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We investigated the effects of subclasses of plasma LpA-I (HDL containing apoA-I but not apoA-II) on cholesterol esterification in plasma and net cholesterol efflux from foam cells. LpA-I was composed of particles of three diameters: large (11.1 nm; Lg-LpA-I), medium (8.8 nm; Md-LpA-I), and small (7.7 nm; Sm-LpA-I). Plasma concentrations of LpA-I were positively correlated only with the level of Lg-LpA-I. Plasma concentrations of Lg-LpA-I were inversely correlated with the rate of cholesterol esterification in plasma and VLDL- and LDL-depleted plasma. Plasma concentrations of Md-LpA-I and Sm-LpA-I did not correlate with the rate of cholesterol esterification in plasma or VLDL- and LDL-depleted plasma. When macrophage foam cells were incubated with Md- and Sm-LpA-I, cellular cholesterol mass was reduced by approximately 70%. In contrast, the cellular cholesterol-reducing capacity of Lg-LpA-I was negligible. Lg-LpA-I inhibited net cholesterol removal from foam cells that was mediated by Md- and Sm-LpA-I and cholesteryl ester production with these particles. These results suggest that Md- and Sm-LpA-I may actively participate in cellular cholesterol removal and cholesterol esterification in plasma and HDL, while Lg-LpA-I may regulate these functions of Md- and Sm-LpA-I.

The combined effects of pravastatin and probucol on high- density lipoprotein (HDL) apolipoprotein (apo) A-I kinetics in cholesterol (Ch)-fed rabbits were investigated. Japanese White rabbits were treated with 0.15% pravastatin and 0.5% Ch (group 1) or 0.15% pravastatin plus 1% probucol and 0.5% Ch (group 2) for 2 months. After treatment, the serum total cholesterol levels in groups 1 and 2 had significantly (p < 0.01) increased (37.4 +/- 6.7 mg/dl vs 117.1 +/- 46.4 mg/dl, and 31.4 +/- 4.9 mg/dl vs 143.0 +/- 84.5 mg /dl, respectively). The serum HDL-cholesterol levels in both groups decreased (18.2 +/- 2.8 mg/dl, vs 16.2 +/- 3.7 mg/dl p < 0.01 for group 1; 18.2 +/- 1.9 mg/dl vs 15.5 +/- 4.5 mg/dl, ns for group 2). Apo A-I kinetics were assessed by injecting (125)I-labeled HDL intravenously into both groups of rabbits, and taking blood samples periodically for 6 days. Kinetic parameters calculated from apo A-I specific radioactivity decay curves showed that the apo A-I fractional catabolic rates in rabbits fed pravastatin and Ch (group 1) were significantly less than those in rabbits fed pravastatin plus probucol and Ch (group 2) (0.546 +/- 0.017 /day vs 0.730 +/- 0.126 /day, p < 0.05), while the synthetic rate of apo A-I was lower in group 2 than in group 1 (14.76 +/- 1.71 mg/kg per day vs 11.21 +/- 2.38 mg/kg per day, respectively, p < 0.01). These data indicate that pravastatin and probucol have different effects on HDL-apo A-I kinetics in a diet which includes cholesterol.

The effects of the administration of slow-release bezafibrate to hypercholesterolaemic patients who were already receiving long-term probucol treatment (mean 865 days, 500-1000 mg.day-1) were investigated. Bezafibrate was administered at either 200 mg.day-1 (13 males, 13 females, mean age 55.2 years) or 400 mg.day-1 (11 males, 14 females, mean age 57.2 years), and blood was taken at 0, 3, 6 and 12 months after the beginning of combination therapy. Overall, serum total cholesterol (TC), triglyceride (TG), very low density lipoprotein (VLDL)-TC, high-density lipoprotein (HDL)-TG, VLDL-TG, VLDL-phospholipid (PL), lipoprotein (a) [Lp(a)], apolipoprotein (apo) C-III, apo E levels and LCAT activity decreased significantly with this combination therapy, while HDL cholesterol (C), HDL3-C, HDL-PL, apo A-I and apo A-II levels significantly increased, as assessed by analysis of variance (ANOVA). Five patients (one receiving 200 mg.day-1, four receiving 400 mg.day-1 bezafibrate) showed drastic reductions in HDL-C (HDL-C levels were reduced by a mean of 46.2%, 59.3% and 61.6% at 3, 6 and 12 months, respectively) after beginning combination therapy. These HDL-C reductions were maintained for the 1 year of combination therapy, but then returned to pre-combination treatment levels 1 month after discontinuation of bezafibrate. Serum probucol concentrations and cholesteryl ester transfer protein (CETP) mass were assayed at 6 months, and the probucol concentration was higher in the HDL-deficient group (56.2 vs 26.5 micrograms/ml). In contrast, CETP mass was significantly lower in HDL-deficient patients than in non-HDL-deficient patients (2.08 vs 2.87 mg.1-1)(ABSTRACT TRUNCATED AT 250 WORDS)

Several studies have reported that a variant allele (S2) of the apolipoprotein (apo) A-I/C-III/A-IV complex is associated with hyperlipoproteinemia in some populations and that the frequency of this allele is two- to fivefold higher in patients with premature coronary heart disease (CHD) than in healthy controls. In the present study in a Japanese population, we were unable to confirm the association of the S2 allele with either coronary heart disease or elevated serum apo C-III levels, as has been previously reported in Caucasians. No genotype difference was observed among the severity of coronary heart disease, as determined by the number of involved vessels (one, two and three vessel disease), compared to controls. In addition, the frequency of the S2 allele among Japanese, in both CHD (0.328) and controls (0.369), was quite different from that in many other populations.

Tangier disease, a familial HDL-deficiency syndrome, was first reported by Fredrickson et al. in 1961. Since then, a great deal research on the mechanism of HDL-deficiency in this disease has been done from the prospective of lipoprotein compositions, in vivo HDL kinetics, cell and receptor interactions and genomic DNA analysis. These studies have found a relatively increased fractional catabolic rate of apo HDL with essentially no change in the synthesis of apo HDL. As yet, no structural defect has been found in the apo A-I gene. However, there have been reports of irregular lipid metabolism and of disorders in the Golgi apparatus and lysosome processing. Interestingly, the frequency of coronary heart disease is low in patients with Tangier disease. In this report, we describe the clinical and biochemical characteristics of Tangier disease and suggest some possible mechanisms for preventing coronary heart disease.

Lp-A-I was isolated by immunoaffinity chromatography and then separated into two fractions of large and small Lp-A-I particles by conventional ultracentrifugation with a cut-off density of 1.125 g/ml. The large and small particle-rich fractions were then radiolabeled with [125I]-Na and [131I]-Na, respectively. Both of the labeled lipoproteins were injected (20 microCi, i.v.) simultaneously into normolipidemic rabbits. The FCR of the large Lp-A-I particles was much less than that of the small Lp-A-I particles (0.801 +/- 0.026/day vs. 2.227 +/- 0.067/day, P < 0.0001). These data indicate that the two particles have distinctly different metabolic pathways and that the lower FCR of larger Lp-A-I particles can effectively raise plasma HDL levels.

A great deal of evidence suggests that insulin resistance, via hyperinsulinemia, contributes to hyperlipoproteinemia and coronary atherosclerosis. When Watanabe heritable hyperlipidemic (WHHL) rabbits, an animal model of familial hypercholesterolemia (FH), are compared with normolipidemic Japanese White (JW) rabbits, an elevated fasting plasma insulin level and a heightened plasma insulin response to an intravenous (i.v.) glucose challenge are found. To elucidate the mechanism behind this phenomenon, a two-compartment model of the glucose/insulin system was fitted to empirical time courses of glucose and insulin concentrations during an i.v. glucose tolerance test (IVGTT) by nonlinear least-square regression, and the model parameters such as the glucose utilization rate constant, insulin degradation rate constant, and pancreas sensitivity were determined. WHHL rabbits showed decreased values of glucose utilization and insulin degradation rate constants and slightly higher values of pancreas sensitivity. This suggests that insulin resistance occurs in extrapancreatic tissues, and that this may be attributable to insulin receptor and/or post-insulin receptor abnormalities. Cholesterol feeding did not significantly change glucose tolerance or insulin action in JW rabbits. The effects of an angiotensin-converting enzyme (ACE) inhibitor, cilazapril, on insulin resistance were also examined in WHHL and JW rabbits. A decreased insulin response to an i.v. glucose challenge and increased glucose utilization and insulin degradation rate constants were observed in WHHL rabbits that had been treated with cilazapril, indicating that cilazapril improved insulin resistance in WHHL rabbits, possibly by increasing the number of insulin receptors. No significant differences were found in glucose tolerance and insulin action in JW rabbits before and after cilazapril administration.(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of the addition of a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, simvastatin, to the medium on sterol synthesis and phosphatidylcholine (PC) synthesis were studied in HepG2 cells. The cells were cultured with simvastatin at concentrations of 10(-7) and 10(-6) mol/L for 6 hours, and radioactive lipid precursors were added 1 hour before harvesting. Simvastatin inhibited cholesterol synthesis from [14C]acetate in a dose-dependent manner. It also decreased the incorporation of [14C]choline into PC by 30%; this decrease was accompanied by a decrease in phosphocholine cytidylyltransferase activity in cell homogenates. Simvastatin had no significant effects on the incorporation of [3H]glycerol into phospholipids. These data indicate that simvastatin has two different functions: inhibition of HMG-CoA reductase and depression of de novo synthesis of PC via the cytidine diphosphate-choline pathway, which, in turn, may result in a decrease in plasma lipid levels.

We recently investigated the in vivo conversion of recombinant human proapolipoprotein A-I (rh-Met-proapo A-I) from E. coli to apolipoprotein (apo) A-I in rabbits. In vitro incubation of rh-Met-proapo A-I with rabbit serum produced mature apo A-I3 isoproteins, as determined by the immunoblotting method. However, at the time we were unable to chemically confirm a newly produced protein band which appeared at the position of human apo A-I3. Since then, we have confirmed the amino acid sequence of the protein using a membrane protein sequence technique, and have concluded that it corresponds to human apo A-I3.

We studied the quantitative and qualitative characteristics of lipoprotein(a) [Lp(a)] as a function of apolipoprotein(a) [apo(a)] phenotypes in 152 patients (123 males, 29 females) undergoing maintenance hemodialysis (HD) with or without diabetes mellitus (DM), in 101 patients with diabetes mellitus without hemodialysis (58 males, 43 females), and in 421 normal controls (333 males, 88 females). Serum Lp(a) levels were significantly (P < 0.01) higher in patients than in controls (26.2 +/- 18.3 mg/dl in HD with DM, 26.4 +/- 22.0 mg/dl in HD without DM, 27.1 +/- 27.3 mg/dl in DM without HD, and 14.9 +/- 13.7 mg/dl in controls, respectively). Apo(a) phenotyping was performed by a sensitive, high resolution technique using SDS-agarose/gradient (3 to 6%) PAGE. In normal controls, the molecular weights of apo(a) isoforms were inversely correlated with plasma Lp(a) levels, and the same tendency was found in patients who were undergoing hemodialysis and/or who had diabetes mellitus. We assumed the differences in apo(a) phenotypes detectable with our method reflected consecutive differences in molecular weights of apo(a). The results of an analysis of covariance and a least square means comparison indicated that the regression lines between serum Lp(a) levels [log Lp(a)] and apo(a) phenotypes in patient groups were significantly (P < 0.01) elevated for every apo(a) phenotype, as compared to the regression line of the control group. Even after the low molecular weight apo(a) phenotypes (A1-A8) were omitted, the same tendency was observed. However, no differences were observed between the patient groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Two novel frameshift mutations were detected in the mutant LDL receptor genes responsible for familial hypercholesterolemia. One was a 5-bp insertion at codon 395 in exon 9, and the other was a one nucleotide deletion at codon 531 in exon 11. Both mutations alter the reading frame and consequently produce a premature stop codon in the region of the mature LDL receptor homologous to the epidermal growth factor (EGF) precursor. With regard to the mechanism responsible for the generation of these frameshift mutations, strand slipped mispairing mediated by short direct repeats is considered to be the most likely. The findings seem to support the hypothesis that a short direct repeat in DNA sequence can have a profound influence on the stability of a given gene and promote human gene mutations.

In a population of Japanese subjects, we surveyed codon 347 of the apolipoprotein (apo) A-IV gene and found that the frequency of a rare allele at this point was extremely low compared to that in western populations. Only one of 850 unrelated samples showed mutation at the enzyme recognition site by agarose gel electrophoresis. However, direct sequencing of the coding region revealed that it did not result from the ACT (Thr) to TCT (Ser) mutation which has been reported in western countries, but from an ACT to ACG (Thr) mutation, which does not affect the primary structure of apo A-IV. Two additional family members showed the same point mutation at codon 347.

In vivo kinetics of lipoprotein(a) [Lp(a)] were investigated in homozygous Watanabe heritable hyperlipidaemic (WHHL) rabbits (an animal model of familial hypercholesterolemia (FH)), and in normolipidemic Japanese White rabbits (controls). 125I-labelled Lp(a) and 131I-labelled LDL were simultaneously injected intravenously. Blood samples were then taken periodically. Kinetic parameters were calculated from the plasma radioactivity decay curves. The fractional catabolic rates (FCRs) of both Lp(a) and LDL (1.355 +/- 0.189 pools per day and 1.278 +/- 0.397 pools per day, respectively) in the WHHL rabbits were significantly (P < 0.005) smaller than those in the control rabbits (2.008 +/- 0.083 pools per day and 2.855 +/- 0.759 pools per day, respectively). In WHHL rabbits, the FCRs of Lp(a) and LDL were similar. However, in control rabbits, the FCR of Lp(a) was significantly (P < 0.01) smaller than that of LDL. In WHHL rabbit organs, the mean ratio of 125I-Lp(a): 131I-LDL, 48 h after injection, normalized to the corresponding isotope ratio in plasma, were 1.525, 1.020, 1.819 and 1.967, in liver, kidney, spleen and bile, respectively. These values were significantly higher than the corresponding values in control rabbits (0.590, 0.677, 0.862 and 0.766, respectively). Our data strongly suggest that Lp(a) clearance is not entirely dependent upon LDL receptors and may be mediated by some other mechanisms.

The kinetics of oxidatively modified high-density lipoprotein (HDL) in vivo were investigated. 125I-labeled oxidized (Ox) HDL and 131I-labeled native (N) HDL were injected simultaneously into control and WHHL rabbits. The fractional catabolic rates of 125I-labeled Ox-HDL were significantly greater than those of 131I-labeled N-HDL in both control (2.52 +/- 0.36/day vs 0.94 +/- 0.02/day) and WHHL rabbits (4.07/day vs 1.32/day). Oxidized HDL was catabolized faster than native HDL and was taken up primarily by the liver, spleen, and kidney.

In oriental medicine there is a hypothesis related to acupuncture that the auricle is a projection of the functional anatomy of the whole human body. In this study reactive electropermeable points (REPP), that is, points on the skin with low electrical resistance, on the auricle were measured on patients with coronary heart disease using a neurometer LC-M. Our findings correlated positively with the particular points--heart I (shin) and heart II (shinzo)*--named by the Chinese group as being related to the functional anatomy of the heart. The incidence of positive REPP test results at the shin and shinzo points for subjects with acute myocardial infarction (AMI) were extremely high, and positive test results for patients with old myocardial infarction (OMI) and angina pectoris (AP) were also significant. There was no significant difference in the incidence rates of REPP at the shin and shinzo points between the OMI and AP groups. High incidence of positive REPP test results at the lung and heart III (shinyu) points occurred only in the AMI group, and this was significantly high when compared with the control group.

In vivo conversion of recombinant human proapolipoprotein AI (rh-Met-proapo AI) from E. coli to apolipoprotein (apo) AI was investigated. rh-Met-proapo AI was labeled with 125I, and then administered intravenously to rabbits. Blood was sampled periodically for 6 days. The plasma decay curves of radioiodinated rt-Met-proapo AI were similar to those of human mature apo AI (fractional catabolic rate (FCR); 1.018 +/- 0.090/day vs. 0.976 1 0.031/day, respectively). In vivo conversion of rh-Met-proapo AI to mature apo AI was examined by autoradiography of the isoelectric focusing (IEF) slab gel, i.e., the HDL fraction from each sampling point was semiquantitatively applied to IEF. It was found that the radioactivity of rh-Met-proapo AI migrated to more acidic isoproteins, the conversion was complete within 24 h, and the FCR of rh-Met-proapo AI was 9.20 +/- 1.34/day. Although the plasma decay curves of both human pro (rh-Met-proapo AI) and mature apo AI were significantly steeper than those of rabbit mature apo AI4 and apo AI5 (FCR; 0.703 +/- 0.027/day and 0.795 +/- 0.031/day, respectively), the conversion rate of human rt-Met-proapo AI to mature apo AI in rabbit was assumed to be 1:1. In vitro incubation of rh-Met-proapo AI with rabbit serum produced mature apo AI isoproteins, as determined by the apo AI immunoblotting method. Prediction of the amino acid sequence at the NH2 terminus of rabbit proapo AI showed that the prosegment consisted of an alpha helix with a high probability of a beta turn at Pro9, which is close to that in humans. Thus, (1) the proteolytic cleavage of proapo AI is an extracellular event, (2) the converting enzyme in rabbits can also process human proapo AI, (3) this converting enzyme does not specifically and directly attack the Gln6-Asp7 bond which links the carboxyl-terminal residue of the hexapeptide to the amino-terminal residue of human mature apo AI. The conformation of proapo AI at the NH2 terminus (alpha helix of the prosegment and a beta turn at Pro9) may have a key role in this cleavage, and (4) the examination of rh-Met-proapo AI in rabbits helps to explain the early events of HDL biogenesis.

To further understand lipoprotein (a) [Lp(a)] and atherosclerosis, we measured serum Lp(a), lipoprotein, and apolipoprotein levels in 55 patients (males, 24-73 years old) on maintenance hemodialysis, and compared them with those of 82 controls (males, 21-81 years old). The serum Lp(a) levels in patients on maintenance hemodialysis were significantly higher than those of the normal controls, while serum total cholesterol (TC), high-density lipoprotein-cholesterol, (HDL-C), HDL2-C, HDL3-C, apolipoprotein (apo) Al, apo All levels, and lecithin-cholesterol acyltransferase (LCAT) activities were significantly (p < 0.05) reduced in the patient group. The frequency distribution of serum Lp(a) levels in the patients was different from that in the control group, and no prognostic tendency of serum Lp(a) levels was noted by the etiology of renal failure as histologically determined by the renal biopsies. In the patient group, we also found that serum Lp(a) levels negatively correlated with serum triglycerides (TG) and total protein (TP) concentrations (p < 0.05), but no correlation was found between the duration of hemodialysis therapy or patient age and the serum levels of TC, TG, apo B and Lp(a) levels when tested for simple regression. Significant (p < 0.05) positive correlations were also found between TP and serum TG, apo B, and LCAT activities. These opposing tendencies of Lp(a) and serum TG, apo B, when measured against TP concentrations, indicate that serum TP levels may not affect serum lipoprotein and Lp(a) levels in the same direction. These data suggest that hemodialysis or end-stage renal disease itself, rather than hypoproteinemia, may hold the key to high serum Lp(a) levels in hemodialysis patients.

Electrocardiographic QTc intervals were measured in twenty-one hypercholesterolemic patients before and after long-term probucol (500-1,000 mg/day for 30 months) treatment. Probucol reduced serum total cholesterol (TC), triglyceride (TG), and high density lipoprotein-cholesterol (HDL-C). Mean QTc interval prolongation after probucol was 17 msec. A positive correlation was found between the change in QTc interval after probucol (delta QTc) and the total amount of probucol administered. delta QTc was negatively correlated to the pre-treatment QTc interval. No correlation was observed between serum probucol concentrations and delta QTc. Neither clinical evidence of cardiotoxicity nor critical arrhythmias were noted during the treatment period.

The effect of co-administration of low doses of pravastatin to hypercholesterolaemic patients already receiving long-term probucol treatment (mean 500-1,000 mg/day for 350 days) were investigated. Pravastatin 5 mg/day (Group 1; 12 m, 13 f; mean age 59.1 y) or 10 mg/day (Group 2; 8 m, 11 f; mean age 60.8 y) was administered, and blood was taken after 0, 3, 6, and 12 months. Both groups showed a significant reduction in serum total cholesterol (TC), phospholipid (PL), low density lipoprotein-cholesterol (LDL-C), LDL-triglyceride (TG), LDL-PL, apolipoprotein (apo) B, and apo E after the combined therapy. These levels were reduced more in Group 2 than in Group 1 subjects. In Group 2, significant falls in serum TG and apo CII were also observed. The changes in TC, PL, LDL-C, apo B, apo CII and apo E were dependent upon the dose of pravastatin, as assessed by two-way analysis of variance. Serum high density lipoprotein (HDL)3-C, apo AI and apo AII were slightly but significantly increased in both groups after 12 months of combined therapy, but the increase was not sufficient to reverse the probucol-induced lowering of the HDL level. We conclude that combined therapy resulted in a significant reduction in atherogenic lipoproteins and apolipoproteins, and an increasing dose of pravastatin (5 mg to 10 mg daily) made the lipid lowering effect more prominent. The reduction in serum HDL-C due to long-term probucol administration was not reversed by the addition of pravastatin.

Forty-five patients with mild to moderate essential hypertension were randomly assigned to receive 10 to 40 mg of manidipine HCl or 15 to 60 mg of delapril daily for 12 months. In the manidipine-treated group were 13 women and 5 men (mean age, 48.2 years) and in the delapril-treated group 11 women and 11 men (mean age, 53.7 years). Blood samples were taken at baseline and after 6 and 12 months of treatment and again at 2 months after treatment discontinuation. Significant reductions in blood pressure were observed in both treatment groups. The reduction in diastolic blood pressure was significantly greater in the manidipine-treated patients than in the delapril-treated patients; no significant between-groups differences in systolic blood pressure were noted. Heart rate increased significantly in the manidipine group. No changes in serum levels of total cholesterol, triglycerides, and high-density and low-density lipoprotein cholesterol were noted during or after treatment. In the manidipine group, a small but significant decrease in apolipoprotein (apo) A-I and an increase in lipoprotein(a) were found at 6 months and a significant increase in apo A-II and apo E at 12 months; in the delapril group a significant decrease in apo A-I was found at 6 months. The results indicate that both manidipine and delapril are lipid-neutral antihypertensive drugs, since neither drug greatly affected serum lipid metabolism.

We investigated the effects of the traditional Chinese herbal drugs, Dai-saiko-to (D) and Saiko-ka-ryukotsuboreito (S) on blood pressure, pulse rates, serum lipids, lipoproteins and apolipoproteins in 30 patients with mild to moderate hypertension in an open, randomised trial. After the drug treatment, BP remained unchanged, but pulse rates declined significantly after 3 months in the S treated group. Serum total cholesterol and triglyceride values did not change, but high density lipoprotein-cholesterol increased significantly (P < 0.05) in both groups. Apo-AI (P < 0.1 in S group) and apo-AII (P < 0.05 in D group, P < 0.1 in S group) tended to increase 3 months after treatment. These data indicate that both of these traditional Chinese medicines have a preferential effect on lipid metabolism with little antihypertensive action.

Fifty-six hypertensive patients were recruited to participate in a 12 week, randomised, multicentre trial to compare the effects of lisinopril (n = 31) and low-dose trichlormethiazide (n = 25) administration on blood pressure and lipoprotein metabolism. Both systolic and diastolic BPs decreased significantly after administration of lisinopril (5-40mg/day, mean dose 11 mg/day) and trichlormethiazide (2.0-4.0 mg/day, mean dose 2.2 mg/day). There were no significant changes in lipids, lipoproteins or apolipoproteins with either drug for 12 weeks and no significant differences between the two drugs for these parameters. It is concluded that lisinopril and low-dose trichlormethiazide administration are effective antihypertensive measures without any adverse effects after 12 weeks on lipoprotein metabolism in patients with mild to moderate essential hypertension.

The subjects were 61 healthy volunteers who received 15 gm of polydextrose daily for two months. A significant increase in the incidence of soft feces and diarrhea and in the volume of feces was reported during polydextrose treatment. These had returned to normal one month after treatment. Serum levels of total cholesterol, triglycerides, and low-density lipoprotein cholesterol did not change during treatment. Levels of apolipoprotein (apo) A-I and A-II were significantly lowered at one month and high-density lipoprotein cholesterol (HDL-C) and apo A-I were significantly decreased at two months; these returned to normal after treatment. Levels of HDL2-C decreased and HDL3-C levels increased significantly during treatment. The results indicate that polydextrose selectively affected the metabolism of HDL and its major proteins, apo A-I and A-II.

To assess the relationship between relatively severe hereditary hypercholesterolemia with Achilles tendon xanthomas and the defect of the low density lipoprotein (LDL) receptor gene, family studies were carried out in 17 hypercholesterolemic families. In 16 out of the 17 families, hypercholesterolemia co-segregated with four different gross rearrangements, six different restriction fragment length polymorphism (RFLP) haplotypes, or an abnormal TaqI band of the LDL receptor gene. These findings are compatible with the interpretation that hypercholesterolemia is caused by defective LDL receptor genes, and that the origin of the mutant LDL receptor genes in Japanese generally differs among different pedigrees. In the remaining family, the proband and his sibling, both having relatively severe hypercholesterolemia and Achilles tendon xanthomas, shared an RFLP haplotype, although the proband's other sibling with moderate hypercholesterolemia but without Achilles tendon xanthomas did not. The mutant gene for familial defective apolipoprotein B-100 was not detected in the 17 probands. These data suggest that most, if not all, of the relatively severe hereditary hypercholesterolemia associated with Achilles tendon xanthomas is caused by a defect of the LDL receptor gene.

Plasma high density lipoproteins (HDL) and their major proteins--apolipoprotein (apo) AI and apo AII--are subnormal in most patients with familial hypertriglyceridemia. However, the pathophysiology of low plasma apo AI and apo AII is unclear. The kinetic parameters (turnover) of HDL apo AI and apo AII were studied in six lean patients with primary HDL deficiency associated with familial hypertriglyceridemia and normolipidemic healthy controls. The radioactivity decay curve of 125I labelled HDL was used for assessment of kinetics. Mean plasma apo AI and apo AII were significantly lower (p less than 0.001) in patients than normals (70.4 +/- 2.7 v 106.9 +/- 7.0; 24.2 +/- 1.6 v 39.2 +/- 0.9 mg/dl, respectively). The mean fractional catabolic rates (FCR) obtained from plasma 125I-HDL, apo AI, apo AII radioactivity decay curves and by Berson and Yalow's method (urine/plasma radioactivity ratios) were significantly greater (p less than 0.05) in patients than in controls (0.387 v 0.299; 0.391 v 0.309; 0.361 v 0.275; 0.272 v 0.207/d; respectively). The synthetic rates (SR of apo AI and apo AII were significantly lower in patients than in controls (11.12 v 14.17 mg/kg body weight/d. p less than 0.05; 3.53 v 4.68 mg/kg body weight/d, p less than 0.05, respectively). Each patient was also investigated for HDL and triglyceride metabolism immediately before and after 8 wk of gemfibrozil (1200 mg/d) treatment. Gemfibrozil significantly increased plasma HDL cholesterol, apolipoprotein (apo) AI, and apo AII by 36%, 29%, and 38% from baseline, respectively. Plasma TG decreased by 54%. Gemfibrozil increased synthetic rates of apo AI and apo AII by 27% and 34%, respectively, without changing the FCR.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of Chinese herbal drug, Dai-saiko-to, on plasma lipids, lipoproteins and liver lipid contents were investigated in guinea pig with/without cholesterol feeding. Guinea pigs were divided into 4 groups (Group 1: normal chow (N) diet, Group 2: N + 1% Dai-saiko-to (D) diet, Group 3: 1% cholesterol (C) diet, Group 4: 1% C+ 1% D diet), and were treated for 5 weeks. Significant body weight reductions were observed in Groups 3 and 4 compared to Groups 1 and 2. Significant reductions of plasma triglyceride (TG) and very low and low density lipoproteins [(V) LDL]-TG were found in Group 3 compared to Groups 1, 2, and 4. (HDL)-TG significantly decreased in Groups 3 and 4 compared to Groups 1 and 2, but no significant difference was noted between Groups 1 and 2, and Groups 3 and 4. Liver lipid contents analysis showed no significant changes between Groups 1 and 2, and Groups 3 and 4, respectively, but the distribution of lipid droplets as pathologically determined using a computer program showed Group 4 had less lipid deposition compared to Group 3. These data suggest that Dai-saiko-to acts on triglyceride metabolism in hypercholesterolemic guinea pigs.

Probucol is a widely prescribed lipid-lowering agent, the major effects of which are to lower cholesterol in both low- and high-density lipoproteins (LDL and HDL, respectively). The mechanism of action of probucol on HDL apolipoprotein (apo) A-I kinetics was investigated in rabbits, with or without cholesterol feeding. 125I-labeled HDL was injected intravenously, and blood samples were taken periodically for 6 days. Kinetic parameters were calculated from the apo A-I-specific radioactivity decay curves. Fractional catabolic rate (FCR) and synthetic rate (SR) of apo A-I in rabbits fed a normal chow and normal chow with 1% probucol were similar. Apo A-I FCR of the rabbits fed 0.5% cholesterol was significantly increased but there were no changes in SR, compared to findings in the normal chow-fed group. Apo A-I FCR of the rabbits fed 1% probucol with 0.5% cholesterol (both 1 month and 2 months) was significantly increased compared to findings in rabbits fed the normal chow as well as 0.5% cholesterol diet group, while SR of apo A-I was significantly reduced in the former groups. Kinetics at 1 month after discontinuation of 1% probucol (under cholesterol feeding) showed a similar FCR of HDL-apo A-I to that of the rabbits fed 0.5% cholesterol, but the SR of apo A-I remained lower. Apo A-I isoproteins kinetics assessed by autoradiography of isoelectric focusing slab gels showed that the synthesis of proapo A-I was significantly reduced in the 1% probucol with 0.5% cholesterol administered, compared to the 0.5% cholesterol group. Thus, the action of probucol on HDL apo A-I kinetics was only prominent in case of higher serum cholesterol levels. The decreased HDL or apo A-I seen with probucol was apparently the result of an increase in FCR and a decrease in SR of HDL-apo A-I. A decreased synthesis of apo A-I remained evident even 1 month after discontinuing probucol. The action of probucol on the intracellular synthetic processes of apo A-I was revealed by the reduced synthesis of proapo A-I.

A monoclonal antibody, SBY1 (IgM, kappa), against the Salmonella O-antigen was generated by using the myeloma cell line Sp2/O-Ag14 as a fusion partner with spleen cells from BALB/c mice immunized with S. senftenberg 963 K. SBY1 was characterized by the slide agglutination and absorption test. SBY1 was believed to show the specificity to O1-, O3- or O19-antigens of Salmonella because S. Senftenberg 963 K (O1, 3, 19) was used as the antigen for immunization. The slide agglutination test with the Salmonella serovars indicated the responsiveness of SBY1. SBY1 was reactive only with strains that possessed O19-antigen. The agglutinating ability of SBY1 was absorbed completely with bacilli possessing O19-antigen. These finding indicates that SBY1 is specific for O19-antigen. Polyclonal factor sera for he serotyping of the O3, 10 group of Salmonella cross-reacted with Salmonella group O1, 3, 19 in the slide agglutination test. In contrast, SBY1 did not cross-react with serovars from several other Salmonella groups. These data suggest the usefulness of SBY1 as a serodiagnostic tool for serotyping of Salmonella.

The 25 hypertensive patients received 20 to 40 mg of TA 3090 daily for 12 weeks. Blood pressures declined significantly during treatment, from a mean of 162/98 to 145/88 mmHg. There were no significant changes in levels of total or very low-density lipoprotein cholesterol or triglyceride, in levels of low-density lipoprotein cholesterol, high-density lipoprotein (HDL) cholesterol, HDL2 cholesterol, HDL3 cholesterol, or in levels of apolipoprotein (apo) B, C-II, C-III, or E. Apo A-I and A-II levels increased significantly from 130 and 29.2 mg/dl before treatment to 152 and 31.4 mg/dl at 12 weeks. Mean serum creatinine levels decreased significantly from 0.92 to 0.80 mg/dl. No other drug-related changes in laboratory test results or side effects were noted. It is concluded that TA 3090 is a safe and effective treatment for mild to moderate hypertension.

S. typhimurium (STM) were isolated from outbreaks of Salmonella enteritis and were studied for their reactivity to monoclonal antibody TMY1 specific for Salmonella O5-antigen with the following results; By using the bacterial agglutination test with TMY1, STM were classified into O5-antigenic molecule positive and negative (copenhagen type) strains, suggesting the usefulness of TMY1 as an exquisite epidemiologic tool for Salmonella enteritis.

Twenty-two patients with mild to moderate hypertension received 20 mg of pinacidil daily for six weeks, followed by 40 mg daily for another six weeks. Levels of serum triglyceride and apolipoproteins C-II and C-III decreased significantly; high-density lipoprotein cholesterol levels increased significantly during treatment. These changes were more prominent in patients with total triglyceride levels of 150 mg/dl or over. The results suggest that pinacidil has a preferential action on triglyceride-rich lipoprotein metabolism.

The relation of alcohol consumption to serum lipids and the severity of coronary atherosclerosis was examined in 212 men undergoing coronary angiography. The severity of coronary atherosclerosis was assessed in terms of the presence of greater than or equal to 75% diameter stenosis and the Gensini severity score. Alcohol consumption was divided into 4 categories: none (0 ml alcohol/week), light (1 to 100 ml alcohol/week), moderate (101 to 300 ml alcohol/week) and heavy (greater than or equal to 301 ml alcohol/week). Alcohol consumption was positively related to high-density lipoprotein cholesterol and inversely related to total cholesterol, but was not associated with triglyceride. After adjustment for these serum lipids as well as for cigarette smoking and systemic hypertension, the risk of coronary stenosis was significantly decreased in the moderate drinkers. A decreased risk among moderate drinkers also was noted in terms of Gensini's severity score. These findings suggest that moderate alcohol consumption may protect against severe coronary atherosclerosis.

To investigate the cardiac function of WHHL rabbit (WHHL), an animal model of familial hypercholesterolemia, electrocardiography (ECG) and echocardiography (UCG) were taken from this species of homozygous type and normolipidemic Japanese White rabbits (controls). In WHHL, two of four had intraventricular conduction disturbances (IVCD) in ECG. UCG study showed that the ejection fraction significantly increased (p less than 0.05) and deceleration time was shortened (p less than 0.01) in WHHL compared to normal controls.

The effects on fibrinolysis of purified normal human plasma lipoproteins and their apolipoproteins (apo) were assessed in an in vitro system containing urokinase, plasminogen, and fibrin. High and very low density lipoproteins (HDL and VLDL, respectively) but not low density lipoproteins (LDL) significantly increased lysis of radiolabeled fibrin or lysis area of plated fibrin compared to controls. Apo HDL, apo HDL2, apo HDL3, apo VLDL (buffer soluble apo), apo AI and AII activated fibrinolysis by 1.3-1.4 fold of control values, whereas apo B (as a narrow density cut of LDL) and non-lipoprotein control proteins (albumin and myoglobin) did not. Addition of HDL in the absence of urokinase failed to activate fibrin lysis. These data demonstrate that the major proteins of HDL - apo AI and apo AII - and possibly certain minor constituent(s) common to HDL and VLDL participate in the fibrinolytic process.

A new technique of laryngoplasty using the function of the suprahyoid muscles (hyoid transposition laryngoplasty) was reported. Total laryngectomy is carried out as usual and the tracheal stump is anastomosed directly to the hypopharynx. The hyoid bone is cut medially, then transpositioned and sutured to the posterolateral margins of the tracheal stump. With this procedure, the new glottis is pressed strongly to the tongue base during swallowing and aspiration is avoided. Postoperative swallowing and speech in the cases operated on with this method were satisfactory, and even nasal respiration was possible in some cases.

The kinetic parameters of high-density lipoprotein (HDL) and its major apolipoproteins (Apo) AI and Apo AII were studied in 2 patients with moderate and severe proteinuria and 2 normal controls after intravenous injection of autologous 125I-HDL. The fractional catabolic rates (FCR) of HDL estimated by urine/plasma radioactivity ratio, and FCR of Apo AI and Apo AII calculated from the radioactivity decay curves were higher in the patients. These results support the concept that high-density lipoproteinuria and renal parenchymal sequestration of HDL found in the nephrotic syndrome contribute to accelerated HDL catabolism.

The daily loss of apolipoproteins into the dialysate from 5 patients on continuous ambulatory peritoneal dialysis (CAPD) was measured. The mean excretion of apolipoprotein (apo) AI and apo AII, major proteins of high-density lipoproteins (HDL), were 84 and 17 mg/day, respectively, while that of apo B, a major protein of low-density lipoproteins (LDL) was 39 mg/day. The peritoneal clearance of apo AI and apo AII were similar; both being significantly greater than that of apo B. The fractional catabolic rates of various proteins found in the CAPD dialysate showed molecular sieving effects of the peritoneal membrane and indicated that the apolipoproteins were excreted as lipoproteins. These findings suggest that there is continuous and selective loss of HDL compared to LDL which may also indicate an increased predisposition of these patients to atherosclerosis.

A 29-year-old woman developed hypopituitarism following removal of a pituitary chromophobe adenoma, and this was complicated by type V hyperlipidemia and obesity.

Gemfibrozil is a potent lipid regulating drug whose major effects are to increase plasma high density lipoproteins (HDL) and to decrease plasma triglycerides (TG) in a wide variety of primary and secondary dyslipoproteinemias. Its mechanism of action is not clear. Six patients with primary familial endogenous hypertriglyceridemia with fasting chylomicronemia (type V lipoprotein phenotype) with concurrent subnormal HDL cholesterol levels (HDL deficiency) were treated initially by diet and once stabilized, were given gemfibrozil (1,200 mg/d). Each patient was admitted to the Clinical Research Center with metabolic kitchen facilities, for investigation of HDL and TG metabolism immediately before and after 8 wk of gemfibrozil treatment. Gemfibrozil significantly increased plasma HDL cholesterol, apolipoprotein (apo) AI, and apo AII by 36%, 29%, and 38% from base line, respectively. Plasma TG decreased by 54%. Kinetics of apo AI and apo AII metabolism were assessed by analysis of the specific radioactivity decay curves after injection of autologous HDL labeled with 125I. Gemfibrozil increased synthetic rates of apo AI and apo AII by 27% and 34%, respectively, without changing the fractional catabolic rates. Stimulation of apo AI and apo AII synthesis by gemfibrozil was associated with the appearance in plasma of smaller (and heavier) HDL particles as assessed by gradient gel electrophoresis and HDL composition. Postheparin extra-hepatic lipoprotein lipase activity increased significantly by 25% after gemfibrozil, and was associated with the appearance in plasma of smaller very low density lipoprotein particles whose apo CIII:CII ratio was decreased. These data suggest that gemfibrozil increases plasma HDL levels by stimulating their synthesis. Increased transport (turnover) of HDL induced by gemfibrozil may be significant in increasing tissue cholesterol removal in these patients.

With increased use of renal angiography and ultrasonography, intrarenal aneurysms and arteriovenous malformations have been easily diagnosed. The authors report a case of small, bilateral intrarenal aneurysms with calcifications that were associated with a visible pulsatile wall motion recorded by M-mode ultrasonography. The finding of selective renal angiography was consistent with bilateral intrarenal aneurysms. Accelerated atherosclerosis and long-term history of hypertension were thought to have caused them.

Very low-density lipoproteins (VLDL) contain sialylated apolipoproteins (apo) (eg, apo CIII1-3) that inhibit apo CII activation of lipoprotein lipase (LPL) and also uptake of triglyceride (TG)-rich lipoproteins by the liver. Hypertriglyceridemic patients can have an excess of sialylated apo CIII (apo CIII1 or apo CIII2) in VLDL. These observations have prompted the notion that sialic acid in VLDL may impede LPL or receptor-mediated clearance of VLDL and thus result in hypertriglyceridemia. The aim of this study was to determine whether desialylation of VLDL altered their property as a substrate for LPL. VLDL isolated from five hypertriglyceridemic patients was desialylated with neuraminidase, labeled with a fluorescent probe, dansyl phosphatidylethanolamine and 600 micrograms of labeled VLDL TG were incubated with a constant amount of purified bovine LPL. The change in fluorescence against time was monitored on a recorder to yield curves representing continuous lipolysis of VLDL by LPL. Mean initial velocity of reaction (Vi) and extent of lipolysis measured as total increase in fluorescence over baseline at 30 minutes (F30/FO) were similar (Vi = 10.2 +/- 0.37 control v 10.2 +/- 0.42 u/min desialylated VLDL; F30/FO = 4.1 +/- 0.15, control v 4.1 +/- 0.07 desialylated VLDL; n = 5). Thus, sialic acid does not influence VLDL catabolism by LPL. Our study does not exclude a possible role of the sialic acid in receptor mediated uptake of remnants produced by initial catabolism of VLDL by LPL.

Recent studies show that the normal and diseased kidney is an important organ in the catabolism of high-density lipoproteins (HDL). However, little is known about the renal handling of HDL. To investigate this aspect, kidneys were isolated from normal rats and rats made nephrotic with puromycin aminonucleoside. They were perfused in a chamber at 37 degrees C with a modified Krebs-Hensleit Bicarbonate Buffer containing 1%, 3%, 6%, and 10% Bovine Serum Albumin (BSA). Presence of 10% BSA in the perfusate prevented glomerular filtration and urine formation. Thus, the filtering and the nonfiltering kidney perfusion models distinguish the renal parenchymal function independently of luminal events that follow filtration. 125I-labeled rat HDL was injected into the perfusate and radioactivity in perfusate, urine, and kidney was examined. At the end of perfusion (30 minutes or four hours), each kidney was flushed with 125I-HDL-free perfusate and kidney radioactivity was measured. At four hours, 1.9% +/- 0.5% of injected radioactivity was present in urine from kidneys perfused with 6% BSA. Kidneys with intact glomerular filtration sequestered significantly more radioactivity (1.1% +/- 0.2% of injected radioactivity) than nonfiltering kidneys (0.7% +/- 0.2%); P less than 0.05. Radioactivity in filtering kidneys was significantly higher than in nonfiltering kidneys (33.9 +/- 7.8 v 15.6 +/- 2.6 cpm/mg kidney tissue protein, respectively; P less than 0.001). Nephrotic kidneys (filtering and nonfiltering) sequestered two to four times more 125I-HDL than normal kidneys. These data support the hypothesis that prior to urinary excretion, partial reabsorption of filtered HDL (or subfractions) occurs in the normal kidney.(ABSTRACT TRUNCATED AT 250 WORDS)

The relationship between plasma fibrinogen levels and the severity of coronary atherosclerosis was examined in 229 patients, aged 25-82 years (162 men and 67 women), undergoing coronary angiography. Severity of coronary atherosclerosis was assessed in terms of the number of vessels with a 75% or greater stenosis and Gensini's severity score. Fibrinogen levels increased progressively with the severity of coronary atherosclerosis, determined by both the number of involved vessels and Gensini's severity score in men, and the relationships were statistically significant. Similar patterns were noted among women, but the trends were not statistically significant. The association was evident even after adjustment for age, hypertension, total cholesterol, cigarette smoking, alcohol intake, high density lipoprotein cholesterol and body mass index. These results provide evidence that in the Japanese also plasma fibrinogen levels can serve as an independent indicator of the progression of coronary atherosclerosis.