Studies on antitumor-active 2,3-dioxopiperazine derivatives. II. Synthesis and structure-antitumor activity relationship of 1-benzyl-2,3-dioxopiperazine derivatives.
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Biomedical subjects
Publications and source records attributed to S Kishimoto.
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In the present study 5 patients with common variable hypogammaglobulinemia (CVH) and 4 patients with selective IgA deficiency (IgA-D) were analyzed for the cellular defects responsible for impaired Ig synthesis with use of peripheral blood lymphocytes stimulated with either PWM or EBV in vitro. By the use of co-culture with PWM, all the patients examined had intrinsic B cell defects restricted to the synthesis of Ig class corresponding to the low or absent Ig class(es) in the sera. Two types of excessive suppressor T activity were found, which were abrogated by irradiation. One was isotype-nonspecific and the other was IgA-specific. Moreover, failure of IgA-specific helper T activity was demonstrated. The use of EBV as an agent that polyclonally activates B cells independently of T cells and monocytes should allow a clearer delineation of the level of the B cell defects. When co-cultured with EBV, B cells from 3 patients with CVH produced normal to subnormal quantities of IgM although they could produce no IgM upon co-culturing with normal T cells and PWM. B cells from 2 patients with CVH could produce IgM normally by stimulation with either PWM or EBV; however, there was no restoration to produce IgG or IgA in these patients. In addition, B cells from 2 patients with IgA-D produced not only IgG and IgM but also IgA almost normally at 4 days after in vitro stimulation with EBV.
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Regional specific antibodies and gel permeation chromatography were used to analyze the molecular forms of motilin in the human gut and plasma and in the porcine gut. The same antibodies were also used for immunocytochemical localization of the cell of origin of motilin. Two main molecular forms of motilin were identified, peak I eluting at a volume suggesting a larger molecular weight substance (Kav = 0.16) and peak II coeluting with the porcine motilin standard (Kav = 0.67). Peak I accounted for over 50% of the total motilin immunoreactivity in the human gut, whereas in the porcine intestine it represented less than 5%. Peak I thus appeared to have a greater N-terminal sequence similarity with the porcine motilin standard. Chromatographic analysis of human plasma showed the presence of both immunoreactive peaks in approximately equal amounts which were both suppressed following infusion of somatostatin. Infusion of porcine motilin resulted in the expected rise of plasma immunoreactivity in the peak II position, whereas peak I was significantly depressed, suggesting the possibility of a negative feedback. Immunocytochemistry revealed that both antibodies immunostained equally the non argentaffin cell, which contained small round, electron-dense granules. In addition some argentaffin enterochromaffin cells were stained predominantly with the N-terminal specific antibody.
The urinary extracts from patients with aplastic anaemia and from healthy donors were investigated in vivo and in vitro for their ability to stimulate megakaryopoiesis and platelet production. There was a significantly higher concentration of thrombopoiesis stimulating factor (TSF) and megakaryocyte colony stimulating factor (MEG-CSF) in the urine from patients with aplastic anaemia than in that from healthy donors. Neuraminidase treatment did not affect the thrombopoietic activity of TSF, whereas coexisting erythropoietin (EPO) in the extract lost in its activity in vivo. These findings suggest that TSF and/or MEG-CSF seems to be different from EPO and that the urine from aplastic anaemia patients would be a good source of TSF and MEG-CSF for purification and characterization.
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In order to investigate the possible involvement of gastrointestinal hormones in functional disorders of the digestive tract, serum motilin, neurotensin and gastrin levels in their response to oral intake of fat and glucose were examined in patients with irritable colon syndrome and dumping syndrome. The following results were obtained. (1) Basal serum motilin levels were higher in patients with irritable colon syndrome than in normal subjects, and remained high after ingestion of either 50 g of butter or 50 g of glucose. (2) No consistent response in serum neurotensin levels was found in patients with irritable colon syndrome or in normal subjects. (3) An immediate increase in serum gastrin levels was found in response to fat ingestion both in patients with irritable colon syndrome and in normal subjects, but there was no difference between these two groups. (4) In a patient with typical dumping syndrome, a markedly high level of fasting serum motilin was found, and the level increased further after the oral intake of glucose. These findings suggest that motilin may be involved in the irritable colon syndrome and dumping syndrome.
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A 28-year-old man with immunodeficiency with hyper IgM was studied. His serum immunoglobulins were characterized by the absence of IgA and low level of IgG associated with high level of IgM. The in vitro pokeweed mitogen (PWM)-induced immunoglobulin synthesis by his peripheral blood lymphocytes was depressed completely for IgA and moderately for IgG although normal numbers and proportions of IgA- and IgG-bearing lymphocytes (on the surface) were demonstrated in the peripheral blood. His T cells could not help IgA production by either normal or his own B cells, whereas they were more efficient helpers for IgM production by his own B cells than were normal T cells. In addition, his B cells produced no IgA and less IgG than normal B cells when co-cultured with normal T cells. This suggests that the failure of IgA specific T helper activity and the maturation arrest of B cells at the stage of the switchover from IgM- to IgG- and/or IgA-producing cells may be the major cause for the hypogammaglobulinaemia in this patient. It is uncertain whether the maturation arrest of B cells is secondary to the T cell defect in helper function for IgA production.
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As determined by 31p-NMR spectroscopy, intracellular pH of hereditary spherocytes was lower (pH 6.7-6.9) than that of normal red cells. The level of adenosine diphosphate in hereditary spherocytes was found to be persistently high. The metabolism of nucleotides and other phosphoryl compounds in human red blood cells have been studied in detail by 31p-MNR spectroscopy. However, to our knowledge, there seems to be no report describing the result of 31p-NMR spectroscopy on red blood cells from hereditary spherocytosis.