[Clinical studies on hyperlipidemia].
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Acyl Coenzyme A↗
Biomedical subjects
H Mabuchi
Publications and source records attributed to H Mabuchi.
Impact of the expression of cyclin-dependent kinase inhibitor p27Kip1 and apoptosis in tumor cells on the overall survival of patients with non-early stage gastric carcinoma.
BACKGROUND: The expression of p27Kip1 and apoptosis have been implicated in tumor aggressiveness and proved to be prognostic predictors for several human malignancies. In this study, the authors sought to investigate the expression of p27Kip1 and apoptosis and their potential significance in determining the prognosis of patients with non-early stage gastric carcinoma. METHODS: Primary gastric tumor specimens from 225 patients were investigated by immunohistochemistry with anti-p27Kip1 and anti-Ki-67 antibodies, and their apoptotic indices were determined with the use of an Apop-Tag in situ detection kit. RESULTS: The median p27Kip1 labeling index (LI) was 48.4%. There was a significant association between the p27 LIs and the apoptotic indices (Als). However, there was no association between the p27 LIs and the Ki-67 LIs. p27 LI was demonstrated to be one of the most significant and independent prognostic factors in multivariate analysis. Although AI was found to be prognostically significant in univariate analysis, it failed to retain an independent and significant value regarding overall survival in multivariate analysis. CONCLUSIONS: Decreased expression of p27Kip1 and reduction of apoptotic potential were two of the most important factors in predicting a poor prognosis for patients with non-early stage gastric carcinoma. These findings support the hypothesis that decreased p27Kip1 expression, which may reflect a decreased rate of apoptosis, is closely related to the aggressiveness of gastric carcinoma. Therefore, the assessment of p27Kip1 expression and apoptotic potential may prove valuable in identifying patients with gastric carcinoma who are at high risk for recurrence and would benefit from adjuvant therapy.
Adenocarcinoma↗
Analysis of serum lipid levels in Japanese men and women according to body mass index. Increase in risk of atherosclerosis in postmenopausal women. Research Group on Serum Lipid Survey 1990 in Japan.
Relatively low serum lipid levels are thought to be an important factor contributing to the low incidence of ischemic heart diseases (IHD) in Japanese. It has been proven that obesity or overweight constitutes a basal condition for several risk factors in atherosclerosis. The purpose of this study is to obtain data on serum lipids and lipoprotein profiles in relation to body mass index (BMI), which will enable us to compare the nature and weight of metabolic risk factors in atherosclerosis between Japanese and people in Western countries. Data of total serum cholesterol, triglyceride, and HDL-cholesterol levels of Japanese men and women obtained from a large-scale survey in 1990 were analysed according to BMI for different age groups. Apolipoprotein A-I and B and Lp(a) were also measured in randomly selected samples and their contribution as a risk factor was estimated especially in postmenopausal women. The subjects in two age groups of men (20-39 and 40 59 years) and women (20 39 and 50-69 years) were graded into quintiles according to the BMI. The middle grades of BMI were 21.9-23.3 and 22.4-23.6 for younger and older men, and 20.0-21.1 and 22.2-23.6 for younger and older women, respectively. These values are much lower than those in Western populations, the border between the IVth and the top quintile almost corresponding to the average for Americans. Total cholesterol showed a tendency to shift into higher ranges in all age groups in both men and women as BMI increased, with the highest distribution remaining in the range of 160-199 mg/dl (4.2-5.2 mmol/l). The average cholesterol levels for the top quintile of BMI were still lower than most of the average values in Western populations. The distribution of cholesterol in higher ranges was much greater and the difference according to BMI was smaller in older women than in men. In both men and women, whether younger or older, about 90% of the subjects in the lower quintiles of BMI had triglyceride levels lower than 150 mg/dl. The distribution in the higher range of triglyceride was small in women, not only at younger ages but also in postmenopausal women at the top quintile of BMI. About 85% of the younger women with a middle grade of BMI had an HDL-cholesterol level higher than 50 mg/dl. The values in postmenopausal women were still higher than in men aged 40-59 years. Shift of the distribution curves of HDL-cholesterol according to BMI was similar in all groups and more remarkable than the change in triglyceride. The average HDL-cholesterol levels at the top quintile were almost comparable to the average values in Western countries; the difference in HDL-cholesterol levels between the two populations can mostly be explained by the difference in BMI. Smokers showed a slightly lower total cholesterol and significantly (3-4 mg/dl) lower HDL-cholesterol levels, although there was no difference in distribution of BMI between smokers and non-smokers. Relatively low total cholesterol levels even in smokers has probably contributed to the low incidence of IHD in spite of the high frequency of smoking in Japanese population. Mean Lp(a) levels showed a tendency to increase after age 40 in women. BMI itself did not have a correlation with serum Lp(a) levels. The distribution curve of Lp(a) shifted to higher levels as total cholesterol increased and the tendency was most remarkable in women around or after the menopause. It was remarkable in older women that as the total cholesterol or apo B level increased there was also an increased prevalence of abnormal ECG with a pattern of myocardial ischemia. Postmenopausal women seem to have a great risk of atherosclerosis regarding the lipid and lipoprotein profile even in the Japanese population.
Adult↗
Opposite effects on serum cholesteryl ester transfer protein levels between long-term treatments with pravastatin and probucol in patients with primary hypercholesterolemia and xanthoma.
Long-term effects of pravastatin and probucol on serum cholesteryl ester transfer protein (CETP) and xanthoma/xanthelasma size were compared. Twenty-three patients with primary hypercholesterolemia and xanthoma/xanthelasma, including 11 patients with heterozygous familial hypercholesterolemia, were treated with pravastatin (20 mg/day) or probucol (1000 mg/day) for 24 months. Serum CETP levels were measured by sandwich ELISA. In 11 patients (six men and five women, 55 +/- 2 [SE] yr) treated with pravastatin, serum cholesterol levels decreased from 262 +/- 13 to 229 +/- 13 mg/dl during the 24-month treatment period (P = 0.05). Serum HDL cholesterol levels were not changed. Serum CETP levels decreased from 2.5 +/- 0.2 to 2.0 +/- 0.2 microg/ml (-21%, P = 0.002). By contrast, in 12 patients (four men and eight women, 57 +/- 4 year) treated with probucol, serum cholesterol levels did not significantly decrease from 236 +/- 11 to 207 +/- 13 mg/dl. Serum HDL cholesterol levels decreased from 44 +/- 2 to 30 +/- 2 mg/dl (P = 0.009). Serum CETP levels increased from 2.3 +/- 0.1 to 2.8 +/- 0.2 microg/ml (+23%, P = 0.02). Xanthelasma regression was found in two of four patients (50%) each treated with pravastatin and probucol, respectively. In contrast, Achilles' tendon xanthoma regressed in four of five patients (80%) treated with pravastatin, but only in two of five patients (40%) treated with probucol. Patients with xanthoma/xanthelasma regression after 2 years treatment had higher baseline levels of serum CETP than those without regression (2.7 +/- 0.2 microg/ml [n = 9] versus 2.1 +/- 0.2 microg/ml [n = 7], P = 0.05). Serial changes in serum CETP levels during treatment with pravastatin and probucol were discordant, but not related to the degree of xanthoma regression. However, higher level of serum HDL3 cholesterol was an independent factor in the smaller size of Achilles' tendon xanthoma at baseline. In addition, higher levels of serum HDL3 triglyceride on lipid-lowering therapy (6 months) appear to be a common predictor of regression of Achilles' tendon xanthoma in the treatment with either pravastatin or probucol.
Achilles Tendon↗
Clinical evaluation of lymph node metastasis in gastric cancer defined by the fifth edition of the TNM classification in comparison with the Japanese system.
BACKGROUND: This study compared the classification of lymph node metastasis according to the number of involved nodes based on the new tumour node metastasis (TNM) system (fifth edition) with the classification by the Japanese Research Society for Gastric Cancer from an anatomical perspective. METHODS: The two classifications were related to long-term results in 1489 patients with gastric cancer who underwent gastrectomy with systematic extended lymphadenectomy. RESULTS: Both classifications performed well as prognostic indicators (5-year survival rates: pathological (p) N0, 89 per cent; pN1, 66 per cent; pN2, 34 per cent; pN3, nil; and M1, 10 per cent by the TNM classification; n0, 89 per cent; n1, 63 per cent; n2, 46 per cent; n3, 20 per cent; and n4, 8 per cent by the Japanese classification). For regional lymph nodes, the TNM classification was a better index of the prognosis. Significant survival differences were observed among patients with M1 disease according to the number of involved lymph nodes (between one and six nodes, 48 per cent; seven to 15 nodes, 12 per cent; more than 15 nodes, 2 per cent), indicating that patients with distant metastatic lymph nodes (M1) should also be classified by the number of involved nodes. On the other hand, the Japanese classification has the added benefit of being a good indicator of the anatomical extent of lymphadenectomy. CONCLUSION: The new TNM classification provided a better index of the prognosis of patients who underwent systematic lymph node dissection. However, both classifications have specific benefits in the surgical treatment of gastric cancer.
Female↗
Elevated serum levels of soluble membrane cofactor protein (CD46, MCP) in patients with systemic lupus erythematosus (SLE).
Membrane cofactor protein (MCP, CD46) is a cell surface complement regulatory protein which acts as a cofactor for the factor I-mediated cleavage of the activated complement components C3b/C4b. To evaluate the clinical usefulness of serum soluble CD46 as a marker of disease activity in patients with SLE, serum levels of sCD46 were measured by ELISA, using two MoAbs (M160 and M177), each of which recognized two different epitopes on CD46 molecule in SLE, other autoimmune diseases and healthy controls. Serum sCD46 levels in active SLE patients (30.5 +/- 14.1 ng/ml) were significantly higher than those of inactive SLE (5.8 +/- 7.1 ng/ml; P = 0.0003), rheumatoid arthritis (14.9 +/- 11.6 ng/ml; P = 0.0218), primary Sjögren's syndrome (12.3 +/- 11.6 ng/ml; P = 0.0039) and normal controls (7.3 +/- 3.6 ng/ml; P = 0.0005). The elevated serum sCD46 levels in active SLE patients significantly decreased from 30.5 +/- 14.1 ng/ml to 8.0 +/- 6.3 ng/ml after effective corticosteroid and immunosuppressant therapy (P = 0.018). Additionally, we found a significant negative association between increasing concentration of sCD46 and decreasing levels of CH50 in SLE (r = -0.598, P = 0.0009). These results suggest that sCD46 reflects in vivo activation of complement system and provides an additional useful serum parameter of active SLE.
Adolescent↗
LDL apheresis as intensive lipid-lowering therapy for cholesterol embolism.
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Aged↗
Plasma homocysteine level and development of coronary artery disease.
BACKGROUND: The plasma level of homocysteine is an independent risk factor for atherosclerotic vascular disease. The relationship between plasma homocysteine level and the onset of coronary artery disease (CAD) has not been established. OBJECTIVE: To investigate the relationship between plasma homocysteine level and the age at which CAD was diagnosed. METHODS: Fifty-seven male patients aged < or = 65 years (mean age 53 years) with angiographically proven symptomatic CAD seen consecutively and 138 age-matched male control subjects (mean age 52 years) free from atherosclerotic vascular disease were studied. They were divided into two subgroups, a group of younger subjects (aged < or = 55 years) and a group of older subjects (aged 56-65 years). RESULTS: Plasma homocysteine levels in CAD patients significantly exceeded those of control subjects (means 13.4 versus 10.6 nmol/ml, P = 0.0002). Plasma homocysteine level of subjects in younger CAD group was significantly higher than that of subjects in older CAD group (15.0 versus 11.3 nmol/ml, P = 0.03), and age and logarithmically transformed plasma homocysteine level exhibited a significant negative correlation (r = -0.28, P = 0.03) for subjects in CAD group. Among control subjects, members of our two age subgroups had similar plasma homocysteine levels. Younger CAD patients had significantly higher plasma homocysteine levels than did younger controls (15.0 versus 10.4 nmol/ml, P < 0.0001). However, for older groups there was no significant difference between plasma homocysteine levels in CAD patients and controls (11.3 versus 10.9 nmol/ml). Multiple regression analysis showed that only logarithmically transformed plasma homocysteine level was a significant predictor for age of onset of CAD. CONCLUSION: An elevated level of plasma homocysteine is more important in the development of premature CAD than it is in that of late-onset CAD among men.
Adult↗
Therapeutic effects of LDL apheresis in the prevention of atherosclerosis.
The efficacy and safety of the therapeutic tool which directly removes LDL particles from circulation (LDL apheresis) has already been established for cholesterol-lowering in patients with refractory hypercholesterolemia, such as homozygous familial hypercholesterolemia. Several angiographic studies have demonstrated that regular LDL apheresis therapy had favorable effects on the progression of coronary atherosclerosis. Recently, two clinical reports described excellent long-term follow-up results for patients with coronary artery disease who had been treated with LDL apheresis using dextran sulfate cellulose columns plus adjunctive cholesterol-lowering drug therapy. In addition, there is increasing evidence that LDL apheresis is effective for the prevention of extra-coronary atherosclerotic disease, and it is also reported to have the potential to improve microvascular disorders. Since the mechanisms of clinical improvement caused by LDL apheresis extend beyond simple and drastic reduction of LDL cholesterol, further investigation based on recent vascular biological evidence is needed.
Arteriosclerosis↗
Abetalipoproteinemia caused by maternal isodisomy of chromosome 4q containing an intron 9 splice acceptor mutation in the microsomal triglyceride transfer protein gene.
Uniparental disomy (UPD), a rare inheritance of 2 copies of a single chromosome homolog or a region of a chromosome from one parent, can result in various autosomal recessive diseases. Abetalipoproteinemia (ABL) is a rare autosomal recessive deficiency of apoB-containing lipoproteins caused by a microsomal triglyceride transfer protein (MTP) deficiency. In this study, we describe a patient with ABL inherited as a homozygous intron 9 splice acceptor G(-1)-to-A mutation of the transfer protein gene. This mutation alters the splicing of the mRNA, resulting in a 36 amino acids, in-frame deletion of sequence encoded by exon 10. We analyzed chromosome 4, including MTP gene (4q22-24), using short tandem repeat markers. The proband has only his mother's genes in chromosome 4q spanning a 150-centimorgan region; ie, segmental maternal isodisomy 4q21-35, probably due to mitotic recombination. Nonpaternity between the proband and his father was excluded using 6 polymorphic markers from different chromosomes (paternity probability, 0.999). Maternal isodisomy (maternal UPD 4q) was the basis for homozygosity of the MTP gene mutation in this patient.
Abetalipoproteinemia↗
Mechanisms of FK 506-induced hypertension in the rat.
-Tacrolimus (FK 506) is a powerful, widely used immunosuppressant. The clinical utility of FK 506 is complicated by substantial hypertension and nephrotoxicity. To clarify the mechanisms of FK 506-induced hypertension, we studied the chronic effects of FK 506 on the synthesis of endothelin-1 (ET-1), the expression of mRNA of ET-1 and endothelin-converting enzyme-1 (ECE-1), the endothelial nitric oxide synthase (eNOS) activity, and the expression of mRNA of eNOS and C-type natriuretic peptide (CNP) in rat blood vessels. In addition, the effect of the specific endothelin type A receptor antagonist FR 139317 on FK 506-induced hypertension in rats was studied. FK 506, 5 mg. kg-1. d-1 given for 4 weeks, elevated blood pressure from 102+/-13 to 152+/-15 mm Hg and increased the synthesis of ET-1 and the levels of ET-1 mRNA in the mesenteric artery (240% and 230%, respectively). Little change was observed in the expression of ECE-1 mRNA and CNP mRNA. FK 506 decreased eNOS activity and the levels of eNOS mRNA in the aorta (48% and 55%, respectively). The administration of FR 139317 (10 mg. kg-1. d-1) prevented FK 506-induced hypertension in rats. These results indicate that FK 506 may increase blood pressure not only by increasing ET-1 production but also by decreasing NO synthesis in the vasculature.
Animals↗
Genetic analysis of aldosterone synthase in patients with idiopathic hyperaldosteronism.
Idiopathic hyperaldosteronism (IHA) is characterized by hypertension with excessive production of aldosterone, potassium loss, and suppression of the renin-angiotensin system. We compared activity of aldosterone synthase and expression of CYP11B2 messenger RNA (mRNA) in mononuclear leukocytes (MNL) from patients with IHA to findings in leukocytes from patients with aldosterone-producing adenoma and normal controls. Aldosterone synthase activity was estimated from conversion of [14C]deoxycorticosterone to [14C]aldosterone. Levels of CYP11B2 mRNA were determined by competitive PCR. In the same subjects, we sought the chimeric CYP11B1/CYP11B2 that is candidate gene for glucocorticoid-remediable hyperaldosteronism. Southern blot analysis and a long PCR method were used to detect the chimeric gene. Direct sequencing of the CYP11B2 also was performed. No chimeric genes or mutations in the coding region of the CYP11B2 were found in genomic DNA from these patients. However, both aldosterone synthase activity and CYP11B2 mRNA expression were greater in mononuclear leukocytes of patients with IHA than those of patients with aldosterone-producing adenoma or controls. These results suggest that regulatory factors of the CYP11B2 gene, e.g. unidentified aldosterone-stimulating substances or abnormalities in the promoter region of the CYP11B2 gene in patients with IHA resulting in oversecretion, may cause overexpression of mRNA of CYP11B2.
Adenoma↗
Long-term efficacy of low-density lipoprotein apheresis on coronary heart disease in familial hypercholesterolemia. Hokuriku-FH-LDL-Apheresis Study Group.
Familial hypercholesterolemia (FH) is characterized by severe hypercholesterolemia and premature coronary heart disease (CHD). The lower the plasma cholesterol level, the more likely it is that CHD can be prevented or retarded; aggressive cholesterol-lowering therapies may be indicated for FH patients with CHD. This study describes the long-term (6 years) safety and efficacy of intensive cholesterol-lowering therapies with low-density lipoprotein (LDL) apheresis in heterozygous FH patients with CHD. One hundred thirty heterozygous FH patients with CHD documented by coronary angiography had been treated by cholesterol-lowering drug therapy alone (n=87) or LDL apheresis combined with cholesterol-lowering drugs (n=43). Serum lipid levels and outcomes in each treatment group were compared after approximately 6 years. Both treatment groups had significant reductions in serum cholesterol, LDL cholesterol, and high density lipoprotein cholesterol levels. LDL apheresis significantly reduced LDL cholesterol levels from 7.42+/-1.73 to 3.13+/-0.80 mmol/L (58%) compared with group taking drug therapy, from 6.03+/-1.32 to 4.32+/-1.53 mmol/L (28%). With Kaplan-Meier analyses of the coronary events including nonfatal myocardial infarction, percutaneous transluminal coronary angioplasty, coronary artery bypass grafting, and death from CHD, the rate of total coronary events was 72% lower in the LDL-apheresis group (10%) than in drug therapy group (36%) (p=0.0088). It is concluded that LDL-apheresis is effective as treatment of CHD in FH heterozygotes, and may become the therapy of choice in severe types of FH.
Aged↗
Clinical efficacy and safety of cerivastatin in the treatment of heterozygous familial hypercholesterolemia.
Patients with heterozygous familial hypercholesterolemia are at especially high risk of premature coronary artery disease and usually require aggressive long-term lipid-lowering drug therapy to decrease plasma low-density lipoprotein (LDL) cholesterol concentrations to normal levels. In the present study, the lipid-lowering effects of cerivastatin in combination with cholestyramine and probucol were investigated in 20 patients with heterozygous familial hypercholesterolemia over a 20-week treatment period. After an initial 4-week treatment with once-daily 0.2 mg cerivastatin, serum total cholesterol and LDL cholesterol levels had decreased by a significant 22% and 25%, respectively (p <0.01). The addition of 8 g/day cholestyramine or 1 g/day probucol to ongoing cerivastatin therapy produced further significant reductions in total cholesterol of 16% and 16%, respectively, and in LDL cholesterol of 22% and 15%, respectively (p <0.01), over the 12-week combination therapy period. The potent lipid-lowering effects of combined treatment were accompanied by excellent toleration of study drugs. Only 2 patients experienced gastrointestinal side effects associated with cholestyramine therapy. There was no evidence of any abnormalities in creatine phosphokinase in either treatment group and only 2 patients exhibited minor increases in hepatic transaminases. This study has shown that cerivastatin can be safely combined with either cholesytramine or probucol to provide a safe and highly effective hypolipidemic treatment regimen for patients with heterozygous familial hypercholesterolemia.
Adult↗
Low-density lipoprotein receptor genotype-dependent response to cholesterol lowering by combined pravastatin and cholestyramine in familial hypercholesterolemia.
We compared the effects of cholesterol-lowering therapy on 2 patient groups genetically defined as heterozygous for familial hypercholesterolemia (FH), 5 with a deletion of exon 15 (FH(Tonami-1)), and 7 with a point mutation at codon 664 (FH(Kanazawa-2)). There were significant differences in both serum and low-density lipoprotein cholesterol reductions between the 2 groups after combination therapy with pravastatin and cholestyramine, and the overall effect of genotype on serial changes in both was significant.
Adult↗
[Hyperlipidemia and arteriosclerosis].
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Anticholesteremic Agents↗
Enzyme immunoassay for cholesteryl ester transfer protein in human serum.
We developed a new simple sandwich-type enzyme immunoassay to measure cholesteryl ester transfer protein (CETP) mass in human serum. In assay validation, Intra- and Inter-assay coefficients of variation were 2.7 to 5.7% and 2.2 to 12.2%, respectively. There was no cross-reactivity with various lipoproteins (apo A-I, apo A-II, apo B, apo C-III). A good correlation between CETP mass and CETP activity (n = 46, correlation coefficient = 0.88) was observed. This assay provided a specific and reproducible method for measuring CETP mass in samples. The average value of CETP in the normal sera of 41 males was 1.8+/-0.6 microg/ml (mean+/-S.D.) and that of 37 females was 2.0+/-0.5 microg/ml. In the study of patients with the CETP gene mutation (Int 14A and D442G), our results on the value of plasma CETP mass reflected to genetic CETP deficiency. In conclusion, this assay for CETP mass in human serum may be a useful tool for clinical investigations involving lipid metabolism related to disease.
Adult↗
Fatal cardiac beta2-microglobulin amyloidosis in patients on long-term hemodialysis.
We report two long-term hemodialysis patients who developed severe congestive heart failure attributable to cardiac heavy amyloid deposition. Both patients became hypotensive during dialysis sessions, gradually making it difficult to continue hemodialysis, and they died of congestive heart failure. At autopsy, left ventricle walls in each case contained diffuse extensive deposits of amyloid. The distribution of amyloid was not localized to vessel walls but was widely disseminated throughout the left ventricle walls and replaced myocardial muscle fibers. Immunohistochemical examination showed positive staining for anti-human beta2-microglobulin antibody. We conclude that cardiac dialysis-related amyloidosis should also be considered in long-term hemodialysis patients with congestive heart failure as a life-threatening complication.
Amyloidosis↗