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Biomedical subjects

M Inaba

Publications and source records attributed to M Inaba.

At least 109 records · Page 6Linked to original sources
PubMed1989

[Experimental and clinical studies on the exclusion and bypassing operation for abdominal aortic and iliac artery aneurysms].

For the purpose of simplifying operative techniques and decreasing operative risks, we evaluated excusion and bypassing operation for infrarenal abdominal aortic and iliac artery aneurysm (AAA) both experimentally and clinically. This method includes dissection and closure of proximal stump of the aneurysm and anatomical bypass technique in principle. In the experiments, the ratio of internal pressure of the excluded aorta (e.Ao) to systemic blood pressure (E.P.I.) was 0.62 +/- 0.03 (n = 7, mean +/- S.D.). The thrombotic occlusion period of the e.Ao was estimated to be about 2 weeks. Clinically, we have carried out exclusion operation in 40 (43.8%) out of 91 cases of AAA since June 1977. In 49% of the cases hypogastric artery aneurysm was present. The excluded aneurysm revealed thrombotic occlusion within 1 month by CT scan and rupture or DIC were seen in none of the cases. There were no operation related mortality and postoperative cumulative survival rate was 94.7% at 1 year, 55.6% at 5 and 9 years. Since this operative technique is highly safe and simple, we consider this exclusion method is valuable not only in high-risk cases of elderly patient as well as in cases with extensive aneurysm of the hypogastric artery but also in many other patients.

Aged↗
PubMed1988

Macrophages phagocytose thymic lymphocytes with productively rearranged T cell receptor alpha and beta genes.

The thymus gland is important for the formation of competent T lymphocytes. However, there is long-standing evidence that greater than 95% of newly formed thymocytes do not emigrate to peripheral lymphoid tissues but instead die locally. We have identified a rapid and selective pathway for thymocyte turnover in vitro. The mechanism entails binding, uptake, and digestion by macrophages. The susceptible cells are a subpopulation of double-positive thymocytes. These thymocytes can be enriched by virtue of their high buoyant density in Percoll and prove to have low levels of surface CD3 and little or no surface TCR. However TCR-alpha and -beta genes have undergone rearrangement, and full length alpha and beta transcripts are abundant. Therefore many double-positive cells rearrange and express TCR genes but do not have normal levels of TCR on the cell surface. We propose that thymocytes that undergo high turnover in situ are unable to form receptors that can be selected by MHC molecules in the thymus, and that these cells are recognized and cleared by the macrophage.

Gene Rearrangement, T-Lymphocyte↗
PubMed1988

A new major transmembrane glycoprotein, gp155, in goat erythrocytes. Isolation and characterization of its association to cytoskeleton through binding with band 3-ankyrin complex.

Erythrocyte membranes from goat contain a considerable amount, more than 10% of the total amount, of a glycoprotein with Mr = 155,000 (gp155) on sodium dodecyl sulfate-polyacrylamide electrophoresis gel. This report describes the first isolation and characterization of gp155. This gp155 has major trypsin-sensitive sites at each side of the plasma membrane to generate membrane-bound fragments, indicating that the gp155 spans the lipid bilayer several times. This protein consists of a single polypeptide containing about 1,200 amino acid residues corresponding to Mr = 134,000 and some complex type N-linked oligosaccharide chains. A fraction (15-20%) of the gp155 is recovered in nonionic detergent-extracted ghosts along with 25-30% of band 3 and other cytoskeletal proteins and is completely released into solution by extraction with 1 M KCl. Immunoprecipitation with anti-gp155 and anti-ankyrin antibodies of detergent-solubilized membranes separated on a gel permeation chromatography column showed that a part of the gp155 is tightly linked to band 3 with a molar ratio of 1:2 to 1:3. This gp155-band 3 complex in turn is associated to ankyrin through the binding of band 3 to ankyrin. These data indicate that, in native erythrocyte membranes, as well as in detergent solution, gp155 could play a physiological role in controlling cellular integrity and elasticity by forming the gp155-band 3-ankyrin complex. Partial amino acid sequences of the tryptic peptides are also determined.

Amino Acid Sequence↗
PubMed1988

Intervention of T-cells in transportation of mouse mammary tumor virus (milk factor) to mammary gland cells in vivo.

Using BALB/c nu/nu, BALB/c nu/nufC3H (BALB/c nu/nu mice raised by C3H/HeN foster mother), BALB/c thymus-engrafted BALB/c nu/nufC3H, BALB/c nu/+, and BALB/c nu/+fC3H mice, we examined what kinds of cells are carriers of blood-borne mouse mammary tumor virus (B-MMTV). A radioimmunoassay and an immunoperoxidase assay revealed the presence of MMTV-gp52 antigen in the mammary glands of all BALB/c nu/+fC3H and BALB/c thymus-engrafted BALB/c nu/nufC3H mice (more than 60 days old) but only of some BALB/c nu/nufC3H mice (more than 120 days old): those that possessed a significant number of functional T-cells. BALB/c nu/+ mice did not show the antigen expression at any age. Transfer experiments of cells or plasma from young (less than 12 weeks) BALB/c nu/nufC3H to BALB/c +/+ virgins revealed that cells besides T-cells can also become carriers of B-MMTV. This was confirmed by Southern blotting analyses; exogenous provirus DNA sequences were found in B-cells as well as T-cells of BALB/c nu/+fC3H mice. However, when young BALB/c nu/nu mice were inoculated with BALB/c nu/nufC3H blood, they did not show the MMTV-gp52 antigen expression. Transfer experiments of purified T-cells, B-cells, natural killer cells, and macrophages from BALB/c fC3H mice to BALB/c nu/nu mice revealed that only T-cells have the ability to transfer viral activity to the mammary glands. These results suggest that B-MMTV is carried from the gastrointestinal tract to the mammary glands by lymphoid cells such as T-cells and B-cells, then transferred to the mammary gland cells by the T-cells.

Age Factors↗
PubMed1988

Correlation between protein 4.1a/4.1b ratio and erythrocyte life span.

Erythrocyte membranes from various healthy mammals contained a doublet of protein 4.1a and 4.1b, which appeared to differ by 2-3 kDa on sodium dodecyl sulfate polyacrylamide gel electrophoresis. The ratio of protein 4.1a/4.1b showed much variety among animal species, and the 4.1a/4.1b ratio correlated to the mean erythrocyte life span, that is, the mean cell age in circulating blood. We also found that the 4.1b is the predominant form in the immature erythroid cells such as reticulocytes and K562 cells. In addition, the 4.1b but not 4.1a protein was metabolically labeled with [35S]methionine in the erythropoietic cells from anemic mouse. Immunological detection showed that there is a doublet of minor variants of protein 4.1 with apparent molecular masses slightly more than those of 4.1a and 4.1b. The ratio of these minor isoforms designated as 4.1a + and 4.1b + revealed the alteration during erythrocyte senescence as observed in 4.1a/4.1b ratio. These results show that protein 4.1 may be synthesized as 4.1b and 4.1b + and intercalated into membrane skeletons at an early stage of erythroidal differentiation, and that the posttranslational modification into 4.1a and 4.1a + appears to occur by a common mechanism in many mammalian species. Feline erythrocytes, however, appeared to lack such a postsynthetic processing of protein 4.1, and exhibited one major component of 4.1b with the other minor variant of 4.1b +.

Animals↗
PubMed1988

Neuraminidase-treated macrophages stimulate allogenic CD8+ T cells in the presence of exogenous interleukin 2.

Prior work has shown that purified, resident, and inflammatory peritoneal macrophages are weak stimulators of the allogeneic MLR. We have identified conditions whereby thioglycollate-elicited macrophages become stimulatory, but primarily for the CD8+ T cell subset. The conditions were to treat the macrophages with neuraminidase and to supplement the MLR with rIL-2. These treatments together led to proliferative and cytotoxic responses by isolated CD8+ but not CD4+ T cells. Likewise when MHC-congenic strains were evaluated, an MLR was observed across isolated class I but not class II MHC barriers. Pretreatment of the macrophages with IFN-gamma further enhanced expression of class I MHC products and stimulatory activity, but did not seem essential. While these treatments did not render macrophages stimulatory for an MLR in purified CD4+ cells, blastogenesis of CD4+ cells was observed when the MLR involved bulk T cells. Small allogeneic B lymphocytes behaved similarly to macrophages, in the pretreatment with neuraminidase and supplementation with rIL-2 rendered B cells stimulatory for allogeneic, enriched, CD8+, but not CD4+, T cells. Spleen adherent cells, which are mixtures of macrophages and dendritic cells, stimulated both CD4+ and CD8+ T cells, and neither neuraminidase nor exogenous IL-2 was required. We think that these data suggest that most macrophages and small B cells lack three important functions of dendritic cells: a T cell-binding function that can be remedied by neuraminidase treatment, a T cell growth factor-inducing function that can be bypassed with exogenous IL-2, and an IL-2 responsiveness function that is required by CD4+ lymphocytes.

Animals↗
PubMed1988

Development of donor-derived thymic lymphomas after allogeneic bone marrow transplantation in AKR/J mice.

The transplantation of bone marrow cells from BALB/c (but not C57BL/6 and C3H/HeN) mice was observed to lead to the development of thymic lymphomas (leukemias) in AKR/J mice. Two leukemic cell lines, CAK1.3 and CAK4.4, were established from the primary culture of two thymic lymphoma, and surface phenotypes of these cell lines found to be H-2d and Thy-1.2+, indicating that these lymphoma cells are derived from BALB/c donor bone marrow cells. Further analyses of surface markers revealed that CAK1.3 is L3T4+ Lyt2+ IL2R-, whereas CAK4.4 is L3T4- Lyt2- IL2R+. Both CAK1.3 and CAK4.4 were transplantable into BALB/c but not AKR/J mice, further indicating that these cells are of BALB/c bone marrow donor origin. The cells were found to produce XC+-ecotropic viruses, but xenotropic and mink cell focus-forming viruses were undetectable. Inasmuch as thymic lymphomas are derived from bone marrow cells of leukemia-resistant BALB/c strain of mice under the allogeneic environment of leukemia-prone AKR/J mice, this animal model may serve as a useful tool not only for the analysis of leukemic relapse after bone marrow transplantation but also for elucidation of the mechanism of leukemogenesis.

Animals↗
PubMed1988

Reversal of resistance to vincristine in P388 leukemia by various polycyclic clinical drugs, with a special emphasis on quinacrine.

We investigated several lipophilic drugs with a polycyclic structure for their effect on the net uptake of vincristine in vincristine-resistant P388 leukemia cells. Fourteen of 23 agents promoted vincristine uptake in the resistant cells. The net increase in vincristine uptake was caused by prevention of its outward transport rather than by stimulation of inward transport. Some of these drugs, e.g., quinacrine, dilazep, syrosingopine, simetride, etc., remarkably potentiated the cytotoxicity of vincristine against the resistant cells in vitro. Quinacrine, an antimalarial drug which had the greatest effect on vincristine uptake and relatively low host toxicity, exhibited potent therapeutic synergism in combination with vincristine in resistant leukemia-bearing mice.

Animals↗
PubMed1988

Long-term corneal endothelial changes after intraocular lens implantation.

We studied the morphologic characteristics of the corneal endothelium in a series of patients who had undergone phacoemulsification with intraocular lens implantation performed by one surgeon. Specular microscopy and computer-assisted morphometry were performed preoperatively and three years after surgery. Nineteen eyes that received posterior chamber lenses with intracapsular fixation had a mean endothelial cell loss of 18.1%, without any significant change in cell size (polymegethism) or shape variability (pleomorphism). Implantation of anterior chamber lenses with the posterior capsule left intact (18 eyes) caused a similar degree of cell loss (23.5%) but caused marked polymegethism and pleomorphism of the cells. Endothelial cell loss (28.5%) and morphologic changes were greatest in five eyes that received anterior chamber lenses because of a rupture of the posterior capsule.

Cataract Extraction↗
PubMed1988

The function of Ia+ dendritic cells and Ia- dendritic cell precursors in thymocyte mitogenesis to lectin and lectin plus interleukin 1.

The response of thymocytes to lectin is a standard tissue culture model for identifying cytokines such as IL-1 that are required for thymocyte mitogenesis. To study accessory cell requirements for these responses, it was necessary to deplete endogenous accessory cells with two techniques: anti-Ia and complement, and passage over nylon wool. Proliferation to Con A was then restored with 0.1-0.3% exogenous splenic dendritic cells, or 30-fold higher levels of peritoneal macrophages. The "costimulatory" action of IL-1, whereby responses to lectin were enhanced 3-10-fold, required the presence of dendritic cells. This effect of IL-1 could be reproduced by culturing the dendritic cells for 12 h in 1 U/ml human or murine rIL-1 alpha before addition to the thymocyte proliferation assay. The function of IL-1-treated dendritic cells was not blocked by a neutralizing anti-IL-1 antibody. The endogenous population of thymic accessory cells was partially characterized. A trace (0.1-0.3%) fraction of Ia+, Ig-, plastic nonadherent dendritic cells was visualized and enriched to a level of 1-10% by depleting CD4+,CD8+, and Ig+ lymphocytes. When this double-negative population was cultured with IL-1 and washed, the treated thymic dendritic cells were 10-fold more active as accessory cells. When the CD4-,CD8-, Ig- populations were depleted of dendritic cells with anti-Ia and complement, the subsequent addition of IL-1 had a second effect. Ia+ dendritic cells redeveloped over a 2-d interval, and they exhibited the same properties as resident dendritic cells in thymus and spleen. The majority were lysed by 33D1 anti-dendritic cell mAb and complement, lacked Fc receptors, and acted as powerful stimulators of the MLR and Con A mitogenesis. The development of dendritic cells did not occur with IL-2, -3, -4 or granulocyte/macrophage colony-stimulating factor or in nylon-nonadherent populations. The IL-1-dependent, Ia- precursor was not detectable in bone marrow. These results begin to analyze the endogenous accessory function of the thymus in culture. Dendritic cells actively stimulate thymocyte mitogenesis. The mitogenic action of IL-1 involves effects on resident Ia+ dendritic cells as well as a new population of thymic, Ia- precursors.

Animals↗
PubMed1988

Corneal endothelial changes associated with aphakic extended contact lens wear.

Wide-field specular microscopy and computer-assisted morphometry were performed on 20 aphakic eyes in 16 patients who had worn a high-water content hydrogel contact lens on an extended wear basis for at least 12 months (mean, 28 months) following intracapsular cataract extraction. When compared with 22 non-lens-wearing aphakic eyes matched for age and postoperative period, the endothelial cell changes in the above patients included a significantly higher coefficient of variation in cell area (polymegathism) and a marked reduction in the frequency of hexagonal cells (pleomorphism) without any significant difference in cell density. Although the clinical significance of these endothelial changes remains unclear, they may indicate hypoxic stress to the corneal endothelium or be an early sign of ongoing cell loss.

Aged↗
PubMed1988

Comparison of cellular basis of drug sensitivity of human colon, pancreatic, and renal carcinoma cell lines with that of leukemia cell lines.

In an attempt to find how much the low therapeutic effectiveness of antitumor drugs against so-called chemotherapy-refractory tumors such as colon carcinoma depends on drug sensitivity at the cellular level, sensitivity of five carcinoma cell lines (three colorectal, one pancreatic, and one renal) to nine typical anticancer agents was compared in vitro with that of four generally chemotherapy-susceptible leukemia cell lines. Sensitivity was assessed in terms of the percentage cell growth in control cultures, which was determined by exposing exponentially growing cells for 48 h to the following antitumor drugs: 1-(4-amino-2-methylpyridine-5-yl)-methyl-3-(2-chloroethyl)3-nitrosourea hydrochloride (ACNU), adriamycin (ADM), bleomycin (BLM), cisplatin (DDP), etoposide (VP-16), 5-fluorouracil (5FU), mitomycin C (MMC), methotrexate (MTX), and vinblastine (VLB). As expected, 10-fold or greater differences in sensitivity were scarcely ever observed between the two kinds of cell lines. Thus, we recorded a result of more (or less) sensitivity when there was a difference of 3-fold or more; and compared the drug sensitivity in every pair of carcinoma and leukemia cell lines (20 pairs for each drug). We found that carcinoma cell lines were less sensitive to VP-16, ADM, DDP, and MTX than leukemia cell lines in 18, 15, 12, and 10 of 20 pairs, respectively; only one opposite case was observed, with DDP. On the other hand, no such tendency between the two groups was observed with BLM, 5FU, or MMC. Overall, significantly different sensitivities were observed between them in 91 out of 180 pairs (i.e., 9 antitumor drugs x 5 carcinomas x 4 leukemias), and carcinoma cell lines were less sensitive than leukemia cell lines in 79 of these 91 pairs. These results suggest that the refractoriness of colon carcinoma, etc. to chemotherapy is, at least in part, due to low drug sensitivity of the tumor cell itself.

Adenocarcinoma↗
PubMed1988

Cell killing action of cell cycle phase-non-specific antitumor agents is dependent on concentration--time product.

Based on a pharmacokinetic model proposed by Jusko, which assumes that the cell killing action of cell cycle phase-non-specific agents occurs as a bimolecular reaction depending on drug concentration and cell density, we derived a cell kill kinetic equation for these drugs, including the decomposition constant in culture medium. This equation revealed that the cell killing activity of these drugs depends on the value of concentration x exposure time or the area under the drug concentration--time curve (AUC). It was also clarified that the curves for concentration--exposure time necessary for 90% cell kill on a log scale simulated on the basis of the equation differ according as whether drugs are stable or unstable in the culture medium, being expected to be linear with a slope of -1 in the former case, and to take the form of an asymptotic curve in the latter. For three cell cycle phase-non-specific agents, mitomycin C (MMC), 1-(4-amino-2-methylpyrimidine-5-yl)-methyl-3-(2-chloroethyl)3-nitrosoure a hydro-chloride (ACNU), and nitrogen mustard (HN2), we assessed the concentrations necessary for 90% cell kill (IC90) with various exposure times and the degradation rate constants under the culture conditions used. MMC was quite stable during the incubation, while ACNU and HN2 were unstable. When IC90's and exposure times were plotted on the above-mentioned graph, a linear relationship with a slope of -1 was seen for MMC, while for ACNU and HN2 the anticipated asymptotic curves resulted. We also ascertained that the decomposition constants for ACNU and HN2 expected on the basis of these curves showed a good agreement with the corresponding experimentally observed values. These results indicate that the cell killing action of cell cycle phase-non-specific drugs can be well described by a pharmacodynamic model and equation employing their decomposition constants and are dependent on the concentration-time product.

Animals↗
PubMed1988

Biological activity of 26,26,26,27,27,27-hexafluorinated analogs of vitamin D3 in inhibiting interleukin-2 production by peripheral blood mononuclear cells stimulated by phytohemagglutinin.

Vitamin D compounds suppress the production of interleukin-2 (IL-2) by peripheral blood mononuclear cells (PBMCs) stimulated with phytohemagglutinin in a dose-dependent manner. We used this suppression to test 26,26,26,27,27,27-hexafluorinated analogs of vitamin D3 for their immunosuppressive activity in PBMCs. 26,26,26,27,27,27-Hexafluoro-1,25-dihydroxyvitamin D3 and 26,26,26,27,27,27-hexafluoro-1,24-dihydroxyvitamin D3 were approximately 10 times more potent than 1,25-dihydroxyvitamin D3 in suppressing IL-2 production. 26,26,26,27,27,27-Hexafluoro-1-hydroxyvitamin D3 was 20 to 30 times less potent than 1,25-dihydroxyvitamin D3 in causing this effect. The relative biopotency of each vitamin D3 analog toward PBMC proliferation was roughly similar to that toward IL-2 production by PBMCs. Suppression of PBMC proliferation by vitamin D3 analogs seemed to be a secondary effect of their inhibition of IL-2 production.

Calcitriol↗
PubMed1988

Wheat germ agglutinin-positive cells in a stem cell-enriched fraction of mouse bone marrow have potent natural suppressor activity.

In the present study we have characterized natural suppressor (NS) cells, which nonspecifically suppress mitogen responses and mixed-lymphocyte reaction. The strongest NS activity was found in a fraction of relatively low-density cells (1.063 less than p less than 1.075) obtained by equilibrium density centrifugation. Further purification and characterization of these NS cells by using a fluorescence-activated cell sorter indicated that wheat germ agglutinin (WGA)-positive cells have potent NS activity, whereas WGA-negative cells have no NS activity. Spleen colony-forming unit (CFU-S) assays demonstrated a significant correlation between the number of CFU-S cells and the NS activity in the bone marrow. However, WGA-positive cells obtained from the bone marrow of animals treated with 5-fluorouracil, which cells in turn were exposed to 5-fluorouracil, showed a marked reduction in NS activity. These results suggest that the pluripotent stem cells have NS activity when the cells are in the cycling phase but not when the cells are in the G0 phase. It seems possible that apparently primitive cells play an important role in down-regulation of immune responses.

Animals↗
PubMed1988

Pharmacokinetic approach to rational therapeutic doses for human tumor-bearing nude mice.

To improve clinical predictability from therapeutic results of various antitumor agents in human tumor/nude mouse models it seems to be important to use a dose pharmacokinetically equivalent to the clinical dose. Thus, we attempted to find the dose of a given drug that can reproduce in the nude mouse a plasma level similar to that seen in human patients treated with an effective dose of the drug based on comparative pharmacokinetic studies between man and nude mouse. As a result, those of 3 alkylating agents, mitomycin C, 3-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-1-(2-chloroethyl)-1-nitrosourea (ACNU) and cyclophosphamide, and those of 2 antimitotic agents, vincristine and vinblastine, were estimated to be one-fourth or one-fifth of their maximum tolerated doses (MTD's). On the other hand, in the case of adriamycin, its MTD was approximately equivalent to its clinical dose pharmacokinetically. In contrast, clinically equivalent doses of 2 antimetabolites tested, 5-fluorouracil and methotrexate, were significantly greater than their MTD's; i.e., their plasma levels did not reach the effective clinical ones even when their MTD's were administered to the nude mice. These results suggest that the antitumor effects of most antitumor agents are over- or underestimated in this model when MTD's are used as a therapeutic dose, and indicate that the use of clinically equivalent doses determined pharmacokinetically is desirable.

Animals↗
PubMed1988

Responsiveness of human gastric tumors implanted in nude mice to clinically equivalent doses of various antitumor agents.

To reproduce clinical effects of various antitumor agents in the human tumor/nude mouse model, we investigated the responsiveness of 11 lines of human gastric tumor xenografts to doses of the agents pharmacokinetically equivalent to the respective clinical doses, which we designated the "rational dose" (RD). We found that the response rates to mitomycin C, 3-[(4-amino-2-methyl-5-pyrimidinyl]methyl-1-[2-chloroethyl]-1- nitrosourea (ACNU), adriamycin, 5-fluorouracil were 18%, and that to vinblastine was 30%; on the other hand, those to vincristine, methotrexate, and cyclophosphamide were poor. In contrast, in our previous study using the maximum tolerated doses, response rates to mitomycin C, ACNU, and vinblastine were as high as 64-82%, and those to adriamycin and 5-fluorouracil were 18%. When these results were compared with the clinical response rates of gastric tumors, as a whole, the results with RD's exhibited much better coincidence with the clinical data in terms of relative therapeutic potency, indicating the validity of the use of clinically equivalent doses instead of maximum tolerated doses in the human tumor model.

Animals↗