Pathogenesis of cardiomyopathy caused by anthracycline antibiotics effect of pulmonary stenosis on the development of cardiomyopathy.

This study was undertaken to elucidate the effect of pressure load on the development of cardiomyopathy induced by daunorubicin in the right ventricle of rabbits on which pulmonary stenosis had been performed. The right ventricular pressure after occlusion of the pulmonary artery was approximately twice that prior to occlusion. Pulmonary stenosis apparently produced hypertrophy of the right ventricular myocardium within approximately 2 weeks of occlusion. In rabbits with pulmonary stenosis, the characteristic myocardial degenerative changes induced by daunorubicin were found on the right ventricular wall. However, in rabbits without pulmonary stenosis, myocardial lesions were observed only on the left ventricular wall. The pressure load acting as a mechanical stress increases myocardial damage induced by daunorubicin. It is well known that anthracyclines take effect on cells in which nucleic acid synthesis is augmented and the pressure load results in the enhancement of protooncogene expression in myocytes and a subsequent increase in protein synthesis. These results suggest that the pressure load may play a significant role in anthracycline cardiomyopathy by increasing protein synthesis in the myocardium.

Cardiotoxicity of a new anthracycline derivative (SM-5887) following intravenous administration to rabbits: comparative study with doxorubicin.

The degree of cardiotoxicity of SM-5887 compared with that of doxorubicin was investigated in rabbits. Two experimental groups were administered high and low doses of SM-5887, respectively. One group was administered doxorubicin and another group was administered the vehicle only were prepared as positive and negative controls, respectively. Drugs were intravenously administered 3 times a week for 8 weeks. At terminus, electrocardiograms were recorded under anesthesia. The blood was collected for haematology and blood biochemistry analyses. Myocardial tissue damage was evaluated using light and electron microscopy. In the electrocardiogram study, prolongation of QTc interval and ST-T change were observed in rabbits administered SM-5887 and doxorubicin. Morphological studies showed that myocardial tissue damage in animals administered SM-5887 was comparable to that in the negative controls, and less than that observed in the positive controls. The general toxicological investigations uniformly indicated lower toxicity in the SM-5887 group than in the doxorubicin group at equivalent dosages. In total, considering the results of antitumor efficacy studies comparing SM-5887 with doxorubicin, these results indicate that the cardiotoxicity of SM-5887 is very slight, and that the general toxicity of SM-5887 is lower than that of doxorubicin.

Serum lipid and lipoprotein metabolism after glucose ingestion in NIDDM and IGT patients. Apolipoprotein-containing particles.

OBJECTIVE: Through analysis of apolipoprotein-containing particles after glucose ingestion, we determined abnormal lipid metabolism in NIDDM patients and subjects with impaired glucose tolerance (IGT) without obesity or hyperlipidemia. RESEARCH DESIGN AND METHODS: Apolipoprotein (apo) AI- or B100-containing particles or remnant-like particles (RLPs) were isolated by immunoaffinity columns prepared with monoclonal antibodies. The cholesterol contents in these particles after glucose ingestion (0, 30, 60, and 120 min) were analyzed in 18 nonobese NIDDM patients, 18 nonobese IGT subjects, and 33 normal control subjects. RESULTS: Changes in cholesterol content in apo B100 particles after oral glucose ingestion decreased significantly in both the NIDDM group and the IGT group; the changes were insignificant in the nondiabetic group. Changes in cholesterol content in the apo AI particles after oral glucose ingestion showed no differences between the three groups. Changes in cholesterol content in RLPs after oral glucose ingestion increased significantly in both the NIDDM group and IGT group; the changes were insignificant in the nondiabetic group. The changes in apo B100 after oral glucose ingestion decreased significantly in the three groups; however, apo AI after oral glucose ingestion showed no change in the three groups. CONCLUSIONS: The cholesterol content in apo B100 particles might decrease and the cholesterol content in RLPs might increase after oral glucose ingestion in not only NIDDM patients but also IGT subjects. The changes may be partially due to insulin resistance.

Apoptosis as a mechanism of skin renewal: Le(y)-antigen expression is involved in an early event of a cell's commitment to apoptosis.

Skin renewal is a typical example of the active participation of a cell in its own death process. Cells arising from mitotic activity in the stratum germinativum of the epidermis continuously migrate upwards to the stratum corneum, where dead cells are eventually desquamated. Recent studies have suggested that apoptosis is involved in the dynamic process of skin renewal. However, this still remains to be further elucidated. In this paper, we investigated the involvement of apoptosis in the skin renewal process. Changes in the morphology of cells in different epidermal layers were compared with histochemical analyses of the extent of DNA fragmentation, as determined by nick end-labelling, and of the reactivities to a monoclonal antibody directed to Le(y)-antigen, difucosylated type 2 chain determinant, which has a close association with apoptosis, and to a monoclonal antibody directed to the proliferating cell nuclear antigen. The results show that apoptosis proceeds concomitantly with cell movement in the epidermis. It seems likely that commitment of a cell to death by apoptosis occurs in the epidermal tissue immediately after completion of cell proliferation, and that Le(y)-antigen expression may be involved in the entire apoptotic process including this early event.

Influence of imidapril on abnormal biochemical parameters in salt-loaded stroke-prone spontaneously hypertensive rats (SHRSP).

Many of the disorders in urinary, biochemical, and hematological parameters induced by salt-loading in stroke-prone spontaneously hypertensive rats (SHRSP) were significantly ameliorated by chronic treatment with angiotensin converting enzyme inhibitors, imidapril (1 and 2 mg/kg) and enalapril (2 mg/kg). Through the improvement of these parameters, the treatment reduced the incidence of stroke but did not suppress the development of hypertension. These results suggest that the prophylaxis of stroke in SHRSP is probably due to systemic improvement as judged from the parameters of renal functions.

[Comparative studies of measuring condition of activated partial thromboplastin time and contact factors in experimental animals].

For establishing the optimal incubation time (OIT) for measurement of the activated partial thromboplastin time (APTT) in dogs, rabbits, guinea pigs, rats and mice, we determined the shortest clotting time of the plasma from each animal species and compared them with that of human plasma. The OIT for APTT determination was 15 to 30 sec in guinea pigs, rats and mice and 5 to 10 minutes in dogs and rabbits. The mouse APTT (about 30 sec) with the OIT thus determined was similar to human APTT, and relatively longer than APTT in other animal species (10-20 sec). To elucidate the mechanism of the species differences in OIT, we examined the plasma of each animal species for the activity of the contact factors such as factor XII, factor XI, high molecular weight kininogen (HMWK) and prekallikrein (PK) and their effect on the coagulation of contact factor-deficient plasma. The total activity of contact factors was higher in dogs and guinea pigs and lower in rabbits and mice than that in humans. Species difference with the factor XII, Factor XI and HMWK was noted in clotting time but not in OIT. These results suggest that the species difference in OIT for APTT is probably due to difference in activity of the plasma contact factors and in the mode of coagulation for each contact factor.

Antitumor activity and toxicity of serum protein-bound platinum formed from cisplatin.

When cisplatin was incubated with mouse serum, its cytotoxicity towards P388 leukemia cells decreased with the formation of non-ultrafiltrable or protein-bound platinum. The cytotoxicity of prepared mouse serum protein-bound platinum at 100 microgram/ml (as the cisplatin-equivalent concentration) was less than that of cisplatin at 0.125 microgram/ml. The prepared protein-bound platinum exhibited antitumor activity against colon adenocarcinoma 26 in mice, when administered iv daily for 9 consecutive days at 32 and 64 mg/kg (as the cisplatin-equivalent dose). Cisplatin similarly administered exhibited antitumor activity at daily doses of only 1 and 2 mg/kg. Administration of the protein-bound platinum at such high doses as 32 and 64 mg/kg (as the cisplatin-equivalent dose) caused elevation of serum BUN and reduction of bone marrow cells in mice. After iv administration of cisplatin to mice at 6 mg/kg, ultrafiltrable platinum was detected in the plasma for the first 30 min. Thereafter platinum was found only in protein-bound form. When mice were iv inoculated with colon adenocarcinoma 26 more than 30 min after cisplatin administration, no prolongation of the life span was observed. From these results, it is concluded that mouse serum protein-bound platinum does not contribute significantly to cisplatin antitumor activity and toxicity in mice.

Construction of a composite thin-element TLD using an optical-heating method.

A composite thermoluminescent dosimeter (TLD), composed of four, thin TL elements with a high-speed reader, has been developed by employing an optical-heating method. Each TL element, which is 15 mg/cm2 thick with a 3 mm dia., is prepared by applying Li2B4O7:Cu or CaSO4:Tm to a plastic substrate 14 mg/cm2 thick. Each element can be heated to 350 degree C within 0.8 sec. by IR radiation from a tungsten lamp. The characteristics of this TLD system include the following: (1) the detection limit of the Li2B4O7:Cu is 3 mR and the limit for CaSO4:Tm is 0.1 mR; (2) the energy-dependence curves are similar to the dose-equivalent curve, showing slight under-responses by 15% near 70 KeV for Li2B4O7:Cu and over-responses by 50% at high energies for CaSO4:Tm; (3) despite quick heating, the residual dose is as low as 0.1% of the last exposure signal; (4) responses are very stable for more than 1,000 cycles of repeated exposure readings; (5) no false signal could be detected, even in the cases of sweat or soil contamination; (6) the thin Li2B4O7;Cu element can be used for skin dose monitoring; and (7) the processing time of the automatic reader for the composite dosimeter is 3 hr/500 dosimeters. This TLD system can be applied to personnel dosimetry, gate monitoring and environmental monitoring.

Effect of common protective antigen vaccination to protect mink from challenge exposure with Pseudomonas aeruginosa.

The protein portion of endotoxin (OEP), or common antigen of Pseudomonas aeruginosa prepared from strain N10 of P aeruginosa, was examined as a possible vaccine against this organism in mink. Mink were given OEP vaccine and challenge exposed by instillation with the inoculum into the nostril. They survived after this exposure with 4 median lethal (LD50) doses of strain NC-5 (protease negative, elastase negative) or with 160 LD50 doses of strain 5 (protease positive, elastase positive). Strain NC-5 belonged to TYPE 5 AND strain 5 belonged to type 8 (according to the serotyping method of Homma). Strain N10, the source of OEP, belonged to serotype 5. Thus, the mink vaccinated with OEP vaccine were able to stand challenge exposure to both homologous and heterologous serotype strains. More mink given OEP vaccine survived the challenge exposure by intranasal spraying with virulent strain 5 than did those in the nonvaccinated control group, with a significant difference. When the surviving mink of the vaccinated group were rechallenge exposed with 300 or 3,000 LD50 doses of the same strain a month later, most of them survived.