Biomedical subjects
H Mabuchi
Publications and source records attributed to H Mabuchi.
Serum apolipoproteins in heterozygous familial hypercholesterolemia.
In order to characterize the abnormalities of the lipoprotein profile in familial hypercholesterolemia (FH), serum apolipoprotein AI, AII, B, CII, CIII, and E levels were determined by the turbidimetric immunoassay in 48 patients with heterozygous FH. Apolipoprotein B levels in FH were about 2.5 fold higher (203 +/- 48 mg/dl, mean +/- S.D.) than the 30 age-matched normolipidemic control subjects (84 +/- 13 mg/dl). Significant increments of apolipoprotein CII, CIII, and E levels were observed in FH (4.6 +/- 1.6, 11.0 +/- 3.6 and 6.4 +/- 1.7 mg/dl, respectively) as compared with those in normal subjects (3.0 +/- 0.9, 7.7 +/- 1.6 and 4.5 +/- 1.1 mg/dl, respectively). Apolipoprotein AI and AII levels in FH were 130 +/- 27 and 32 +/- 6.0 mg/dl, respectively, which were not significantly different from the levels in normal subjects (131 +/- 18 and 31 +/- 5.4 mg/dl, respectively). The ratio of low density lipoprotein (LDL) cholesterol to apolipoprotein B was significantly higher in FH (1.3 +/- 0.3) than that in normal subjects (1.2 +/- 0.1). This indicates that the LDL of FH was cholesterol-rich in comparison with that of normal subjects. The ratio of high density lipoprotein (HDL) cholesterol to apolipoprotein AI in FH (0.34 +/- 0.07) was significantly lower than that in normal subjects (0.39 +/- 0.05). This difference might possibly be produced by an abnormal HDL metabolism of FH patients, a topic which remains to be elucidated by further investigation.
Compound heterozygote of cholesteryl-ester transfer protein deficiency in a patient with hyperalphalipoproteinemia.
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Enhanced cholesteryl ester transfer protein activities and abnormalities of high density lipoproteins in familial hypercholesterolemia.
Cholesteryl ester transfer protein may play a role in the cholesteryl ester metabolism between high density lipoproteins (HDL) and apolipoprotein B-containing lipoproteins. To investigate relationship between HDL and cholesteryl ester transfer protein (CETP) activity in the development of atherosclerosis, the present study has focused on CETP activity in the patients with familial hypercholesterolemia (GH). HDL-C and HDL-C/apo A-I mass ratio in heterozygous FH were lower than those in normolipidemic controls. There was a 2-fold increase in total CETP activity in incubated FH serum compared with normolipidemic controls. Assays for CETP activity in the lipoprotein deficient serum (d greater than 1.215 g/ml) were carried out by measuring the transfer of radioactive cholesteryl ester from HDL (1.125 less than d less than 1.21 g/ml) to LDL (1.019 less than d less than 1.060 g/ml). CETP activities in heterozygous FH (79 +/- 4 nmol/ml/h) was significantly higher than those in normolipidemic controls (54 +/- 6 nmol/ml/h). The increased total cholesteryl ester transfer mainly results from increased CETP activity in the d greater than 1.215 g/ml, possibly reflecting an increase in CETP mass in serum. Increased CETP activity in the d greater than 1.215 g/ml was correlated positively with IDL-cholesterol/triglyceride mass ratio (r = 0.496, p less than 0.01), and negatively with HDL-cholesterol/apo A-I mass ratio (r = -0.334, p less than 0.05). These results indicate that the enhanced CETP activities may contribute to increase risk for developing atherosclerosis in FH by changing the distribution of cholesteryl ester in serum lipoproteins.
Effects of metabolic control on ventricular function in type 2 diabetic patients.
The effects of the metabolic changes of type 2 diabetic patients on ventricular function, especially diastolic ventricular function were investigated. An examination was performed before and after treatment of 18 diabetic patients divided into 3 groups: insulin therapy, oral hypoglycemic drugs and diet therapy (6 patients each). The results indicated that both systolic and diastolic ventricular dysfunctions observed were improved by the correction of hyperglycemia. Therefore it is necessary to treat diabetes mellitus as early as possible for the prevention of both cardiac dysfunction and microangiopathy.
Hereditary angioedema complicated with chronic renal failure: report of sibling cases.
Hereditary angioedema (HAE) is known as a deficiency state of C1 inhibitor (C1 INH), an important protease inhibitor protein involved in the complement system. As with other components of the classical pathway of the complement system, a state of its deficiency often causes clinical immunoregulatory disorders. A 45-yr-old brother and a 63-yr-old sister with HAE both developed chronic renal failure, probably due to chronic glomerulonephritis, and required regular hemodialysis. This is, to our knowledge, the first report of sibling cases of HAE associated with chronic renal failure.
[Response of coronary arteries to intracoronary acetylcholine infusion in patients with familial hypercholesterolemia].
Loss of the vasodilator response to acetylcholine (Ach), an endothelium-dependent vasodilator, has been demonstrated in animal models of atherosclerosis and in atherosclerotic coronary arteries of humans studied in vitro. The response of normal coronary arteries on angiograms to the intracoronary injection of Ach in patients with familial hypercholesterolemia (FH) was studied. Ten patients with FH (mean age, 53.6 +/- 6.5 years) with a mean serum total cholesterol of 334.8 mg/dl and 12 controls (mean age, 55.8 +/- 14.5 years) with a total cholesterol level of 183.6 mg/dl, and with normal coronary arteries on angiograms were studied. Patients with clinical histories suggestive of coronary spastic angina were excluded from this study. A bolus of 20, 50 micrograms Ach and 2 mg isosorbide dinitrate (ISDN) were infused into the left coronary artery in each subject. Changes in coronary diameters were measured after each injection with a videodensitometric analysis system. In the control group, the diameter at the middle segments of the left anterior descending artery (LAD) and at the proximal and middle segments of the left circumflex artery (LCX) increased significantly in response to Ach; whereas, in the FH group the diameter at the proximal segments of the LAD decreased significantly. There were significant differences in the coronary diameter changes in response to 50 micrograms Ach at the proximal and middle segments of the LAD and the LCX between the 2 groups. In contrast, between these 2 groups, there were no significant differences in the vasodilator responses to ISDN, a direct vascular smooth muscle dilator. The vasodilator response of coronary artery to Ach was diminished in patients with FH.
Serum lipoprotein lipid concentration and composition in homozygous and heterozygous patients with cholesteryl ester transfer protein deficiency.
Six homozygous, 10 heterozygous and 8 unaffected subjects in a CETP deficient family confirmed by CETP gene analysis were studied to characterize serum lipoproteins separated by ultracentrifugation, and to examine the relations between CETP levels and lipoprotein lipid concentration and composition. The serum CETP levels were measured by radioimmunoassay using 125I-labeled monoclonal antibodies (TP2). The serum CETP levels in the homozygotes were undetectable and those in the heterozygotes were significantly lower than those in the unaffected subjects (1.5 +/- 0.1 vs. 2.2 +/- 0.5 microgram/ml, P less than 0.01). In the HDL fraction, esterified cholesterol (EC) levels in the homozygotes were significantly increased (P less than 0.01), and those in the heterozygotes were slightly increased (n.s.), in comparison with those in the unaffected and the normolipidemic controls. The EC levels in the IDL fractions were lower in the homozygotes than in the normolipidemic controls. The EC/triglyceride (TG) molar ratios in IDL, the fraction obtained from the homo- and heterozygotes, were lower than those from the unaffected subjects (P less than 0.01 and less than 0.01, respectively), and the EC/TG ratios in the HDL fraction obtained from the homo- and heterozygotes were higher than those from the unaffected subjects (P less than 0.01 and n.s., respectively). Linear regression analysis showed that positive correlates of the serum CETP levels in all subjects were: IDL-EC (r = 0.463), HDL-TG (r = 0.603) and VLDL- and IDL-EC/TG ratio (r = 0.698 and 0.843).(ABSTRACT TRUNCATED AT 250 WORDS)
A family of familial hypercholesterolemia with cerebral infarction and without coronary heart disease. An unusual case with corneal opacity, polyneuropathy and carpal tunnel syndrome in the family: therapy with probucol and tocopherol nicotinate.
A study is presented of a 48-year-old female patient and her three siblings with familial hypercholesterolemia. The family members had episodes of cerebral infarction and apparently had atherosclerosis of the internal carotid artery, but no coronary heart disease due to their almost normal level of cholesterol. The laboratory studies of the family members revealed the elevations of serum lipid peroxides, serum lipoprotein(a), leukotriene C4 in blood, the thromboxane B2/6-keto-prostaglandin F1 alpha ratio in plasma and serum hydroxyl radical. Therefore, it is suspected that these factors accelerating atherosclerotic process caused the cerebral infarction. The patient demonstrated corneal opacities, palpebral xanthomas, thickened Achilles tendons, polyneuropathy and the carpal tunnel syndrome. Laboratory studies revealed an elevation in the OKT4/8 ratio, monocyte dysfunction with respect to phagocytosis and chemotaxis, and the presence of the 46XX/45XO mosaic chromosome. Lipid deposits were observed in the Achilles tendon, the transverse carpal ligament, the Schwann's cells and axons of the sural nerve, and in the keratocytes and stroma of the cornea. Following the administration of tocopherol nicotinate and probucol, the patient's serum lipid peroxide normalized and there was improvement in her palpebral xanthomas, thickening of the Achilles tendons and polyneuropathy. We conclude that the lipid deposits in this patient were due to the abnormal oxidative metabolism of low-density lipoprotein and a disturbance of the scavenger pathway due to the monocyte dysfunction.
Effects of aldose reductase inhibitor (ONO-2235) on human erythrocyte sorbitol concentrations in 75 g oral glucose tolerance tests.
In order to evaluate the effects of the aldose reductase inhibitor, ONO-2235, on the short-term response of human erythrocyte sorbitol to hyperglycemia in vivo, eleven diet-treated Type 2 (non-insulin-dependent) diabetic patients were studied twice in 75 g oral glucose tolerance tests - with and without ONO-2235 (200 mg p.o.) premedication. The erythrocyte sorbitol concentrations increased with the increments of blood glucose and erythrocyte glucose concentrations in the test performed without ONO-2235. The erythrocyte sorbitol response in the test performed with administration of ONO-2235 30 min prior to glucose load was lower than that in the test performed without ONO-2235 (F = 5.782, P less than 0.05). No significant differences were found between the two tests in blood glucose and erythrocyte glucose concentrations (F = 0.092, P = 0.761; F = 0.029, P = 0.860, respectively). It is concluded that human erythrocyte sorbitol concentrations change promptly in response to rapid changes in erythrocyte glucose concentrations and that administered ONO-2235 is effective in inhibiting the human erythrocyte sorbitol pathway in man.
[Restriction fragment length polymorphisms in apolipoprotein genes in diabetes mellitus].
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[A large gastric tumor composed of adenoma and carcinoma with rich Paneth cells].
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Familial cholesteryl ester transfer protein deficiency is associated with triglyceride-rich low density lipoproteins containing cholesteryl esters of probable intracellular origin.
The net transfer of core lipids between lipoproteins is facilitated by cholesteryl ester transfer protein (CETP). We have recently documented CETP deficiency in a family with hyperalphalipoproteinemia, due to a CETP gene splicing defect. The purpose of the present study was to characterize the plasma lipoproteins within the low density lipoprotein (LDL) density range and also the cholesteryl ester fatty acid distribution amongst lipoproteins in CETP-deficient subjects. In CETP deficiency, the conventional LDL density range contained both an apoE-rich enlarged high density lipoprotein (HDL) (resembling HDLc), and also apoB-containing lipoproteins. Native gradient gel electrophoresis revealed clear speciation of LDL subclasses, including a distinct population larger in size than normal LDL. Anti-apoB affinity-purified LDL from the CETP-deficient subjects were shown to contain an elevated triglyceride to cholesteryl ester ratio, and also a high ratio of cholesteryl oleate to cholesteryl linoleate, compared to their own HDL or to LDL from normal subjects. Addition of purified CETP to CETP-deficient plasma results in equilibration of very low density lipoprotein (VLDL) cholesteryl esters with those of HDL. These data suggest that, in CETP-deficient humans, the cholesteryl esters of VLDL and its catabolic product, LDL, originate predominantly from intracellular acyl-CoA:cholesterol acyltransferase (ACAT). The CETP plays a role in the normal formation of LDL, removing triglyceride and transferring LCAT-derived cholesteryl esters into LDL precursors.
Increased high-density lipoprotein levels caused by a common cholesteryl-ester transfer protein gene mutation.
BACKGROUND AND METHODS: The plasma cholesteryl-ester transfer protein (CETP) catalyzes the transfer of cholesteryl esters from high-density lipoprotein (HDL) to other lipoproteins. We recently described a Japanese family with increased HDL levels and CETP deficiency due to a splicing defect of the CETP gene. To assess the frequency and phenotype of this condition, we screened 11 additional families with high HDL levels by means of a radioimmunoassay for CETP and DNA analysis. RESULTS: We found the same CETP gene mutation in four families from three different regions of Japan. Analysis of restriction-fragment-length polymorphisms of the mutant CETP allele showed that all probands were homozygous for the identical haplotype. Family members homozygous for CETP deficiency (n = 10) had moderate hypercholesterolemia (mean total cholesterol level [+/- SD], 7.01 +/- 0.83 mmol per liter), markedly increased levels of HDL cholesterol (4.24 +/- 1.01 mmol per liter) and apolipoprotein A-I, and decreased levels of low-density lipoprotein cholesterol (1.99 +/- 0.80 mmol per liter) and apolipoprotein B. Members heterozygous for the deficiency (n = 20), whose CETP levels were in the lower part of the normal range, had moderately increased levels of HDL cholesterol and apolipoprotein A-I and an increased ratio of HDL subclass 2 to HDL subclass 3, as compared with unaffected family members (1.5 +/- 0.8 vs. 0.7 +/- 0.4). CETP deficiency was not found in six unrelated subjects with elevated HDL cholesterol levels who were from different parts of the United States. CONCLUSIONS: CETP deficiency appears to be a frequent cause of increased HDL levels in the population of Japan, possibly because of a founder effect. The results that we observed in heterozygotes suggest that CETP normally plays a part in the regulation of levels of HDL subclass 2. There was no evidence of premature atherosclerosis in the families with CETP deficiency. In fact, the lipoprotein profile of persons with CETP deficiency is potentially antiatherogenic and may be associated with an increased life span.
Separation of albumin-binding ligands present in uremic serum by high-performance affinity chromatography.
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Alterations of lipoprotein(a) in patients with diabetic nephropathy.
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Novel gene mutations at the low density lipoprotein receptor locus: FH-Kanazawa and FH-Okayama.
Gene mutations at the low density lipoprotein (LDL) receptor locus were screened in 210 alleles of Japanese patients with familial hypercholesterolaemia (FH). In the present study, two types of novel mutation were identified by genomic Southern blotting using human LDL receptor cDNA probes. An approximately 12 kb deletion including exons 2 and 3 (and possibly 4) was identified in a patient (M.I.). The patient with this mutant gene will be referred to as 'FH-Kanazawa'. Two patients born in Okayama Prefecture in Japan had another unique 13 kb partial deletion, from exons 7 to 14, in their LDL receptor genes (FH-Okayama). This mutant allele is the first reported case in which the central portion of the LDL receptor gene, the epidermal growth factor (EGF) precursor homology region, is eliminated.
Mutations in the low density lipoprotein receptor gene in Japanese patients with familial hypercholesterolemia.
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