD) with a three base pair deletion (delGAG 291) in the ALD gene. A variety of phenotypes were observed within this family. While the proband (patient 1) was classified as having a rare intermediate type of adult cerebral and cerebello-brain stem forms, his younger brother (patient 2) and nephew (patient 3) had a childhood ALD type. Another nephew (patient 4) of patient 1 was classified as having an adolescent form. The tau level in the cerebrospinal fluid (CSF) in patient 1 was as high as that of patients with Alzheimer's disease (AD). His brain magnetic resonance image (MRI) showed abnormalities in the bilateral cerebellar hemispheres and brain stem, but not in the cerebral white matter, where marked reductions of the cerebral blood flow and oxygen metabolism were clearly demonstrated by positron emission tomography (PET). In patients 2 and 3, the autopsy findings showed massive demyelination of the cerebral white matter with sparing of the U-fibers, compatible with the findings of childhood ALD. Oleic and erucic acids (Lorenzo's Oil) were administered to patients 1 and 4, but sufficient effectiveness was not obtained. The findings in this family suggest that delGAG291 is part of the cause of Japanese ALD with phenotypic variations. Moreover, although the scale of the study is limited, there is a possibility that PET can detect an insidious lesion which is undetectable by computed tomogram (CT) or MRI analysis, and that the higher level of tau reflects the process of neuronal degeneration in ALD. Lorenzo's Oil should be given in the early stage.

Adrenoleukodystrophy↗
PubMed1998

Combination assay of CSF tau, A beta 1-40 and A beta 1-42(43) as a biochemical marker of Alzheimer's disease.

Cerebrospinal fluid samples from a total of 157 subjects consisting of 55 patients with sporadic Alzheimer's disease (AD), 34 normal controls, 23 patients with non-AD dementia, and 45 with other neurological diseases were examined by ELISA of tau, A beta 1-40, and A beta 1-42(43). The AD group had a significantly higher level of tau than the normal control group (P < 0.001), and the diagnostic sensitivity was 31% and specificity was 94%. CSF A beta 1-40 levels did not show any significant differences. Although the level of A beta 1-42(43) was decreased significantly in the AD group compared to the control group (P < 0.005), the overlap of A beta 1-42(43) levels among all groups meant that none of the AD samples exceeded the cut-off value, the mean 2SD of normal control subjects. Reduction of A beta 1-42(43) levels in AD resulted in a significant increase in the ratio of A beta 1-40 to A beta 1-42(43) (A beta ratio) as an improved marker. The diagnostic sensitivity and specificity of A beta ratio were 51% and 82% respectively. The three indexes, using the tau level and A beta ratio (tau or A beta ratio, deviation score and tau x A beta ratio), showed better sensitivity (58%, 67%, 69%) and specificity (82%, 86%, 88%) than previously reported methods. Combination assay for CSF tau, A beta 1-40 and A beta 1-42(43) in CSF is a biological marker of AD and may be useful to biochemically monitor subjects under treatment.

Adult↗
PubMed1998

Analysis of spinocerebellar ataxia type 2 in Gunma Prefecture in Japan: CAG trinucleotide expansion and clinical characteristics.

We analyzed 13 patients with spinocerebellar ataxia type 2 (SCA2) in seven unrelated families who live in Gunma Prefecture, Japan (population approx. 2,000,000), and documented the clinical and molecular properties correlated with the CAG repeat expansion. Twelve of the 13 patients and one presymptomatic female were genetically examined, and the CAG repeat number of the expanded and normal alleles was 40.8+/-4.8 (mean+/-S.D., n=13) and 22+/-0 (n=13), respectively. The repeat size of the expanded alleles was inversely correlated with the patients' age at onset. Paternal anticipation was observed, accompanied by an increase of the CAG repeat size. The patients presented here were clinically characterized by a relatively higher frequency of slow saccades, hyporeflexia, hypotonia, and tremor. A number of peaks in the expanded allele on polyacrylamide gel electrophoresis showed the presence of cell mosaicism in SCA2 as well. In Gunma Prefecture, SCA2, Machado-Joseph disease and spinocerebellar ataxia type 6 are almost equally present and at higher frequencies than spinocerebellar ataxia type 1 and hereditary dentatorubropallidoluysian atrophy, which are rare. Thus, the difference of frequency of autosomal dominant spinocerebellar ataxias may be present in Japan.

Adolescent↗
PubMed1998

Expression of HuD protein is essential for initial phase of neuronal differentiation in rat pheochromocytoma PC12 cells.

HuD is a neuronal-specific, RNA-binding protein. Here we examined the change in the expression of HuD protein during nerve growth factor-mediated differentiation of PC12 cells. As cells differentiated and extended neurites, expression of HuD gradually increased up to 1.5-fold. When HuD expression was counteracted by antisense oligonucleotide, neurite extension was completely inhibited, yet the morphology of differentiated cells remained unchanged even after that treatment. Furthermore, this morphological change correlated well with the downregulation of cyclin-dependent kinase 2 activity. These results suggest that the HuD is critically involved in the initial phase of neuronal differentiation.

Animals↗
PubMed1998

Longitudinal study of cerebrospinal fluid levels of tau, A beta1-40, and A beta1-42(43) in Alzheimer's disease: a study in Japan.

To clarify the alterations of tau, amyloid beta protein (A beta) 1-40 and A beta1-42(43) in the cerebrospinal fluid (CSF) that accompany normal aging and the progression of Alzheimer's disease (AD), CSF samples of 93 AD patients, 32 longitudinal subjects among these 93 AD patients, 33 patients with non-AD dementia, 56 with other neurological diseases, and 54 normal control subjects from three independent institutes were analyzed by sensitive enzyme-linked immunosorbent assays. Although the tau levels increased with aging, a significant elevation of tau and a correlation between the tau levels and the clinical progression were observed in the AD patients. A significant decrease of the A beta1-42(43) levels and a significant increase of the ratio of A beta1-40 to A beta1-42(43) were observed in the AD patients. The longitudinal AD study showed continuous low A beta1-42(43) levels and an increase of the ratio of A beta1-40 to A beta1-42(43) before the onset of AD. These findings suggest that CSF tau may increase with the clinical progression of dementia and that the alteration of the CSF level of A beta1-42(43) and the ratio of A beta1-40 to A beta1-42(43) may start at early stages in AD. The assays of CSF tau, A beta1-40, and A beta1-42(43) provided efficient diagnostic sensitivity (71%) and specificity (83%) by using the production of tau levels and the ratio of A beta1-40 to A beta1-42(43), and an improvement in sensitivity (to 91%) was obtained in the longitudinal evaluation.

Aged↗
PubMed1998

Familial spinocerebellar ataxia with cerebellar atrophy, peripheral neuropathy, and elevated level of serum creatine kinase, gamma-globulin, and alpha-fetoprotein.

Here, we report a familial spinocerebellar ataxia (FSCA), which has clinical features similar to Friedreich's ataxia, an ataxia with isolated vitamin E deficiency, and ataxia telangiectasia. However, the serum levels of creatine kinase, gamma-globulin, and alpha-fetoprotein were elevated, and biochemical and genetic analyses ruled out diagnosis of these three ataxias as well as other FSCAs. Thus, this family is thought to have a new type of FSCA.

Adult↗