Thrombocytosis in subjects with chronic myelocytic leukemia in blastic metamorphosis. Clinical remarks and therapeutic considerations (5 case reports).
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Biomedical subjects
Publications and source records attributed to F Patrone.
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The colony-forming capacity of normal peripheral blood mononuclear cells and of TG-depleted cell suspensions induced by PHA was investigated in the presence of different concentrations of levamisole. The results obtained demonstrate that: (1) the drug enhances significantly the number of colonies formed by both mononuclear cells and TG-depleted cells at concentrations ranging from 5 x 10(-6) to 5 x 10(-8 M; (2) this stimulatory activity results from a direct effect on T cells; and (3) adherent accessory cells are unaffected by the in vitro treatment with levamisole.
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Ascorbic acid is able to stimulate neutrophil oxidative metabolism in normal neutrophils, as well as other several functions of these cells, either in the normal state or in the defective one. In the present study, we have investigated the effects of ascorbic acid on the hexose monophosphate shunt (HMPS) and on the bactericidal activity of neutrophils from Chronic Granulomatous Disease (CGD) patients. Furthermore, we have investigated the effects of ascorbic acid on the antibody dependent cell cytotoxicity (ADCC) of normal neutrophils. Ascorbic acid in vitro was able to significantly improve both HMPS activity and bacterial killing of CGD neutrophils. Its prolonged administration to such patients led to consistent clinical improvement, possibly related to the enhancement of chemotaxis, although the effects on HMPS and bacterial killing seen in vitro could not be confirmed. Ascorbic acid was also able to interfere with neutrophil ADCC with different results depending on its concentration and the experimental conditions.
The effects of the sulfydryl donor drug N-(2-mercaptopropionyl)-glycine (MPG) on neutrophil chemotaxis, adhesiveness, phagocytosis, and hexose monophosphate shunt activity were investigated in vitro. The drug significantly enhanced all the neutrophil functions tested when used at appropriate concentrations. The results, which are in accord with the well known inhibition of neutrophil function by sulfydryl-blocking agents, suggest the possible therapeutic usefulness of the drug in clinical conditions with defective neutrophil function.
The effects of the sulphydryl group donor N-(2-mercaptopropionyl) glycine on neutrophil locomotion were evaluated in vitro. The drug, when used at a concentration of 10(-3) M was found to stimulate the random migration and chemotaxis of normal neutrophils as a result of an enhanced rate of locomotion. The true chemotactic response was unaffected. N-(2-mercaptopropionyl) glycine appeared to exert its effect on the whole moving cell population.
Immunopathological studies in a case of Sweet's syndrome revealed IgM- and IgE-bearing polymorphonuclear leucocytes in involved skin when the direct immunofluorescence technique was used. Circulating polymorphonuclear neutrophils showed defective chemotaxis with normal random migration, phagocytosis, killing, and hexose monophosphate shunt activity.
Rosettes with ox erythrocytes coated with purified IgG antibody were used to detect Fc receptors on neutrophils from 60 patients with solid neoplasias and from 55 normal controls. The mean average of the rosettes in the patients was 48.10%, and that in normal controls was 79.42%, with a highly significant difference according to the Wilcoxon test [negative probability, P(w)-4.47 . 10(-5)]. The low proportion of patients' rosettes ws related to the presence of a serum factor, which also inhibited normal neutrophil rosette formation. Patient neutrophils (or normal neutrophils treated with patient sera) recovered their rosetting capacity when cultured in vitro. No correlation was found between low percentages of rosette-forming cells and the level of circulating immune complexes of the individual patients. Additional evidence also supported the finding that IC and the serum factor are probably unrelated.
The in vitro effects of the peptide N-formyl-L-methionyl-L-phenylalanine on granulocytes adhesiveness and chemotaxis were investigated. N-formyl-L-methionyl-L-phenylalanine, when used at concentration chemotactically effective, increased significantly granulocyte adhesiveness. When granulocyte adhesiveness was inhibited by colchicine, the inhibition could not be reversed by subsequent treatment with N-formyl-L-methionyl-L-phenylalanine. These results suggest that microtubular system is involved in the stimulation of granulocyte adhesiveness by N-formyl-L-methionyl-L-phenylalanine.
The effects of histamine and cimetidine on neutrophil locomotion were studied in vitro in experimental conditions able to dissociate random from truly directional motility. Histamine 10(-4) mol/l inhibited the true chemotactic response. Cimetidine was able to reverse the histamine-induced inhibition of true chemotaxis. Since histamine-induced inhibition of neutrophil chemotaxis may play a role in allergic patients with repeated infections, and since cimetidine has been shown to enhance cell-mediated immunity in vivo, often impaired in such cases, the use of cimetidine is suggested for the prevention of recurrences in these patients.
Neutrophil function was studied in several patients with recurrent infections, mainly of the skin. Twelve patients showed impairment of neutrophil functions, either chemotaxis or bacterial killing and phagocytosis. Levamisole was given in four cases: improvement of neutrophil function and long-lasting clinical remission occurred in three of them, whilst in the fourth the drug was not tolerated. Ascorbic acid was administered to three other patients, with satisfactory improvement of neutrophil function and long-lasting clinical remission.
The effects of ascorbic acid on neutrophil locomotion were studied in experimental conditions able to dissociate random from truly directional motility. It was shown that the significant enhancement of chemotaxis achievable with high ascorbic acid concentrations was due to an increase of the true chemotactic response. With lower concentrations of ascorbic acid, chemotactic values were unaffected as the result of an increase in the rate of neutrophil locomotion with a concomitant inhibition of the true chemotactic response. Ascorbic acid appeared to exert its effect on the whole moving cell population.
Experiments were performed to investigate the in vitro effects of inosiplex on the locomotion and oxidative metabolism of human neutrophils. The drug, when used at the concentration of 500 micrograms/ml, significantly increased neutrophil random migration and chemotaxis. Enhancement of chemotaxis was due to an increased rate of locomotion as well as toan increased true chemotactic response. Inosiplex appeared to exert its effect on the whole migrating cell population. No significant effect on the oxidative metabolism of both resting and phagocytizing neutrophils was found. The results suggest that the effect of inosiplex may be related chiefly to its effect on neutrophil locomotion.
The effects of the three synthetic chemotactic N-formyl-L-methionyl peptides, namely f-met-phe, f-met-val and f-met-ala, on neutrophil chemotaxis, adhesiveness, oxidative metabolism, phagocytosis and killing were evaluated in vitro. The three peptides displayed different stimulating properties, with relative activity f-met-phe greater than f-met-val greater than f-met-alal for all functions tested. Experiments performed with chemotactically deactivated neutrophils showed that deactivation does not interfere with neutrophil functions other than chemotaxis and does not prevent further stimulation by the same chemo-attractant. The results demonstrate that the interaction of a single chemotactic agent with neutrophil membrane can trigger different cellular responses, dependent in their type and intensity on the concentrations of the chemotactic factor and on the functional state of the cell.
Neutrophils pretreated with a chemotactic factor become deactivated, that is, unresponsive to a subsequent chemotactic stimulus. A decay of surface esterase activity, an increased adhesiveness, an auto-oxidative damage of the cell structures and microtubule hyperpolymerization have been previously proposed as the cause of the chemotactic deactivation. To further understand the cellular mechanisms involved in this process, we have studied the locomotory behaviour of deactivated neutrophils in an experimental system allowing differentiation among the various types of migratory cellular response to chemotactic factors. Thus, we have found that deactivated neutrophils retain a normal capacity of random locomotion, but entirely lose their true chemotactic responsiveness. Diamide, which disrupts assembled microtubules in concanavalin A-treated cells, was able to completely restore the true chemotactic response of deactivated cells. These observations suggest that neutrophil deactivation is a reversible cellular event dependent on the functional state of the microtubular system.
2 children with undue susceptibility to skin infections and isolated defective neutrophil bacterial killing are described. Since the NBT-reducing capabilities of granulocytes were normal, a mild form of chronic granulomatous disease was excluded. Ascorbic acid was effective in delaying and eventually suppressing infectious episodes.
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