Long-term (14 years) effect of LDL apheresis on obstructive changes in aortocoronary saphenous-vein bypass grafts in a case of heterozygous familial hypercholesterolemia with the LDL receptor proline664 to leucine mutation.

A 61-year-old Japanese woman with heterozygous familial hypercholesterolemia (FH), type 2 diabetes mellitus and coronary artery disease underwent coronary artery bypass grafting (CABG) utilizing a saphenous vein graft at the age of 46, in June 1984, 6 months before low density lipoprotein (LDL) apheresis was started. She had received LDL apheresis every two weeks, along with combined drug treatment since the age of 47 (December 1984). She had bilateral xanthelasma and Achilles tendon xanthomas. Her fasting baseline serum total cholesterol and triglyceride level were 464 mg/dl and 57 mg/dl, respectively at the age of 47 when she visited our hospital for the first time. Analysis of the genomic DNA from the patient revealed heterozygous amino acid substitution of Leu for Pro664 in the LDL receptor gene. She was diagnosed as type 2 diabetes mellitus at the age of 53. Combined treatment in the steady state yielded a pretreatment LDL cholesterol level of 230+/-14 mg/dl and a posttreatment level of 57+/-7.6. All grafts were widely patent after as long as 14 years since CABG, suggesting that LDL apheresis combined with drug therapy is highly effective in preventing the occlusion of bypass grafts in a patient with heterozygous FH and type 2 diabetes mellitus.

Carvastatin suppresses intimal thickening of rabbit carotid artery after balloon catheter injury probably through the inhibition of vascular smooth muscle cell proliferation and migration.

In order to test whether a 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor has an anti-atherogenic activity, the effects of carvastatin, a newly developed potent inhibitor, and pravastatin were examined on the intimal thickening of the artery after the endothelial denudation induced by balloon catheter injury. Rabbits were divided into four groups; control, pravastatin-treated (20 mg kg(-1) day(-1)) and two of carvastatin-treated groups (10 or 20 mg kg(-1) day(-1)). Two weeks after balloon catheter injury, the areas of intima and media of the injured carotid arteries were determined, and the ratios of intima to media (I/M) were calculated as an index of intimal thickening. Average I/M ratios of the injured artery were 0.42+/-0.05 for control, 0.49+/-0.07 for pravastatin, 0.19+/-0.03 (10 mg kg(-1) day(-1)) and 0.20+/-0.04 (20 mg kg(-1) day(-1)) for carvastatin-treated rabbits, respectively. Thus, carvastatin reduced I/M ratio of the injured artery to approximately half versus control, but pravastatin failed to suppress the intimal thickening. For in vitro study, vascular smooth muscle cells (SMC) from rabbit aorta were explanted, then cultured, and the effects of carvastatin on SMC migration and SMC proliferation were also examined. Carvastatin inhibited dose-dependently SMC migration and SMC proliferation with IC50 values of 0.5 microM and 1 microM, respectively. These inhibitory effects of carvastatin were cancelled by the coexistence of mevalonate, a metabolite of cholesterol synthesis. Our results suggest that carvastatin may be useful in rabbits as an anti-atherogenic drug by means of the inhibition of SMC migaration or SMC proliferation.

New type of the internalization-defective low-density lipoprotein receptor owing to two-nucleotide deletion (2199delCA or 2201delCA) in Japanese patients with familial hypercholesterolaemia.

BACKGROUND: In mutations of the low-density lipoprotein (LDL) receptor gene, the defect of internalization is caused by a mutation in the cytoplasmic domain of the receptor linked with exons 17 and 18, and the O-linked sugar domain linked with exon 15 has been speculated not to affect the function of the receptor. Here, we describe a novel mutation of the O-linked sugar domain of the LDL receptor gene, designated familial hypercholesterolaemia (FH)-Mishima with Japanese pedigree, which resembles but still differs from classical defective internalization cases. METHODS: LDL metabolism was examined in cultured skin fibroblasts from patients. Immunoprecipitation and immunohistochemical techniques were applied for the detection of the receptor protein size and distribution. Screening of the mutant exon(s) of the LDL receptor gene was performed using the polymerase chain reaction-single-strand conformation polymorphism technique (PCR-SSCP), and sequencing of the mutated alleles was carried out using the dideoxy chain termination method. RESULTS: LDL-binding activity at 4 degrees C in skin fibroblasts from patients was similar to normal, but that at 37 degrees C with the ligand decreased time dependently and was lost at 6 h, resulting in the defect of internalization and degradation of LDL. The receptor protein on the cell surface was detected at 4 degrees C by IgG-C7, an anti-LDL receptor antibody, but was not detected after incubation with LDL at 37 degrees C. The size of the receptor was 112 kD as determined by immunoprecipitation analysis. A deletion of two nucleotides in exon 15 was detected in the DNA sequence of the LDL receptor gene. The deletion results in a shift of the reading frame after Thr-713 of the mutant and makes a stop codon at amino acid 759. CONCLUSION: Deletion of the two nucleotides caused novel amino acid sequences after the O-linked sugar domain, which has the ability of sorting on the cell membrane at 4 degrees C, but not at 37 degrees C in vivo, resulting in the complete cessation of activity of the LDL receptor.

[Reproductive and developmental toxicity study of a new antineoplastic agent, S-1 (I)--Fertility study in rats by oral administration].

S-1 is a newly developed antineoplastic agent consisting of the mixture of tegafur (FT), 5-chloro-2, 4-dihydroxypyridine (CDHP), and potassium oxonate (Oxo) in a molar ratio of 1:0.4:1. As part of a reproductive and developmental toxicity study of S-1, a fertility study was carried out in Sprague-Dawley rats. Twenty-four male rats were administered S-1 orally starting at 64 days before mating and 24 female rats were administered S-1 orally from 15 days before mating to day 7 of pregnancy at doses of 0, 1, 4, or 7 mg/kg/day (as a dose of FT) in order to investigate the effect of S-1 on the reproductive ability and development of embryos and fetuses. There were no dose-related changes in clinical signs. Body weight gains and food consumption were decreased and were associated with the decreased weights of thymus, testis and epididymis in male rats receiving S-1 at the 7 mg/kg/day group. In females, the only organ affected was the kidney at 7 mg/kg/day. There were no dose-related changes in copulation, fertility, pre-implantation loss and implantation. Decreases in live fetal body weight and retardation of fetal ossification were observed in the 7 mg/kg/day group. There were no dose-related changes in post-implantation loss, and no fetal malformations were observed. The results suggest that the non-observed effects dose level of S-1 for general toxicity in male and female rats in 4 mg/kg/day, for reproductive toxicity in adults is more than 7 mg/kg/day, and for developmental toxicity in utero is 4 mg/kg/day.

[Reproductive and developmental toxicity study of a new antineoplastic agent, S-1 (II)--Teratological study in rats by oral administration].

S-1 is a newly developed antineoplastic agent consisting of the mixture of tegafur (FT), 5-chloro-2, 4-dihydroxypyridine (CDHP), and potassium oxonate (Oxo) in a molar ratio of 1:0.4:1. The teratogenic potential of S-1 was studied in rats given S-1 at the daily oral doses of 0, 1, 3, 5 and 7 mg/kg/day (as a dose of FT). S-1 was given from day 7 to day 17 of pregnancy. The study included postnatal evaluation of the growth, development, and reproductive performance of the F1 generation. In rats receiving 7 mg/kg of S-1, maternal body weight gain and food consumptions were reduced, stillbirths increased, livebirths decreased slightly and F1 viability decreased. Fetal body weights decreased significantly in rats receiving 5 mg/kg or more of S-1. External and skeletal anomalies did not increase, but hydrocephaly increased slightly and total number of visceral anomalies increased significantly in the fetuses of rats receiving 7 mg/kg of S-1. Hydrocephaly was observed also in F1 offspring from the rats receiving 7 mg/kg of S-1 during lactation period. Body weight gains of F1 offspring from the rats receiving 7 mg/kg of S-1 during lactation period was reduced. Functional development, emotional tests, learning tests, reproductive performance of the F1 generation and development of the F2 generation were not effected by the S-1 administration. In conclusion, under the condition of this study, the non-observed effect dose levels (NOELs) of S-1 for general toxicity for dams was 5 mg/kg/day, however, NOELs of S-1 was determined to be 7 mg/kg/day or more for reproductive ability. The NOELs of S-1 for the offspring was established to be 3 mg/kg/day.

[Reproductive and developmental toxicity study of a new antineoplastic agent, S-1 (III)--Teratological study in rabbits by oral administration].

S-1 is a newly developed antineoplastic agent consisting of the mixture of tegafur (FT), 5-chloro-2, 4-dihydroxypyridine (CDHP), and potassium oxonate (Oxo) in a molar ratio of 1:0.4:1. As part of a reproductive and developmental toxicity study of S-1, a teratogenicity study was carried out in rabbits administered daily oral doses of S-1 0, 0.5, 1, or 1.5 mg/kg/day (as a dose of FT). S-1 was administered from day 6 to day 18 of pregnancy. Two additional studies were conducted in order to evaluate the effect on embryos or fetuses at higher S-1 dosage. One study (additional study I) tested during organogenesis dividing it into 3 periods (Day 6-10, Day 10-14, and Day 14-18) at doses of 2, 4 or 6 mg/kg/day. Another study (additional study II) tested during organogenesis dividing it into 4 periods (Day 8 x 9, Day 10 x 11, Day 12 x 13, and Day 14 x 15) at doses of 3 or 6 mg/kg/day due to many embryo deaths at high dose level in the additional study I. The results were as follows. 1. Teratogenicity study One dam died on day 16 of pregnancy and there was a weak teratogenic potential in the 1.5 mg/kg/day group. There were no remarkable other changes in dams and fetuses. The non-observed effects dose level of S-1 for general toxicity in dams was 1 mg/kg/day, for pregnancy in dams was 1.5 mg/kg/day, and for development of fetuses was 1 mg/kg/day under the conditions of this study. 2. Additional study I Abortion was observed at 6 mg/kg/day in the day 14-18 administration group. General toxicity in dams were observed in all administration groups. Fetal lethality was observed at 4 mg/kg/day or more in the day 6-10 and day 10-14 groups, and at 6 mg/kg/day in the day 14-18 administration group. Inhibition of fetal growth was observed at 2 mg/kg/day in the day 10-14 group and at 2 mg/kg/day or more in the day 14-18 administration group. There was a week teratogenic potential at 2 mg/kg/day or more in the day 10-14 groups and at 4 mg/kg/day in the day 14-18 administration group. 3. Additional study II Abortion was observed at 6 mg/kg/day in the day 8-9, day 10-11, and day 12-13 administration groups. General toxicity in dams were observed in all administration groups. Fetal lethality was observed at 3 mg/kg/day in the day 8-9 group and at 6 mg/kg/day in all administration groups. Inhibition of fetal growth and teratogenic potential were clearly observed at 3 mg/kg/day in the day 8-9 and day 10-11 groups, and at 6 mg/kg/day in the day 12-13 and day 14-15 administration groups. 4. In conclusion, when S-1 was administered at a low dose (< = or 1.5 mg/kg/day) during organogenesis effects were not detected clearly. When higher doses were administered (2-6 mg/kg/day), fetal lethality, inhibition of fetal growth, and teratogenicity were observed.

Slow beta-migrating lipoprotein: an atherogenic subclass of low density lipoproteins.

OBJECTIVE: To clarify the possibility that midband Lp in LDL fractions might act as an atherogenic lipoprotein in their interaction with macrophages. DESIGN AND METHODS: Low density lipoproteins (LDL) isolated by zonal ultracentrifugation from midband lipoprotein-positive serum in type lib hyperlipidemics were subjected to polyacrylamide gel disc electrophoresis. RESULTS: A part of midband lipoprotein was observed between pre beta-and beta-band, in addition to the main beta-band. We named this midband lipoprotein "slow beta-migrating Lp (slow beta-Lp)." The larger LDL subfraction from midband-lipoprotein positive serum on Sepharose 2B column chromatography contained much slow beta-Lp, named slow beta-Lp-rich LDL. The smaller LDL subfraction contained a little slow beta-Lp, named slow beta-Lp-poor LDL. Slow beta-Lp-rich LDL had similar composition to the control LDL except for apolipoprotein E. The uptake of [3H]cholesteryl linoleate-labeled slow beta-Lp-rich LDL by J774 macrophages was higher than that of control LDL. The cholesterol ester content of J774 macrophages incubated with slow beta-Lp-rich LDL increased significantly compared with slow beta-Lp-poor LDL, beta-VLDL, and control LDL. CONCLUSION: These results suggest that slow beta-Lp in type llb might generate foam cells from macrophages in atherosclerotic lesions.

Evaluation of double filtration plasmapheresis, thermofiltration, and low-density lipoprotein adsorptive methods by crossover test in the treatment of familial hypercholesterolemia patients.

A comparative assessment has been made regarding efficacy and safety of the double filtration plasmapheresis (DFPP), thermofiltration (TFPP), and low-density lipoprotein (LDL) adsorptive (PA) methods by making a crossover test on heterozygous familial hypercholesterolemia patients. Treatments by DFPP, TFPP (secondary membrane Evalux 5A), and PA (Liposorber LA-40) were carried out 5 times each, with a 2-week interval, in 5 patients with heterozygous familial hypercholesterolemia. The same plasma separator (Plasmacure PS-60, polysulfone) was used in all cases, and the volume of plasma processed was set at 4 L. High removal rates were obtained of total cholesterol, LDL cholesterol, triglycerides TG, and apolipoprotein B (apoB) by all three methods, and no differences were observed. Lipoprotein (a), apoA-2, apoC-3, fibrinogen, and immunoglobulin M (IgM) showed significantly high removal rates by the DFPP and TFPP methods compared with the PA method. The sieving coefficient of albumin and high-density lipoprotein (HDL) cholesterol at 2 and 4 L of plasma processed exhibited high permeabilities using all three methods. Supplementing albumin was not necessary. An increase of the transmembrane pressure was observed in 1 case treated by DFPP but was not observed when using the TFPP or PA method. No changes were observed in serum interleukin 1beta (IL-1beta) or tumor necrosis factor-alpha (TNF-alpha) before and after treatment by any of the three methods. No remarkable side effects were observed using either the DFPP or TFPP method. The DFPP and TFPP methods showed efficacy and safety that was not inferior to the PA method in conventional LDL apheresis, and the dead-end method of the filter operation without the discarding of plasma was shown to be possible.

Enhancement of CDDP cytotoxicity by caffeine is characterized by apoptotic cell death.

The ability of caffeine, an agent that suppresses cell replication by inhibiting deoxyribonucleic acids (DNA) repair, to modulate the cytotoxicity of cis-diamminedichloroplatinum (CDDP) was investigated in murine lymphoma cell line EL-4. EL-4 cells were precultured with or without 20 micrograms/ml CDDP for 1 h and then cultured in the presence of 5 mM caffeine up to 48 h after reseeding. In CDDP-pretreated cells, suppression of cell growth and decrease in cell viability from 24 h were observed. Cell cycle arrest in G2 + M phase and a concomitant increase in both rhodamine 123 (R123) uptake and cell size (forward scatter) were observed in these cells. Treatment with caffeine alone suppressed growth rate, R123 uptake, cell size, and frequency of S phase fraction in the cell cycle. Combination of the two agents, CDDP+caffeine, strongly suppressed not only cell viability but also R123 uptake and cell size, compared with CDDP pretreatment alone. DNA histogram analysis by flow cytometry revealed that cultivation with caffeine hastened G2 + M arrest in CDDP-pretreated cells by reduction in the time of passing through S phase. DNA fragmentation was observed following incubation of CDDP-pretreated cells with caffeine for 16 h when marked accumulation in G2 + M phase was observed. The intensity of these ladder fragments increased in a time-related manner. These results demonstrate that enhancement of cytotoxic activity against CDDP-treated cells by caffeine is characterized by an acceleration of DNA degradation in G2 + M phase, namely apoptotic cell death. The fact that induction of DNA fragmentation during G2 + M phase by caffeine modulates the cytotoxicity of CDDP may give rise to a new combination regime of chemotherapy against malignant tumor cells.

The 'midband' lipoprotein is a coronary risk factor in Japanese patients with familial hypercholesterolaemia.

The relationship between coronary stenosis and 'midband' lipoprotein, which was observed between low density lipoproteins and very low density lipoproteins by 3% polyacrylamide gel electrophoresis, was studied in patients with heterozygous familial hypercholesterolaemia (FH). The subjects were 46 patients with FH, who were evaluated by coronary angiography. The groups with and without coronary artery disease (CAD) were compared. Age, sex ratio, total cholesterol, triglyceride, HDL-cholesterol and lipoprotein(a) levels were matched in these two groups. In addition, Achilles tendon thickness and the incidence of risk factors such as diabetes mellitus, hypertension and smoking between these two groups were matched. Under these conditions, the frequency of midband was higher in the patients with CAD (20/26) than that in patients without (4/20). The results suggest that the presence of a midband among Japanese is an independent risk factor for coronary stenosis even in cases of FH who have severe hypercholesterolaemia.

Therapeutic effect of granulocyte colony-stimulating factor and cephem antibiotics against experimental infections in neutropenic mice induced by cyclophosphamide.

Effects of recombinant human granulocyte colony-stimulating factor (rhG-CSF) against severe infections in cyclophosphamide (CY)-induced neutropenic mice were investigated by its single use or by its combination with cephem antibiotics. Treatment with rhG-CSF increased the number of peripheral blood leucocytes and strikingly shortened the duration of the neutropenic state. Most of the regained population in the peripheral blood leucocytes were neutrophils. Functions of neutrophils, such as phagocytic activity, superoxide release, and expression of Mac-1 molecules, were remarkably enhanced by administration of rhG-CSF. When rhG-CSF was administered to CY-induced neutropenic mice before infection, protective effects against various kinds of bacteria were remarkable. On the other hand, such remarkable effects were not observed when rhG-CSF was administered after infections. However, even in the case of post-infectious treatment, a combination therapy of rhG-CSF with cephem antibiotics, particularly with Cefodizime (CDZM), showed a significant improvement in the survival rate and a decrease in the number of viable bacteria in the liver. These results suggest that a combination therapy of rhG-CSF with cephem antibiotics, especially with CDZM, is an efficient regime against severe infections in patients with neutropenia induced by a heavy anti-tumour chemotherapy.

Characteristic features of long-living patients with familial hypercholesterolemia in Japan.

OBJECTIVE: To assess characteristics of long-living familial hypercholesterolemics (FHs) in comparison with younger patients. DESIGN: Cross-sectional study. SETTING: Lipid clinics of a university hospital and 14 related medical institutions. PATIENTS: A total of 335 heterozygous FHs including 17 patients over 70 years old. The average ages of the aged (> or = 70 years old) and the younger groups were 73.5 +/- 3.7 and 46.5 +/- 15.0 years, respectively. MEASUREMENTS: Medical history, serum lipids and apolipoproteins, and radiographic measurement of Achilles tendon xanthomas. MAIN RESULTS: Age distribution of FHs suggests shorter life of FHs compared with the general population. The age distribution of FH females was shifted to older age compared with that of FH males (P < 0.01). No significant differences were found between the levels of serum lipids and apolipoproteins in the aged and the younger groups. The thickness of the Achilles tendon was positively correlated with the product of excess total serum cholesterol and age in the patients (P < 0.01). Progression of Achilles tendon thickening was less in females than in males. A few cases of longevity could not be explained by any of the anti-atherogenic factors including female gender, a relatively low concentration of serum total cholesterol, a high concentration of HLD-cholesterol, a non-smoking habit, and a familial predisposition for longevity. CONCLUSIONS: The female gender was found to be one of the most important factors for long survival of FHs. The different progression of Achilles tendon thickening in females and males may be related to the slower development of atherosclerosis and higher survival rate of the female patients.

Endocrine disorders and body fat distribution.

To evaluate the role of hormones in formation of regional fat distribution, the ratios of visceral fat (V) to subcutaneous fat (S) in the abdomen of rats with various endocrine disorders were determined by computer tomography. Abdominal fat index (AFI), which was obtained by ultrasonography, correlated with V/S. In Cushing's syndrome, seven out of nine patients showed visceral type and V/S ratio positively correlated with cortisol levels. In acromegaly, three out of four patients showed visceral type and V/S ratio correlated not only with growth hormone level, but also with insulin level. All three insulinoma patients showed visceral type. During pregnancy, AFI decreased at the late stage of pregnancy. These results suggest that in visceral fat formation, insulin is the most important factor, and estrogen is an important factor for subcutaneous formation. In vitro experiments showed that visceral fat was much more sensitive to insulin in terms of glucose uptake and triglyceride synthesis than visceral fat. Fibroblast-like cells derived from adipose tissue were cultured. Estrone enhanced cell growth of fibroblast-like cells derived from subcutaneous fat tissue more than that from visceral fat tissue. The results suggested that hyperinsulinism primarily promotes visceral fat tissue enlargement and that estrogen might promote subcutaneous fat tissue enlargement.

Long term effect of LDL apheresis in Japan. LDL Apheresis Study Group.

LDL-apheresis is introduced in many cases all over Japan. Among them, evaluation of long-term effect on ischemic heart disease (IHD) has made on 10 cases with homozygous familial hypercholesterolemia (FH) and 49 cases with heterozygous FH. As to homozygous FH, 3 patients had angina pectoris. Mean duration of treatment was 26 months (52 treatments). The changes in total cholesterol (TC) in each treatment was from 426 mg/dl to 151 mg/dl. Improvement in IHD was observed in 5 out of 10 cases. As to heterozygous FH, 17 cases had history of myocardial infarction and 12 had angina pectoris. Mean duration of treatment was 13 months (19 treatments). Mean TC was decreased from 271 mg/dl to 126 mg/dl by each treatment. Regression in Achilles tendon thickenting or skin and palpebral xanthomas was observed. Frequency of anginal attacks decreased in 8 out of 17 cases. Ischemic change in ECG were improved in 3 out of 26 cases. Coronary angiography performed with 2 to 3 years of interval in some cases revealed regression or no progression in coronary stenosis. As a whole, IHD improved in 15 cases and exacerbated in 2 cases. Main side effect was hypotension attack. Bradycardia and anginal attack during treatment were observed in some cases. LDL-apheresis was judged as effective in 25 out of 44 patients with IHD or xanthoma.

Frequency and role of apo E phenotype in familial hypercholesterolemia and non-familial hyperlipidemia in the Japanese.

The frequencies of the major apolipoprotein E(apo E) phenotypes in 65 normal, 426 hyperlipidemics, and 92 familial hypercholesterolemic Japanese subjects (FH) were studied, and features of hyperlipidemia compared between non-FH hyperlipidemia and FH. The frequencies of apo E phenotypes 3/3, 4/3, 3/2, 4/4 were almost the same in normal, non-FH hyperlipidemic, and FH subjects. The incidence of apo E7 was about 0.5% of total subjects. In type IV and V hyperlipidemias, incidence of E4/3 was higher than in any other hyperlipidemia. Incidence of E3/2 was also high in types III and V. In type II non-FH hyperlipidemia, incidence of E3/2 in type IIb was higher than in type IIa. VLDL-triglyceride, VLDL-cholesterol, apo C-II, apo C-III, and apo E levels were higher in E3/2 than in E3/3. But, in type IIa FH and type IIb FH, the incidence of E3/2 was the same, and lipid and apolipoprotein levels between 3/2 and 3/3 in FH were the same. These results indicate that allele epsilon 2 may be involved in the retention of VLDL or IDL, but not in FH.

Effects of long-term treatment with probucol on serum lipoproteins in cases of familial hypercholesterolemia in the elderly.

The effect of probucol in lowering serum lipoprotein in young and middle-aged (YM) and elderly (E) patients with familial hypercholesterolemia were compared. Probucol at 1000 mg/day was administered orally to 37 YM patients and 14 E patients for an average of 10 months. Probucol treatment for this period caused significant reductions in the serum levels of total cholesterol, low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol, and apoprotein AI, AII, B, and CIII in both groups. The decreases in the levels of total cholesterol, LDL-C, and apoprotein B were greater in the E group than in the YM group (total cholesterol: YM, -19.3%, E, -31.3% [P less than .001]; LDL-C: YM, -17.0%, E, -35.4% [P less than .001]; apoprotein B: YM, -12.3%, E, -28.1% [P less than .01]). The decreases in other parameters in the two groups were not significantly different. The serum probucol concentrations in the YM and E groups were not significantly different. No significant side effects were observed in any patient. Thus probucol reduced the serum level of LDL more in the E group than in the YM group, and did so without any increase in the serum concentration of the drug or in side effects, suggesting that probucol is safe and beneficial for use in elderly patients.

A familial hyperalphalipoproteinemia with low uptake of high density lipoproteins into peripheral lymphocytes.

A patient with an extremely high level of high density lipoprotein (HDL)-cholesterol and HDLc-like particles in the serum is discussed. The patient was a 46-year-old female with a serum total cholesterol concentration of 382 mg/dl and HDL-cholesterol level of 214 mg/dl. The HDL-cholesterol levels of her mother, brother, sister and 2 of her daughters were 82 mg/dl, 82 mg/dl, 74 mg/dl, 82 mg/dl and 82 mg/dl, respectively (mean HDL-cholesterol levels of control subjects: 52 +/- 6 mg/dl in males and 55 +/- 8 mg/dl in females). Her serum apolipoprotein A-I and E levels were elevated. Zonal ultracentrifugal analysis of her serum lipoproteins showed that the increased level of HDL-cholesterol was mainly due to HDL2; HDLc-like particles were also recognized between the LDL and HDL fractions. The incorporation of the patient's HDL and HDLc-like particles into cultured HepG2 cells was almost the same as that of HDL (1.063 less than d less than 1.21) from normal control serum. The incorporation of normal control HDL into the patient's peripheral blood lymphocytes was markedly less than that into lymphocytes from normal controls. These findings are discussed in terms of the reason for hyperalphalipoproteinemia in this patient.