Biomedical subjects
Publications and source records attributed to M Pospísil.
Combined treatment with dipyridamole and adenosine monophosphate enhances cell proliferation in the hemopoietic tissue of normal and gamma-irradiated mice. This effect can be explained by the elevation of extracellular adenosine, and the receptor-mediated activation of the cell adenylate cyclase system.
In whole-body 1Gy-irradiated mice a modification of early cellular damage by means of preirradiation dipyridamole and adenosine monophosphate (AMP) treatment was investigated. Both drugs were given either alone or in combination, AMP being administered i.p. at doses of 5, 10 and 15 mg, dipyridamole s.c. at the dose of 2 mg, 20 min before AMP. The thymidine level in plasma and the amount of free polynucleotides in the thymus and spleen, both estimated at the interval of 4 h after irradiation, were used as indices of early cellular damage in vivo. The elevated level of thymidine observed in the plasma of irradiated controls decreased significantly after the administration of AMP (5 mg) alone to 71%, after the combination of dipyridamole and AMP a still deeper significant fall to 60% was observed. Such a protective effect was observed when injecting AMP 15 min before irradiation. Using the interval of 65 min between AMP administration and irradiation, no protection was detected. The higher doses of AMP (10, 15 mg) enhanced the protective effect manifested in plasma thymidine level only moderately. The amount of free polynucleotides, elevated in the thymus and spleen of irradiated mice, was significantly decreased in the thymus of mice pretreated with the combination of dipyridamole and AMP. The results suggest that the treatment used decreases the radiation damage of the sensitive thymocyte population. It is proposed that the joint use of AMP, an adenosine prodrug, and dipyridamole, a drug inhibiting adenosine uptake by cells, leads to an elevation in extracellular adenosine which activates cell surface adenosine receptors.(ABSTRACT TRUNCATED AT 250 WORDS)
Mannan-binding proteins found in the liver and serum of several vertebrate species are supposed to play an important role in the intracellular transport of glycoproteins, as well as in several protective reactions including complement activation and elimination of various pathogens. To study these protective functions at molecular level it is necessary to understand the fine oligosaccharide specificity and mutual relation among various forms of these soluble lectins. We have isolated mannan-binding protein as peripheral membrane proteins of porcine lymphocytes. This lectin was purified to homogeneity and shown to possess many properties in common with the well studied rat liver proteins (mol. mass, subunit composition and general organization of the molecule). Binding studies performed with three series of defined oligosaccharides (high mannose, hybrid type, and complex) on native lectin molecules as well as isolated carbohydrate-binding domains revealed distinctive features of this mannan-binding protein, including its impaired ability to bind the oligosaccharide ligand after reduction and decyclization at core N-acetyl-D-glucosamine 1.
An impairment of the survival of mice subjected to whole-body gamma-irradiation with a lethal dose of 10 Gy and treated with a repeated postirradiation administration of prostaglandin synthesis inhibitors (PGSIs), indomethacin or diclofenac, was observed. Morphological examination of the gastrointestinal tract and the estimation of blood loss into its lumen in animals treated with diclofenac did not show serious damage such as haemorrhages or perforation, but revealed structural injury to the intestinal mucosa indicating inflammatory processes. The lesions found are supposed to be connected with increased intestinal permeability which leads to endotoxin escape from the gut and a subsequent increased mortality rate of irradiated animals. It may be concluded that PGSIs are not suitable for the management of radiation sickness after an exposure to lethal doses of ionizing radiation.
It was shown in experiments on mice that the radioprotective effects of adenosine monophosphate (AMP) or of a combination of Mg aspartate and AMP join with those induced by hypobaric hypoxia. The hypotensive effects of these drugs lead probably to hypoxia in radiosensitive tissues which acts additively with hypoxia elicited by way of respiration. Furthermore, Mg aspartate and AMP decrease the toxicity of high degrees of hypobaric hypoxia. These effects can be explained by the ability of adenosine liberated from AMP and of magnesium to increase brain and heart blood perfusion and/or to mitigate excessive sympathetic activity. The pharmacological effects of AMP and Mg aspartate are thus not only radioprotective but also energy preserving and protecting vitally important organs against hypoxia toxicity. These effects may be of favourable importance in hypoxic radiotherapy.
The authors evaluated the incidence of late ventricular potentials (LVP) in 84 patients (63 men and 21 women) with programmed stimulation of the ventricles. At the same time they described the relationship of the mentioned potentials to the finding of ventricular ectopic arrhythmias during ECG monitoring and left ventricular function (ultrasonographic examination). Non-invasive recording of late ventricular potentials is due to the assessed sensitivity, i.e. 73%, and specificity i.e. 67% (in relation to the results of programmed ventricular stimulation) a useful method for evaluation of the arrhythmogenic substrate of the heart muscle. The authors detected LVP in 35% of 37 subjects without arrhythmias, in 58% of 31 subjects with premature ventricular contractions class 3 to 5 according to Lown and in 60% of 15 subjects with relapsing ventricular tachycardias. LVP are more frequent in patients with impaired left ventricular function. They were recorded during the ejection fraction of the left ventricle beneath 50% in 69% of 16 subjects and in the left ventricular ejection fraction above 50% in 44% of 68 subjects.
The effects of diclofenac (inhibitor of prostaglandin production) and carboxymethylglucan (immunomodulator and an agent stimulating hematopoiesis), when given to mice 1 day before gamma-irradiation, were studied. Both of the agents were administered either alone or in combination. The investigations included the assessment of post-irradiation hematopoietic recovery in terms of bone marrow and spleen cellularity and endogenous spleen colony formation, as well as the determination of the survival of lethally irradiated mice. The results demonstrated at least additive radioprotective effects when mice were given diclofenac and carboxymethylglucan in combination. Experimental evidence provided by the increased 125iodo-deoxyuridine incorporation into the spleen and elevated hydroxyurea kill of endogenous spleen colony-forming units indicated that the beneficial action of the combined treatment could be a consequence of increased cell proliferation in the hematopoietic tissue. It is likely that the inhibition of prostaglandin production (diclofenac action) and the concomitant increased release of growth factors (glucan action) shift the regulatory balance towards the predominance of positive hematopoietic control.
We previously reported that natural killer cell stimulatory factor (NKSF), a heterodimeric lymphokine purified from the conditioned medium of human B lymphoblastoid cell lines, induces interferon gamma (IFN-gamma) production from resting peripheral blood lymphocytes (PBL) and synergizes with interleukin 2 in this activity. In this study, we show that human NKSF induces IFN-gamma production from both resting and activated human PBL and from freshly isolated murine splenocytes. Human T and NK cells produce IFN-gamma in response to NKSF, but resting PBL require the presence of nonadherent human histocompatibility leukocyte antigens DR+ (HLA-DR+) accessory cells to respond to NKSF. The mechanism(s) by which NKSF induces IFN-gamma production results in accumulation of IFN-gamma mRNA, is insensitive to cyclosporin A, and synergizes with those mediated by phytohemagglutinin, phorbol diesters, anti-CD3 antibodies, and allogeneic antigens, but not by Ca2+ ionophores. The ability of NKSF to directly induce IFN-gamma production and to synergize with other physiological IFN-gamma inducers, joined with the previously described ability to enhance lymphocyte cytotoxicity and proliferation, indicates that this lymphokine is a powerful immunopotentiating agent.
Metalloproteinase (MP) produced by the majority of Staphylococcus aureus strains exerts, in a wide concentration range (0.1-100 micrograms/ml), no cytotoxic action on mononuclear leukocytes of human peripheral blood. The enzyme itself does not appreciably stimulate proliferation and differentiation of lymphocytes in culture, but affects the stimulation of both T and B lymphocytes by polyclonal activators. The action is dose-dependent. High doses of MP (100 micrograms/ml) lower the blastic transformation after stimulation with Con A, SpA, NDCM, S. aureus strain Wood 46 and with suboptimal doses of PWM. Optimal concentrations of the enzyme potentiate the stimulation of lymphocytes by PWM, PHA, S. aureus strains Cowan 1 and Wood 46, and by NDCM. The same potentiation effect was achieved whether the enzyme was added concurrently with the mitogen or 18 h later. This implies that the beginning of cell activation is not affected. A high MP concentration decreases the production of Ig in culture after stimulation with PWM whereas lower concentrations of MP enhance this production. Production of Ig after stimulation with NDCM and Wood 46 is decreased by MP. The possible action of exoproteinase from S. Aureus on the immune response during infection is discussed.
The authors subjected 34 patients (27 men and 7 women) to invasive electrophysiological examination. All patients had early ventricular contractions class 3-5 according to Lown which were recorded during ECG monitoring in bed or by Holter's system. A pathological excitability of the ventricular myocardium was found during programmed stimulation in 29% of the subjects. The excitability of the heart muscle was substantially enhanced by the incidence of ischaemic heart disease and reduced left ventricular function. The decreased frequency and severity of early ventricular contractions during bicycle ergometry, the absence of palpitations and syncopes increases the probability of normal excitability of the ventricular myocardium.
Carboxymethylglucan, a novel soluble derivative of beta-1,3-glucan, was found to enhance hemopoietic recovery in sublethally gamma-irradiated mice and to increase survival in lethally irradiated animals when given 24 hours prior to irradiation. Postirradiation treatment with carboxymethylglucan also induced favourable effects in terms of survival when used in combination with preirradiation cystamine administration.
The slight radioprotective action of inosine, when injected intraperitoneally to mice shortly before gamma-irradiation, can be enhanced by the administration of magnesium aspartate. This effect can be explained by the additivity of the vasodilatory actions of both agents. Inosine increases the radioprotective effectiveness of hypobaric hypoxia (10% O2), probably due to the additivity of the hypoxic effects in radiosensitive tissues. Acute hypoxic toxicity, however, is decreased by inosine administration. The cumulation of radioprotective effects of inosine and of its antihypoxic action in vitally important organs can have a favourable influence in hypoxic radiotherapy.
The authors submitted to electrophysiological examination a total of 100 patients (66 men and 34 women) with brief disorders of consciousness where they ruled out extracardiac causes of unconsciousness, impaired blood flow through the heart and the syndrome of s-a node dysfunction. Forty-three subjects had severe arrhythmias during ECG monitoring in bed or by Holter's system (20 subjects paroxysms of ventricular tachycardia, 14 subjects ventricular extrasystoles according to Lown class 3-5, six subjects had transient high-grade a-v blocks, three subjects had symptomatic paroxysms of supraventricular tachycardia). In 57 patients ECG monitoring did not reveal ectopic arrhythmias and high-grade a-v blocks. Invasive examination confirmed or diagnosed arrhythmic syncopes in 49% of the entire group of 100 patients. It assessed the arrhythmic cause of syncopes in 33% of 57 subjects without severe arrhythmias and in 70% of 43 subjects with severe arrhythmias detected during ECG monitoring.
The combined preirradiation administration of indomethacin and cystamine was found to enhance synergistically the recovery of hemopoiesis in sublethally gamma-irradiated mice. This effect can be explained by a common operation of two mechanisms of radioprotection, i.e. of an increased survival of hemopoietic stem cells due to cystamine action and of stimulatory effects of indomethacin on the proliferation of surviving cells, mediated by the inhibition of prostaglandin synthesis. Attempts to prove such enhancement of protective effects on irradiated mice in terms of postirradiation lethality were unsuccessful. The reason seems to be the influence of toxic effects of the indomethacin-cystamine combination on the gastrointestinal tract. When using the less toxic combination, i.e. diclofenac and WR-2721, the additivity of protective effects is manifested even in the survival of lethally irradiated mice. The results suggest that under suitable conditions avoiding the unfavourable toxic effects, non-steroidal anti-inflammatory drugs can be successfully used with the aim to enhance the efficiency of sulfhydryl radioprotectors.
The possibilities of combined radioprotection, using preirradiation peroral cystamine and postirradiation intraperitoneal glucan administration in sublethally and lethally whole-body gamma-irradiated mice were investigated. The results demonstrated at least additive radioprotective effects of both agents, manifested in the enhancement of postirradiation haemopoietic recovery and increased survival of irradiated mice. The effects appear to depend on the sequential cell protection mediated by cystamine and enhanced haemopoietic repopulation induced by glucan.
The authors investigated in a group of 83 patients with chronic obstructive pulmonary disease the prognostic impact of some indicators of pulmonary function, haemodynamics and oxygen transport. They demonstrated that the prognosis is less favourable in patients with a lower one-second vital capacity with a higher median pressure in the pulmonary artery, with a lower oxygen tension in the arterial blood and higher haemoglobin concentration. They did not reveal significant differences between those who died and those who survived for more than five years, after the examination, as regards oxygen supply of tissues, oxygen consumption, coefficient of oxygen extraction and values of oxygen tension in mixed venous blood. Oxygen inhalation led to an increased oxygen supply of tissues and increased oxygen tension in mixed venous blood to normal values in all examined groups. This observation may be one of the explanations of the more favourable prognosis of patients with respiratory insufficiency, associated with chronic pulmonary obstructive disease, who have permanent oxygen therapy during domiciliary care.
In a group of 14 patients with a malignant pleural effusion treated by intrapleural administration of Corynebacterium parvum, in addition to other treatment of the generalized malignant process the activity of Nk cells was investigated before administration, on the 7th and 21st day after instillation of the vaccine. The mean rise of this activity was significant at the 5% level of significance. The activity of Nk cells was equally significantly influenced by age. The survival of patients, although longer in patients who responded positively, was not significantly correlated with the increased activity of Nk cells. Its increase was observed more frequently in the group of patients given the English preparation Coparvax. In the discussion some aspects of the relationship of Nk activity and anti-tumourous immunity are discussed.
The authors investigated the influence of some vasodilatory drugs on pulmonary and systemic haemodynamic parameters in 69 patients with pulmonary hypertension secondary to chronic obstructive pulmonary disease (with the exception of two patients with diffuse pulmonary fibrosis and one patient with recurrent pulmonary thromboembolism). The investigated vasodilatory drugs were as follows: Dihydralazine Spofa--8 patients, Corinfar--10 patients, Ketanserin--13 patients, Nit-Ret 7 patients, Nitroglycerin Spofa--10 patients, Nitro-Mack--11 patients, Iso-Mack retard--10 patients. The haemodynamic parameters were measured before and at various time intervals after the administration of the vasodilatory agent (Dihydralazine 50 mg perorally--30th and 60th minute, Corinfar--20 mg sublingually--60th minute, and in 7 patients following a 6 months period of 30-60 mg Corinfar daily dose, Ketanserin--10 mg intravenously--10th, 20th and 40th minute, Nit-Ret--2.5 mg perorally--30th and 60th minute, Nitroglycerin Spofa--0.5 mg sublingually--10th and 30th minute, Nitro-Mack--1 mg intravenously--immediately following the end of a slow i. v. infusion for 20 minutes, Iso-Mack retard--20 mg perorally, 60th minute). The blood gases were measured at the same time intervals, too. The results in various groups were as follows: Dihydralazine administration was not followed by any significant change in PAP, CO, PVR, while a significant decrease in AOP and SVR was ascertained. A significant decrease of PaCO2 and no change in PaO2 were measured. Following Corinfar administration, no change in PAP, CO or PVR and a significant decrease of PaCO2 and no change in PaO2 were measured. Following Corinfar administration, no change in PAP, CO or PVR and a significant decrease in AOP were determined. No significant changes in blood gases were measured. Following a 6 month Corinfar treatment period in 7 subjects, no significant changes in pulmonary haemodynamics or blood gases values were found. No clinical benefit of this drug could be estimated. Ketanserin administration was not followed by any changes in pulmonary haemodynamics, whereas a significant decrease in AOP and SVR were found. The administration of Nit-Ret was followed by a significant decrease of CO, whereas no changes in PAP, AOP or PVR and SVR were found. No significant changes in the blood gas tenses values were measured. The administration of Nitroglycerin Spofa was followed by a significant decrease in RAP, PAP, AOP, RVEDP as well as in CO. No significant changes in blood gases were observed. The application of 1 mg Nitro-Mack intravenously was followed by a significant decrease in RAP, PAP, AOP and CO.(ABSTRACT TRUNCATED AT 400 WORDS)