Novel mutations in ABCA1 gene in Japanese patients with Tangier disease and familial high density lipoprotein deficiency with coronary heart disease.

Mutations in the ATP-binding cassette transporter 1 (ABCA1) gene have been recently identified as the molecular defect in Tangier disease (TD) and familial high density lipoprotein deficiency (FHA). We here report novel mutations in the ABCA1 gene in two sisters from a Japanese family with TD who have been described previously (S. Ohtaki, H. Nakagawa, N. Kida, H. Nakamura, K. Tsuda, S. Yokoyama, T. Yamamura, S. Tajima, A. Yamamoto, Atherosclerosis 49 (1983)) and a family with FHA. Both probands of TD and FHA developed coronary heart disease. Sequence analysis of the ABCA1 gene from the patients with TD revealed a homozygous G to A transition at nucleotide 3805 of the cDNA resulting in the substitution of Asp 1229 with Asn in exon 27, and a C to T at nucleotide 6181 resulting in the substitution of Arg 2021 with Trp in exon 47. Sequence analysis of the ABCA1 gene from the FHA patient revealed a homozygous 4 bp CGCC deletion from nucleotide 3787 to 3790 resulting in premature termination by frameshift at codon 1224. These mutations were confirmed by restriction digestion analysis, and were not found in 141 control subjects. Our findings indicate that mutations in the ABCA1 gene are associated with TD as well as FHA.

[A comparative long-term trial of sodium cerivastatin, a new HMG-CoA reductase inhibitor, in patients presenting with primary hypercholesterolemia]. / Essai comparatif à long terme de la cérivastatine sodique, un nouvel inhibiteur de l'HMG-CoA réductase, chez des patients présentant une hypercholestérolémie primaire.

Cerivastatin sodium a synthetic and pure enantiomeric 3-hydroxy-3-methylglutaril-coenzyme A (HMG-CoA) reductase inhibitor, is considered effective in the treatment of mild-to-moderate primary hypercholesterolemia (total cholesterol < or = 220-259 mg/dL) at a daily dose of 0.15 mg. We compared the efficacy and tolerability of a dosage of 0.3 mg/d with those of a dosage of 0.15 mg/d in patients with severe primary hypercholesterolemia (serum total cholesterol > or = 260 mg/dL). After a minimum of 4 week's lead-in with placebo, 73 patients with severe primary hypercholesterolemia were randomly assigned to receive either 0.15 or 0.3 mg of cerivastatin sodium once daily after the evening meal for 12 weeks. In 58 patients, the same drug was continued at a flexible dosage for an additional 36 weeks or longer to assess the long-term efficacy and tolerability of cerivastatin sodium. During the 12-week treatment period, serum total cholesterol levels decreased significantly from baseline in both dosage groups, but the percentage reduction was significantly greater in the 0.3-mg group (range, 24.4% to 25.6%) than in the 0.15-mg group (range, 19.4% to 21.6%). The percentage reduction in levels of low-density lipoprotein cholesterol, triglycerides, and apolipoprotein B and the percentage increase in levels of high-density lipoprotein cholesterol were significantly greater in the 0.3-mg group than in the 0.15-mg group. When the results for the 0.3- and 0.15-mg groups were combined, the percentage of change in serum lipid levels at 48 weeks remained as stable as at 12 weeks. No serious adverse reactions were observed. We concluded that the higher dose of cerivastatin sodium was more effective than the lower dose, with comparable tolerability, in the treatment of patients with severe primary hypercholesterolemia.

A novel mutant, ApoA-I nichinan (Glu235-->0), is associated with low HDL cholesterol levels and decreased cholesterol efflux from cells.

A novel variant of apolipoprotein (apo) A-I associated with low high density lipoprotein (HDL) cholesterolemia has been identified in a Japanese family during screening for apoA-I variants by isoelectric focusing (IEF) gel analysis. ApoA-I (Glu235-->0) Nichinan was caused by a 3-bp deletion of nucleotides 1998 through 2000 in exon 4 of the apoA-I gene. Four subjects in the family were heterozygous carriers for this mutation; the mean plasma concentrations of apoA-I and HDL cholesterol of affected family members were 30% and 32% lower, respectively, than those of unaffected family members. There were no differences in the levels of very low density lipoprotein and low density lipoprotein cholesterol, triglycerides, and other apolipoproteins between the carriers and the noncarrier family members. In the proband, plasma lecithin:cholesterol acyltransferase activity was normal. Functional consequences of the mutation were examined by expressing the mutated and wild-type proapoA-I cDNAs in Escherichia coli. Cholesterol efflux to recombinant proapoA-I Nichinan from mouse peritoneal macrophages loaded with [3H]cholesterol-labeled acetylated low density lipoprotein was decreased by 54% when compared that of normal recombinant proapoA-I. In vivo turnover studies in normal rabbits demonstrated that the recombinant proapoA-I Nichinan was rapidly cleared (22% faster) compared with normal recombinant proapoA-I. We conclude that apoA-I (Glu235-->0) Nichinan induced a critical structural change in the carboxyl-terminal domain of apoA-I for cellular cholesterol efflux and increased the catabolism of apoA-I, resulting in low HDL cholesterol levels.

A long-term comparative trial of cerivastatin sodium, a new HMG-CoA reductase inhibitor, in patients with primary hypercholesterolemia.

Cerivastatin sodium, a synthetic and pure enantiomeric 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor, is considered effective in the treatment of mild-to-moderate primary hyper-cholesterolemia (total cholesterol < or = 220-259 mg/dL) at a daily dose of 0.15 mg. We compared the efficacy and tolerability of a dosage of 0.3 mg/d with those of a dosage of 0.15 mg/d in patients with severe primary hypercholesterolemia (serum total cholesterol > or = 260 mg/dL). After a minimum of 4 weeks' lead-in with placebo, 73 patients with severe primary hypercholesterolemia were randomly assigned to receive either 0.15 or 0.3 mg of cerivastatin sodium once daily after the evening meal for 12 weeks. In 58 patients, the same drug was continued at a flexible dosage for an additional 36 weeks or longer to assess the long-term efficacy and tolerability of cerivastatin sodium. During the 12-week treatment period, serum total cholesterol levels decreased significantly from baseline in both dosage groups, but the percentage reduction was significantly greater in the 0.3-mg group (range, 24.4% to 25.6%) than in the 0.15-mg group (range, 19.4% to 21.6%). The percentage reduction in levels of low-density lipoprotein cholesterol, triglycerides, and apolipoprotein B and the percentage increase in levels of high-density lipoprotein cholesterol were significantly greater in the 0.3-mg group than in the 0.15-mg group. When the results for the 0.3- and 0.15-mg groups were combined, the percentage of change in serum lipid levels at 48 weeks remained as stable as at 12 weeks. No serious adverse reactions were observed. We concluded that the higher dose of cerivastatin sodium was more effective than the lower dose, with comparable tolerability, in the treatment of patients with severe primary hypercholesterolemia.

[Juvenile cerebral infarction with familial hyperlipoproteinemia (a)--case report].

A 34-year-old male with a history of angina pectoris suddenly developed weakness in the right upper and lower limbs, and consulted our hospital. Computed tomography (CT) and magnetic resonance imaging (MRI) suggested cerebral infarction. Cerebral angiography revealed stenosis at the M1 portion of the left middle cerebral artery. Hypertension, diabetes, tobacco or hyperlipidemia were not considered as risk factors for cerebral infarction. The lipoprotein (a) [Lp(a)] level was high. In the present case, medication with a nicotinic acid agent, niceritrol, for hyperlipoproteinemia and low density lipoprotein (LDL) apheresis were performed. Concerning family history, the patient's mother and younger sister had hyperlipoproteinemia. Recent studies have reported that increased Lp(a) levels are an independent risk factor even in cerebral infarction and coronary artery disease. Measurement of Lp(a) levels and treatment for increased Lp (a) levels may be important.

Regional cerebral blood flow in diabetic patients: evaluation by N-isopropyl-123I-IMP with SPECT.

Regional cerebral blood flow (rCBF) was measured using N-isopropyl-123I-iodoamphetamine (123I-IMP) with single photon emission computed tomography (SPECT) in 27 patients with diabetes mellitus with an average age of 64.1 years and with an average fasting plasma glucose of 145 mg dl-1. Their data were compared with those of 12 non-diabetic subjects with an average age of 64.6 years. None had cerebral infarction on computed tomographic (CT) studies. There were no significant differences in the physiological or laboratory data between the diabetic and non-diabetic groups except for their fasting plasma glucose and HbA1c levels. A reference sampling method using continuous arterial blood sampling was employed to quantify the rCBF. The average rCBF in each region of the cerebrum and cerebellum was significantly lower in the diabetic group than in the non-diabetic group (P < 0.01). Although a definite cause was obscure, the rCBF of the diabetic patients was reduced even in the absence of findings indicative of cerebral infarction on a CT study.

Tuberculous liver abscess treated by percutaneous infusion of antituberculous agents.

Tuberculous liver abscess has been reported in only fourteen patients in Japan and in twenty-nine patients outside Japan. Only nine of the non-Japanese patients and none of the Japanese patients have been treated for this condition without laparotomy. We report a patient who developed tuberculous liver abscess during treatment of tuberculous peritonitis. Diagnosis was made by ultrasound-guided aspiration biopsy, and the patient was treated with percutaneous drainage and transcatheter infusion of antituberculous agents. Direct infusion of antituberculous agents has more direct effects in the treatment of an abscess than systemic chemotherapy alone. Therefore, if a percutaneous catheter can be safely placed, the use of transcatheter infusion of antituberculous agents should be considered.

[Regional cerebral blood flow in diabetic patients].

N-isopropyl-p-123I-iodoamphetamine (IMP) was used to quantify the regional cerebral blood flow (r-CBF) in 11 diabetic patients (average age; 67.9 years) and 12 non-diabetic subjects (average age; 67.4 years), none of whom had CVD (Cerebrovascular disease) on CT studies. A reference sampling method by continuous arterial blood sampling was used to quantify r-CBF. There were no significant differences in physiological or laboratory data between diabetic and non-diabetic groups except for fasting plasma glucose and HbA1C levels. The average of r-CBF in each region of cerebrum and cerebellum was significantly lower in diabetic group than that in the control group (p < 0.01). These observations show that r-CBF of diabetic patients is reduced, even in the absence of findings of CVD on a CT study.

The characteristics of human plasma lipoprotein metabolism: influence of low caloric diet on hyperlipidemia.

We have classified hyperlipidemia into three groups according to different levels of VLDL-TG, and postulated the effect of low calorie-diets on plasma TCh are as follows: 1) Low calorie-diets are effective on VLDL-TG in every type of hyperlipidemia, except hyperlipidemia with VLDL-TG under 180 mg/100ml; 2) There was a reciprocal relation between the decreased amount of plasma TCh and the change VLDL-TG induced by the diet; 3) Catabolism of VLDL was accelerated by an increased esterification of VLDL-FC; 4) In the the group with VLDL-TG less than or equal to 180 mg/100ml, the LDC showed a high level of TCh: protein ration, and in the group with VLDL-TG greater than or equal to 260 mg/100ml, there was to be low level of TG: protein ratio in VLDL: 5) In hyperlipidemia with plasma TCh unchanged by the diet LDL-TCh increased significantly without any increase in LDL protein and LDL-TG.

Effect of low protein diet on cardiac function and ultrastructure of spontaneously hypertensive rats loaded with sodium chloride.

The effects of low protein diet on cardiac metabolic and structural changes subsequent to an extremely high pressure load were investigated. Spontaneously hypertensive rats(SHR) were divided into four groups, and fed the following diets for four weeks: 1) Group A: regular diet (23% protein) and water, 2) Group B: regular diet and 1% saline, 3) Group C: low protein diet (10% protein) and water, and 4) Group D: low protein diet and 1% saline. Two weeks after the start of feeding, there was no significant difference in the left ventricular ultrastructures between the corresponding regular and low protein diet groups. Four weeks after, degenerative findings such as streaming of Z lines, dilatations of smooth endoplasmic reticulum, and disarrangements of myofilaments appeared Group D, while in Group B electron microscopic findings indicated hypertrophy. Incorporation of [14C] leucine into the myocardial myosin B in Group D was significantly low, with a resulting fall of the LVdP/dtmax per integrated isometric pressure (IIP) and a rise of the left ventricular end-diastolic pressure (LVEDP), as compared to that in Group C at four weeks after the start of feeding. These observations suggest that, in the heart with an extremely high pressure load, low protein diet hinders the development of hypertrophy to the load with resulting heart failure.