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Biomedical subjects

K Sekita

Publications and source records attributed to K Sekita.

At least 19 recordsLinked to original sources
PubMed1992

Disposition of beta-hexachlorocyclohexane, p,p'-DDT, and trans-chlordane administered subcutaneously to monkeys (Macaca fascicularis).

To evaluate skin lipid analysis for the accumulation level of environmental pollutants, the correlations between organochlorine pesticide residues in adipose tissue, blood, and skin lipids of monkeys were studied. The mixture of beta-hexachlorocyclohexane (beta-HCH), p,p'-DDT, and trans-chlordane was subcutaneously given to monkeys once weekly for 5 weeks at dose levels of 1 and 10 mg/kg. The chemicals distributed in adipose tissue, blood, and skin lipids were determined six times after the last dosing at intervals of 4 to 9 weeks. Oxychlordane and p,p'-DDE were detected in all tissues together with the administered chemicals. In blood and adipose tissue, trans-chlordane decreased rapidly and oxychlordane and p,p'-DDE increased gradually and then remained at constant levels. beta-HCH and p,p'-DDT in adipose tissue increased until the 12th week and then decreased in all animals. The correlation coefficients between blood and adipose tissue regardless of dose level and collection time for each chemical ranged from 0.83 to 0.94. Correlation coefficients between skin lipids and adipose tissue varied with the chemical, namely, 0.31, 0.72, 0.81, 0.81, and 0.83 for p,p'-DDE, trans-chlordane, p,p'-DDT, beta-HCH, and oxychlordane, respectively. The results indicated that skin lipid analysis may be useful for the evaluation of specific pollutants in the body burden.

Adipose Tissue↗
PubMed1992

[Studies on reinforcing effects of methylephedrine, caffeine and their mixture with intravenous-self administration in rhesus monkeys].

The reinforcing effects of methylephedrine hydrochloride (ME), anhydrous caffeine (CA) and their mixture (ME+CA) were studied by the intravenous cross self-administration experiment and by the progressive ratio experiment in four male rhesus monkeys each. In the intravenous cross self-administration experiment, ME, CA and ME+CA were found to have reinforcing effects. Self-administration rates above the level of cocaine, a typical reinforcing drug, were not observed in ME or CA alone, but observed in their mixture (120 + 126 micrograms/kg/inj.: M dose or 480 + 504 micrograms/kg/inj.: H dose). The minimum reinforcing doses were 120 micrograms/kg/inj. (M dose) for ME, 126 micrograms/kg/inj.: (M dose) for CA, and ME 30 micrograms+CA 32 micrograms/kg/inj. (L dose) for the mixture. Vomiting was observed during the session in monkeys which showed higher self-administration rates of ME and the mixture, and decreases in the rates were observed in these animals on the next day. One animal at H dose of the mixture, which showed a high self-administration rate on both the 1st and 2nd days, died after the end of the session on the 2nd day. In the progressive ratio experiment, the final ratios at 120 micrograms/kg/inj. of ME, 126 micrograms/kg/inj. of CA and the mixture of ME 120 micrograms/CA 126 micrograms/kg/inj. were almost equal to or less than that of saline (negative control). Thus, these drugs didn't show reinforcing effects at the above levels. However, a reinforcing effect was observed in three out of four monkeys administered 1920 micrograms/kg/inj. of ME, 2016 micrograms/kg/inj. of CA, and the mixture of ME 1920 and CA 2016 micrograms/kg/inj.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

[Experimental studies on the efficacy of PAM against sumithion poisoning].

The efficacy of 2-Pyridine aldoximide methiodide (PAM) for lethal acute poisoning by fenitrothion (FNT) was investigated in mice and dogs. Sumithion (FNT 51.7%, emulsifiers 12.5% and xylol 35.8%) was used as fenitrothion. 1. FNT at 1500 mg/kg was administered orally to mice. After ten minutes 50 mg/kg of PAM was injected once iv, and plasma, erythrocyte, brain, liver and kidney ChE activities were investigated 30 and 60 min later. Recovery in ChE activity was found in every organ but the brain at 30 min, but no efficacy of PAM was observed at 60 min. 2. After administering 1500 mg/kg of FNT orally to mice, the life-saving effect was studied from the changes in mortality due to variation of PAM route, dosage and number of administrations. With oral administration of 1500 mg/kg of FNT, 75 to 85% of the animals died. The mortality ranged from 80 to 95% when the animals received a single intravenous injection of 50 mg/kg of PAM between zero and 60 min following the FNT administration. Thus, a single intravenous administration of PAM at 50 mg/kg showed no life-saving effect on the animals given FNT. However, the mortality was reduced to 45% when the animals received repeated subcutaneous injections of 20 mg/kg of PAM at a 3-hr interval from just after administration of FNT over 24-hr. In other repeated subcutaneous injection experiments, the mortality ranged from about 55 to 65%. In any PAM-treated group, the survival time was prolonged. This life-prolonging effect was more marked in the case of repeated subcutaneous injections of PAM by 12-hr and even more by 24-hr, than in the case of a single intravenous injection. FNT treatment caused marked salivation and watery diarrhea, and PAM clearly inhibited these signs of the muscarinic action of FNT. There was a high relationship between this inhibitory effect of PAM on the muscarinic action and its life-prolonging or life-saving effect. 3. PAM (150 mg/animal/shot, iv) was given 12 or 13 times during 7 hr from 10 min (4 animals), 3 hr (1 animal) and 6 hr (2 animals) after administration of FNT at 150 mg/kg. The effects of PAM on survival, plasma ChE activity, plasma protein (TP) and hematocrit (Ht) values were examined. The 3 dogs given FNT alone all died within 53 hr of administration, whereas 6 out of 7 animals treated with PAM survived.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1991

Relationship of intraglomerular coagulation and platelet aggregation to glomerular sclerosis.

In order to investigate the relationship between intraglomerular coagulation and glomerular sclerosis, the distribution of fibrin-related antigen (FRA) in glomeruli without extracapillary lesions was examined by immunoperoxidase microscopy in 80 patients with IgA nephropathy (IgA-N). A total of 302 glomeruli were examined, including 20 with global sclerosis, 31 with segmental sclerosis (SS glomeruli), and 251 nonsclerosed glomeruli. In the nonsclerotic areas of SS glomeruli, the deposition of FRA was significantly greater than in the nonsclerosed glomeruli. In the nonsclerosed glomeruli FRA was mainly found in the mesangium, while in the nonsclerotic areas of SS glomeruli FRA was not only present in the mesangium but also in the endothelium of the glomerular capillary loops. FRA-positive microclots were also often observed attached to the endothelium of the capillaries of the nonsclerotic areas of SS glomeruli. Cross-linked FRA was also observed in the endothelium of the same capillaries using the monoclonal antibody DD3B6/22. Deposition of von Willebrand factor (vWF) was greater in the endothelium than in the mesangium in the same areas. Aggregated platelets adhering to the glomerular capillary walls in these areas were frequently detected using the monoclonal antibody P2. Such distribution of platelets and vWF showed that the endothelium of the nonsclerotic areas of SS glomeruli was more severely damaged than that of nonsclerosed glomeruli. These findings suggest that endothelial cell damage might activate the intraglomerular coagulation, which might be one of the factors in the development of global glomerular sclerosis.

Antigens, Human Platelet↗
PubMed1991

Chronic toxicity of 2,4,6-tri-tert-butylphenol in rats.

In order to study the chronic toxicity of 2, 4, 6-tri-tert-butylphenol (TTBP), groups of 40 Slc: Wistar rats of either sex were fed diet containing 0, 30, 100, 300 or 1000 ppm of TTBP for up to 24 months. Hematological, biochemical and histopathological examinations performed periodically revealed slight microcytic anemia, changes in some biochemical parameters relating to liver function and focal necrosis of liver cells following TTBP administration, and these changes observed in females were severer than those in males. No neoplastic responses following TTBP administration were noted. Noticeable changes were not observed in the 30 ppm group throughout the experimental period. Thus, it was concluded that TTBP causes liver injury characterized by focal necrosis with microcytic anemia and elevations of serum phospholipids and cholesterol levels presumably occurring as secondary effects following the liver injury.

Anemia↗
PubMed1990

[Evaluation of immunotoxicity testings using azathioprine-treated rats: the International Collaborative Immunotoxicity Study (Azathioprine)].

The immunotoxicological effects of azathioprine (AZP) were examined by enhanced histopathological and function tests in the rat which is routinely used in toxicological tests. Male F344 rats were orally administered AZP in doses of 0, 2.5, 12.5 and 25.0 mg/kg/day for 28 days. Reductions in the organ weights of the thymus, spleen, liver, kidney, and testis in a dose-dependent manner were confirmed. Hematological examination revealed a marked decrease in the number of WBCs, which was associated with a decrease in the number of lymphocytes. In the femoral bone marrow, a significant reduction in the total cell number attributed to the decrease in the number of lymphocytes and granulocytes was observed. Histopathologically, atrophy and obfuscation of the corticomedullary junction in the thymus, the decrease of lymphocytes in the thymus and spleen, and the disappearance of germinal centers in the lymph nodes were observed. As for the functional testings, azathioprine treatment did not affect remarkably the PFC number and the NK cell activity per unit spleen cell number. However, the total spleen cell number per spleen was decreased in a dose-dependent manner. Therefore, the total functional activities (PFC and NK) per spleen were decreased. Thus, in the AZP-treated F344 rats, it was shown that the enhanced histopathological tests were useful to evaluate potential risks to the immune system.

Animals↗
PubMed1989

Long-term observations of autoimmune-prone mice treated for autoimmune disease by allogeneic bone marrow transplantation.

Long-term effects of allogeneic bone marrow transplantation (ABMT) across major histocompatibility complex barriers were studied in (NZB x NZW)F1 (B/W), BXSB, and MRL/Mr-lpr-lpr (MRL/lpr) mice with established autoimmune disease at the time of ABMT. In the BXSB or B/W mice, ABMT cured all aspects of autoimmune disease. Glomerular damage, revealed by histological study was dramatically improved. Serological abnormalities and immunologic functions also were normalized. Correction of autoimmune disease and advanced renal disease in BXSB and B/W mice regularly lasted greater than 5-6 mo and even 1 yr after ABMT. In the MRL/lpr mice, however, autoimmune and renal disease at first improved but then recurred after ABMT, apparently because of intolerance of mice for high doses of irradiation and a high degree of resistance of recipient stem cells to irradiation. In this model, H-2 typing revealed that by the time of relapse, immunocompetent cells of the chimeric mice had been replaced by host (MRL/lpr; H-2k) cells. B220+ Ly-1+ cells, present in increased numbers in untreated MRL/lpr mice, initially returned to normal levels after ABMT but then reappeared in the MRL/lpr mice that had received marrow from donors having few such lymphocytes. Thus, our results show that MRL/lpr mice possess abnormal radioresistant stem cells and provide impressive evidence that the origin of autoimmune diseases in this strain, as in the several other strains studied, residues in abnormalities present in stem cells.

Animals↗
PubMed1989

Immunoelectron microscopic localization of fibrin-related antigen in human glomerular diseases.

The distribution of fibrin-related antigen (FRA) in glomeruli was examined by immunoelectron microscopy in 9 patients with idiopathic membranous nephropathy (MN), 8 patients with minimal-change nephrotic syndrome, and 10 patients with IgA nephropathy (IgA-N), using antisera against human gamma--chain, alpha-chain, mu-chain, and fibrinogen. Electron-dense reaction products of FRA were observed in the endothelium, subendothelium, and/or in electron-dense deposits (EDD). Among the three glomerular diseases, the amount of electron-dense reaction products of FRA in the endothelium was highest in MN. This suggests that coagulation occurs on the endothelium in MN. Although the mesangial EDD of IgA-N were intensely stained with reaction products of FRA, the staining was weak in the subepithelial EDD of MN. This suggests that FRA hardly penetrates into the subepithelial EDD in MN.

Antigens↗
PubMed1989

Ultrastructural distribution of von Willebrand factor in human glomerular diseases.

The distribution of the von Willebrand factor (vWF) as the factor-VIII-related antigen in glomeruli was examined by immunoelectron microscopy in 10 patients with idiopathic membranous nephropathy (MN), 8 patients with minimal-change nephrotic syndrome (MCNS), and 11 patients with IgA nephropathy (IgA-N). Electron-dense reaction products of vWF were observed in the endothelium and mesangium in all specimens examined. However, they were not detected in subepithelial electron-dense deposits of MN. The amount of electron-dense reaction products of vWF in the endothelium was significantly higher in MN than that in MCNS or IgA-N. This finding suggests that the glomerular endothelium in MN is the site of the local activation of coagulation and platelet aggregation system in glomerular capillary wall lesions.

Glomerulonephritis, IGA↗
PubMed1988

B cell-stimulating activity of lymphoid cell membrane fractions.

We had previously found that a mutagenized subline of the mouse thymoma EL4 very efficiently stimulates B cells via direct cell-cell contact, thereby inducing the responsiveness of B cells to cytokines. In the present study, we investigated whether this effect could also be mediated by plasma membranes of EL4 (and other) cells. By equilibrium centrifugation of cell homogenates, four cell membrane fractions of different densities were obtained. These were tested for (a) stimulation of B cell proliferation in conjunction with EL4 supernatant as source of cytokines, and (b) enhancement of B cell proliferation at suboptimal concentration of lipopolysaccharide. It turned out that all membrane fractions from a variety of T lineage cells (mutant EL4, parent EL4, BW5147, P198 thymomas, normal T cells) and B lineage cells (BCL1 lymphoma, X63Ag8 cytoplasma, normal B cells) exhibited similar B cell stimulating activity in both assays. Interleukin 1 activity was not detected in the membrane fractions. Heat treatment abolished all activity showing that protein at least was involved. Either protease treatment or extraction with detergent abolished the activity of subcellular fractions rich in intracellular membranes but not that of fractions most enriched in surface membranes. Finally, erythrocyte membranes also displayed B cell-stimulating activity sensitive to protease and detergent extraction. In contrast, and in confirmation of a previous study, liver cell membrane was inhibitory in the B cell proliferation assay with lipopolysaccharide. In conclusion, the effects of cell membranes did not reflect the unique activity of intact mutant EL4 cells. However, with respect to our data it is conceivable that membrane proteins with relatively nonspecific activity and wide distribution among lymphoid cells could play a role in T cell help together with molecules specialized in cell adhesion and cell triggering.

Animals↗
PubMed1988

Immunologic and clinical studies on murine experimental autoimmune gastritis induced by neonatal thymectomy.

Experimental autoimmune gastritis (AIG), defined by the appearance of auto antibodies to parietal cells, was induced by neonatal thymectomy in BALB/c nu/+mice 3 days after birth. Vitamin B12 absorption and intrinsic factor in the stomach extract decreased compared with those in AIG-negative control groups. No decrease of the serum A/G ratio in AIG-bearing mice was observed. Although development of anemia, as evaluated by a decrease in hematocrit value, was poor until 12 mo of age and the gastric mucosa was hypertrophic, the AIG resembled human pernicious anemia rather than Ménétrier's disease. Adoptive transfer of spleen cells, but not sera, of AIG-bearing nu/+ into BALB/c nu/nu mice caused AIG in all animals 1 mo later, indicating the involvement of lymphocytes in the induction mechanism of AIG. Cytofluorometric and immunohistochemical analysis of lymphocytes in the gastric mucosa revealed T-cell infiltration at an early stage (1.5-3 mo) followed by B cell infiltration (6 mo). When the fraction enriched with parietal cells, which were intensively stained with sera of AIG-bearing mice and fluorescent antibody to mouse immunoglobulin G, was injected into the foot pads of AIG-bearing nude mice, typical delayed-type hypersensitivity reaction was observed in all animals. This was not seen in the mice injected with the cell fraction enriched with chief cells, although a few of them were stained by the immunofluorescent technique. Thus, the delayed-type hypersensitivity reaction seems to be directly involved in the mechanism of tissue damage.

Anemia, Pernicious↗
PubMed1987

Theoretical and practical aspects of B-cell activation: murine and human systems.

We have reviewed observations which were made during studies of murine and human B-cell responses in vitro. One currently faces difficulties in drawing any clear schema as to which external signals elicit which responses (activation, proliferation, differentiation) in B cells. However, the most potent antigen-dependent or polyclonal B-cell responses in vitro occur when, in addition to various cytokines, accessory cells, serum etc., the cultures contain either a) intact T-helper cells which enter into cell-to-cell contact with B cells, or b) some B-cell "mitogen" (T-independent antigen). Murine B cells activated with LPS and anti-Ig antibodies represent a model for the study of IL2 receptor expression and function. LPS does not act on human B cells. Certain mutant EL-4 thymoma cells are potent activators of murine and human B cells via a direct cell-to-cell interaction. The majority of human B cells can be induced to proliferate and generate a few hundred antibody-secreting cells each in the presence of such thymoma cells and a mixture of cytokines. From a practical point of view, this observation should be useful in a variety of investigations such as the analysis of the human B-cell specificity repertoire.

Animals↗
PubMed1987

Treatment of systemic and organ-specific autoimmune disease in mice by allogeneic bone marrow transplantation.

Autoimmune diseases have been clinically divided into those which are systemic and organ-specific. (NZB X NZW) F1, MRL/1, and BXSB mice have been utilized as models for systemic autoimmune diseases. When these mice which had already developed autoimmune diseases were irradiated and reconstituted with T cell-depleted allogeneic bone marrow cells, the recipient survived for more than 5 months without showing graft-versus-host reaction. Immunohistopathological studies revealed that deposits of immunoglobulin and complement into the glomeruli were markedly reduced. In addition, levels of circulating immune complexes and auto-antibodies such as anti-dsDNA and anti-Sm antibodies decreased. Three months after bone marrow transplantation, T cell dysfunction was restored, and hyperfunction of B cells and macrophages were normalized. These data prompted us to examine whether or not organ-specific autoimmune diseases can be treated by allogeneic bone marrow transplantation. NOD mice which develop insulitis and overt diabetes were used for this experiment. The mice showed marked infiltration of T cells into the pancreatic islets which resulted in selectively destroying beta cells. Most of the T cells are Lyt-1+, and some are Lyt-2,3+. When NOD mice (6 months old) were irradiated and reconstituted with bone marrow cells of young BALB/c nu/nu mice (less than 2 months), the NOD mice exhibited neither insulitis nor overt diabetes. Deposits of immunoglobulin in the mesangial area of the glomeruli disappeared 3 months after bone marrow transplantation. Assays for immunological functions revealed that NOD mice showed hyperfunction of T cells, B cells, and macrophages. In NOD mice reconstituted with BALB/c nu/nu bone marrow cells, these functions were normalized. Newly developed T cells are found to be tolerant of both bone marrow donor-type and host-type major histocompatibility complex determinants. These results suggest that bone marrow transplantation is a strategy to be considered as an approach to the treatment for both systemic and organ-specific autoimmune diseases in humans.

Animals↗