Serum theophylline concentration levels and preventative effects on exercise-induced asthma.
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Adolescent↗
Biomedical subjects
N Sakaguchi
Publications and source records attributed to N Sakaguchi.
Hypoalbuminemia, oliguria and peripheral cyanosis in an infant with severe atopic dermatitis.
A six-month old male infant with severe atopic dermatitis was admitted with hypoalbuminemia, oliguria and cyanosis of the extremities. There was marked edema and generalized eczema with foul, yellowish exudates. The patient's major clinical manifestations were attributed to the loss of albumin through the skin. Although atopic dermatitis is a common disease in children, here we want to show that systemic disturbances may arise from such condition, describe the total care given the patient, and emphasize the wholistic approach in managing cases of severe atopic dermatitis. Intensive treatment was instituted and the patient was discharged after three weeks and remained in a stable condition.
Cyanosis↗
Thyroid cell proliferation-inhibiting activity in serum of patients with chronic renal failure on hemodialysis.
To investigate the possible humoral factor(s) influencing thyroid cell activity in chronic renal failure, we measured serum activity which stimulates or inhibits the [3H]thymidine incorporation by using a cultured functioning rat thyroid cell line (FRTL-5 cells) in 17 patients on hemodialysis and 19 healthy controls. Polyethylene glycol-treated serum was centrifuged and FRTL-5 cells were cultured with the supernatant. Thyroid stimulating activity was determined by [3H]thymidine incorporation after incubation for 72 h. There was no significant difference in [3H]thymidine incorporation between cultures incubated with patient and normal serum, suggesting the absence of the stimulating activity. But when patient serum was added to cultures together with 20 or 50 microU/ml of TSH, the TSH-stimulated increase in [3H]thymidine incorporation was significantly decreased, indicating the presence of thyroid inhibiting activity, which possibly inhibits the thyroid cell growth. This activity was not significantly altered by hemodialysis. No significant correlation was observed between this activity and serum levels of thyroid hormones or the iodine concentration. Patients on hemodialysis therefore have serum thyroid inhibiting activity which is nondialysable, differs from iodine, and could influence the thyroid cell growth.
Adult↗
Four subclones with distinct immunoglobulin light chain phenotypes. (kappa+lambda+, kappa+, lambda+ and kappa-lambda-) from acute leukemia.
A human acute lymphoblastic leukemia (ALL) cell line, BALM-9, was established from the peripheral blood specimen of a immunoglobin (lg) phenotype, the established BALM-9 cell line expressed both kappa and lambda light (L) chains simultaneously in a range of 30-80%. Two-color flow cytometric analysis demonstrated that there was a distinct population of kappa lambda double positive cells as well as kappa single, lambda single, and double negative populations. Therefore, subclones were obtained from each population by limiting dilution and were designated BALM-9KL (kappa+lambda+), BALM-9K (kappa+lambda-), BALM 9N (kappa-lambda-). Western blotting confirmed the results of the immunofluorescence test at the protein level. In BALM-9N, L chains were absent even in the cytoplasm as demonstrated by Western blotting. Evidence that the subclones have the same ancestry was provided both by cytogenetic analysis and by Southern blotting, which revealed the 14q32 chromosomal rearrangement as a common abnormality and the same IgH gene arrangement among the subclones. The existence of a kappa lambda positive B cell population suggests a transient stage of normal B cell maturation. These subclones might represent such a stage and thus provide a useful means of analyzing the mechanism of this double light chain expression.
Antigens, CD↗
[Clinical reliability of a new IgE detection system using chemiluminescent enzyme immunoassay named LUMIWARD immunoassay system].
The measurement of allergen-specific IgE antibodies and total IgE was performed with LUMIWARD immunoassay system (chemiluminescent enzyme immunoassay) using 406 serum samples obtained from patients with various allergic diseases and 81 serum samples from normal donors. These were collected by departments of internal medicine, pediatrics, dermatology and otorynolaryngology at eleven institutes in Japan. In addition to a comparative study with CAP RAST, skin tests were also performed to establish a clinical diagnosis. Simultaneous measurements were performed and an excellent correlation with CAP RAST was observed with a concordance rate of 92.6% and correlation coefficient of 0.922. The specificity determined by the normal serum samples was 96.4% for CAP RAST and 96.2% for LUMIWARD. The sensitivity determined by the samples, of which etiological allergens were identified clinically, was 84.8% for CAP RAST and 85.5% for LUMIWARD. Among them, the sensitivity of skin test was 91.8%. The concordance rate with clinical diagnosis was as high as 90.6% and 90.8% for CAP RAST and LUMIWARD. The normal upper limit of total IgE by cumulative 95% value was calculated to be 170 IU/ml for adult subjects. These results indicate the clinical usefulness of the LUMIWARD immunoassay system in evaluating IgE antibodies and total IgE.
Adult↗
Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases.
Approximately 10% of peripheral CD4+ cells and less than 1% of CD8+ cells in normal unimmunized adult mice express the IL-2 receptor alpha-chain (CD25) molecules. When CD4+ cell suspensions prepared from BALB/c nu/+ mice lymph nodes and spleens were depleted of CD25+ cells by specific mAb and C, and then inoculated into BALB/c athymic nude (nu/nu) mice, all recipients spontaneously developed histologically and serologically evident autoimmune diseases (such as thyroiditis, gastritis, insulitis, sialoadenitis, adrenalitis, oophoritis, glomerulonephritis, and polyarthritis); some mice also developed graft-vs-host-like wasting disease. Reconstitution of CD4+CD25+ cells within a limited period after transfer of CD4+CD25- cells prevented these autoimmune developments in a dose-dependent fashion, whereas the reconstitution several days later, or inoculation of an equivalent dose of CD8+ cells, was far less efficient for the prevention. When nu/nu mice were transplanted with allogeneic skins or immunized with xenogeneic proteins at the time of CD25- cell inoculation, they showed significantly heightened immune responses to the skins or proteins, and reconstitution of CD4+CD25+ cells normalized the responses. Taken together, these results indicate that CD4+CD25+ cells contribute to maintaining self-tolerance by down-regulating immune response to self and non-self Ags in an Ag-nonspecific manner, presumably at the T cell activation stage; elimination/reduction of CD4+CD25+ cells relieves this general suppression, thereby not only enhancing immune responses to non-self Ags, but also eliciting autoimmune responses to certain self-Ags. Abnormality of this T cell-mediated mechanism of peripheral tolerance can be a possible cause of various autoimmune diseases.
Animals↗
Molecular cloning of a cDNA clone encoding a phosphoprotein component related to the Ig receptor-mediated signal transduction.
We have shown previously that a 52-kDa phosphoprotein (p52) co-precipitated with Ig receptor (IgR)-associated MB-1 protein was inducibly phosphorylated by the stimulation with 12-O-tetradecanoyl-phorbol-13-acetate. By immunizing the 52-kDa protein co-precipitated with MB-1, we prepared a mAb (19-14), which can immunoprecipitate the p52 and the associated kinase molecule. Immune complex kinase assay with the 19-14 mAb showed that the p52 is associated with a novel kinase molecule and is involved in IgR-mediated signal transduction. Here we isolated a cDNA clone (alpha 4) from a murine bone marrow cDNA library in lambda gt-11 vector by the 19-14 mAb. The alpha 4 cDNA encodes a novel protein of 340 amino acids with multiple potential phosphorylation sites. The 1.4-kb alpha 4 mRNA is expressed in various cells including cell lines of B lineage, T lineage, monocytic, fibroblast, and normal organs such as liver, spleen, thymus, and brain. To study the molecule encoded by the alpha 4 cDNA, we produced a chimeric protein of the glutathione S transferase (GST)-alpha 4 in pGEX-3X expression vector. The 19-14 mAb binds to the GST-alpha 4 fusion protein. Rabbit anti-alpha 4 Ab prepared by immunizing the GST-alpha 4 fusion protein immunoprecipitated a 52-kDa phosphoprotein from WEHI-231 cells. The 52-kDa phosphoprotein immunoprecipitated by the anti-alpha 4 Ab is tightly associated with kinase activity that is similarly observed with the p52 protein reported previously. Moreover, the 52-kDa phosphoprotein immunoprecipitated with the anti-alpha 4 Ab is identical to the p52 by the protein comparison on non-equilibrium pH gradient gel electrophoresis/SDS-PAGE, isoelectric focusing/SDS-PAGE, and V8 protease mapping. The 52-kDa phosphoprotein is associated with functional components that are inducibly phosphorylated by anti-IgM stimulation. These results suggested that the alpha 4 gene-encoded molecule is functionally involved in the IgR-mediated signal transduction in B cells.
Amino Acid Sequence↗
Improved detection of medically important fungi by immunoperoxidase staining with polyclonal antibodies.
This study was performed to identify pathological fungi of eight species [Aspergillus fumigatus, Candida albicans, Torulopsis (Candida) glabrata, Cryptococcus neoformans, Fusarium anthophilum, Rhizopus oryzae, Sporothrix schenckii and Trichosporon beigelii] in formalin-fixed, paraffin-embedded tissue sections by indirect immunoperoxidase staining. Mature albino rabbits were immunized with formalin-killed organisms. Antibodies were prepared by precipitation. Immunoperoxidase staining was applied to the paraffin-embedded tissue sections of experimentally infected mice and human autopsy and surgical specimens. Although the cell walls of each fungus stained clearly, many cross-reactivities appeared. However, it was possible to obtain specificity for the eight species by absorption and dilution of the antisera.
Animals↗
Anti-CD40 monoclonal antibody induces the proliferation of murine B cells as a B-cell mitogen through a distinct pathway from receptors for antigens or lipopolysaccharide.
To study the activation and differentiation of murine B cells, we prepared a hybridoma secreting monoclonal antibody, LB429, which can directly induce the proliferation of murine B cells in vitro. LB429 recognizes a B cell specific surface molecule of 45 kDa. It recognizes an epitope of murine CD40 produced as a soluble fusion protein with glutathione S-transferase. LB429 stains COS-7 transfectant with murine CD40 cDNA and mature B-cell lines but does not stain pre-B cell lines. Two color staining demonstrated that the epitope recognized with LB429 appears on the surface of B220+ cells of spleen and bone marrow. LB429 can induce a strong proliferation of murine B cells from spleen in the absence of initial triggering with anti-IgM antibody or with anti-IgM antibody + IL-4. LB429 induced the cell size enlargement and the cell cycle transition of resting B cells as well as lipopolysaccharide (LPS). LB429 and LPS stimulate B cells synergistically in vitro by accumulating 44.7% of cells in S/G2/M phases of cell cycle. However, stimulation of spleen B cells with LB429 resulted in the increase of sIgM high+ sIgD(high)+ B cells, in contrast LPS showed the proliferation of both sIgM(high)+ sIgD(high)+ B cells and sIgM(low)+ sIgD(high)+ B cells. These results suggested that LB429 and LPS cause the proliferation of B cells through different stimulatory pathways. This anti-mouse CD40 antibody (LB429) is a very useful reagent to study the activation and differentiation of B cells in vitro.
Animals↗
Intussusception of the appendix: a report of three cases with different clinical and pathologic features.
Three cases of intussusception of the appendix (IA) with distinctive pathologic changes were reported. All patients were women with different clinical presentations. Grossly, a complete intussusception was found in one case (case 1), while the others (cases 2 and 3) showed a partial intussusception. In case 1, almost the total segment of the appendix bearing the villous adenoma with focal malignant transformation became completely telescoped into the cecum. In case 2, no underlying appendiceal lesion was disclosed. In case 3, appendiceal endometriosis was found as the point of traction. Awareness of such a rare complication associated with various appendiceal lesions provides a clue for making an accurate diagnosis and selecting appropriate surgical management.
Abdominal Pain↗
Selective induction of cell death in cancer cells by gallic acid.
Gallic acid (3,4,5-trihydroxybenzoic acid) is a naturally occurring plant phenol obtained by the hydrolysis of tannins and is know to show some pharmacological activities. In screening anti-cancer agents in traditional Chinese medicines, gallic acid was found to show cytotoxicity against all cancer cells that we examined in this study (IC50s: 4.8-13.2 micrograms/ml). Gallic acid was found to show cytotoxicity against primary cultured rat hepatocytes and macrophages, and lesser cytotoxicity against fibroblasts and endothelial cells. Cell death in dRLh-84 cells occurred within 6h after gallic acid treatment at a concentration of more than 20 micrograms/ml. A study of structurally related compounds suggested that the cytotoxicity shown by gallic acid was not a common feature in phenolic compounds, but was a fairly specific characteristic of gallic acid. That is, three adjacent phenolic hydroxyl groups of gallic acid were responsible for the cytotoxicity, and the carboxyl group was not responsible, but seemed to be implicated in distinguishing between normal cells and cancer cells.
Animals↗
Pharmacokinetics and pharmacodynamics of the tulobuterol patch, HN-078, in childhood asthma.
BACKGROUND: Recently, a novel percutaneous adhesive tulobuterol preparation, HN-078, has been developed and tests using healthy adult subjects have indicated it to be effective for controlling exacerbations early in the morning if applied at bedtime. In children, percutaneous application is very important to eliminate side effects, including abdominal pain and appetite loss. OBJECTIVE: We report the pharmacokinetics and pharmacodynamics of tulobuterol patch, HN-078, in the treatment of childhood asthma. METHODS: Single applications of HN-078 were applied transdermally in six children with asthma who had been admitted to a hospital. Subjects weighing less than 30 kg received 1 mg of tulobuterol while subjects weighing 30 kg or above received 2 mg on the chest for 24 hours. Serum tulobuterol levels and peak expiratory flow rate were determined before and after each application. RESULTS: Cmax of tulobuterol was determined to be 1.33 +/- 0.21 ng/mL, Tmax was 14.0 +/- 2.0 hours, and AUCO-t was 27.1 +/- 4.2 ng.hr/mL. These pharmacokinetic parameters per body surface area of children were nearly equivalent to those of adults obtained in other studies. Peak expiratory flow rate values obtained after application of HN-078 significantly increased in comparison to those obtained before application. No significant changes were observed in pulse rate or blood pressure, and no side effects were found with regard to the subjective symptoms and skin conditions. CONCLUSIONS: These results suggest that the patch formulation of tulobuterol, HN-078, will be very useful for the treatment of pediatric asthma. It is especially significant that no side effects were observed.
Administration, Cutaneous↗
[Investigation into the therapeutic efficacy of continuous isoproterenol inhalation in relation to respiratory infections in asthmatic children].
In our Department, continuous isoproterenol inhalation therapy has been conducted on status asthmatics over the last 10 years. In the present study, we investigated whether there are any differences in the therapeutic efficacy of continuous inhalation of isoproterenol in the presence or absence of respiratory infections which may induce or aggravate asthma attacks. The treatment period was significantly longer in patients with pneumonia. Further prolongation of the treatment period was noted in patients with atelectasis. However, there were no apparent differences in therapeutic efficacy according to age or the severity of attacks. These findings suggest that continuous inhalation of isoproterenol is very effective for status asthmatics if respiratory infections are thoroughly controlled.
Administration, Inhalation↗
Antioxidant, gallic acid, induces apoptosis in HL-60RG cells.
Gallic acid, a naturally occurring plant phenol with antioxidative activity, was found to induce cell death in promyelocytic leukemia HL-60RG cells, although many antioxidants are well known to protect the cell from oxidative stress. Morphological and biochemical studies indicated that the gallic acid-induced cell death is apoptosis. Flow cytometric analysis revealed that the apoptosis was not triggered at a specific phase of the cell cycle and that 2 h exposure of gallic acid to HL-60RG cells was enough to induce apoptosis. The inhibitory assay suggested that gallic acid-induced cell death was mediated by reactive oxygen species such as hydrogen peroxide, superoxide anion in addition to Ca2+ ion, calmodulin-dependent enzymes. Structure-activity analysis suggests that gallic acid induces apoptosis in HL-60RG cells, depending on its distinctive feature derived from the structure but not on its antioxidative activity.
Animals↗
B cell Ag receptor mediates different types of signals in the protein kinase activity between immature B cell and mature B cell.
Ig receptor (IgR) on the surface of B cells mediates the Ag-specific stimulatory signal for B cell proliferation and differentiation. In immature B cells, the stimulatory signal causes an inhibitory effect which is believed to be a key phenomenon in B cell tolerance or B cell anergy. Here, we studied the molecular mechanism of the inhibitory response of the IgR-mediated signal transduction that results in the programmed cell death of immature B cells. To analyze the downstream molecules of the IgR-mediated signal transduction, we prepared a mAb against a 160-kDa membrane protein (p160) that can coprecipitate the kinase molecule(s) acting on serine, threonine, and tyrosine residues. Anti-IgR stimulation induces the increase of the kinase activity coprecipitated with the p160 protein in mature B cell BAL17 and normal adult spleen B cells. This result suggest that the p160-associated kinase activity is one of the downstream events of the IgR-mediated signal transduction cascade. Interestingly, immature B cell lymphoma WEHI-231 and the neonatal spleen B cells showed the adverse reaction of the p160-associated kinase which results in the transient loss of the kinase activity. Moreover, the transient decrease of the p160-associated kinase was caused by the tyrosine phosphatase activity induced by the stimulation of IgR in WEHI-231. The results suggest that this molecular difference in the downstream events of the IgR-mediated signal transduction between immature B cells and mature B cells already begins at the transmembrane level in the IgR-mediated signal transduction pathway.
Animals↗
Identification of a 52-kDa molecule (p52) coprecipitated with the Ig receptor-related MB-1 protein that is inducibly phosphorylated by the stimulation with phorbol myristate acetate.
Triggering of the Ig receptor (IgR) induces the activation in multiple intracellular signal transduction reactions including protein tyrosine phosphorylation, activation of phospholipase C, increased inositoltriphosphate, increased diacylglycerol, intracellular Ca2+ mobilization, and activation of protein kinase C. The IgR-complex, composed of mu-chain, L chain, Ig-alpha (MB-1), and Ig-beta (B29) proteins, is a functional unit both for expression of IgR and for signal transduction into cells, possibly by physical association with the down-stream functional molecules. An important functional motif ((D or E)-X7-(D or E)-Y-X3-L-X7-Y-X2-(L or I)) in the cytoplasmic domain of MB-1 molecule was shown to bind with several phosphoprotein components including src-type tyrosine kinases and phosphatidylinositol-3 kinase. To further study the functional components, we analyzed the phosphoprotein molecules coprecipitated with MB-1 protein. We found that a 52-kDa protein is coprecipitated with MB-1 protein and is inducibly phosphorylated by the stimulation with PMA. A rat mAb, prepared by immunizing the 52-kDa protein purified from SDS-PAGE, could detect the similar 52-kDa phosphoprotein (p52) expressed on the cell surface. In comparison with the 52-kDa protein in the immunoprecipitate of MB-1, the p52 migrated to the same position on 2-D gel electrophoresis (nonequilibrium pH gradient gel electrophoresis/SDS-PAGE). An in vitro kinase reaction analysis demonstrated that the p52 is tightly associated with the tyrosine kinase molecule(s), one of which is an 80-kDa protein containing an apparent autophosphorylation activity. These molecules would provide the informations of the down-stream molecules in the cascade reactions of the IgR-mediated signal transduction.
Amino Acid Sequence↗
Ionizing radiation and autoimmunity. Induction of autoimmune disease in mice by high dose fractionated total lymphoid irradiation and its prevention by inoculating normal T cells.
Ionizing radiation can functionally alter the immune system and break self-tolerance. High dose (42.5 Gy), fractionated (2.5 Gy 17 times) total lymphoid irradiation (TLI) on mice caused various organ-specific autoimmune diseases, such as gastritis, thyroiditis, and orchitis, depending on the radiation dosages, the extent of lymphoid irradiation, and the genetic background of the mouse strains. Radiation-induced tissue damage is not the primary cause of the autoimmune disease because irradiation of the target organs alone failed to elicit the autoimmunity and shielding of the organs from irradiation was unable to prevent it. In contrast, irradiation of both the thymus and the peripheral lymphoid organs/tissues was required for efficient induction of autoimmune disease by TLI. TLI eliminated the majority of mature thymocytes and the peripheral T cells for 1 mo, and inoculation of spleen cell, thymocyte, or bone marrow cell suspensions (prepared from syngeneic nonirradiated mice) within 2 wk after TLI effectively prevented the autoimmune development. Depletion of T cells from the inocula abrogated the preventive activity. CD4+ T cells mediated the autoimmune prevention but CD8+ T cells did not. CD4+ T cells also appeared to mediate the TLI-induced autoimmune disease because CD4+ T cells from disease-bearing TLI mice adoptively transferred the autoimmune disease to syngeneic naive mice. Taken together, these results indicate that high dose, fractionated ionizing radiation on the lymphoid organs/tissues can cause autoimmune disease by affecting the T cell immune system, rather than the target self-Ags, presumably by altering T cell-dependent control of self-reactive T cells.
Animals↗
Induction of autoimmune disease in mice by germline alteration of the T cell receptor gene expression.
Germline expression of rearranged TCR alpha-chain transgenes with the Ig H chain enhancer reproducibly elicits T cell-mediated autoimmune disease in the thyroid gland, gastric mucosa, Langerhans islets, salivary gland, ovaries, and testes in selected strains of normal mice. Multiple organs are destroyed in a single transgenic mouse and the same organ in transgenic strains with different MHC background, suggesting the transgene expression can elicit self-reactive T cell clones having different Ag specificities and MHC restrictions. Construction of this autoimmune-inducing TCR alpha EH transgene does not require particular V alpha J alpha gene segments or Ag specificities. Moreover, the autoimmune disease can be adoptively transferred to syngeneic normal mice by T cells expressing endogenous TCR alpha-chains. Taken together, these results indicate that the TCR alpha EH transgene expression does not suppress endogenous alpha-chain gene rearrangement and may trigger the expansion/activation of various self-reactive T cells expressing endogenous TCR alpha- and beta-chains. Furthermore, it appears that the transgene-induced autoimmune T cells are not deleted in the normal thymus or rendered anergic upon contact with the normal target self Ag, but can be controlled by a T cell-dependent mechanism, since transfer of the transgenic bone marrow cells to histocompatible SCID mice produces the same autoimmune disease as in the donors, and the autoimmune development in the SCID mice is effectively prevented by co-transfer of syngeneic nontransgenic T cells. This novel autoimmune model produced by genetic manipulation of the T cell lineage, not the target self Ag or the environment of T cell differentiation/selection, should be useful for elucidating the immunologic and genetic basis of autoimmune disease.
Age Factors↗