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The ability of plasma lipoproteins to act as carriers in site-specific drug delivery systems was evaluated by determining the disposition and pharmacological effects of beta-sitosteryl-beta-D-glucopyranoside (SG, 3). In the disposition studies, [3H]SG was absorbed from the intestinal tract by the formation of chylomicrons and was specifically associated with lipoproteins in vivo. [3H]SG was incorporated into various rat plasma lipoproteins in vitro. [3H]SG complexed with the lower density lipoproteins (d less than 1.063 g/mL), especially with the intermediate density lipoproteins (1.006 less than or equal to d less than 1.019 g/mL) which following intravenous administration to rats. In pharmacological studies, the hemostatic effect of SG in mice and the inhibitory effect of SG on vascular permeability in rats were only observed after intravenous administration of the complexes of SG with the lower density lipoproteins. The same results were obtained after the intravenous administration of the complexes of SG with human and mouse lipoproteins.

To identify the risk factors of borderline hypertension in the development of established hypertension, the relationship between the changes in blood pressure over 10 years and the clinical features in the initial year was investigated in a Japanese urban population. The occurrence of cardiovascular complications in cases with borderline hypertension were also studied. The prevalence of borderline hypertension in the initial year was 18.2%. On the basis of the blood pressure changes over 10 years, these subjects could be classified into the following 5 groups: (I) those with developing established hypertension, 19.0%; (II) those with fluctuating between hypertension and borderline hypertension, 27.4%; (III) those with remaining with borderline hypertension, 19.6%; (IV) those with fluctuating between borderline hypertension and normotension, 22.9%; (V) those with improving to normotension, 11.2%. The later development of established hypertension was found in only 2.4% of normotensives in the initial year. Obesity and glucose intolerance were more frequently observed in group I (38.2% and 29.4%, respectively) than in the other groups. Diastolic blood pressures in the initial year were significantly higher in groups I and II than in III, IV and V. As for the occurrence of cardiovascular complications during the observation period, electrocardiographic abnormalities and hypertensive and/or arteriosclerotic retinopathy were not infrequently observed even in borderline hypertensives. Therefore, in subjects with borderline hypertension, continuous medical management, including correction of obesity as well as glucose intolerance, is necessary to prevent the development of established hypertension and subsequent cardiovascular complications.

For direct identification of phosphotyrosine-containing proteins in lysates of various cells, phosphotyrosine (P-Tyr) was coupled to carrier proteins and anti-P-Tyr antibodies were raised in rabbits and mice. The antibodies were highly specific for P-Tyr and did not cross-react with phosphoserine or phosphothreonine. The mean association constant of rabbit anti-P-Tyr antibody to N-acetyl-P-Tyr was about four times that of rabbit anti-azobenzene phosphonate antibody. In addition, anti-P-Tyr antibody scarcely cross-reacted with the 5'-monophosphate of ribosyladenine or the 5'-monophosphate of ribosylinosine, whereas anti-azobenzene phosphonate antibody cross-reacted appreciably with these compounds. Anti-P-Tyr antibody immunoprecipitated three oncogenic gene products from cells transformed with Rous sarcoma virus, Fujinami sarcoma virus, and Abelson murine leukemia virus, respectively. The immunoprecipitates with anti-P-Tyr antibody from cells transformed with these three retroviruses all manifested tyrosine kinase activity including activity for phosphorylations of oncogene products. In addition to the proteins reported previously, the following new phosphotyrosine-containing proteins were immunoprecipitated from the respective retrovirus-transformed cells by anti-P-Tyr antibody: Mr 230,000, 74,000, and 24,000 proteins (Rous sarcoma virus); Mr 230,000, 69,000, and 24,000 proteins (Fujinami sarcoma virus); and Mr 230,000, 62,000, and 54,000 proteins (Abelson murine leukemia virus).

The properties of rat brain kininase that degrade bradykinin (BK) at the Phe5-Ser6 peptide bond were compared using two different assay systems. After an enzymatic reaction, the residual BK was bioassayed using a guinea pig ileum. BK and its degraded products were also determined fluorometrically by the combined procedures of microdansylation and thin-layer chromatography. The optimal pH of the kininase was within the neutral range in both assay systems. In the bioassay system, EDTA activated the kininase without dependency on its concentrations, while sulfhydryl (SH) reagents tended to inhibit the activity at a high concentration. However, in the fluorometric assay system, EDTA did not show any effect, while SH reagents activated the kininase. Furthermore, SQ14225 did not inhibit the kininase even at a high concentration. The effect could not be determined by bioassay because the compound increased the potential for a contractile response of the ileum induced by BK. These findings suggest that the results obtained using a bioassay should be compared with those from a chemical assay for the exact elucidation of the nature of some kininases.

Oxetanocin is a novel nucleoside containing a 4-membered sugar, oxetanosyl-N-glycoside, and adenine. The effects of oxetanocin and related compounds on the infectivity of human immunodeficiency virus (HIV) were examined. They inhibited HIV infectivity in vitro. Allopurinol and mycophenolic acid produced additive anti-HIV effects when added with these compounds.

A 56-year old diabetic patient of over 20 years duration was admitted with gangrene of right foot. About a month prior to admission he injured the fourth toe of the right leg when he cut the toe nail. Two weeks later necrotic ulcer was present on it with cellulitis and 2nd, 3rd and 5th toes were also affected. Then his entire right leg was swollen and he developed fever. In spite of the treatment with antibiotics and insulin, gangrenous lesions progressed and subcutaneous emphysema was palpable beneath the inflamed area. On the 9th hospital day amputation was carried out below the knee. He had a good recovery 6 weeks after the amputation. Aerobic and anerobic cultures from the foot yielded bacteroides and pseudomonas aeruginosa. Clostridia were not isolated. A review was also carried out on ten diabetic cases of nonclostridial gas gangrene in the lower limb in Japan.

The prevalence of peripheral vascular disease (PVD) was determined in 296 Japanese diabetics (mean age 55.2 years, range 19 to 79 years), using a Doppler ultrasonic technique. PVD was diagnosed in 11.5% of the diabetic patients (7.6% females, 14.6% males). In 88% of all patients with PVD, asymptomatic impaired circulation was diagnosed. There was a clear increase of PVD with age. It was found that the increase of PVD was gradual in patients under the age of 70, from 4.3% in the younger group to 10% in patients in their 7th decade, while the frequency of PVD rose sharply to 25% in patients in their 8th decade and over. The occurrence of PVD was significantly correlated with hypertension, hypertriglyceridemia and past obesity, but not with glycemic control, serum cholesterol levels or smoking habits. Also, PVD was closely associated with persistent proteinuria, retinopathy at a rather advanced stage and calcification of leg arteries. These findings suggest that the frequency of PVD in Japanese diabetics is lower by one third and progression of PVD is more gradual than that found in similar studies in Western countries. Another distinctive feature of PVD in Japanese diabetics was the markedly high percentage of asymptomatic cases.

The left ventricular function was assessed in 70 diabetics under 60 years of age without clinically evident heart disease using established non-invasive methods, these include systolic time interval method and echocardiography. The ratio of pre-ejection period to left ventricular ejection time (PEP/ET) was remarkably elevated in diabetics with severe microangiopathy (0.431 +/- 0.037). Even in diabetics without microangiopathy PEP/ET ratio was significantly higher (0.374 +/- 0.037) compared with that in controls (0.331 +/- 0.023, P less than 0.01). Most of diabetics with a PEP/ET value of higher than 0.40 were not under proper care with regard to diabetic control. A tendency toward normalization of PEP/ET values was often observed with the improvement in diabetic control during six to twelve months among the inadequately controlled diabetics. Isovolumic relaxation time in diabetics was longer than in controls (80 +/- 14 msec, 59 +/- 11 msec, P less than 0.005). Our results suggest that abnormalities of left ventricular function in diabetics may be related to not only severity of microangiopathy but also the state of diabetic control. The maintenance of adequate control of diabetes seems to play an important role in the prevention of congestive heart failure in patients with diabetes mellitus.