Search PubMed⌕ Search

Biomedical subjects

H Mabuchi

Publications and source records attributed to H Mabuchi.

At least 163 records · Page 9Linked to original sources
PubMed1995

Effect of FK 506 on the expression of endothelin receptor mRNA in the vasculature.

Tacrolimus (FK 506) is a new, more powerful immunosuppressant and is more effective in the prevention and treatment of allograft rejection in humans than cyclosporine (CysA). The present study was conducted to determine whether FK 506 increases ET(A) receptor mRNA in blood vessels in rats. FK 506 5 mg/kg/day for 4 weeks increased blood pressure and expression of ET(A) receptor mRNA in mesenteric arteries of Wistar-Kyoto rats. However, 0.5 mg/kg/day of FK 506 did not increase blood pressure or ET(A) mRNA levels in the vasculature. The dose of 0.1 microM CysA used in clinical practice induced expression of ET(A) receptor mRNA in cultured rat vascular smooth-muscle cells (VSMCs). A clinical dose (0.01 microM) of FK 506 did not increase expression of ET(A) receptor mRNA in VSMCs. However, 0.1 microM FK 506 increased the levels of ET(A) receptor mRNA in VSMCs. These results indicate that the upregulating effect of FK 506 on the ET(A) receptor in the vasculature may contribute to the genesis of FK 506-induced hypertension. The lower incidence of complications seen with FK 506 may be due in part to its use at a lower clinical dose compared to that of CysA.

Animals↗
PubMed1994

Genetic cholesteryl ester transfer protein deficiency caused by two prevalent mutations as a major determinant of increased levels of high density lipoprotein cholesterol.

Genetic determinants of HDL cholesterol (HDL-C) levels in the general population are poorly understood. We previously described plasma cholesteryl ester transfer protein (CETP) deficiency due to an intron 14 G(+1)-to-A mutation(Int14 A) in several families with very high HDL-C levels in Japan. Subjects with HDL-C > or = 100 mg/dl (n = 130) were screened by PCR single strand conformational polymorphism analysis of the CETP gene. Two other mutations were identified by DNA sequencing or primer-mediated restriction map modification of PCR products: a novel intron 14 splice donor site mutation caused by a T insertion at position +3 from the exon14/intron14 boundary (Int14 T) and a missense mutation (Asp442 to Gly) within exon 15 (D442G). The Int14 T mutation was only found in one family. However, the D442G and Int14 A mutations were highly prevalent in subjects with HDL-C > or = 60 mg/dl, with combined allele frequencies of 9%, 12%, 21% and 43% for HDL-C 60-79, 80-99, 100-119, and > or = 120 mg/dl, respectively. Furthermore, prevalences of the D442G and Int14 A mutations were extremely high in a general sample of Japanese men (n = 236), with heterozygote frequencies of 7% and 2%, respectively. These two mutations accounted for about 10% of the total variance of HDL-C in this population. The phenotype in a genetic compound heterozygote (Int14 T and Int14 A) was similar to that of Int14 A homozygotes (no detectable CETP and markedly increased HDL-C), indicating that the Int14 T produces a null allele. In four D442G homozygotes, mean HDL-C levels (86 +/- 26 mg/dl) were lower than in Int14 A homozygotes (158 +/- 35 mg/dl), reflecting residual CETP activity in plasma. In 47 D442G heterozygotes, mean HDL-C levels were 91 +/- 23 mg/dl, similar to the level in D442G homozygotes, and significantly greater than mean HDL-C levels in Int14 A heterozygotes (69 +/- 15 mg/dl). Thus, the D442G mutation acts differently to the null mutations with weaker effects on HDL in the homozygous state and stronger effects in the heterozygotes, suggesting dominant expression of a partially defective allele. CETP deficiency, reflecting two prevalent mutations (D442G and Int14 A), is the first example of a genetic deficiency state which is sufficiently common to explain a significant fraction of the variation in HDL-C in the general population.

Adult↗
PubMed1994

Synthesis and platelet-activating factor (PAF)-antagonistic activities of 1,4-disubstituted piperazine derivatives.

During the screening of novel platelet-activating factor (PAF) antagonists, we found that 1-(6-methoxy-3,4-dihydro-2-naphthoyl)-4- (3,4,5-trimethoxybenzyl)piperazine and its 4-(3,4,5- trimethoxybenzoyl)piperazine derivatives (1b, 2b) exerted in vitro and in vivo PAF-antagonistic activities. Modifications of the 1-acyl group, the substituent at the 4-position and the piperazine ring of 1a and 2b were examined and from this series 1-(2,3-dimethoxy-6,7-dihydro-5H-benzocyclohepten-8-ylcarbonyl++ +)-4- (3,4,5-trimethoxybenzoyl)piperazine (2g) was found to be one of the most potent PAF antagonists.

Animals↗
PubMed1994

Synthesis and platelet-activating factor (PAF)-antagonistic activities of trisubstituted piperazine derivatives.

2- or 3-Substituted 1-(2,3-dimethoxy-6,7-dihydro-5H-benzocyclohepten-8- ylcarbonyl)-4-(3,4,5-trimethoxybenzoyl)- and 4-(3,4,5-trimethoxybenzyl)piperazines (2a-s, 3a, b) were prepared and evaluated for antagonistic activities against platelet-activating factor (PAF)-induced platelet aggregation and blood pressure reduction. The 2-methoxymethyl derivative (2f) showed the most potent activities in this series. The enantiomers (R)-(+)-2f and (S)-(-)-2f were synthesized from carbobenzoxy-O-benzyl-L- and D-serine in several steps. In the binding experiment, (S)-(-)-2f showed thirty times greater affinity than the R isomer for the PAF receptor.

Animals↗
PubMed1994

[CETP deficiency].

Four different CETP gene mutations have been reported to be causes of increased levels of HDL cholesterol by us and other investigators; two splice donor site mutations involving intron 14, one missense mutation of D442G in exon 15, and one nonsense mutation of Q309X in exon10. Two splice donor site mutations are G (+1)-to-A transition (Int14A) and T insertion at the +3 position (Int14T), and both mutations result in null phenotype as well as a nonsense mutation. In contrast, D442G mutation is partially defective in CETP activity. Two mutations of Int14A and D442G are common mutations in the general Japanese population with a high frequency of the heterozygotes of 2% and 7%, respectively. Heterozygous CETP deficiency is sufficiently common to explain a significant fraction of the variation in HDL-C level in the general Japanese population.

Carrier Proteins↗
PubMed1994

[Carbon-11 labeled diacylglycerol for signal transduction imaging: effect of the solubilizer on the distribution and radiation dosimetry].

Carbon-11 labeled diacylglycerol (11C-DAG) has been developed as a signal transduction imaging agent for the CNS, and it can visualize the second messenger. For clinical application by positron CT (PET), the 11C-DAG solution must be prepared for intravenous injection. However, the 11C-DAG does not dissolve in water because of its lipophilicity and requires a solubilizer such as human serum albumin (HSA) and Tween 80 (TW-80). We examined the influence of these solubilizers on the tissue distribution of 11C-DAG, and estimated the radiation dosimetry. In the brain, uptake of 11C-DAG dissolved with HSA was 1.3-1.8 times higher than that of dissolved with TW-80. On the other hand, the lung and spleen showed a higher uptake of 11C-DAG using TW-80 than when using HSA. Especially, the lungs showed 20-40 times higher uptake than when using HSA. Also, the washout of radioactivity from tissue was slower, and the dose of radiation exposure was estimated to be higher, with TW-80 than with HSA. Therefore, between TW-80 and HSA with different solubilizing mechanisms, the later was suggested to be a better solubilizer of 11C-DAG.

Animals↗
PubMed1993

Rapid detection and prevalence of cholesteryl ester transfer protein deficiency caused by an intron 14 splicing defect in hyperalphalipoproteinemia.

A deficiency of plasma cholesteryl ester transfer protein (CETP) is one of the genetic causes of increased serum high density lipoprotein (HDL)-cholesterol levels (hyperalphalipoproteinemia). A splicing defect (G-->A mutation) at the +1 position of intron 14 of the human CETP gene is a common mutation in the Japanese CETP deficiency. A rapid screening method for the splicing defect by means of primer-specified restriction map modification was described. The frequency of the mutation in hyperalphalipoproteinemia was determined, and its frequency in the general population was estimated. During polymerase chain reaction (PCR) with a modified primer, a novel NdeI restriction endonuclease site was created from the mutated allele in the PCR products, which could be visualized after electrophoresis of the digested products. As a result, 21 of 121 unrelated hyperalphalipoproteinemic subjects with HDL-cholesterol > or = 60 mg/dl (1.55 mmol/l), were found to have the G-->A mutation. Of the 21 individuals, 8 were found to be homozygous for the mutation. Allele frequency of the mutation was 1.5% (1/68), 2.8% (2/72), 7.1% (4/56), and 47.8% (22/46) in the groups with HDL-cholesterol levels of 60-79 mg/dl, 80-99 mg/dl, 100-119 mg/dl, and > or = 120 mg/dl, respectively. Based on the percentage of the area under the computed normal distribution curve of serum HDL-cholesterol, the frequency of the mutated allele in the general population was estimated to be 0.81% from the present results. This rapid detection method facilitates large-scale screening of CETP deficiency caused by the splicing defect. The mutation was frequent in Japanese subjects with hyperalphalipoproteinemia, especially in the group with HDL-cholesterol > or = 120 mg/dl.

Adult↗
PubMed1993

Quantification of coronary artery calcification using ultrafast computed tomography: reproducibility of measurements.

BACKGROUND: Ultrafast computed tomography (CT) is a non-invasive method of visualizing and quantifying coronary artery calcification; its reproducibility, however, has not been fully elucidated. METHODS: To assess intra-observer, inter-observer, and inter-study reproducibility, 75 consecutive patients (51 men and 24 women) were studied. CT images were obtained using the volume mode of ultrafast CT (Imatron C-100). A total coronary calcification score (TCS) was calculated from the lesion area (> or = 2 pixels) and its peak CT density (> or = 130 HU). RESULTS: There was no intra-observer variability in two experienced observers. The TCS provided by these observers disagreed in 18 out of 75 (24%) cases, and the differences were -5.1 +/- 53 (mean +/- SD) for TCS and 0.014 +/- 0.13 for In(1 + TCS). They resulted from either 10 incorrect identifications of small coronary branches, or eight variations in determination of the ostial margin. The former was much smaller than the latter in TCS (0.66 +/- 3.0 and -48 +/- 165, respectively), but both were quite similar in In(1 + TCS) (0.082 +/- 0.31, 0.017 +/- 0.22, respectively). Between two scans, 50 out of 75 patients (67%) had different TCS values. The mean differences (95% confidence interval) were 1.8 +/- 106 (-210 to 214) in TCS, and -0.015 +/- 0.46 (-0.94 to 0.91) in In(1 + TCS). Because the differences increased with the mean values, the determination of TCS assumed a constant variance with increasing mean level. A comparison of scan images indicated that partial volume effects were responsible for this constant variance. CONCLUSION: Partial volume effects play a key role in producing the variability of TCS determination, and log transformation should be used to interpret TCS values. Thus, for clinical purposes, we recommend that two scans be performed in rapid succession, and that the average of these two scans be used to determine TCS.

Adolescent↗
PubMed1993

Abdominal aortic aneurysms in familial hypercholesterolemia--case reports.

Familial hypercholesterolemia (FH) is a genetic disease characterized by high serum cholesterol levels and premature coronary atherosclerosis. Hypercholesterolemia is one of the factors promoting the arteriosclerotic process and is a major cause of aortic aneurysm. Few data are available, however, about abdominal aortic aneurysms (AAAs) in patients with FH. In this study, the clinical and angiographic characteristics of AAAs found in patients with FH were investigated. Thirty-one cases (23 men, 8 women, aged fifty +/- fourteen years) were examined by coronary angiography, thoracic and abdominal aortography, and clinical data. Abdominal aortography detected abdominal aneurysms in 8 cases (26%), all of whom were men, including 4 cases (50%) that were complicated by diabetes mellitus. The abdominal aneurysm patients manifested severe coronary atherosclerosis, severe abdominal aortic irregularity, and higher blood pressure than the nonaneurysm FH patients. These findings suggest that AAAs are an important and prevalent feature in FH, especially in men with diabetes mellitus and high blood pressure.

Adult↗
PubMed1993

[New approach to pathogenesis of genetic hyperlipoproteinemias].

Genetic hyperlipoproteinemias are produced by defects or abnormalities of several enzymes, apolipoproteins and transfer proteins relating to lipoprotein metabolism. Abnormalities of the LDL receptor cause familial hypercholesterolemia (FH) and the deficiency of cholesteryl-ester transfer protein (CETP) causes familial hyperalphalipoproteinemia. Here, abnormalities of the LDL-receptor genes and CETP gene are described. More than 70 mutants of LDL-receptor gene have been reported, and we discovered 4 mutants in the Hokuriku district of Japan. Compared with FH-Tonami-1, FH-Tonami-2 showing a partial defect of the LDL-binding domain of the receptor, is a genetically determined mild type of FH. Only 10% of the LDL receptor abnormalities in FH have been clarified, and the causes of the remaining 90% are unknown at present. CETP catalyzes the transfer of cholesteryl ester from HDL to other lipoproteins. We found a familial hyperalphalipoproteinemia produced by the CETP deficiency. A point mutation in the splice donor site of intron 14 in the CETP gene was found in all Japanese patients with CETP deficiency. CETP deficiency produces an antiatherogenic lipoprotein profile in high HDL-cholesterol level and low IDL- and LDL-cholesterol levels. We developed a rapid screening method for the splicing defect of CETP gene, by means of primer-specific restriction map modification. The frequency of the mutated allele in the general population was estimated to be 0.81%, and the mutant was frequent in Japanese subjects with hyperalphalipoproteinemia. In summary, the detection of gene abnormalities is essential for understanding lipoprotein abnormalities and clinical manifestations in genetic hyperlipoproteinemias.

Adult↗
PubMed1993

[Alterations of Lp (a) lipoprotein in patients with chronic renal failure treated by continuous ambulatory peritoneal dialysis].

Cerebrovascular and cardiovascular diseases are important predictors for survival in patients undergoing continuous ambulatory peritoneal dialysis (CAPD), and account for about half the deaths in these patients. Lipoprotein(a) [Lp(a)] is known to show high values in diabetics with proteinuria, and albuminuric renal disease. The purpose of this study was to determine Lp(a) levels and to investigate the association of Lp(a) and atherosclerotic risk factors in patients treated by CAPD. Lp(a) concentration were measured in 20 CAPD patients in the age range 31 to 83 years. Mean (+/- SD) levels of serum Lp(a) were elevated in the CAPD patients compared to age, sex matched 17 controls (49.5 +/- 27.7 vs. 15.5 +/- 12.4 mg/dl, p < 0.001). The levels of Lp(a) were significantly higher in the diabetic CAPD patients than in non-diabetics. There were significant positive correlations between serum Lp(a) concentrations and fasting blood sugar. However, when the above two groups were matched for age, sex, body mass index and FBS, Lp(a) concentrations were also significantly higher in CAPD patients than those in normal controls. We found no statistically significant correlations of Lp(a) with either age, body mass index, blood pressure, serum lipoprotein, apoprotein, glycated hemoglobin, BUN, creatinine or serum protein levels. There were no correlations between serum Lp(a) levels and albumin and LP(a) concentrations in the dialysate in all CAPD patients. Along with assessment of other known established cardiovascular risk factors such as elevated blood pressure, atherogenic abnormalities of plasma lipids and lipoproteins, and impaired glucose tolerance, we suggest that elevated levels of Lp(a) may lead to the accelerated atherosclerosis in these patients.

Apoproteins↗
PubMed1993

[Arteriosclerosis obliterans].

Arteriosclerosis obliterans (ASO) has become one of major health problems in the elderly people in Japan. This paper reviews the recent progress in the diagnosis and treatment of ASO. Both medical and surgical treatments, such as atherectomy catheters, endovascular metallic stenting, laser angioplasty and LDL-apheresis have recently been greatly developed. As atherosclerosis is a generalised disease, patients with ASO tend to have other atherosclerotic diseases, i.e., cerebrovascular disease, coronary heart disease and renal vascular disease. For the selection of treatments, we have to consider the whole background of the patients, including a quality of life.

Angioplasty, Laser↗