Adenosine deaminase in adult T cell leukemia.
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Biomedical subjects
Publications and source records attributed to N Taniguchi.
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A sensitive enzyme immunoassay method for rat gamma-glutamyl transpeptidase was developed that was able to quantitate between 5 to 500 ng of the enzyme. The enzyme contents of fetal liver, adult liver, hyperplastic nodules, and various tissues including hepatoma were determined. Normal rat liver contained very little enzyme, while fetal liver and hepatoma tissue contained high levels. The gamma-glutamyl transpeptidase content of the liver was assayed during the process of 3'-methyl 4-dimethyl-aminoazobenzene-induced hepatocarcinogenesis. The content was increased at an early stage, then decreased, and again increased at the stage when hepatoma developed. The change of the enzyme content determined by an enzyme immunoassay was highly consistent with that determined by enzymatic assay. This indicates that the increased activity of the enzyme as previously reported was accompanied by an increased immunoreactive enzyme protein. Immunohistochemical studies on the hyperplastic nodule revealed the presence of gamma-glutamyl transpeptidase in the hepatocyte membrane.
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A successful embolization for life-threatening uterine hemorrhage is described in a patient with acute promyelocytic leukemia and disseminated intravascular coagulation. On admission the patient was in the 6th week of gestation with incomplete abortion and uterine hemorrhage. In addition to combination chemotherapy and anticoagulant therapy, dilatation and curettage were also performed. After the operation the uterine hemorrhage was progressively increased in amount and was not responsive to usual measures. Embolization of bilateral uterine arteries using Gelfoam was performed with a dramatic improvement of the hemorrhage.
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The in vivo expression of T-cell activation antigens defined by means of an OKT series of monoclonal antibodies and the anti-Tac antibody was evaluated in peripheral T lymphocytes obtained from patients with infectious mononucleosis and in cerebrospinal fluid (CSF) cells collected from individuals with mumps meningitis by the immunoperoxidase method. Although Tac antigen was definitely expressed on about 10% of CSF cells in mumps meningitis, Tac+ T cells could not be identified on any peripheral blood T cells in infectious mononucleosis, which expressed OKIa 1+, OKT10+, and OKT9+ determinants, as a probable sign of in vivo activation. The coexpression of Ia+ antigens on a T-cell functional subset might be important for their functional properties. Our kinetic study and cell cycle analysis of the expression of these activation antigens suggested that Tac antigen might be expressed at the early stage of the G1 phase of the cell cycle; OKT9+ antigen at the late stage of the G1; and Ia+ and OKT10+ determinants might be expressed at the S phase or later on in vitro, probably one after another.
A comparative study using hydrazinolysis has revealed that the oligosaccharide pattern of gamma-glutamyltranspeptidase purified from rat AH-66 hepatoma cells is very different from that of the enzyme from rat liver. Studies of oligosaccharides in each fraction have clarified the structural basis of the difference found in the sugar chains of the two enzymes. The sugar chains of the liver enzyme were all acidic, while 28% of those of the hepatoma enzyme were neutral, the latter being composed of high-man-nose-type and complex-type sugar chains. Three prominent structural differences were found in the acidic sugar chains of the two enzymes: (a) the sugar chains of the liver enzyme have complete outer chains, Gal beta 1 leads to 4GlcNAc beta 1 leads to, while many of those of the hepatoma enzyme have incomplete outer chains without galactose (Gal); (b) the Gal beta 1 leads to 4GlcNAc beta 1 leads to Gal beta 1 leads to 4GlcNAc beta 1 leads to group is found in the sugar chains of the liver enzyme but not in those of the hepatoma enzyme; (c) more than 40% of the sugar chains of the hepatoma enzyme contain bisect N-acetylglucosamine (GlcNAc) residue which is not found in those of the liver enzyme. Furthermore, the total number of asparagine-linked sugar chains in one molecule of hepatoma enzyme was about 4 times that found in one molecule of liver enzyme.
The biosynthesis of gamma-glutamyl transpeptidase was studied in a yolk sac tumor cell line. Cell suspensions were labeled with [14C]leucine; immunoprecipitates were obtained with anti-gamma-glutamyl transpeptidase antibody and analyzed on SDS-polyacrylamide gel electrophoresis++. A radioactive 80 000 dalton peak and peaks identical to heavy and light subunits were detected in the immunoprecipitates from the extract which was labeled for 15 min. After 45 min labeling, the 80 000 dalton species disappeared, although the two subunits were still observed. Tunicamycin-pretreated cells were labeled with [3H]glucosamine and [14C]leucine for 3.5 h. The 80 000 dalton species was glycosylated, and accumulated to a great degree compared to non-treated cells.
Activities of beta-hexosaminidase A and beta-hexosaminidase B (Hex B) were measured both in human lung carcinoma and the adjacent normal tissues of 47 patients. The specific activity of total beta-hexosaminidase in the tumors was considerably higher than in the adjacent normal tissues, irrespective of histological types. In isoelectric focusing experiments, Hex B purified from normal lung exhibited a single peak with an isoelectric point (pI) of 7.9, while Hex B purified from adenocarcinoma contained two forms with pI 7.6 and 7.9. With respect to heat stability, Hex B from the normal lung was very stable at 52 degrees, while the tumor Hex B (mixture of pI 7.6 and 7.9 forms) was unstable. After treatment of the tumor enzyme with dithiothreitol, heat stability was restored. When the tumor pI 7.6 form was treated with dithiothreitol and subjected to polyacrylamide gel electrophoresis, the enzyme converted to a pI 7.9 form similar to that of the normal lung. Determination of the sulfhydryl group of the tumor pI 7.6 form under nondenaturing conditions showed that the enzyme had some easily reducible disulfide bonds on its surface. These findings indicate that the formation of mixed disulfide bonds in the tumor Hex B increases the net negative charge and results in the appearance of a heat-labile form.
We have found convincing evidence for the presence of Na-K-ATPase and high potassium (K) and low sodium (Na) concentrations in the erythrocytes of some dogs associated with hereditary high concentrations of erythrocyte glutathione and some amino acids, glutamate, glutamine, and aspartate. The Na-K-ATPase activity of the erythrocyte membranes of the dogs was about 3 times that of human erythrocyte membranes, whereas the enzyme activity was not detected in control dogs with a normal level of blood glutathione. The Michaelis constant of the enzyme for ATP (Km ATP) was 6.6 X 10(-3)M in the dogs' erythrocytes and 5.0 X 10(-4)M in the human erythrocytes. The concentration of K in the erythrocytes in the dogs examined was about 11 times that of the controls, whereas the erythrocyte Na concentration in the dogs was about one-third that of the controls. The concentrations of K and Na in the plasma of the dogs were equal to those of the controls. Furthermore, L-3H-glutamate and L-3H-aspartate uptake by those cells with high activity of Na-K-ATPase greatly increased, while L-3H-glutamine uptake was unchanged. It appeared that Na+ and K+ gradients created by Na-K-ATPase across the cell membrane might stimulate glutamate and aspartate uptake by the cells, thus causing the high accumulation of such amino acids in the cells.
Recent studies have indicated that a monoclonal antibody, termed anti-Tac, may recognize the receptor sites or closely associated structures for interleukin 2 on activated human T cells. The Tac antigen, definable by anti-Tac antibody and usually found on mitogen- or alloantigen-stimulated T cells, was not expressed to any appreciable extent on normal circulating T cells. In the present study, we showed that an increase in circulating T cells expressing Tac antigen as well as Ia determinants occurred in normal individuals after immunization with tetanus toxoid. The expression of Tac antigen and Ia determinants on T cells was evaluated by the rosette method with Staphylococcal protein A-(SPA) coated bovine red blood cells (BRBC) or the indirect immunofluorescence method with monoclonal anti-Tac and anti-Ia antibodies. An increase in Tac-positive or Ia-positive T cells was more evident with the use of the rosette method with SPA-coated BRBC than with conventional immunofluorescence. The percentage of Ia-positive T cells showed a peak between 24 and 48 hr after toxoid injection, and remained at high levels until 2 wk after immunization. In contrast to Ia-positive T cells, the appearance of Tac-positive T cells was transient and at a rather early period of toxoid immunization. The maximum increase of Tac-positive T cells was apparent around 12 hr after toxoid injection, and Tac-positive T cells disappeared abruptly from circulation by 24 hr after inoculation. Ia-positive T cells were induced in both Leu-2 suppressor/cytotoxic and Leu-3 helper/inducer subsets, whereas Tac-positive T cells were generated only within the Leu-3 subset. The fact that induction of Tac-positive and Ia-positive T cells might occur at different stages of T cell activation and in different subsets of T cells seemed to be important for elucidating their roles in the in vivo T cell proliferation and differentiation.
Seventy-five patients with severe infection accompanying hematologic disorder, including leukemia and malignant lymphoma, were treated with cefotaxime (CTX). CTX was administered by intravenous drip infusion at a daily dose ranging from 4 to 16 g for terms of 3 to 21 days. The total doses were ranged from 12 to 226 g. The results obtained were as follows: Clinical effects: Excellent in 20 cases, good in 21 cases, fair in 7 cases and poor in 27 cases. The efficacy rate was 54.7% (41/75). Clinical effectiveness on isolated organisms (27 cases): In single infection (21 cases), the efficacy rates were 80% for Gram-positive cocci, including S. aureus and 63.6% for Gram-negative bacilli other than P. aeruginosa. In mixed infection (6 cases), the rate was 50.0%. There were no significant differences in the efficacy rates for those patients who were grouped by the initial number of neutrophil (less than 100, 101--500 and over 501/mm3). There were no significant difference in the efficacy rates for those patients who were grouped by the initial number of lymphocyte (less than 500 and over 501/mm3). Side effects and abnormal laboratory findings: One case of skin rash and 2 cases of elevated GOT and GPT were observed. CTX was therefore considered as a clinically useful antibiotic for the severe infections even in neutropenic state in patients suffering from malignant hematological diseases.
A total of 117 cases with hematological malignancies were treated with MCNU at doses of 70-100 mg/m2. Following are the results obtained. 1. MCNU showed a marked depression of cells in the cases with CML, polycythemia vera and thrombocythemia. The low level of cells was maintained for 2 to 7 months. 2. A good response was observed in several cases with blastic crises of CML. 3. No response was observed in two cases with acute leukemia. 4. Although a fair response was observed in several cases with malignant lymphoma or multiple myeloma, moderate bone marrow suppression was observed in a majority of the cases.
Results of recent studies indicated that a monoclonal anti-Tac antibody might recognize the receptor sites or closely related structures for T cell growth factor (TCGF) on activated human T cells. In the present study, we examined the effect of cyclosporin A (CsA) on the expression of Tac antigen by mitogen-stimulated T cells. CsA inhibited the proliferative response of T cells to Con A and PHA in a dose-dependent manner. Both Con A- and PHA-induced cellular proliferation were decreased to about 10% of controls at 5 micrograms/ml of CsA. When T cells were stimulated with these mitogens, many of them expressed Tac antigen on their surfaces, assessed by the immunoperoxidase method. The appearance of Tac-positive cells occurred earlier than a rise of cellular DNA synthesis. Characteristically, CsA showed no inhibitory effect on the expression of Tac antigen by mitogen-stimulated T cells, even at a relatively high concentration of 5 micrograms/ml, whereas the expression of other "activation" antigens reactive with monoclonal anti-Ia, OKT9, or OKT10 antibodies by T cells was blocked completely by CsA. Morphologically, the majority of Tac-positive cells in culture with mitogens alone showed the characteristics of blastoid cells; Tac-positive cells in the culture containing CsA mainly consisted of medium-sized cells, indicating these cells probably accumulated at a stage of partial activation. T cells, once stimulated with Con A or PHA for 3 days whether in the presence or in the absence of CsA, were able to absorb TCGF activity from TCGF-containing media similarly. In addition, T cells, even stimulated in the presence of CsA with these mitogens for 24 hr, were capable of responding to TCGF with the same grade of proliferation as did T cells stimulated with mitogen alone. CsA showed no appreciable inhibition in a TCGF-dependent proliferation of such prestimulated cells. These functional properties of activated T cells might be correlated with their ability to express Tac antigen. These experimental findings present some evidence that CsA might not prevent the expression of probable functional receptor sites for TCGF in mitogen-dependent activation of human T cells.
Our previous study provided a new two-dimensional echocardiographic technique for detecting peripheral "right" coronary artery aneurysms in Kawasaki disease using a subcostal approach. In the present paper, we presented an additional study for detecting peripheral "left" coronary artery aneurysms. Because the left anterior descending artery runs along the anterior interventricular sulcus and the left circumflex artery around the mitral valve ring, both coronary regions are difficult to search by a conventional method. Then coronary aneurysms of these regions were searched using the subcostal approach in this study. First, the sector beam was directed toward the heart on a plane parallel to a line between the patient's shoulders which allowed simultaneous visualization of four chambers (P1). The area around the mitral valve ring in this plane was examined for coronary aneurysms of the peripheral left circumflex artery. Secondary, the beam section was positioned parallel to the line cutting both the long axes of the sternum and spinal column which allowed visualization of the right ventricular outflow tract, pulmonary valves, interventricular septum, mitral valves and left atrium (P2). Thirdly, the sector plane was angled to the left (P3), and still more to the left (P4) until the left atrium just disappeared. By scanning from P2 to P4, the area around the mitral valve ring was examined for coronary aneurysms of the peripheral left circumflex artery. By scanning from P4 to the cardiac apex (P5), the anterior interventricular sulcus was searched for coronary aneurysms of the peripheral left anterior descending artery. Of 143 patients with Kawasaki disease, aged two months to 8 years, 7 peripheral left coronary aneurysms were visualized in five patients. These were three aneurysms in the left circumflex artery at the origin of the obtuse marginal artery, two aneurysms in segment 13, and two aneurysms in the left anterior descending artery at the origin of the second diagonal branch. These echocardiographic features coincided well in size, shape and anatomic location with angiographic appearances. In one patient whose echocardiogram in sector P2 showed a small echo-free space (2 X 2 mm) at the area around the mitral valve ring, the angiographic study showed the intact left circumflex artery, suggesting that there was a limitation to distinguish a very small coronary aneurysm from a normal one. There was no false negative diagnosis. These results showed that this new echocardiographic technique is useful for detecting peripheral left coronary aneurysms in patients with Kawasaki disease.
Fosfomycin (FOM) was administered intravenously to 65 cases of severe infections complicated with 62 cases of several haematological disorders. Out of 65 cases, 45 were treated with high doses FOM, i.e., 8 g per day or more. Another 20 cases were treated in usual doses of 4--6 g per day. Causative organisms were isolated from 52 cases of which 32 cases were Gram-negative bacilli and 19 cases were Gram-positive cocci. The effective rate of FOM was 57.8% in the high-dose treatment group (26/45) and 45.0% in the usual-dose treatment group (9/20), but the significant difference was not defined. Among 32 cases with Gram-negative bacilli infections, including Pseudomonas aeruginosa or Serratia marcescens, 15 cases were effective (47%). On the contrary, 14 out of 19 cases with Gram-positive cocci infections were effective (74%). Thirteen cases (50.0%) were effective even in which neutrophils were less than 500/cmm before FOM administration. Severe side effects were not observed, without 2 cases. One was skin eruption due to drug allergy and the other was suspected to be interstitial pneumonitis, but not confirmed pathologically. These data suggest that high dose treatment of FOM were useful for the severe infections even in neutropenic state in haematological disorders.
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A total of 48 patients with various malignant disorders, mostly from hemopoietic organs, entered to phase I study of MCNU given orally. Fifty-six percent of the patients given MCNU at the doses of 50-125 mg/m2 complained of gastrointestinal symptoms including nausea and vomiting, which were however mild and well tolerated. In the following study employing administration of 50 mg/day of MCNU for consecutive 2-6 days, the gastrointestinal toxicities were reduced to 26.1%, and hematological toxicities of delayed leukopenia and thrombocytopenia were derived 4-6 weeks after oral intake of the drug. The hematological recovery required 1-2 weeks after the nadir of leukocyte and thrombocyte count. A recommended dose for phase II study of MCNU by the route of oral administration was 50 mg/body/day for consecutive 4-6 days in every 8 weeks interval. The peak value of blood concentration of MCNU was obtained 60-120 minutes after p.o. administration at the doses of 50-100 mg. Elimination half-life was estimated to be 40-45 minutes. No concentration of the drug was detected in blood 24 hours after the administration.