Haruo Uzawa

Cerebral and aortic atherosclerosis in Hisayama, Japan

This study of autopsy cases in the general population of the town, Hisayama, describes the incidence and severity of aortic and cerebral atherosclerosis in Japan. Atherosclerosis was more severe in the aorta than in the cerebral arteries of all age groups and its disparity became more conspicuous with age. In hypertensive cases, atherosclerosis was more severe in both the aorta and the cerebral arteries from and beyond the 6th decade of age. The severity of atherosclerosis in the aorta in those with systolic hypertension was lower under the age of 79 and higher after the age of 80 than in diastolic hypertension; the cerebral arteries were afflicted similarly by the two forms of hypertension. The serum cholesterol level correlated better with the severity of aortic than cerebral atherosclerosis.

Effect of plasmapheresis on familial type III hyperlipoproteinemia associated with glomerular lipidosis, nephrotic syndrome and diabetes mellitus

Abstract A 59-year-old woman, one of 5 cases with familial type III hyperlipoproteinemia reported at our clinic to date, had nephrotic syndrome and diabetes mellitus, but had neither coronary atherosclerosis nor xanthoma. A renal biopsy specimen revealed a massive cluster of foam cells containing apolipoprotein B and E in the mesangial region of the kidney. A restricted diet intake combined with lipid-lowering drugs such as cholestyramine, clinofibrate, and bezafibrate, in addition to methylprednisolone was not very effective in lowering serum triglyceride and cholesterol levels within physiological ranges. Therefore, plasmapheresis, using a dextran sulfate-cellulose column, was performed. Repeated plasmapheresis resulted in a marked decrease in both serum total cholesterol and triglyceride. A second renal biopsy specimen performed 2 years later revealed a marked reduction in foam cells with concurrent improvement in her nephrotic syndrome and glucose intolerance. These results suggest that familial type III hyperlipoproteinemia may be responsible for glomerular lipidosis resulting in nephrotic syndrome. They also indicate that plasmapheresis using a dextran sulfate-cellulose column is very effective in the removal of abnormal lipoproteins such as β-very low density lipoprotein and intermediate density lipoprotein in a case of familial type III hyperlipoproteinemia.

Physical fitness Its contribution to serum high density lipoprotein

The effects of exercise conditioning on serum high density lipoprotein cholesterol (HDL-C) were studied using 20 members of a regular joggers club and other healthy non-member subjects of varying degrees of habitual physical activity (253 males and 391 females). Both the HDL-C and HDL-C/serum total cholesterol (TC) levels were significantly higher with the 20 regular joggers than with the sedentary controls matched for age, TC, serum triglycerides (TG) and weight index (WI). A significant correlation was found between HDL-C/TC and the exercise conditioning value obtained by using the results of the 12-min performance test as an index among the non-member subjects. In order to ascertain the relative significance of exercise conditioning in influencing HDL-C/TC, a multiple regression analysis was conducted using HDL-C/TC as the variable criterion. The results showed that TG affected HDL-C/TC the most among both males and females, while exercise conditioning affected it second among males and fourth among females.

Increased platelet phospholipase activity in diabetic subjects

We studied platelet phospholipase activity in 35 diabetes mellitus (DM) patients and 27 age-matched controls. In the diabetics, the mean activity was 9.73±0.54 n mol/mg prot/30 sec, significantly higher (p<0.005) than in the controls (7.80±0.43). The degree of phospholipase was not significantly different between insulin-dependent and noninsulin-dependent diabetics, and between patients treated or not with insulin. DM patients with complications manifested the highest activity (11.45±1.16,n=14, p<0.005). The addition of platelet-poor plasma (PPP) to autologous 14C-arachidonate-labeled platelet suspensions generally lowered the phospholipase level. In the presence of PPP, phospholipase values were higher in diabetics with complications (p<0.05); overall, the DM values were not significantly different from the controls. Dietary therapy decreased serum lipids but not phospholipase; the reverse applied upon insulin or glibenclamide treatment. A dose-dependent decrease of phospholipase by in vitro insulin addition was observed only in diabetics; glucose had no effect on phospholipase of control platelets. The mechanism of increased phospholipase activity observed in DM is discussed.

Influence of apolipoprotein E polymorphism on plasma lipid and apolipoprotein levels, and clinical characteristics of type III hyperlipoproteinemia due to apolipoprotein E phenotype E2/2 in Japan

Apolipoprotein (apo) E phenotype was examined in 188 healthy subjects and in 447 patients seen between 1984 and 1986. The frequency of the apo E2, 3, and 4 genes in the clinically healthy subjects was 0.035 +/- 0.0288, 0.872 +/- 0.0310, and 0.093 +/- 0.0152, respectively. The frequency of the apo E3 gene was higher and that of the apo E genes 2 and 4 lower than that reported in western countries. Clinical features and apo E phenotype are presented from the 5 patients with type III hyperlipoproteinemia (HLP) due to apo E phenotype E2/2 (E2-III); all patients in E2-III were post-menopausal women. In contrast to the clinical characteristics so far reported, no notable findings of atherosclerosis, such as coronary angiographic findings or xanthoma, were evident in any of these 5 patients. Glucose intolerance was seen in 4 of them. Four patients were normolipidemic with apo E phenotype E2/2 (E2-N). In addition, plasma lipid and apolipoprotein concentrations were determined in patients with different apo E phenotypes. Plasma total cholesterol (TC) and apo B levels were elevated in the order of E2-N, E2/3, E2/4, E3/3, E3/4 and E4/4 except for E2-III. The plasma apo E level was highest in E2-III but was not significantly different from other phenotypes. The apo B/apo E and apo C-III/apo E ratios were significantly lower in E2/2 than in other phenotypes. The TC/apo B ratio was significantly higher in E2/2 than in other phenotypes.

Role of α2-Adrenergic Receptor in Platelet Activation During Insulin-Induced Hypoglycemia in Normal Subjects

The effects of α2-adrenergic-receptor blocker mianserin on the responses of blood glucose, plasma β- thromboglobulin (β-TG), and various counterregulatory hormones to insulin-induced hypoglycemia were studied in nine healthy male subjects. The α2-adrenoceptor- blocking action of mianserin was confirmed by its inhibitory effect on platelet activation in vitro. Mianserin was given orally 90 min before insulin injection; the same study without mianserin was performed on another day as the control study. The time courses of blood glucose and serum C-peptide (0, 20, 45, and 180 min after the insulin injection) were identical in both studies, indicating that mianserin has no effect on these parameters. However, a significant increase of p-TG at 45 min after insulin injection was completely suppressed by the administration of mianserin (mean ± SE, 68.5 ± 6.0 vs. 28.8 ± 7.6 ng/ml, n = 6, P < .05). No significant differences were obtained between the two studies in the responses of plasma or serum catecholamines, cortisol, glucagon, growth hormone, thromboxane B2, and 6-ketoprostaglandin F1a. These results suggest that epinephrine is responsible for some, if not all, of the β-TG release from the platelets during insulin-induced hypoglycemia.

Extensive arterial calcification of unknown etiology in a 29-year-old male

SummaryA 29-year-old male with generalized arterial calcification is presented. The roentgenogram showed extensive calcification bilaterally in the facial, brachial, renal, external iliac, femoral, and popliteal arteries. There was also calcification around the joints of the fingers, toes, elbows, and shoulders. The uniformity of arterial calcification in the radiograph differentiated this lesion from Mönckebergs arteriosclerosis. The serum concentration levels of calcium, phosphorus, alkaline phosphatase, and calcium regulatory hormones were normal. The patient did not have diabetes mellitus, renal disease, or connective tissue disease, thus the etiology of the calcification was not identified. However, a bone scintigram showed that the uptake of 99 mTc-methylene diphosphate was significantly increased in the calcified arteries. Therefore, increased metabolic activity was associated with the derangement leading to arterial calcification.

Unusual familial lipoprotein C-III associated with apolipoprotein C-III-0 preponderance

Among 256 consecutive subjects so far studied in our laboratory, we found one subject (a 63-year-old female) whose very low density lipoprotein (VLDL) and high density lipoprotein (HDL) contained unusually high amounts of apolipoprotein C-III-O among apolipoprotein C-III polymorphic forms. Identification of apolipoprotein C-III-O was achieved by a combination of basic polyacrylamide gel electrophoresis, isoelectric focusing and sialidase treatment of plasma apolipoproteins. This unusual lipoprotein was inherited by two of her four children without the manifestation of clinical symptoms. Triacylglycerols and cholesterol concentrations of VLDL, low density lipoprotein (LDL) and HDL fractions, and serum apolipoprotein C-III levels of the three subjects with apolipoprotein C-III-O were within the normal range, as estimated by rocket immunoelectrophoresis. Our results clearly demonstrated that the unusual lipoproteins with the preponderance of apolipoprotein C-III-O among apolipoprotein C-III polymorphic forms were genetically determined. These cases may be a new type of genetic lipoprotein disorder.

Hydrolysis of succinyl-trialanine p-nitroanilide by two enzymes associated with human high-density lipoproteins

Succinyl-trialanine p-nitroanilide (Suc-Ala3-pNA), a synthetic substrate for the determination of elastase activity, was hydrolyzed in sequence by two enzymes that were found to be associated with human high-density lipoproteins. The enzymes involved in the sequence of reaction were separated by ion-exchange chromatography from apo-lipoprotein A-I and A-II, major apoproteins of high-density lipoproteins. One, designated as fraction MK, cleaves Suc-Ala3-pNA to succinyl-dialanine and alanine p-nitroanilide (Ala-pNA), and the other, designated as fraction U, cleaves Ala-pNA to alanine and p-nitroaniline. Fraction MK was inhibited by dithiothreitol, EDTA, and 1,10-phenanthroline, whereas fraction U was inhibited by 1,10-phenanthroline and bestatin. In addition to these findings, fraction MK also hydrolyzed 2,4-dinitrophenyl-prolyl-glutaminyl-glycyl-isoleucyl-alanyl-glycyl-glutaminyl- arginine (DNP-octapeptide), a specific substrate for the determination of vertebrate collagenase. Neither native elastin nor native collagen was hydrolyzed by a mixture of the two enzymes. Fraction U was very similar to aminopeptidase M with respect to its enzyme characteristics studied.

Relationship between platelet phospholipase activity and plasma in ischemic heart disease

Platelet phospholipase plays an important role in the metabolic responses of platelets to exogenous stimuli. The platelet phospholipase activity (PLA) was therefore studied in 38 patients with ischemic heart disease (IHD) and in 26 age-matched normal subjects who served as controls. The mean platelet PLA in the IHD group was 12.72 +/- 1.03 nmol/mg protein/30 sec which was significantly (p less than 0.005) higher than that of the normal controls (8.72 +/- 0.76). When they were classified into acute stage, such as unstable angina or acute myocardial infarction (AMI), and chronic stage, such as stable angina or old myocardial infarction (OMI), there was no significant difference between them. On the other hand, about two-fold activation of platelet PLA was observed in acute stage IHD, and 20-30% inhibition of it was demonstrated in chronic stage IHD following the addition of autologous plasma to washed platelet suspensions, suggesting that certain plasma factor(s) are responsible for such phenomena. In an attempt to identify these plasma factor(s), various substances such as serum albumin, high density lipoprotein, prostaglandin E1 (PGE1) and E2 (PGE2), and platelet activating factor were assessed by in vitro experiments. Only PGE1 and PGE2 revealed a significant effect on the platelet PLA. The relationship between plasma and platelet activity in terms of platelet PLA deserves attention since it varies according to the type and stage of IHD.