Failure to stimulate antibodies in man after 7 days' high-dose treatment with rifampicin.
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Biomedical subjects
Publications and source records attributed to A Wood.
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Both basal and prostaglandin E1 (PGE1)-stimulated human platelet adenylate cyclase activity are inhibited by Na+ and other monovalent cations. Inhibition occurs when the cations are present in concentrations of 20 to 120 mM. Inhibition of basal activity by epinephrine requires the presence of GTP but not Na+. In the presence of epinephrine and GTP, Na+ further reduces basal activity, and the combined effects of all three ligands results in a 70% reduction of basal activity. Sodium, however, does not increase the fractional inhibition of basal activity attributable to epinephrine. Sodium increases the concentrations of epinephrine and of PGE1 required for half-maximal inhibition and stimulation of adenylate cyclase but does not alter the apparent km for Mg2+ or ATP. The rate and extent of adenylate cyclase activation by the GTP analog guanyl-5'-yl imidodiphosphate is reduced by Na+, although the cation does not prevent the acceleration of activation by guanyl-5'-yl imidodiphosphate induced by PGE1. Other monovalent cations also inhibit the platelet cyclase with an order of potency of Na+ greater than Li+ greater than K+ greater than choline+. In addition to demonstrating that Na+ is not required for hormonal inhibition of platelet adenylate cyclase, these studies demonstrate the multiple inhibitory effects which can be induced by Na+ and other monovalent cations. The pattern of these effects suggests that the cations interfere with functional coupling between receptors, guanine nucleotide binding units, and catalytic units of the adenylate cyclase complex.
Human blood mononuclear cells exposed to concanavalin A or phytohemagglutinin secrete a soluble factor that arrests the growth of human synovial fibroblastic cells in culture. Once the growth-inhibitory effect is initiated it cannot be reversed by washing the fibroblastic cells, by refeeding with nonconditioned fresh serum-containing medium, by trypsinization, EDTA treatment, or a combination of these procedures. Media from nonstimulated mononuclear cells, fibroblastic cells, or the lectins themselves do not contain similar inhibitory activity that can be detected by the present culture systems. This lectin-dependent, growth-inhibitory activity does not have a cytotoxic effect on the fibroblasts but increases their adhesiveness to plastic or glass surfaces, and the cells tend to assume a less fibroblastic morphology. The growth-inhibitory activity is stable in the cold and is nondialyzable or ultrafilterable, but the activity is rapidly lost at temperature between 60 degrees and 70 degrees C and at pH 2.0. The growth-arrested cells secrete more glycosaminoglycan per cell in the medium and synthesize more cell surface glycosaminoglycan than the controls. However, the increased glycosaminoglycan synthesis cannot be explained as being entirely secondary to a cell density effect as it is also observed when adjustments are made for the differences in growth rates.
Combination chemotherapy with VM-26 and ara-C was given to 14 children with acute lymphocytic leukemia who had not responded to initial treatment with prednisone, vincristine, daunomycin, and asparaginase. Nine of these patients had also received ara-C. At diagnosis, five children were classified as having standard prognostic features and nine as being at high risk for treatment failure. The drug combination was administered by vein twice a week for four weeks at dosages of 165 mg/m2 for VM-26 and 300 mg/m2 for araC. Nine complete remissions, five in patients with high-risk leukemia, were induced with acceptable toxicity; all 9 subsequently were given continuation therapy with oral mercaptopurine and methotrexate. Four of the 9 patients have relapsed at 2--21 months. All treatment was stopped in 2 patients after 30 months of complete remission. Combinations of VM-26 and ara-C represent an alternative remission induction treatment for patients who fail to attain initial remission with agents of established effectiveness. These agents may especially benefit patients with prognostic features indicating a high risk of treatment failure.
On the basis of previous findings at this institution, VM-26 and Cytosine Arabinoside (ara-C) were used in combination to treat 33 children with refractory acute lymphocytic leukemia (ALL). Chemotherapy was given by vein twice a week for four weeks at dosage of 300 mg/m2 for ara-C and 50, 75, 110, 165, or 200 mg/m2 for VM-26. Ten marrow remissions (nine complete and one partial) were induced, with hypotension (2/33) and bone marrow hypoplasia (20/33) the most significant side effects observed. Therapeutic responses were obtained with each dosage of VM-26 except 75 mg/m2; myelosuppression developed at all dosages, being most prolonged at 200 mg/m2. Ten of the 23 non-responders did not complete their planned courses of therapy. The significance of this information is that combinations of VM-26 and ara-C were effective in patients who were either in late stages of their leukemia or had never achieved an initial remission. All had been previously treated with prednisone, vincristine, daunomycin and L-asparaginase. In addition, seven of the 10 responders had previously received ara-C in other drug combinations. The use of VM-26 and ara-C in combination may be warranted for newly diagnosed patients who are at high risk for treatment failure with first-line drugs.
A longitudinal study of 49 children with acute lymphocytic leukemia (ALL) assessed the long-term effects of central nervous system (CNS) prophylaxis on brain function. From 10 to 12 electroencephalograms (EEGs) were done before and at intervals during after 30 months of treatment that included 2,400 rads of CNS irradiation plus intrathecal methotrexate therapy. None of the children had CNS leukemia, and all remained in first complete remissions. All 49 had abnormally slow EEG background frequencies during the four-year study, and 29 (60%) developed somnolence syndrome six to eight weeks after CNS prophylaxis. During this syndrome, EEG background frequencies decreased more than 3 standard deviations below the expected mean values for normal children. Thereafter, 7 of the 29 began to show signs of learning disabilities and 7 developed recurrent seizures. Of the 20 children who did not have the syndrome, none showed later evidence of CNS dysfunction. Somnolence may be an early indicator of long-term neurological sequelae after cranial irradiation.
The rate of synthesis of RNA during early germination of wheat and soybean embryos was investigated by ascertaining the incorporation of radioactive uridine into RNA. In wheat embryos, where the lag period preceding rapid growth is 5.5 hours, there is a 2-fold increase in RNA synthesis between 1.5 and 5.5 hours, with half of the increase occurring by 3.5 hours. In soybean axes, where the lag period is 9.5 hours, the increased rate of RNA synthesis is 5.5-fold between 1.5 and 9.5 hours, with three fourths of this increase occurring after 4 hours.Analysis of the ratio of radioactivity incorporated into the 18S and 26S rRNAs of the germinating embryos provided a further measure of the increased rates of RNA synthesis. With wheat embryos, the 26S/18S ratio increased from 1.0 at 1.5 hours to 1.5 at 3.5 hours, while with the soybean axes, distinct ribosomal patterns were obtained only after 4 hours and the 26S/18S rRNA ratio increased from 0.4 at 4 hours to 1.0 at 9 hours. The extent of methylation of the rRNA synthesized at 4 and 9 hours in the soybean axes was similar, indicating that the methylating capacity of the axes is probably not rate limiting to rRNA synthesis. In both seed embryo systems the level of UTP increased 2 to 3-fold during the lag phase of germination. With wheat embryos, the time course of the increase in UTP correlated approximately with the change in the rate of RNA synthesis. With the soybean axes, however, the increase in the rate of RNA synthesis occurred predominantly after the rise in the level of UTP.
A method for preparing human platelet membranes with high adenylate cyclase activity is described. Using these membranes, epinephrine and GTP individually are noted to inhibit adenylate cyclase slightly. When present together, epinephrine and GTP act synergistically to cause a 50% inhibition of basal activity. The epinephrine effect is an alpha-adrenergic process as it is reversed by phentolamine but not propranolol. The quasi-irreversible activation of adenylate cyclase by Gpp(NH)p is time, concentration, and Mg2+-dependent but is not altered by the presence of epinephrine. Adenylate cyclase activated by Gpp(NH)p, and extensively washed to remove unbound Gpp(NH)p, is inhibited by the subsequent addition of Gpp(NH)p, GTP, and epinephrine. This effect of epinephrine is also an alpha-adrenergic phenomenon. In contrast to epinephrine which inhibits the cyclase, PGE1 addition results in enzyme stimulation. PGE1 stimulation does not require GTP addition. PGE1 accelerates the rate of Gpp(NH)p-induced activation. Low GTP concentrations (less than 1 x 10(-6) M) enhance PGE1 stimulation while higher GTP concentrations cause inhibition. These observations suggest that human platelet adenylate cyclase possesses at least two guanine nucleotide sites, one which interacts with the alpha-receptor to result in enzyme inhibition and a second guanine nucleotide site which interacts with the PGE1 receptor and causes enzyme stimulation.
Glycosaminoglycan (GAG) synthesis and glucose uptake by rheumatoid (R) and nonrheumatoid (NR) synovial cells were studied at the second subculture during four different sets of nutritional conditions and at sequential, defined intervals of the growth cycle. Synovial fibroblastic cells in monolayer cultures secrete both hyaluronic acid and sulfated GAGs in a ratio of about 8 : 1. With increasing cell density the ability to sulfate GAGs appears to decrease. No significant differences in GAG synthesis between rheumatoid and nonrheumatoid lines on a per cell basis could be detected during any interval in the growth cycle. Similarly, no significant differences of glucose uptake per cell could be demonstrated between rheumatoid and nonrheumatoid lines under the various protocols applied throughout the growth cycle. The most important factor determining glucose uptake per cell is the availability of glucose in the medium which is in turn closely correlated with cell number.
This controlled study of children with ALL was designed to test the efficacy and toxicity of one-, two-, three- and four-drug therapy during remission and whether more aggressive therapy in the first eight weeks prolongs remission in patients with features associated with a particularly poor prognosis. After inducing remission with prednisone, vincristine and asparaginase, patients received cranial irradiation and IT methotrexate and were randomized to receive: 1--methotrexate alone; 2--methotrexate plus mercaptopurine; 3--same as in group 2 plus cyclophosphamide; and 4--same as in group 3 plus arabinosyl cytosine. Patients with CNS leukemia at diagnosis received IT methotrexate weekly during the induction period and a higher dose of CNS irradiation. Patients with anterior mediastinal enlargement at diagnosis received radiotherapy to the mass during the induction period. Patients who failed to attain bone marrow remission after four weeks of therapy were given daunorubicin and prednisone for 2--4 additional weeks. Of the 282 patients entering this study between January 1972 and November 1975, 268 (95%) attained complete remission and 228 (85%) were randomized to receive continuation chemotherapy with 1, 2, 3 or 4 drugs. In Group 1 (methotrexate alone), 14 of 20 patients relapsed and 9 developed leukoencephalopathy without antecedent CNS leukemia apparently due to higher doses of intravenous methotrexate; in Groups 2, 3 and 4 the results were equivalent, but without leukoencephalopathy in initial CR. The addition of cyclophosphamide and arabinosyl cytosine increased toxicity and complications without demonstrably increasing the leukemocidal effect. In the 40 patients given additional early therapy, the modalties employed in this study did not prolong remission.
The growth kinetics of subcultured human synovial fibroblasts from 16 patients with inflammatory and noninflammatory arthropathies were studied in antibiotic free media. The experimental design allowed a clear distinction between the growth rates and final saturation densities achieved. The effects of refeeding and of the serum concentration were evaluated for each line. Inflammatory lines achieved significantly higher final saturation densities and growth rates than noninflammatory lines for most protocols, but the differences between rheumatoid and nonrheumatoid groups were less marked. Inflammaroty fibroblasts demonstrated a greater independence to nutritional and growth stimulatory factors in their microenvironment than noninflammatory fibroblasts.
In an attempt to describe the use and usefulness of closed-circuit televisions (C.C.T.V), a preliminary follow-up study of 27 veterans was undertaken by the Western Blind Rehabilitation Center. The veterans had been loaned C.C.T.V.'s by the Veterans Administration and represented a wide range of ages, backgrounds, and pathologies. On the basis of the present data, it is concluded that C.C.T.V. significantly improve the functioning of the majority of users and that this improvement appears to be a long-term benefit.
Improved therapeutic approaches to childhood cancer not only have produced remarkable extensions in survival, but also have introduced major new problems into the field of pediatric oncology nursing. Care of the patient whose normal immune responses have been suppressed by irradiation and prolonged chemotherapy is one problem. The immunosuppressed child is highly susceptible to infections, and the nurse must devise a plan of care that is designed to reduce the risks that lead to these infectious complications. Because of the stresses associated with aggressive cancer therapy the patient may experience serious emotional difficulties that require the nurse's attention. Most important, the nurse's attitude toward the childhood cancer patient must be broadened to include the concept that many of these children are possibly cured of their cancer and should be encouraged to lead normal lives.
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