Kiyoyasu Nagai

Diminution of contractile response of the aorta from endotoxin-injected rats

The contractility of a helical strip of the thoracic aorta was studied in rats injected intraperitoneally with endotoxin. The contractile response to any of the agonistic agents, KCl, norepinephrine or 5-hydroxytryptamine was time dependently diminished in the endotoxin-injected rats compared to the controls. This diminution preceded the depression of blood pressure. When the external calcium concentration was increased from 2.5 to 7.5 mM after the KCl (80 mM)-induced contractile response reached a plateau, the diminished contractile response was reversed in the endotoxin-injected group. The strips from the endotoxin-injected rats showed a higher 45CaCl2 uptake into the vascular tissue with the KCl-stimulated contraction. These findings suggest that the blood pressure depression during endotoxic shock may be attributed partially to the diminished contractility of the blood vessels and that this diminution is induced by a disorder of calcium utilization within vascular smooth muscle during vascular contraction.

Modulation of vascular tonus by the endothelium in experimental diabetes

The role of the vascular endothelium in the contractile response of aortas from streptozotocin-induced diabetic rats was investigated using selected agents. Contractile response to KCl was not affected by removal of the endothelium in both diabetic and control groups, but was diminished in the diabetic rats compared to the control rats. Contractile response to clonidine markedly increased after removal of the endothelium in the control group, with the increment being less in the diabetic group. After removal of the endothelium, contractile response to clonidine was poorer in the diabetic group than the control group. Vascular relaxation induced by acetylcholine disappeared when the endothelium was removed in both diabetic and control groups. The degree of reaction to acetylcholine did not significantly differ between the two groups. These results suggest that in diabetic rats, abnormality of the endothelium-dependent vascular relaxation is specific for alpha 2 receptor while that of the vascular smooth muscle reactivity is not receptor-specific.

Mechanism of Hematuria in Glomerular Disease

From an electron-microscopic study in a case of diffuse membranous glomerulonephritis, we would like to propose a possible mechanism of hematuria in glomerular disease. There are several factors we sh

Inhibitory effect of vitamin E (α -tocopherol) on spontaneous platelet aggregation in whole blood

Abstract Vitamin E (D-α-tocopherol) inhibited spontaneous human platelet aggregation in whole blood in the 20–200 μ g/ml range. When α -tocopherol (20 μ g/ml) and aspirin (0.5 mM), or α -tocopherol and the mixture of phosphocreatine (1.5 mM) and creatine phosphokinase (50 U/ml) (CP/CPK) were added to this reaction system, a synergic inhibitory effect on aggregation was observed. On the other hand, when both α -tocopherol and the specific inhibitor of platelet activating factor (CV-3988 : 0.38 mM) were added to this system, the inhibition was the same as that caused by the addition of CV-3988 alone, suggesting there was no synergism, i.e., that the effect of α -tocopherol is related to the inhibition of platelet activating factor (PAF)-induced platelet aggregation in whole blood. However, α -tocopherol (20 or 50 μ g/ml) did not inhibit PAF (10 nM) induced platelet aggregation in platelet rich plasma (PRP). These results suggest that the inhibition of platelet aggregation in whole blood by α -tocopherol is due to the inhibition of PAF synthesis, and is unrelated to adenosine diphosphate (ADP) or thromboxane A2.

Clonal evolutions during long-term cultures of bone marrow from de novo acute myeloid leukaemia with trilineage myelodysplasia and with myelodysplastic remission marrow.

Summary. We previously established a long‐term bone marrow culture (LTBMC) system in which novel abnormal karyotypes could emerge in vitro prior to the appearance of the same karyotypes in vivo in patients with myelodysplastic syndrome (MDS). We extended our study to examine whether acute myeloid leukaemia (AML) transformed from MDS (MDS/AML) and de novo AML with trilineage myelodysplasia (AML/TMDS) show clonal evolution in LTBMC similar to that of typical AML or MDS. We also analysed the cytogenetic changes in cultures with bone marrows from AML with myelodysplastic remission marrow (AML/MRM) as well as chronic myeloid leukaemia (CML) to compare them with typical AML with respect to the liability of clonal evolution. Among the 34 AML cases, abnormal karyotypes were newly detected in four of seven MDS/AML, three of six AML/TMDS and three of three AML/MRM. Novel abnormal karyotypes were also observed in nine out of 13 CML cases after culture. In contrast, no other abnormal karyotypes were found after culture in 18 typical AML without myelodysplasia. These findings suggest that AML/TMDS and AML/MRM are different from typical AML and are similar to MDS/AML and CML in view of their potential for disease progression from latent multiple clones. Typical AML may develop from a single abnormal clone without any subclones.

Desensitization of alpha-1 adrenergic receptor mediated smooth muscle contraction in aorta from endotoxic rats

Desensitization of vascular smooth muscles in endotoxemia was studied using the aorta from intraperitoneally endotoxin-injected rats. The KCl- and phenylephrine-induced contractions were significantly decreased in the endotoxic aorta compared to the control. In the endotoxic aorta the phenylephrine-induced contracture showed a gradual tension decrease after reaching a plateau and was attenuated by prior exposure to high concentration of phenylephrine, while KCl produced a sustained contraction and it was not affected by prior exposure to phenylephrine. The phenylephrine- and KCl-induced contractures of the control aorta showed stable plateaus and were not affected by prior exposure to phenylephrine. Neither diminished contractile force nor in vitro desensitization of phenylephrine contracture of isolated aorta was prevented by pretreatment of endotoxic rats with an alpha-adrenergic antagonist, phentolamine. These findings suggest that the contractile response to phenylephrine is easily desensitized in the endotoxic aorta compared to the control and neither this in vitro desensitization nor the diminution of contractile force is caused by in vivo exposure of aorta to a high concentration of catecholamines during endotoxemia.

The role of platelet hyperfunction in thrombus formation in hyperlipidemia

The mechanism of thrombus formation in hyperlipidemia was studied. Attempts at artificial creation of an arterial thrombus in control rabbits stenosing the femoral artery by ligature were not successful unless ellagic acid was administered by injection. However, in rabbits with hyperlipidemia, mere creation of stenosis in the femoral artery resulted in a high percentage of thrombus formation. In rabbits with hyperlipidemia, both thromboxane (Tx) A2 biosynthesis in platelets and prostacyclin (PGI2) biosynthesis in the aorta were increased and these changes were noted at the level of cyclooxygenase in the arachidonic acid metabolic pathway. Therefore, these results suggest that thrombi are likely to be formed in hyperlipidemia and that such thrombus formation is due largely to platelet hyperfunction.

Suppression of mitogen- and alloantigen-induced proliferation by chronic lymphocytic leukemia cells of T-cell origin

Abstract Leukemic T cells from a patient with chronic lymphocytic leukemia (T-CLL cells), which could neither respond to mitogens and alloantigens nor stimulate responder cells in one-way mixed lymphocyte culture, markedly suppressed the mitogen- and alloantigen-induced proliferation of normal lymphocytes. This suppression was not attributed to the nonspecific effect of T cells or leukemic cells, and not due to the direct cytotoxic effect of the T-CLL cells. The suppressor activity of these cells was resistant to mitomycin C and a low or moderate dose of irradiation, but sensitive to a high dose of irradiation. They functioned in a genetically nonrestricted fashion. These functional T-CLL cells are suggested to be a neoplastic form of a T-cell subset which possessess suppressor activity.

Presence of pluripotent haemopoietic precursors in vitro (CFU-mix) in haemopoietic tissues from mice of W/Wv genotype

Abstract. The presence or absence of haemopoietic precursors, which produce mixed colonies in vitro (CFU‐mix) was examined in the bone marrow and spleen of (WB x C57BL/6) F1‐W/Wv mice. Despite the failure of macroscopically evident colonyformation in the spleens of irradiated mice, haemopoietic cells of W/Wv mice did produce macroscopically‐evident mixed colonies containing erythroid cells, macrophages, and often megakaryocytes, in culture medium. The size and constitution of mixed colonies derived from W/Wv mice were comparable to those of mixed colonies from congenic +/+ mice. The present results appear consistent with in vivo haemopoiesis in the W/Wv mice, which is obviously deficient, but sufficient for survival.

Efficacy of sulbactam/cefoperazone for the treatment of infections in patients with hematologic diseases

The efficacy and safety of sulbactam/cefoperazone (SBT/CPZ) was studied in 94 patients with severe infections and concomitant hematologic diseases. All of the study patients were included in the evaluation for safety, and 76 cases were evaluable for efficacy. Clinical efficacy was excellent in 13 cases (17.1%), good in 27 cases (35.5%), fair in seven cases (9.2%), and poor in 29 cases (38.2%). The bacteriologic eradication was 66.7% for Gram-negative bacilli and 50.0% for Gram-positive bacteria. The efficacy rate for neutropenic patients with counts less than 50 mm3 and 100 mm3 were 47.5 and 42.9%, respectively. Efficacy in patients for whom other antibiotic therapy before treatment with SBT/CPZ had been ineffective was 46.2%. Side effects were reported in one case (1.1%), and abnormal serum liver tests in five cases (5.3%); both returned to normal after discontinuation of the study medication. SBT/CPZ was an effective antibiotic for the treatment of severe infections in the presence of concurrent hematologic diseases.