Genetic cholesteryl ester transfer protein deficiency caused by two prevalent mutations as a major determinant of increased levels of high density lipoprotein cholesterol.

Genetic determinants of HDL cholesterol (HDL-C) levels in the general population are poorly understood. We previously described plasma cholesteryl ester transfer protein (CETP) deficiency due to an intron 14 G(+1)-to-A mutation(Int14 A) in several families with very high HDL-C levels in Japan. Subjects with HDL-C > or = 100 mg/dl (n = 130) were screened by PCR single strand conformational polymorphism analysis of the CETP gene. Two other mutations were identified by DNA sequencing or primer-mediated restriction map modification of PCR products: a novel intron 14 splice donor site mutation caused by a T insertion at position +3 from the exon14/intron14 boundary (Int14 T) and a missense mutation (Asp442 to Gly) within exon 15 (D442G). The Int14 T mutation was only found in one family. However, the D442G and Int14 A mutations were highly prevalent in subjects with HDL-C > or = 60 mg/dl, with combined allele frequencies of 9%, 12%, 21% and 43% for HDL-C 60-79, 80-99, 100-119, and > or = 120 mg/dl, respectively. Furthermore, prevalences of the D442G and Int14 A mutations were extremely high in a general sample of Japanese men (n = 236), with heterozygote frequencies of 7% and 2%, respectively. These two mutations accounted for about 10% of the total variance of HDL-C in this population. The phenotype in a genetic compound heterozygote (Int14 T and Int14 A) was similar to that of Int14 A homozygotes (no detectable CETP and markedly increased HDL-C), indicating that the Int14 T produces a null allele. In four D442G homozygotes, mean HDL-C levels (86 +/- 26 mg/dl) were lower than in Int14 A homozygotes (158 +/- 35 mg/dl), reflecting residual CETP activity in plasma. In 47 D442G heterozygotes, mean HDL-C levels were 91 +/- 23 mg/dl, similar to the level in D442G homozygotes, and significantly greater than mean HDL-C levels in Int14 A heterozygotes (69 +/- 15 mg/dl). Thus, the D442G mutation acts differently to the null mutations with weaker effects on HDL in the homozygous state and stronger effects in the heterozygotes, suggesting dominant expression of a partially defective allele. CETP deficiency, reflecting two prevalent mutations (D442G and Int14 A), is the first example of a genetic deficiency state which is sufficiently common to explain a significant fraction of the variation in HDL-C in the general population.

Quantitative measurement of vibratory perception threshold using a new vibrometer TM-31A.

The need for standardization and validation of quantitative tests for vibratory sensitivity has been increasingly recognized. Conventional vibrometers have been of limited use for the assessment of vibratory perception threshold (VPT) due to wide intraindividual variations. This study describes the determination of VPT for the medial malleolus (MM), the styloid process of the radius (SPR), and the pulp of the index finger (PIF) in normal subjects, using a new vibrometer, the TM-31A. This apparatus expresses results in terms of actual vibration amplitude and has a feedback mechanism that avoids damping of the stimulator in tissue. Repeated VPT measurements revealed good reproducibility of the test. The intraday and day-to-day variations of VPT were fairly small. VPT was found to differ significantly among sites (MM > SPR > PIF). The distribution in MM was substantially log-normal, whereas the SPR and PIF were normal. VPT values on each site correlated with advancing age, especially on the MM. It is concluded that TM-31A provides a reliable and valid assessment of VPT and contributes to the standardization of VPT testing.

Reduction of lipoprotein(a) by LDL-apheresis using a dextran sulfate cellulose column in patients with familial hypercholesterolemia.

Lipoprotein(a) (Lp(a)) was eliminated by LDL-apheresis using a dextran sulfate cellulose column in 3 homozygous and 10 heterozygous familial hypercholesterolemic patients. Immediately after LDL-apheresis by the LA-15 system (continuous LDL apheresis), there were significant reductions in Lp(a) concentrations (28.6 +/- 11.8 mg/dl (mean +/- S.E.) to 9.6 +/- 5.6 mg/dl (P < 0.01)), and in LDL-cholesterol concentrations (156 +/- 32 mg/dl to 48 +/- 18 mg/dl (P < 0.01)). Immediately following LDL-apheresis, Lp(a) and LDL-cholesterol were reduced by 67.4% +/- 11.6% and 68.3% +/- 11.8%, respectively. The removal of Lp(a) paralleled that of LDL-cholesterol. The reduced levels of Lp(a) nearly returned to baseline within 7 days. In 6 of the heterozygous FH patients the rates of recovery of LDL cholesterol and Lp(a) were calculated, according to Apstein's equation after discontinuing lipid altering drug treatment for 4 weeks. Mean constant k values of LDL cholesterol and Lp(a) were 0.354 (range: 0.136-0.752) and 0.427 (range 0.112-0.933), respectively. The average concentration during the 7 days following LDL-apheresis was calculated. Average reductions were 28% in LDL cholesterol and 18% in Lp(a). Pravastatin treatment, which continued for 4 weeks, significantly decreased LDL cholesterol (P < 0.01); however, before LDL-apheresis pravastatin treatment significantly increased Lp(a) levels (P < 0.05) in a small number (n = 6) of the FH patients, who had been regularly treated with LDL-apheresis. These results suggest that LDL-apheresis using the dextran sulfate cellulose column is an effective treatment to reduce levels of serum Lp(a) and LDL proportionally. This therapy may be of value in the prevention and regression of coronary artery disease in FH patients.

Effects of aldose reductase inhibitor (ONO-2235) on human erythrocyte sorbitol concentrations in 75 g oral glucose tolerance tests.

In order to evaluate the effects of the aldose reductase inhibitor, ONO-2235, on the short-term response of human erythrocyte sorbitol to hyperglycemia in vivo, eleven diet-treated Type 2 (non-insulin-dependent) diabetic patients were studied twice in 75 g oral glucose tolerance tests - with and without ONO-2235 (200 mg p.o.) premedication. The erythrocyte sorbitol concentrations increased with the increments of blood glucose and erythrocyte glucose concentrations in the test performed without ONO-2235. The erythrocyte sorbitol response in the test performed with administration of ONO-2235 30 min prior to glucose load was lower than that in the test performed without ONO-2235 (F = 5.782, P less than 0.05). No significant differences were found between the two tests in blood glucose and erythrocyte glucose concentrations (F = 0.092, P = 0.761; F = 0.029, P = 0.860, respectively). It is concluded that human erythrocyte sorbitol concentrations change promptly in response to rapid changes in erythrocyte glucose concentrations and that administered ONO-2235 is effective in inhibiting the human erythrocyte sorbitol pathway in man.

Effects of CS-514 on serum lipoprotein lipid and apolipoprotein levels in patients with familial hypercholesterolemia.

Effects of CS-514, a new competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, on serum lipoprotein lipid and apolipoprotein levels were studied in 13 heterozygous patients with familial hypercholesterolemia. Treatment with 10 mg of CS-514 twice daily reduced total serum cholesterol, low-density lipoprotein (LDL), and intermediate-density lipoprotein (IDL) cholesterol levels by 25%, 33%, and 33%, respectively, and increased high-density lipoprotein (HDL) cholesterol levels by 15%. Apolipoprotein B, E, and C-II levels decreased by 24%, 20%, and 19%, and apolipoproteins A-I and A-II levels increased by 10% and 7%, respectively. One patient showed abnormally high levels of SGOT, SGPT, and serum alkaline phosphatase, which returned to normal levels immediately after the cessation of CS-514. No other adverse effects were observed. Thus, CS-514 reduces atherogenic lipoproteins and apolipoprotein B, and increases HDL and apolipoprotein A-I and A-II, and appears to be a useful drug for heterozygous familial hypercholesterolemia.

Utilización de modelos matemáticos para la organización de los servicios de atención médica de urgencia en Cuba / Use of mathematical models for the organization of emergency medical care in Cuba

Se exponen modelos matemáticos de aplicación en la República de Cuba para la planificación de camas de hospitalización y de estaciones de ambulancias, en la organización del servicio de atención médica de urgencia en un territorio dado

Utilización de modelos matemáticos para la organización de los servicios de atención médica de urgencia en Cuba / Use of mathematical models for the organization of emergency medical care in Cuba

Se exponen modelos matemáticos de aplicación en la República de Cuba para la planificación de camas de hospitalización y de estaciones de ambulancias, en la organización del servicio de atención médica de urgencia en un territorio dado