Effect of valproic acid on the expression of acyl-CoA dehydrogenases in various tissues.
Explore the source record for details and available documents.
Animals↗
Biomedical subjects
M Nagao
Publications and source records attributed to M Nagao.
Apraxia of speech associated with an infarct in the precentral gyrus of the insula.
It has been postulated that the precentral gyrus in the left insula is responsible for co-ordination of speech. We report a patient with this disturbance who showed an acute infarct limited to this region.
Aged↗
Does the sequence of onset of rigor mortis depend on the proportion of muscle fibre types and on intra-muscular glycogen content?
We examined the postmortem changes in the levels of ATP, glycogen and lactic acid in two masticatory muscles and three leg muscles of rats. The proportion of fibre types of the muscles was determined with NIH image software. The ATP levels in the white muscles did not decrease up to 1 h after death, and the ATP levels 1 and 2 h after death in the white muscles were higher than those in the red muscles with a single exception. The glycogen level at death and 1 h after death and the lactic acid level 1 h after death in masticatory muscles were lower than in the leg muscles. It is possible that the differences in the proportion of muscle fibre types and in glycogen level in muscles influences the postmortem change in ATP and lactic acid, which would accelerate or retard rigor mortis of the muscles.
Adenosine Triphosphate↗
Mutation screening of phenylketonuria in the Far East of Russia.
We analyzed mutant genotypes at the human phenylalanine hydroxylase (PAH) locus among phenylketonuria (PKU) patients in the Far East of Russia. A total of 60 variant alleles from 30 PKU families were analyzed for prevalent Caucasian mutations and restriction fragment length polymorphism/variable number of tandem repeats (RFLP/VNTR) haplotypes. Seventy-eight percent of all variant alleles carried six mutations. The most prevalent mutation was R408W (63%), with a haplotype background of 2.3. It also showed a very high degree of homozygosity (43%). The other five mutations (R158Q, R261Q, R252W, R261X, and IVS12nt-1) accounted for 1.7%-6.7% of all PKU alleles, and a single haplotype was associated with each genotype, except for R261Q. The genetic structure of PKU patients in the Far East of Russia seems to be relatively homogeneous, compared with that in the other Slavic and Oriental populations of surrounding countries. Prediction of a clinical phenotype and carrier detection will be feasible using DNA tests.
Child↗
Low density lipoprotein particle diameter in young, nonobese, normolipidemic Japanese men.
BACKGROUND: prospective studies have demonstrated that a predominance of small, dense LDL particles (pattern B) precedes the clinical onset of coronary heart disease. Prevalence and characteristics of subjects with this LDL size abnormality were studied in young, nonobese, Japanese normolipidemic men. METHODS AND RESULTS: LDL peak particle diameter (PPD) was measured by continuous disc polyacrylamide gel electrophoresis in 223 nonobese normolipidemic men aged 18-20 years (mean+/-S.D. body mass index: 21.9+/-3.7 kg/m2, total cholesterol: 180+/-29 mg/dl, triglyceride: 62+/-34 mg/dl, HDL cholesterol: 58+/-12 mg/dl). Men with small LDL (PPD < 25.8 nm) were found in only 5.4% (n=12) whereas 197 men (88.3%) had a preponderance of large LDL (PPD 26.3 nm). As compared with men in a top tertile (PPD 27.5 nm) those in a low tertile (PPD < 26.9 nm) had higher serum levels of LDL cholesterol (120+/-31 vs 104+/-24 mg/dl), triglyceride (72+/-39 vs 49+/-16 mg/dl) and apolipoprotein (apo) B (84+/-21 vs 68+/-14 mg/dl), and lower HDL cholesterol (54+/-10 vs 60+/-12 mg/dl). They also had greater body mass index (23.2+/-4.6 vs 20.9+/-3.1 kg/m2) and percent body fat (21.5+/-7.7 vs 17.5+/-4.9%). LDL-PPD was positively correlated with HDL cholesterol (R=0.20, P=0.002) and was negatively correlated with apoB (R=0.34, P < 0.001), triglyceride (R=0.32, P < 0.001). percent body fat (R=0.26, P < 0.001), body mass index (R=0.24, P < 0.001), fat mass (R=0.23, P=0.001), total cholesterol (R=0.20, P=0.002). In multiple regression analysis, apoB, triglyceride, HDL cholesterol, apoAI and percent body fat explained 18% of LDLPPD variability. CONCLUSION: even in young, nonobese, normolipidemic men, LDL size appears to be associated with triglyceride-rich lipoprotein metabolism and body fat.
Adolescent↗
Closely linked polymorphic markers for determining the autosomal dominant allele (Cy) in rat polycystic kidney disease.
The Han:SPRD strain is an SD-background strain known to be a model of polycystic kidney disease (PKD) expressed through an autosomal dominant gene (Cy). However, different genotypes of this strain cannot be identified in the neonatal period. First, to establish an accurate method of determining the genotypes (Cy/Cy, Cy/+, +/+) which cause different disease progressions, we used polymorphic markers on rat chromosome 5. PCR products of tissue DNA templated with D5Rat9 showed distinct patterns on electrophoresis indicating three genotypes. Second, to determine whether the same locus plays a major role in expressing PKD, we performed linkage analyses in a [BN x (BN x Han:SPRD)F1] backcross. Cy/Cy and Cy/+ also caused PKD in a BN background. In this backcross, we discovered that D5Rat11 is located closer to the Cy locus than D5Mgh10, which is regarded as one of the closest loci. We conclude that D5Rat9 and D5Rat11 are useful markers for determining the presence of the Cy allele, which is regarded as the gene responsible for PKD.
Alleles↗
Expressions of four major protein Ser/Thr phosphatases in human primary leukemic cells.
Activity and expression of four major protein serine/threonine (Ser/Thr) phosphatases, protein phosphatase type 1 (PP1), protein phosphatase type 2A (PP2A), protein phosphatase type 2B (PP2B) and protein phosphatase type 2C (PP2C) were evaluated in normal peripheral leukocytes, and in various leukemic cells from patients with acute myelogenous leukemia (AML), common acute lymphocytic leukemia (cALL), or chronic lymphocytic leukemia (CLL). PP1 was the most abundant phosphatase in blood cells, and relative abundance of each phosphatase was: PP1 > PP2A > PP2B approximately = PP2C. PP1 activity and its expressions were higher in blasts of AML-M4 and -M5 than in cells of AML-M1, cALL and CLL. PP2A activity and its expression were higher in blasts of AML-M3, -M4 and -M5 than in cells of AML-M1, cALL and CLL. Activity and expression of both PP1 and PP2A in normal monocytes were highest, and PP2A activity in normal neutrophils was lowest among normal leukocytes. PP2B activity and its expression were higher in blasts of AML-M2, -M3 and normal lymphocytes. PP2C activity and its expression were relatively constant in various leukemic cell types. Activities of PP1 and PP2A of AML blasts correlated positively with the expression of CD11b, whereas activities of PP1 and PP2B correlated negatively with the expression of CD7. Thus, each phosphatase was ubiquitously but differently expressed in various leukemic cell types and in normal leukocytes. These data also suggest that expressions of PP1, PP2A and PP2B are relatively low in leukemic blasts arresting at the stage of early pluripotent stem cells, and are differently modulated during the course of myelomonocytic commitment and maturation.
Acute Disease↗
Incidence of occlusal contacts with complete dentures during mastication using a 6-channel telemetry system: preliminary measurements.
The purpose of this study was to observe the incidence of occlusal contact with complete dentures during mastication using a 6-channel telemetry system whose accuracy had been improved. The telemetry system consisted of the transmitter unit and the receiver unit. The transmitter unit was embedded in the lower complete denture. This system detects occlusal contacts by the shift of frequency in 100 kHz. The transmitter allowed 6 channels for the occlusal contacts. The data was telemetered by a time division multiplex communication method. A special switch was designed to measure excursive movement on the occlusal surface. After careful occlusal adjustment, the special switches were inserted in the lower first molars. On the basis of preliminary measurements on a 64-year-old edentulous male, it appears that the width of the gliding on the occlusal surface at the lower first molar was mostly 0.2-1.2 mm and the majority of the excursive movements ended at the centric occlusal position.
Dental Occlusion↗
Influence of valproic acid on the expression of various acyl-CoA dehydrogenases in rats.
BACKGROUND: Valproic acid (2-propyl-N-pentanoic acid, VPA) causes severe hepatic dysfunction, similar to Reye's syndrome, in a small number of patients. An enhanced excretion of dicarboxylic acids by patients indicates an interference with mitochondrial beta-oxidation. We investigated the expression of various acyl-coenzyme A (acyl-CoA) dehydrogenases (ACD), which catalyze the first step of beta-oxidation in VPA-treated rats. METHODS: The control group received normal saline and the experimental group received VPA (500 mg/kg per day) by intraperitoneal injections for 7 days. Various clinical chemistry parameters in rat blood and free and total carnitine levels in plasma and tissue were determined. Mitochondria were isolated from rat liver and heart and the relative amount of each ACD protein was determined by immunoblot analysis. Total RNA was prepared from various tissues and the mRNA levels for various ACD were measured by slot-blot hybridization analysis using respective cDNA probes. RESULTS: Administration of VPA to rats caused various metabolic effects including hypoglycemia, hyperammonemia and decreased beta-hydroxybutyrate concentration. Free carnitine levels in plasma and heart were also decreased. Enzyme activities of various acyl-CoA dehydrogenases, which are involved in fatty acid oxidation, decreased moderately in heart (57-79%), and slightly in liver (78-95%). The most prominent effects were observed in mRNA levels involved in fatty acid oxidation (short-, medium- and long-chain acyl-CoA dehydrogenase). Each mRNA increased in the liver, kidney, skeletal muscle and heart to varying degrees when rats were fed ad libitum. The increase of short- and medium- chain acyl-CoA dehydrogenase mRNA in the heart were particularly large. However, 3 day starvation strongly inhibited expression of ACD in VPA-treated rats. There was an apparent decrease in the amount of ACD mRNA and proteins in VPA-treated liver. CONCLUSIONS: Valproic acid causes enhanced expression of fatty ACD mRNA, especially in the heart, by a feedback mechanism related to inhibition of beta-oxidation in rats fed ad libitum. However, it impairs the expression of ACD in the liver when there is a drastic change in nutritional state.
Acyl-CoA Dehydrogenase↗
Preferential induction of guanine deletion at 5'-GGGA-3' in rat mammary glands by 2-amino- 1-methyl-6-phenylimidazo[4,5-b]pyridine.
2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is known to induce a characteristic mutation, G deletion at the 5'-GGGA-3' site, preferentially in the lacI transgene of the colonic mucosa of Big Blue((R)) rats (BBR) and mice and specifically in the Apc gene of rat colon tumors. In this study, lacI mutations of the mammary glands in PhIP-treated rats were investigated. Six-week-old female (BBRxSprague-Dawley)F(1) rats were administered 10 gavages of 65 mg/kg/day PhIP. Mammary ducts were collected from the macroscopically normal mammary tissue of PhIP-treated and untreated rats at 56-69 weeks of age by collagenase treatment. The mutant frequencies were 25 +/- 2.1x10(-6) in control rats and 323 +/- 44x10(-6) in the PhIP-treated rats. By sequencing 40 and 177 mutants in the control and PhIP-treated groups, respectively, 34 and 149 mutations were considered independent mutations. In the control group, G:C-->A:T transitions at CpG sites dominated and no G:C deletions were detected. In the PhIP-treated group, G:C-->T:A transversions were most frequent (43%), followed by single base pair deletions of G:C (21%). A total of nine deletions were at 5'-GGGA-3' sites, accounting for 29% of the G:C deletions and 6% of the 149 total mutations. Clusters of more than three mutations at one nucleotide position were observed at 12 positions and two were G deletions at 5'-GGGA-3' sites. Comparison of the PhIP-induced mutations in the mammary glands with those previously reported in the colon revealed that G:C-->T:A transversions occurred at a significantly higher frequency in the mammary glands and that G:C deletions occurred at a significantly lower frequency. However, the signature mutation, G deletion at the 5'-GGGA-3' site, was commonly observed in both tissues.
Animals↗
Strain differences of rats in the susceptibility to aberrant crypt foci formation by 2-amino-1-methyl-6-phenylimidazo- [4,5-b]pyridine: no implication of Apc and Pla2g2a genetic polymorphisms in differential susceptibility.
2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), the most abundant mutagenic heterocyclic amine contained in cooked food, induces colon tumors in F344 male rats when administered orally. In the present study, PhIP was introduced to various rat strains, and susceptibility to the induction of aberrant crypt foci (ACFs) was analyzed as a biomarker for colon carcinogenesis. BUF/Nac rats were highly susceptible, giving rise to 12.2 +/- 1.7 ACFs per rat. F344 rats were intermediate and ACI/N rats were resistant, giving 3.5 +/- 1.8 and 0.9 +/- 0.7 ACFs per rat, respectively. In spite of this, the extent of DNA damage by PhIP in F344, in terms of the level of PhIP-DNA adducts, was significantly lower than that in ACI/N. The differences in formation of ACFs could be, in some part, implicated in the differential susceptibility to colon carcinogenesis induced by PhIP, especially in a step later than adduct formation. In an attempt to determine the genetic factors implicated in the susceptibility to formation of ACFs, a possible involvement of the adenomatous polyposis gene (Apc) and its modifier secretory phospholipase A2 (Pla2g2a) was analyzed. No genetic polymorphisms in either Apc or Pla2g2a showed a significant correlation to susceptibility to formation of ACFs among rat strains.
Animals↗
A new modification of the 32P-post-labeling method to recover IQ-DNA adducts as mononucleotides.
To obtain accurate estimates of DNA adduct levels yielded by genotoxic compounds, it is essential to completely digest adducted nucleotides to mononucleotides. We previously developed a suitable method, called modified method I, to obtain DNA adducts of heterocyclic amines as 32P-labeled-mononucleoside adduct 5'-phosphate forms, by use of nuclease P1 (NP1) and phosphodiesterase I (PDEI) to digest adducted oligonucleotides. In this study, we applied method I to 2-amino-3-methylimidazo[4,5-f]quinoline (IQ)-DNA adduct analysis and found that one of the IQ-DNA adducts, 5-(deoxyguanosin-N2-yI)-2-amino-3-methylimidazo[4,5-f]quinoline 3',5'-diphosphate (pdGp-N2-IQ), was resistant to the 3'-phosphatase activity of NP1, but sensitive to that of T4 polynucleotide kinase (PNK). DNA obtained from the liver of rats fed IQ was 32P-labeled by the standard method and the 32P-labeled nucleotides obtained were incubated with PNK and NP1 to remove 3'-phosphate groups and then digested with PDEI. Three spots were obtained. One major spot was identified as N-(deoxyguanosin-8-yl)-2-amino-3-methylimidazo[4,5-f]quinoline 5'-phosphate (pdG-C8-IQ) and a second abundant adduct as pdG-N2-IQ. The third spot, of which the structure is unknown, was minor. The new method is called modified method II. Modified method II could be applicable to a wide variety of chemicals.
Animals↗
Two concentric protein shell structure with spikes of silkworm Bombyx mori cytoplasmic polyhedrosis virus revealed by small-angle neutron scattering using the contrast variation method.
The overall and internal structures of the silkworm Bombyx mori cytoplasmic polyhedrosis virus was investigated by small-angle neutron scattering using the contrast variation method. Data were collected in aqueous buffer solutions containing 0, 50, 75, and 100% D2O in the q range of 0.002 to 0.0774 A-1 at 5 degrees C. The radius of gyration at infinite contrast was estimated to be 336 A. The contrast matching point of the virus was determined to correspond to about 50% D2O level, evidence that the virus is composed of protein and nucleic acid. The virus was basically spherical and had a diameter of about 700 A. The main feature of its structure is the clustering of protein into two concentric shells separated by about 100 A. Most of the RNA moieties are located in the central core and between these two protein shells. However, the distance distribution function P(r) showed a minor distribution beyond a distance of r = 700 A, with a maximum particle distance of the virus of 1350 A. This is indicative of an external structure region with very low scattering density, in addition to the basic spherical structure. This external region is thought to correspond to twelve pyramidal protruding spikes shown by electron microscopic studies.
Animals↗
Difference in target organs in carcinogenesis with a heterocyclic amine, 2-amino-3,4-dimethylimidazo[4,5-f]quinoline, in different strains of mice.
2-Amino-3,4-dimethylimidazo[4,5-f]quinoline (MeIQ) induces cancers in the forestomach and liver, but not in the colon, of CDF1 male and female mice, which are thought to be resistant to induction of colon cancer by 1,2-dimethylhydrazine. In this study, we examined the carcinogenicity of MeIQ in C57BL/6N female mice, which are susceptible to 1,2-dimethylhydrazine. This strain of mice developed carcinomas of the cecum, colon and liver, but not the forestomach, when given a diet containing 300 ppm of MeIQ. This fact indicates that the target organs of a chemical carcinogen change depending on the strain of a given animal species.
1,2-Dimethylhydrazine↗
Regional cerebral blood flow in schizophrenia using stable xenon-enhanced computed tomography.
To investigate the regional cerebral blood flow (rCBF) and the factors affecting the rCBF in schizophrenia, we measured the rCBF using stable xenon-enhanced computed tomography in 118 schizophrenic patients and 21 healthy subjects. A multiple regression analysis was applied to assess the potential affecting factors, i.e. age, gender, duration of illness, dose of antipsychotics and usage of antiparkinsonism and antianxiety drugs. The rCBF of the schizophrenic patients was significantly lower than that of the healthy subjects in all regions except for the occipital region. The rCBF was decreased with increasing age in both groups to the same extent. The dosage of antipsychotic drugs taken had a significant regression relationship with the rCBF in the bilateral thalamus.
Adult↗
A rat model system for predisposition to stomach cancer.
Explore the source record for details and available documents.
Animals↗
[Effects of propiverine hydrochloride (propiverine) on the muscarinic receptor binding affinity in guinea pig tissues and on salivation in conscious dogs].
Propiverine is a drug for the treatment of incontinence and pollakiuria. Such micturitional disorders are principally caused by a hyperactive bladder. The effects of propiverine, its active metabolite, 1-methyl-4-piperidyl benzilate N-oxide (DPr-P-4 (N-->O)), oxybutynin and terodiline on muscarinic receptors in guinea pig urinary bladder, salivary glands, cerebral cortex, ileal longitudinal muscle and heart were compared. Both propiverine and DPr-P-4 (N-->O) competitively inhibited specific binding of 3H-quinuclidinyl benzilate (3H-QNB) to membrane fractions of these tissues. Oxybutynin, terodiline, pirenzepine and atropine also competitively inhibited the binding of 3H-QNB. The order of these drugs in terms of their affinity for muscarinic receptors was as follows: atropine > oxybutynin > pirenzepine, DPr-P-4 (N-->O), terodiline > propiverine. Propiverine and DPr-P-4 (N-->O) had no selectivity for muscarinic receptors in these tissues, the same as atropine. In contrast, pirenzepine, a M1-selective drug, had 10.1 times greater affinity for muscarinic receptors in the cerebral cortex than in urinary bladder, and the affinity of oxybutynin for muscarinic receptors in salivary glands and in cerebral cortex was 10.9 times and 13.9 times higher, respectively, than in urinary bladder. The affinity of terodiline for muscarinic receptors in the cerebral cortex was 4.4 times higher than in urinary bladder. In this study, the effect of propiverine and oxybutynin on pilocarpine (1 mg/kg, s.c.)-induced salivation in conscious dogs was also compared. Propiverine (5 mg/kg, i.v.) had no effect on pilocarpine-induced salivation, whereas oxybutynin (0.1 mg-0.5 mg/kg, i.v.) inhibited it significantly and dose-dependently. The ID50 values (95% confidence limits) for propiverine and oxybutynin during the 20 min after intravenous administration were 6.88 mg/kg (4.71-15.67) and 0.154 mg/kg (0.115-0.205), respectively. These findings suggest that although propiverine, its active metabolite DPr-P-4 (N-->O), oxybutynin and terodiline competitively inhibit the binding of 3H-QNB to muscarinic receptors, the affinity of these drugs for the muscarinic receptors of these tissues is very different and that propiverine has less effect on salivation than oxybutynin.
Animals↗
Linkage mapping of the rat Msh2 DNA mismatch repair gene on chromosome 6.
Explore the source record for details and available documents.
Animals↗