Biomedical subjects
Publications and source records attributed to A Dvilansky.
Acquired aplastic anemia is usually fatal. During recent years autoimmune disturbances have been implicated in bone marrow depression. This has led to a novel therapeutic approach based on immune suppression to enable bone marrow recovery. We report 4 adult patients who were treated with antithymocyte globulin.
Recently, a new preservation medium consisting of ammonium chloride added to adenine, glucose, mannitol, citrate, and potassium phosphate, was described. Unexpectedly, the predominant effect on red cell storage was an initial elevation of ATP levels, followed by remarkable maintenance of these levels at 12 to 18 weeks with acceptable 24-hour survival. The aim of the study reported here was to investigate the reasons for the advantageous effects of the different constituents. With the new preservation medium, ATP content was maintained at acceptable levels for at least 8 weeks with low spontaneous hemolysis. However, similarly high ATP levels were also maintained in the absence of ammonium chloride. Comparable results were obtained on substituting sodium for potassium salts in the new medium. When the main cation in the preservation medium was replaced by sodium, the addition of ammonium or rubidium chloride did not provide an advantage. Therefore, ammonium chloride was not essential for this medium, whereas mannitol does seem to be essential in a solution whose content of nonpermeant solutes is hypotonic.
Exposure of HL-60 promyelocytic leukemia cells to a combination of interferon-gamma (IFN gamma) and 5-fluorouracil (5-FU), at concentrations ineffective by themselves, induced a significant differentiation into monocyte-like cells. This phenomenon was accompanied by a synergistic antiproliferative effect. Further characterization of these two activities of the IFN gamma/5-FU combination on HL-60 cells was carried out. Whereas a brief pretreatment of the cells with IFN gamma followed by 5-FU was sufficient to exert the synergistic antiproliferative action, the effect on differentiation was dependent on a prolonged concomitant exposure to both drugs. In an attempt to gain more insight into the biochemical mechanisms of these phenomena, we have examined the effects of RNA and protein synthesis inhibitors and of cytoskeleton disrupting agents on the actions of IFN gamma. Inhibition of RNA or protein synthesis by actinomycin D or cycloheximide did not prevent the antiproliferative action of IFN gamma nor the induction of monocytic differentiation, yet these two compounds blocked the priming effect of IFN gamma on the potentiation of 5-FU action. Actinomycin D synergistically potentiated the antiproliferative action of IFN gamma. Colchicine, vinblastine, and cytochalasin B, disrupting the microtubular and microfilament structure, did not interfere with the actions of IFN gamma; higher concentrations of the drugs even improved the priming effect. Exogenous thymidine, known to counteract the antiproliferative effect of 5-FU, also blocked the antigrowth action but not the differentiation induced by the IFN gamma/5-FU combination. The results suggest the existence of two different mechanisms of the IFN gamma/5-FU synergism: one governing the antiproliferative action via an effect on thymidine synthetase, inducible by a short-term IFN gamma pretreatment and dependent on de novo RNA and protein synthesis; and the other mediating the induction of differentiation requiring a long-term exposure of the cells to both drugs. From a clinical point of view, drug combinations such as IFN gamma and 5-FU, inducing differentiation as well as inhibiting proliferation, may suggest a new approach to the treatment of leukemia.
Growth of the promyelocytic cell line HL60 and the erythroleukemia cell line K562 is inhibited by 'uremic toxins': creatinine, guanidino propionic acid and guanidino succinic acid in a concentration range similar to that of uremic sera. Among the tested compounds, creatinine exhibits the strongest and most dose-dependent inhibitory effect on both kinds of cells. These results provide a better understanding of the mechanism involved in the anemia of uremic patients.
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Beta-thromboglobulin (BTG) has been shown to be a specific platelet protein and can be used as a marker of platelet activation in preeclampsia. Concomitant studies of BTG levels in plasma and urine were performed with eight primiparous severe preeclamptic patients and eight normal primiparous women matched for age. The mean plasma BTG in the severe preeclamptic patients was 186.62 +/- 29.93 ng/ml, and in the control group 45.38 +/- 31.84 ng/ml. The P-value for the difference was highly significant (P = 0.000). In contrast, the mean urine BTG in the study group was 8.42 +/- 4.61 ng/ml, while the mean value for the control group was similar, 5.00 +/- 3.20 ng/ml. The P-value for the difference was not significant (0.05 less than P less than 0.10). These results show that urinary BTG cannot be considered an indicator of platelet activation in severe preeclampsia. A low urinary BTG concentration in the presence of high plasma BTG levels may rather express renal impairment. Failure of BTG renal clearance would contribute to further raising the level of plasma BTG.
Plasma levels of antithrombin III were tested during pregnancy in a control group of normal patients and in a study group that included patients with moderate and severe pre-eclampsia and chronic hypertension. The control group showed mean antithrombin III activity of 97.9 +/- 20.9%, the severe pre-eclamptic patients 22.33 +/- 18.22%, the moderate pre-eclamptic patients 56.0 +/- 7.56%, and the chronic hypertensive patients 77.5 +/- 6.69%. The difference between normal pregnancy and moderate pre-eclampsia was significant at P less than 0.002, normal pregnancy and severe pre-eclampsia P less than 0.002, moderate and severe pre-eclampsia P less than 0.002, chronic hypertension and normal pregnancy P less than 0.1, and chronic hypertension and severe pre-eclampsia P less than 0.002. All the severe pre-eclamptic patients and 2 out of 6 of the moderate pre-eclamptic women were below 55.7% (mean - 2S.D.) of normal antithrombin III activity. Patients with heavy proteinuria had depressed antithrombin III activity. However, chronic hypertensive pregnancies, although rather a small group, had almost normal values of plasma antithrombin III activity. The plasma antithrombin III value may thus help to distinguish between chronic hypertension and severe pre-eclamptic disease.
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Chronic lymphocytic leukaemia (CLL) is a lymphoproliferative disorder which sometimes also affects the erythrocytes. In this study we investigated erythrocyte involvement in 23 CLL patients. We found increased erythrocyte osmotic fragility in 15 CLL patients, but this finding was not accompanied by increased permeability to acidified glycerol (decreased AGLT50). Only those CLL patient who had positive direct antiglobulin test (DAT) had significantly decreased AGLT50. AGLT cannot serve as a predictor test for the future development of autoimmune haemolytic anaemia in CLL patients. ATP content was unaffected by the lymphoproliferative disease, but whole blood filterability was markedly decreased in CLL patients. Our study supports the hypothesis that erythrocytes are indeed affected by the lymphoproliferative disorder, even in the absence of overt autoimmune haemolytic processes.
The 'uremic toxin', guanidino propionic acid (GPA), which was detected in uremic serum in correlation with BUN level, modified the mitogenic response of normal lymphocytes to phytohemagglutinin (PHA). Mild modifications can be detected in the concentrations which are found in uremic patients. Other guanidino compounds which have been detected in uremic sera, such as guanidino succinic acid (GSA), guanidino butyric acid (GBA) and guanidino acetic acid (GAA), show similar inhibitory pathways. It is suggested that guanidino compounds contribute to the immunological disturbances in uremia. The complexity of their action on lymphocyte mitogenic response is probably the cause of the conflicting results which have been reported in the literature.
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A retrospective study of 42 patients bitten by Echis colorata in the last 26 years is reported. Twenty-eight patients received and 14 patients did not receive specific antivenin. The clinical findings, laboratory studies, and course of hospitalization revealed hemostatic disturbances in most of the patients. One of the untreated patients died in the period when antivenin was not available. We recommend that antivenin be given, following appropriate clinical and laboratory assessment, to patients bitten by E. colorata who have progressive local signs and major alterations in the clotting mechanism. The usual precautions against allergic reactions should be taken.
The structure-activity relationship of the inhibition of ADP-induced platelet aggregation by cannabinoids was studied. A marked specificity was revealed: derivatives in which the two asymmetric centers have a configuration opposite to that of the natural cannabinoids and have a dimethylheptyl (DMH) side-chain were most inhibitory. It is concluded that the mode of inhibition includes a specific interaction of the cannabinoids with some membrane proteins, possibly including the receptor for ADP.
Platelet surface glycoproteins IIb-IIIa are considered to function as the binding site for fibrinogen. Fibrinogen binding is essential for platelet aggregation and several amines have been shown to inhibit this binding. The present study compares the binding properties of 125I-fibrinogen and [3H]lysine with platelets activated by the Ca2+ ionophore A23187. Many lines of similarities in the binding properties are apparent; however, several differences were also found. The similarities are listed below and the differences are pointed out in parentheses. Marked enhancement by platelet activation; deficiency of binding by thrombasthenic platelets lacking the glycoproteins IIb-IIIa; saturability (fibrinogen binding approaches saturation at more than 12 microM, within 10 min; lysine binding at more than 100 mM within 1 min); Ca2+-dependence (at 1 mM Ca2+ lysine binding is minute and fibrinogen binding is half-saturated); reversibility; the binding achieved within 10 min is exchangeable; dissociation depends upon time and external ligand concentration; inhibition by the oligoamines His-Lys and Lys4; inhibition by serum from a thrombasthenic patient who developed anti-glycoproteins IIb-IIIa antibodies; specificity; alanine neither binds to activated platelets nor inhibits fibrinogen binding; it thus appears that the lysine which associates with activated platelets is mostly bound onto the surface of the cells rather than being incorporated. Moreover, the major site of lysine binding seems to be the complexed glycoproteins IIb-IIIa.
Beta-thromboglobulin was tested in blood and urine in a study group of pre-eclamptic patients. The control group comprised a subgroup of normal non-pregnant women and a second subgroup of normal pregnant women. The results of the plasma beta-thromboglobulin blood test revealed no significant difference between the groups, whereas the urine of the pre-eclamptic group showed a significantly increased concentration of beta-thromboglobulin. This difference may reflect renal involvement in the pre-eclamptic patients; the turnover of platelets may be increased but the plasma level of beta-thromboglobulin is apparently maintained by the increased renal clearance.
The effects were assessed of delta'THC (the psychoactive component of cannabis) and CBD and DMHP-CBD (the non-psychomimetic components of marijuana derivatives) on 14C labelled serotonin release from normal platelets, when incubated with patient's plasma obtained during migraine attack. A statistically significant inhibitory effect (p greater than 0.005) of 14C serotonin release was found at 10(-5)M, 10(-6)M, 10(-7)M delta'THC concentrations. Plasma of migraine patients obtained in attack-free periods revealed no significant inhibitory effect on 14C serotonin release from normal platelets using the same delta'THC concentration. CBD and DMHP-CBD had no significant inhibitory effect on 14C serotonin release from normal platelets when tested either at migraine-free period plasma or plasma obtained during migraine attack.
Several disturbances in platelet function have been reported in migraineurs including serotonin (5-HT) metabolism and abnormal aggregability of platelets. The present work compared platelets taken from migraineurs during attacks and at headache-free periods with those of controls. The results demonstrated a tendency to increased aggregability during attacks compared to headache-free periods, and lower still in controls. Kinetic analysis of 5-HT uptake revealed normal Km, increased Vmax values and lower imipramine inhibition in migraineurs (both during headache and at headache-free periods). However, although the differences were significant statistically, they were small, and their clinical relevance remains to be proven.