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A study of a polymer composite containing as filler of magnetite and cementite nanoparticles dispersed in a diamagnetic carbon matrix, which was synthesized by the carburization of nanocrystalline iron is made. An abrupt change in the ferromagnetic resonance temperature was observed with a sharp anomaly resolved in the temperature derivative of the ac conductivity.

Ferromagnetic resonance (FMR) and ac conductivity have been applied to study a polymer composite containing as filler a binary mixture of magnetite (Fe3O4) and cementite (Fe3C) nanoparticles (30–50 nm) dispersed in a diamagnetic carbon matrix, which was synthesized by the carburization of nanocrystalline iron. Ac conductivity measurements showed thermally activated behavior involving a range of activation energies and power law frequency dependence at high frequencies similar to conducting polymer composites randomly filled with metal particles. Ferromagnetic resonance measurements revealed a relatively narrow FMR line at high temperatures indicating the presence of ferromagnetic nanoparticles, where thermal fluctuations and interparticle interactions determine the FMR temperature variation. An abrupt change of the FMR spectra was observed at T<81 K (ΔT<=1 K) coinciding with a sharp anomaly resolved in the temperature derivative of the ac conductivity. This behavior is attributed to the Verwey transition of Fe3O4 nanoparticles, where the concurrent skin depth variation unveils the FMR of large magnetite conglomerates and thus allows discriminating their contribution from relatively isolated nanoparticles. [ABSTRACT FROM AUTHOR]

The carburisation of nanocrystalline iron with ethylene has been studied. The carburisation processes were carried out under atmospheric pressure, under the flow of pure ethylene or ethylene-hydrogen mixture at a constant temperature in the range of 310-550 °C. The process was controlled using a spring thermobalance and cathetometer, with the accuracy of 0,1 mg. The phase composition of the samples after carburisation was determined by means of X-ray diffraction (XRD). As a result of the carburisation of nanocrystalline iron with ethylene, the formation of iron carbide Fe3C occurs, followed by the formation of carbon deposits. Under a C2H4/H2 gas mixture, these two reaction steps can be separated, while under pure ethylene the reactions are much faster and the simultaneous formation of iron carbide and carbon deposits is observed. Depending on temperature and on the carburisation degree, various forms of carbon deposits can be observed using TEM: spherical, helicoidal, and nanotubes. The diameter of these carbon forms is below 100 nm. [ABSTRACT FROM AUTHOR]

Angiotensin-(1-7) [Ang-(1-7)] is the bioactive peptide which may be responsible for some of the pharmacological effects of losartan. Our previous study has demonstrated the antithrombotic action of losartan in a model of experimental thrombosis. In the present study, we compared the antithrombotic action of losartan and Ang-(1-7).Acute (10 mg/kg, p.o.) and chronic (10 mg/kg, p.o., three weeks) losartan administration to spontaneously hypertensive rats (SHR) induced a decrease in thrombus weight (1.6±0.6 mg and 1.2±0.3 mg respectively vs. control 2.9±0.8 mg; p<0.05, p<0.05). A similar reduction was observed in two-kidney, one-clip hypertensive rats (2K-1C) receiving acute losartan administration (1.39±0.29 mg vs. 3.25±0.62 mg; p<0.01). Infusion of Ang-(1-7) to 2K-1C rats also reduced the thrombus weight (1.01±0.34 mg, 1.23±0.38 mg and 2.17±0.36 mg for 1, 10, 100 pmol/kg/min, respectively vs. 3.58±0.6 mg control; p<0.01, p<0.01, p<0.05). Losartan produced a decrease in systolic blood pressure (BP) in SHR as well as in 2K-1C rats, while Ang-(1-7) infusion had no effect on BP. Acute losartan dosing to 2K-1C rats decreased platelet adhesion to fibrillar collagen (24.9±1.0% vs. control 31.5±1.1%, p<0.001). The incubation of platelet samples with Ang-(1-7) (10-6 and 10 —5 M) also reduced adhesion to fibrillar collagen (38.4±0.1% and 33.8±0.8% respectively vs. control 40.0±0.6%; p<0.05, p<0.001). There were no apparent changes in prothrombin time, activated partial thromboplastin time and euglobulin clot lysis time in losartan and Ang-(1-7)-treated groups. We conclude that, like losartan, Ang-(1-7) is able to act as an antithrombotic agent. [ABSTRACT FROM PUBLISHER]

Background: Severe side effects during venom immunotherapy (VIT) are associated with a variety of risk factors., Objective: Our aim was to evaluate the association of baseline serum tryptase concentration (BTC) and of other parameters, which are routinely recorded during patient evaluation, with the frequency of severe reactions requiring an emergency intervention during the buildup phase of VIT., Methods: In this observational prospective multicenter study, we enrolled 680 patients with established honeybee or vespid venom allergy who underwent VIT. Data were collected on tryptase concentration, age, sex, culprit insect, cardiovascular medication, degree of preceding sting reaction, preventive antiallergic medication before therapy, time between last preceding sting reaction and VIT, venom specific IgE concentration, and type of buildup procedure. Relative rates were calculated with generalized additive models., Results: Fifty-seven patients (8.4%) required an emergency intervention during buildup because of a severe systemic reaction. The frequency of interventions increased significantly with higher BTC (log-linear association; adjusted odds ratio, 1.56; 95% CI, 1.15-2.11; P < .005). The predictive power of BTC was markedly greater when VIT was performed for vespid venom allergy than for bee venom (for bee VIT, no significant association; for vespid VIT, log-linear association; adjusted odds ratio, 2.33; 95% CI, 1.28-4.26; P = .005). The most important other factor significantly associated with severe reactions during the buildup phase of VIT was bee venom allergy., Conclusion: Before vespid VIT, measurement of baseline serum tryptase concentration should be used to identify patients with a high risk for side effects. Patients with bee venom allergy require a particularly high degree of surveillance during VIT., (Copyright 2010 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

Background: Severe anaphylaxis to honeybee or vespid stings is associated with a variety of risk factors, which are poorly defined., Objective: Our aim was to evaluate the association of baseline serum tryptase concentrations and other variables routinely recorded during patient evaluation with the frequency of past severe anaphylaxis after a field sting., Methods: In this observational multicenter study, we enrolled 962 patients with established bee or vespid venom allergy who had a systemic reaction after a field sting. Data were collected on tryptase concentration, age, sex, culprit insect, cardiovascular medication, and the number of preceding minor systemic reactions before the index field sting. A severe reaction was defined as anaphylactic shock, loss of consciousness, or cardiopulmonary arrest. The index sting was defined as the hitherto first, most severe systemic field-sting reaction. Relative rates were calculated with generalized additive models., Results: Two hundred six (21.4%) patients had a severe anaphylactic reaction after a field sting. The frequency of this event increased significantly with higher tryptase concentrations (nonlinear association). Other factors significantly associated with severe reactions after a field sting were vespid venom allergy, older age, male sex, angiotensin-converting enzyme inhibitor medication, and 1 or more preceding field stings with a less severe systemic reaction., Conclusion: In patients with honeybee or vespid venom allergy, baseline serum tryptase concentrations are associated with the risk for severe anaphylactic reactions. Preventive measures should include substitution of angiotensin-converting enzyme inhibitors.

Animal models of asthma have been used for over 100 years. The accuracy of extrapolations from animal models to human asthmatics is highly dependent on the species of animal selected. The rat, in comparison with other animals, demonstrates many features of airway allergy and allergic asthma that are similar to the human conditions. The following features of human asthma can be effectively investigated in a rat model of the disease: cellular infiltration of the lung, antigen-specific IgE production, and a predominant Th2 response. The majority of available models of asthma are restricted to the acute inflammatory response following a short period of allergen exposure. The frequently used model of ovalbumin (OVA) sensitization and challenge replicates the inflammatory process in the airways.

Asthma is a chronic inflammatory disease that involves the immune system activation. Evidence is accumulating about the role of kynurenine pathway in the immune system regulation. The kynurenine pathway includes several metabolites of tryptophan, among others kynurenine (KYN). To study the immunological system regulation in asthma a simple and sensitive models of asthma are required. In the present study we induced rat model of asthma using ovalbumin (OVA) sensitization followed by challenge with OVA. The development of asthma has been confirmed by plasma total IgE measurement and the histological examination. The concentration of KYN has been determined in plasma, lungs and liver by high-performance liquid chromatography (HPLC). In OVA sensitized rats the concentration of total IgE was statistically significantly increased as compared to VEH sensitized control groups (437.6 +/- 97.7 kU/l vs 159.2 +/- 22.7 kU/l, respectively; p< 0.01). In asthmatic animals, the number of eosinophils, neutrophils and mast cells increased considerably, and epithelial lesion and the increase in airway epithelium goblet cells and edema of bronchial mucosa were present. We did not observe any significant changes in the concentration of KYN in plasma, lungs or liver between studied groups. In conclusion, the concentration of KYN remains unchanged in asthmatic animals as compared to control groups. Further studies using rat model of asthma are warranted to establish the role of kynurenine pathway regulation in asthma.

Gastroesophageal reflux disease (GERD) depends on acid reflux into the distal oesophagus. The typical symptoms of GERD are heartburn, dysphagia, chest discomfort and acid regurgitation. Besides typical symptoms GERD could by manifested by extraesophageal signs. There is increasing number of studies showing that GERD and respiratory diseases coexist frequently.

Background: Increased serum tryptase has been linked to the severity of the reaction after Hymenoptera stings. The aim of the study was to measure basal tryptase levels in patients with Hymenoptera venom allergy and investigate the possible correlation between these levels and the severity of sting reaction., Methods: One hundred nine patients were included in the study. Sixty-three were wasp venom-allergic and 46 were honey bee venom-allergic. Basal serum tryptase levels were measured by UniCAP., Results: Basal serum tryptase levels were elevated in 12 (11%) of the 109 patients. Levels were 5.14 pg/L (3.62-5.84), 5.3 microg/L (2.94-6.54), 5.18 microg/L (3.71-6.25), and 6.98 microg/L (4.78-12.6), for patients with sting reactions of grade I, II, III and IV (as classified by Mueller), respectively. Basal serum tryptase levels correlated significantly with the sting reaction severity (r = 0.2752; P = .004) and with age (r = 0.2906; P = .002). Sting reaction severity also correlated with age (r = 0.3654; P = .001)., Conclusions: Basal serum tryptase levels were found to be elevated in 11% of venom allergic patients and correlated significantly with both sting reaction severity and age.

Increased thrombin generation occurs in the airways of asthmatic patients. Thrombin activatable fibrinolysis inhibitor (TAFI) is a carboxypeptidase B-like proenzyme which after activation by a thrombin-thrombomodulin complex inhibits fibrinolysis. The aim of this study was to evaluate TAFI concentration and activity in plasma of bronchial asthma patients challenged with Dermatophagoides pteronyssinus (Dp) extracts. The study was performed on 23 asthma patients mean age 28.7 +/- 9.8 years with a typical history and positive skin prick test with Dp allergens. Seventeen patients developed both early asthmatic reaction (EAR) and late asthmatic reaction (LAR), 6 patients developed only EAR. Blood was collected before allergen challenge (AO), 1 (A1), 8 (A2) and 24 hours (A3) after allergen challenge. Five healthy persons, mean age 24.5 +/- 3.6 years with negative skin prick tests to common aeroallergens served as negative controls. Healthy controls underwent sham bronchial provocation with 0.9% solution of NaCl. TAFI antigen and activity, levels of thrombin-antithrombin III complexes (TAT) and prothrombin fragments F 1+2 were measured in plasma by ELISA method. At A0 in dual responders mean TAFI concentration (101.4 +/- 23.82%) and activity (19.6 +/- 5.92 microg/ml) were higher than in healthy controls (69.35 +/- 21.49%; p < 0.05 and 10.49 +/- 3.53 microg/ml; p = 0.01; respectively). Significant fall in TAFI plasma concentration was detected at A1 and the decreased concentration of TAFI persisted until A3 (85.15 +/- 26.36%; p < 0.05). No significant change in plasma TAFI concentration was observed in healthy controls or in patients who responded with an EAR only. Allergen induced inflammation is associated with significant changes in plasma TAFI concentration.

Allergic asthma is characterized by bronchial inflammation and repair processes at the same time, that cause increased airway obstruction. Recent evidences suggest that monocytes and macrophages may play important role in allergic inflammation. Activated by proinflammatory factors they can express tissue factor (TF) and tissue factor pathway inhibitor (TFPI). The aim of the present study was to evaluate TF and TFPI in plasma of bronchial asthma patients. The study was performed on 17 asthma patients with documented Dermatophagoides pteronyssinus (Dp) allergy. 15 healthy persons served as negative control. Specific bronchial challenge with Dp extracts was performed in asthma patients. Blood was collected before allergen challenge--A0, during the early asthmatic reaction (EAR)--A0 during the late asthmatic reaction (LAR)--A2, and 24 hours after administration of the first allergen dose--A3. The concentrations of TF and TFPI were measured by ELISA method. The concentration of TF in asthmatic patients was significantly higher as compared with healthy controls. In patients that developed only EAR, the concentration of TF increased at A1, then decreased at time when LAR should be developed (A2) and it was comparable with beginning values 24 hours after starting the challenge. In patients that developed EAR and LAR, the mean TF concentration increased during EAR (A,) with subsequent decline during LAR (A2). 24 hours after starting the challenge the TF concentration was higher than beginning values (A3). The concentration of TFPI in patients that developed only EAR was significantly higher than the values in healthy controls. It decreased during EAR (A1) and increased 24 hours after starting the challenge (A3). The mean concentration of TFPI in patients that developed EAR and LAR was not significantly higher than the values in healthy controls. It increased during EAR and LAR with the highest values 24 hours after starting the challenge. Coagulation system seems to be activated during allergic inflammation after allergen challenge. Increased levels of TF and TFPI in asthma patients may be connected with chronic bronchial inflammation and remodeling of bronchial wall.

Angiotensin converting enzyme inhibitors (ACE-Is) are the main drugs used in the treatment of essential hypertension and congestive heart failure in adults. Recently, we have demonstrated the antithrombotic effect of captopril (CAP) and enalapril (ENA) in venous thrombosis model in adult rats. One might also suggest the beneficial effect of those drugs on hemostasis in young individuals. Two months old male Wistar rats were used in the study. Acute administration of CAP at a dose of 50 and 100 mg kg(-1) significantly reduced the venous thrombus weight. Dose-dependent reduction in the thrombus weight was also observed in ENA (3, 10, 30 mg kg(-1))-treated rats. Strong reduction in the thrombus weight was also seen after chronic administration of CAP (2 x 25 mg kg(-1)) and ENA (1 x 15 mg kg(-1)). Both drugs given chronically reduced the frequency of thrombi. Systolic blood pressure was reduced to similar extent after acute and chronic application of the drugs. CAP shortened euglobulin clot lysis time (ECLT) when given acutely (100 mg kg(-1)) and chronically (2 x 25 mg kg(-1)). ENA decreased ECLT only when given at multiple doses (1 x 15 mg kg(-1)). None of the drugs changed prothrombin time or activated partial tromboplastin time. We conclude that CAP and ENA possess antithrombotic effect in young individuals. Activation of the fibrinolytic pathway seems to play an important role in the mechanism of their antithrombotic action.

The aim of this study was to determine whether AT1-receptor antagonists could inhibit platelet activation-dependent pulmonary thromboembolism in mice and to investigate the involvement of nitric oxide in this action. Losartan, its active metabolite EXP3174, and valsartan given intraperitoneally 1 hour before the thrombotic challenge (in doses of 3, 10, or 30 mg/kg) protected mice from death or hind-limb paralysis in response to intravenous injection of a mixture of collagen and epinephrine; losartan was effective in all doses used, whereas EXP3174 and valsartan reduced mortality only in the two higher doses. The protective action of EXP3174 and valsartan was abolished when nitric oxide synthase was inhibited with l-NAME, whereas that of losartan was only partially reduced. Moreover, only losartan protected mice from death caused by intravenous injection of the thromboxane A2 mimetic U46619 and this action was preserved in l-NAME-pretreated animals. Our results demonstrate the ability of AT1-receptor antagonists to inhibit platelet activation in vivo in a nitric oxide-dependent mechanism. Stronger antiplatelet activity of losartan, most likely due to its blockade of thromboxane A2/prostaglandin H2 receptor, could be of potential clinical relevance, particularly in conditions in which synthesis of endogenous nitric oxide is impaired.

Recent studies suggest that the plasmin system plays an active role in tissue remodeling. Plasmin degrades the extracellular matrix (ECM), either directly removing glycoproteins from ECM or by activating matrix metalloproteinases (MMPs). PAI-1 blocking MMPs may prevent ECM degradation, but inhibiting fibrinolysis leads to fibrin accumulation and fibrosis. Components of the plasmin system including tissue plasminogen activator (t-PA), urokinase plasminogen activator (u-PA), and plasminogen activator inhibitors PAI-1 and PAI-2 are synthesised by airway cells, and inflammatory mediators affect their expression. The plasmin system, in turn, actively influences the production of inflammatory mediators and growth factors, extending pathological structural changes in the airway. Modulation of the plasmin system might be a new pharmacological strategy that could inhibit the development of airway remodeling.

Angiotensin-(1-7) [Ang-(1-7)] is an active member of renin-angiotensin system (RAS). It counterbalances vasoconstriction, mitogenic, arrhythmogenic and prothrombotic actions of Ang II. Inducing natiuresis and diuresis opposes also the water and sodium retention produced by Ang II. Till now the specific receptor side for Ang-(1-7) has been not cloned, but the current data strongly suggest that an interaction (cross-talk) between angiotensin receptors may play a role in the effects of Ang-(1-7).

It is well established that renin-angiotensin system blockers exert NO/prostacyclin-dependent antithrombotic effects. Because some beneficial effects of these drugs are mediated by angiotensin (Ang)-(1-7), in the present study we examined if their antithrombotic action could be mediated by Ang-(1-7). Intravenous infusion of Ang-(1-7) (1, 10, or 100 pmol/kg per minute for 2 hours) into rats developing venous thrombosis caused 50% to 70% reduction of the thrombus weight. This effect was dose-dependently reversed by cotreatment with A-779 (selective Ang-[1-7] receptor antagonist) or EXP 3174 (angiotensin type 1 receptor antagonist) but not by PD 123,319 (angiotensin type 2 receptor antagonist). Similarly, the antithrombotic effects of captopril (ACE inhibitor) and losartan (angiotensin type 1 receptor blocker) were attenuated by A-779 in a dose-dependent manner. The effect of Ang-(1-7) was completely abolished by concomitant administration of NO synthase inhibitor (N(G)-nitro-L-arginine methyl ester) and prostacyclin synthesis inhibitor (indomethacin), as has been shown previously for captopril and losartan. Thus, the antithrombotic effect of renin-angiotensin system blockers involves Ang-(1-7)-evoked release of NO and prostacyclin.

The aim of the study was to evaluate the effect of losartan on rat platelet adhesion to fibrillar collagen. Washed platelets were counted before and after 15 minutes incubation with collagen (50 microg/ml) and the percentage of adhering platelets was calculated as the index of their adhesion. When the platelets were incubated with collagen 40.8 +/- 0.3% of the platelets adhered. Losartan produced a dose dependent decrease in a number of adhering platelets both when the drug was administered to the animals ex vivo at doses of 3, 10 and 30 mg/kg (p < 0.01-0.001) or was added to the preparation of washed platelets in vitro in concentrations of 10(-8)-10(-5) M (p < 0.01-0.001). In the next step of the study we assessed the influence of L-NAME (10 mg/kg ex vivo, 30 microM in vitro) and indomethacin (2.5 mg/kg ex vivo, 30 microM in vitro) on the antiadhesive effect of losartan (10 mg/kg ex vivo, 10(-6) M in vitro). Blockade of nitric oxide synthase with L-NAME partially reversed the antiadhesive effect of losartan both ex vivo and in vitro. Indomethacin diminished the inhibitory effect of losartan on platelet adhesion when administered ex vivo, but it failed to modify this parameter when added to the suspension of platelets in vitro. In conclusion, losartan reduces platelet adhesion to fibrillar collagen in a dose-dependent manner. The observed action of losartan seems to be mediated mainly by endothelium- and platelet-derived nitric oxide.

Clinical and experimental data have recently accumulated for antithrombotic action of angiotensin-converting enzyme inhibitors (ACE-1s). We have shown previously that captopril (which contains a thiol group in the moiety) exerts more pronounced antithrombotic activity than does an equipotent dose of enalapril (the drug devoid of the thiol group). To clarify the relative importance of the presence of the thiol group in the molecule versus angiotensin-converting enzyme (ACE) inhibitory properties in the antithrombotic action of captopril, rats were treated with captopril (5 mg/kg twice daily; CAP), epicaptopril (stereoisomer of captopril devoid of ACE-inhibitory properties; 5 mg/kg twice daily; EPI), N-acetylcysteine (3.75 mg/kg twice daily; ACC), enalapril (3 mg/kg once daily; ENA), or distilled water (VEH) for 10 days, per os. After ligation of the vena cava, the incidence of the venous thrombosis and/or the thrombus weight decreased significantly in all but the ENA-treated groups when compared with control rats. The effect of CAP, EPI, and ACC was accompanied by a marked reduction of euglobulin clot lysis time and, with the exception of ACC, by an increase in prothrombin time in the blood collected from the site of the thrombus formation. Antithrombotic activity of EPI was completely abolished by nitric oxide synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME) or indomethacin, with the parallel reversal of fibrinolytic and coagulation parameters toward normal. Activated partial thromboplastin time, mean blood pressure, and bleeding time were not altered by either of the administered drugs. Thus, we demonstrated that thiol compounds exert antithrombotic activity by increasing fibrinolysis and/or suppression of the extrinsic pathway of the coagulation cascade in a nitric oxide/prostacyclin-dependent manner.

In previous studies, we have shown that losartan possesses nitric oxide-dependent antithrombotic properties in various models of hypertension in rats. It was demonstrated that stimulation of AT2-receptors plays an important role in the pharmacological effects of AT1-receptor antagonists. Thus, in this study, we examine the participation of AT2-receptors in the antithrombotic action of losartan in renal hypertensive rats on venous thrombosis induced by a two-hour ligation of the vena cava. Losartan administration(30 mg/kg, p.o.) resulted in a marked decrease in thrombus weight (by 85%, p<0.001). PD123319, an AT2-receptor antagonist (10 mg/kg, i.v.), administered concomitantly with losartan, abolished its antithrombotic effect, whilst it had no influence on thrombus weight when given alone. A significant decrease in systolic blood pressure was observed in animals given losartan. PD123319 administration didnot abolish this action of losartan and did not alter blood pressure when given alone. No changes in prothrombin time, activated partial thromboplastin time, or euglobulin clot lysis time were observed in animals administered losartan and/or PD123319.Similarly, primary haemostatics evaluated by bleeding time and platelet count did not change in any group of rats. In conclusion, we have shown that AT2-receptor stimulation is involved in the antithrombotic action of losartan in renal hypertensive rats.

Recent data suggest that hypotensive effect of losartan may not be attributed solely to AT1-receptor blockade, but also to excessive AT2 or other receptors stimulation by elevated angiotensin II and its derivative peptides. Therefore in the present study we examined the effect of angiotensin II on mean blood pressure after AT -receptor blockade with losartan. Male Wistar rats were anaesthetised and received injection of either losartan (30 mg/kg, 1 ml/kg, i.v.) or saline (the same volume and route) followed by bolus injection of angiotensin II (100, 300 or 1,000 ng/kg; 1 ml/kg, i.v.) or 1-hour infusion of angiotensin II (200 ng/kg/min; 2.5 ml/kg/h, i.v.). Control animals received saline instead. Angiotensin II, given either as the injection or the infusion, caused an evident increase in mean blood pressure (p ranged from 0.05 to 0.001 depending on the experimental group). Losartan caused a rapid drop in mean blood pressure and blunted the hypertensive effect of angiotensin II (p < 0.01). Moreover, in the losartan-pretreated animals the hypotensive phase was enhanced by the infusion, but not single injection of angiotensin II, which was most evident from the 30 th minute of observation (p < 0.05 vs control). In conclusion, hypotensive effect of losartan may be amplified by simultaneous increase in angiotensin II level, the situation observed during chronic AT1-receptor blockade.