Targeted eicosanoid lipidomics of exhaled breath condensate provide a distinct pattern in the aspirin-intolerant asthma phenotype.

BACKGROUND: Eicosanoids, important signaling and inflammatory molecules, are present in exhaled breath condensate (EBC) in very low concentrations, requiring highly sensitive analytic methods for their quantification. OBJECTIVE: We sought to assess a vast platform of eicosanoids in different asthma phenotypes, including aspirin-intolerant asthma, by means of a recently developed analytic approach based on mass spectrometry. METHODS: EBC from 115 adult asthmatic subjects (62 with aspirin intolerance) and 38 healthy control subjects were assessed quantitatively for 19 eicosanoids by using complementary HPLC, gas chromatography-mass spectrometry, or both. Palmitic acid concentrations were used as a marker for dilution of condensate samples. RESULTS: Asthma was characterized by an increase in arachidonate lipoxygenase products and cysteinyl leukotrienes. The COX pathway was also significantly upregulated in asthmatic subjects. Subjects with aspirin-intolerant asthma were distinguished by a sharp increase in the level of prostaglandin D(2) and E(2) metabolites; their 5- and 15-hydroxyeicosateraenoic acid levels were also higher than in aspirin-tolerant subjects. A classical discriminant analysis permitted us to classify correctly 99% of asthmatic subjects within the study population; the specificity of the analysis was 97%. The eicosanoid profiling allowed for 92% correct classification of aspirin-intolerant subjects. CONCLUSIONS: The highly sensitive eicosanoid profiling in EBC makes it possible to detect alterations in asthma, especially in its distinct phenotype characterized by hypersensitivity to aspirin and other nonsteroidal anti-inflammatory drugs. This permits us to discriminate asthmatic subjects from healthy subjects, as well as to distinguish the 2 asthma phenotypes based on the presence or absence of aspirin hypersensitivity.

The course of asthma in Churg-Strauss syndrome.

OBJECTIVES: Asthma is one of the key features of Churg-Strauss syndrome (CSS); however its course in the disease is unclear. The aim of this study was to analyze the asthma course in CSS patients. PATIENTS AND METHODS: We conducted a retrospective study of 22 CSS patients. Medical documentation was studied and patients were questioned about asthma symptoms during follow-up visits, which took place at four points of the disease. These points, at which lung function tests were performed, were CSS diagnosis; introduction of treatment at hospital discharge; and assessment of the first and last clinical and laboratory CSS remissions. Asthma control and severity were assessed in compliance with current guidelines. RESULTS: In the asthmatic group examined, 21 patients had an adult-onset asthma, with a mean age of onset 35.5 ± 11.8 years, preceded by sinusitis (100%) and nasal polyposis (36%). Asthma at its onset was severe in 68.5%, moderate in 27%, and very poorly controlled in 21 patients. Atopy was present in 64% of patients. Onset of vasculitic symptoms and CSS diagnosis was accompanied by high blood eosinophilia (maximal 7.2 x 10(3)/l [1.2 - 32], asthma exacerbation with airway obstruction in 16 patients (mean values of FEV1 68.8 ± 17.5% and FVC 84.8 ± 19.6%), and lung involvement. After introducing the treatment and achieving stable remission, asthma severity/control and lung function tests (forced expiratory volume in 1 s 92.7 ± 13.3%, and forced vital capacity 101 ± 15.5%; p < .001) improved. CONCLUSIONS: Asthma in CSS, although severe as its onset improves after achieving CSS remission.

The presence of rhinovirus in lower airways of patients with bronchial asthma.

RATIONALE: The common cold virus, human rhinovirus (HRV), is the most frequent cause of asthma exacerbations. However, a possible contribution of HRV to the pathogenesis of chronic, persistent asthma has not been defined. OBJECTIVES: To determine if patients with stable asthma, who are free of clinical signs of a respiratory infection for at least 3 weeks, harbor HRV in their bronchi more frequently than nonasthmatic control subjects, and whether clinical features of asthma are associated with the presence of HRV. METHODS: Immunohistochemistry and the indirect in situ reverse transcription-polymerase chain reaction method were used to detect the presence of HRV in bronchial mucosal biopsies in patients with asthma and nonasthmatic control subjects. MEASUREMENTS AND MAIN RESULTS: HRV was found by immunohistochemistry in 9 of 14 bronchial biopsies from subjects with asthma (64.3%) and 2 of 6 nonasthmatic control subjects (33.3%) (P = 0.38). With the more sensitive indirect in situ reverse transcription-polymerase chain reaction method, HRV was found in the mucosal biopsies of 73% of patients with asthma and 22% of nonasthmatic control subjects (P < 0.001). Subjects positive for HRV had lower pulmonary function, higher numbers of blood eosinophils and leukocytes, and eosinophilic infiltration in bronchial mucosa. CONCLUSIONS: HRV was detected in the lower airway tissue of patients with asthma significantly more often than in nonasthmatic subjects, and its presence was associated with clinical features of more severe disease.

Common polymorphisms of cyclooxygenase-2 and prostaglandin E2 receptor and increased risk for acute coronary syndrome in coronary artery disease.

The arachidonic acid metabolites participate in development of coronary artery disease (CAD) and the plaque's instability. We assessed two common genetic polymorphisms: of cyclooxygenase-2 (COX-2) (COX2.8473, rs5275) and prostaglandin EP2 receptor gene (uS5, rs708494) in patients with CAD. Out of 1,368 patients screened by coronary arteriography, two groups fulfilled the entry criteria and were studied: stable coronary disease (sCAD, n = 125) and acute coronary syndromes (ACS, n = 63). They did not differ in the main characteristics. All patients were on aspirin at least seven days prior to the study. In 70 control subjects, the same genotypes were ascertained, expression of cyclooxygenases in peripheral blood monocytes was assessed by flow cytometry, and in-vitro biosynthesis of PGE(2) was measured by mass spectrometry. COX-2 CC homozygotes (variant allele), were more common, while EP2 GG homozygotes (wild-type) were less common in ACS (p = 0.03 and p = 0.017) than in the sCAD group. A combined genotype characterized by the presence of the wild-type COX2.8743T allele and the wild type homozygous EP2uS5 genotype (TT or CT | GG) decreased risk ratio of ACS in CAD patients (relative risk 0.41; 95% confidence interval 0.21-0.81). COX-2 polymorphism in control subjects did not affect the enzyme expression or PGE(2) production by peripheral blood monocytes, but production of PGE(2) increased by 40.1% in the subjects homozygous for EP2 receptor allele uS5A following lipopolysaccharide stimulation. In conclusion, the combined COX-2 (COX2.8473) and the EP2 receptor (uS5) genotypes seem to influence CAD stability, but in peripheral blood monocytes only EP2 receptor modulates PGE(2) production.

Eicosanoids in exhaled breath condensates in the assessment of childhood asthma.

The value of measurements of eicosanoids in exhaled breath condensate (EBC) for the evaluation of childhood asthma is still inconclusive most likely because of the limited value of the methods used. In this case-control study in 48 asthmatic and 20 healthy children, we aimed to characterize the baseline profile of the inflammatory mediators cysteinyl leukotrienes (cysLTs), 9(alpha)11(beta)PGF(2), PGE(2), PGF(2alpha), 8-isoprostane (8-iso-PGF(2alpha)) within EBC in asthmatic compared with healthy children using new methods. In addition, we investigated their relation to other inflammatory markers. The assessment included collection of EBC, measurement of fractional exhaled nitric oxide (FE(NO)) and evaluation of urinary excretion of leukotriene E(4.) cysLTs were measured directly in EBC by radioimmunoassay and prostanoids were measured using gas chromatography negative-ion chemical ionization mass spectrometry. Only cysLT levels were significantly higher in asthmatic compared with healthy children (p = 0.002). No significant differences in cysLTs were found between steroid naïve and patients receiving inhaled corticosteroids. In contrast, FE(NO) was significantly higher in steroid naïve compared with steroid-treated asthmatic and healthy children (p = 0.04 and 0.024, respectively). The diagnostic accuracy of cysLTs in EBC for asthma was 73.6% for the whole group and 78.2% for steroid-naïve asthmatic children. The accuracy to classify asthmatic for FE(NO) was poor (62.9%) for the whole group, but improved to 79.9% when only steroid-naïve asthmatic children were taken into consideration. cysLTs in EBC is an inflammatory marker which distinguishes asthmatics, as a whole group, from healthy children.

Rapid and inexpensive detection of alpha1-antitrypsin deficiency-related alleles S and Z by a real-time polymerase chain reaction suitable for a large-scale population-based screening.

alpha(1)-Antitrypsin (AAT) deficiency is one of the most common genetic disorders in Caucasians, leading to early onset pulmonary emphysema and/or liver disorders. Accumulating data suggest that AAT deficiency is commonly under-recognized or misdiagnosed by physicians. The need for a rapid, timesaving, and relatively inexpensive but reliable detection method for the two most common deficiency alleles was developed using real-time polymerase chain reaction (PCR) genotyping. We designed and validated a 5'-nuclease assay for typing of the PI*S and PI*Z alleles using dual-labeled target-specific fluorescent probes. As a reference method, we used restriction fragment length polymorphism. The real-time PCR method was tested on a large, cross-sectional epidemiological trial. Overall, we genotyped about 1200 samples and found a very good concordance with AAT serum levels and restriction fragment length polymorphism results. In addition, external interlaboratory validation confirmed the accuracy of the real-time PCR method. In our experience, the real-time qualitative PCR using 5'-nuclease assay is suitable as a genetic test for AAT deficiency. This method offers an acceptable balance between reliability and expenses. It seems appropriate for both population-based screening and clinical diagnosis of the deficiency.

The additive antiplatelet action of clopidogrel in patients with coronary artery disease treated with aspirin.

We searched for additional anti-platelet effects of clopidogrel in coronary artery disease (CAD) patients treated with aspirin. Response to clopidogrel was also stratified according to aspirin resistance. Out of 76 screened aspirin-treated CAD male patients, five were aspirin-resistant based on arachidonic acid (AA) and ADP aggregometry. These five patients and 15 aspirin-sensitive patients entered the proper study. Platelet function was assessed at baseline and after one week of additional clopidogrel treatment using aggregometry, flow cytometry (ADP, TRAP-6) and platelet reactivity index (PRI) based on VASP (vasodilatorstimulated phosphoprotein) expression. We evaluated the same markers in 15 healthy men after aspirin treatment. In healthy subjects aspirin did not affect resting or ADP-induced activated GPIIb/IIIa and P-selectin expression. The P-selectin expression on ADP-activated platelets was increased (p < 0.01) in aspirin treated ASA-resistant CAD patients as compared to ASA-sensitive group or aspirin-treated healthy subjects. Clopidogrel significantly decreased ADP and AA-induced platelet aggregation and overcame aspirin resistance in four of five patients. Expression of ADP-induced activation markers was significantly lowered after clopidogrel in all patients. Out of 20 patients, five did not respond to clopidogrel (<10% inhibition of ADP aggregation), and this group showed no change in expression of ADP-induced activation markers after clopidogrel. Clopidogrel treatment significantly reduced PRI only in the clopidogrel-sensitive group. In conclusion, the addition of clopidogrel to aspirin provides greater inhibition of platelets and can overcome aspirin resistance. Flow cytometric analysis of platelets is useful for monitoring of clopidogrel therapy.

Blood coagulation at the site of microvascular injury in healthy and coumadin-treated subjects heterogenous for factor V Leiden mutation.

There is little knowledge regarding the in-vivo course of coagulation reactions in subjects with factor (F)V Leiden (G1691A, R506Q). The aim of the current study was to evaluate the effect of FV Leiden on coagulant reactions triggered by vascular injury. At the site of microvascular injury, prothrombin activation and FVa formation and inactivation have been evaluated in 16 apparently healthy subjects and 16 patients on long-term anticoagulation with acenocoumarol, with eight heterogenous carriers of FV Leiden in the healthy and in the anticoagulated group. Thrombin formation, measured by levels of thrombin-antithrombin complexes (TAT) and thrombin B-chain, proceeded at similar rates in the bleeding-time blood in carriers and non-carriers of FV Leiden. The onset and rate of FV activation did not differ significantly among the four groups. When healthy carriers of FV Leiden were compared to healthy non-carriers, the onset of FVa inactivation by activated protein C (APC) was delayed by 60 to 90 seconds (p=0.01). Anticoagulated individuals also showed the same pattern of FV Leiden associated differences in the time of occurrence of the 30 kD FVa heavy-chain fragment (p=0.021). Our results indicate that when blood clotting is triggered by microvascular injury, the heterozygous expression of FV Leiden has no effect on thrombin generation in healthy or coumadin-treated subjects. Inactivation of FVa by the APC mechanism is attenuated significantly in carriers of FV Leiden but the magnitude of this effect is smaller than that observed in most purified systems.

Antithrombotic effects of aspirin based on PLA1/A2 glycoprotein IIIa polymorphism in patients with coronary artery disease.

OBJECTIVE: The diallelic glycoprotein IIIa polymorphism P1A1/A2 was attributed to be an inherited risk factor for coronary events. Whether this polymorphism affects response to aspirin in patients with coronary artery disease is not known. METHODS: We assessed thrombin generation (prothrombin fragment F1+2) in consecutive blood samples collected from bleeding-time wounds in 28 men with coronary artery disease; P1A2 carriers, n=9; P1A1/A1, n=19. Thrombin generation and bleeding time were measured before and after 2 weeks of aspirin 300 mg/day. RESULTS: Aspirin-depressed thrombin generation in A1 homozygotes (p=0.04), but not in A2 carriers. Bleeding time after aspirin was also prolonged in A1 subjects only (p=0.02). CONCLUSION: Genotyping for glycoprotein IIIa polymorphism might be helpful in predicting antithrombotic action of aspirin in secondary prevention of coronary artery disease.

Plasma homocysteine affects fibrin clot permeability and resistance to lysis in human subjects.

OBJECTIVE: Homocysteine (Hcy) is a risk factor for thrombosis. We investigated a hypothesis that the clot permeability and its resistance to fibrinolysis is associated with plasma total Hcy (tHcy) in human subjects. METHODS AND RESULTS: We studied healthy men not taking any medication (n=76), male patients with advanced coronary artery disease (CAD) taking low-dose aspirin (n=33), men with diabetes mellitus diagnosed recently (median hemoglobin A(1c) 7.65%; n=16), and patients with isolated hypercholesterolemia (>7.0 mmol/L; n=15). We assessed clot permeability and turbidimetric lysis time as the determinants of fibrin clot structure. In a regression model, including age and fibrinogen, plasma tHcy was an independent predictor of clot permeation and fibrinolysis time in healthy subjects (R2=0.88, P<0.0001 and R2=0.54, P<0.0001, respectively). In CAD patients, tHcy and fibrinogen were stronger predictors of the permeation coefficient (R2=0.84; P<0.0001) than was fibrinogen alone (R2=0.66; P<0.0001), whereas tHcy was the only predictor of lysis time (R2=0.69; P<0.0001). Elevated tHcy levels observed after methionine load were not associated with any of the fibrin clot properties. In patients with diabetes or hypercholesterolemia, the influence of Hcy on permeation and, to a lesser extent, on the lysis time was obscured by dominant effects of glucose and cholesterol. In 20 asymptomatic men with hyperhomocysteinemia treated with folic acid, reduction in tHcy levels resulted in increased clot permeability (P=0.0002) and shorter lysis time (P<0.0001). CONCLUSIONS: Our results indicate that plasma tHcy predicts clot permeation and susceptibility to fibrinolysis in healthy men and CAD patients. Our data are consistent with a mechanism of thrombosis in hyperhomocysteinemia, which involves modification of fibrinogen by Hcy-thiolactone.

The prevalence of alpha(1)-antitrypsin deficiency in a representative population sample from Poland.

AIM: Severe alpha(1)-antitrypsin (AAT) deficiency is one of the most common genetic disorders in Caucasians. The aim of the present study was to assess an unbiased frequencies of PI*S and PI*Z alleles using genotyping of a representative sample from the general population of Poland. METHODS: A random sample of age- and gender-stratified residents, aged 20 years or older, was drawn from the municipal directory of Kraków, Poland. The two most common deficiency alleles: PI*S and PI*Z were genotyped with qualitative real-time PCR using degenerative dual-labeled allele-specific fluorescent probes. RESULTS: In the total population of 859 adult subjects (mean age: 49.5 years; range: 20-90), 28 heterozygotes MS, 18 heterozygotes MZ and one homozygote S were diagnosed. The frequency of PI*S allele was 17.5 (95% CI: 11.6-23.9) per 1000; and that of PI*Z was 10.5 (95% CI: 5.8-15.7) per 1000. Therefore, the estimated prevalence of inherited severe AAT deficiency (homozygotes Z) in Poland is 1/9110 (95% CI: 1/4057-1/29,727). CONCLUSIONS: In the whole population of Poland comprising 38 millions, one may expect of about 4189 (95% CI: 1284-9406) subjects with severe AAT deficiency. These numbers are high enough to consider genetic testing being introduced into a common clinical practice.

Zileuton added to low-dose inhaled beclomethasone for the treatment of moderate to severe persistent asthma.

OBJECTIVE: To assess the therapeutic effects of oral zileuton tablets combined with low-dose beclomethasone compared to doubling the dose of beclomethasone, in improving lung function and reducing asthma symptoms. METHODS: Randomized, active-control, double-blind, parallel, multi-center study of zileuton (400 or 600 mg QID)+200 microg beclomethasone dipropionate (BDP) BID versus placebo+BDP 400 microg BID in asthmatics with baseline FEV(1) percent predicted values between 40% and 80% following a single-blind ICS (BDP 200 microg BID) 2-week run-in. During the 3-month double-blind treatment period, assessments included safety, daytime and nighttime symptoms, acute asthma exacerbations, beta(2)-agonist use, AM and PM peak expiratory flow (PEF) and FEV(1). RESULTS: The addition of a 5-lipoxygenase (5-LO) inhibitor added to a low-dose of BDP showed no significant difference in FEV(1) compared to doubling the dose of BDP. FEV(1) improved in all 3 treatment groups, with mean increases of 10% with zileuton 600 mg QID+BDP 200 microg BID, 12% with zileuton 400mg QID+BDP 200 microg BID, and 11% with BDP 400 microg BID by study end. Within each treatment group, there were significant improvements in asthma symptoms and AM and PM PEF compared to baseline. No significant differences were observed between groups with regards to salbutamol use, acute asthma exacerbations, the requirement for oral/parenteral corticosteroids and adverse clinical events. CONCLUSIONS: The addition of a 5-LO inhibitor added to low-dose beclomethasone may be an alternative to higher-doses of ICS in patients unable to achieve sufficient asthma control on low-dose ICS therapy.

Interleukin-6 -174 G/C promoter polymorphism and effects of fenofibrate and simvastatin on inflammatory markers in hypercholesterolemic patients.

To evaluate whether the interleukin-6 (IL-6) -174 G/C polymorphism might alter the effects of micronized fenofibrate or simvastatin therapy on inflammatory markers, we measured IL-6, C-reactive protein, CD40 ligand, adhesion molecules, P-selectin and monocyte chemoattractant protein-1 in hypercholesterolemic patients both before and after a 30-day treatment. Serum IL-6 levels were significantly higher in patients with the GC or CC genotypes (P=0.04). The presence of the C allele was associated with greater absolute reduction of IL-6 levels (P=0.04) following fenofibrate treatment. There was no significant association between the -174 G/C IL-6 polymorphism and the effects of simvastatin treatment. A relationship between the -174 G/C IL-6 polymorphism and the anti-inflammatory action of fenofibrate reported might be useful in the optimization of the treatment regimen in patients receiving this class of drugs.

Towards a multidisciplinary and integrated strategy in the assessment of adverse health effects related to air pollution: the case study of Cracow (Poland) and asthma.

Complex interaction between anthropogenic activities, air quality and human health in urban areas, such as in Cracow sustains the need for the development of an interdisciplinary and integrated risk-assessment methodology. In such purpose, we propose a pilot study performed on asthmatics and based on a combined use of a biomarker, such as metallothionein 2A (MT-2A) in the characterization of human exposure to one or a mixture of pollutants and of Geographical Information Systems (G.I.S.) which integrates climatic and urban anthropogenic parameters in the assessment of spatio-temporal dispersion of air pollutants. Considering global incidence of air pollution on asthma and on peripheral blood lymphocytes MT-2A expression should provide a complementary information on biological risks linked to urban anthropogenic activities. Such study would help for the establishment of a sustainable development in urban areas that can maintain the integrity of air quality and preserve human health.

Aspirin alters the cardioprotective effects of the factor XIII Val34Leu polymorphism.

BACKGROUND: The mechanism underlying decreased risk for myocardial infarction in carriers of the Leu34 polymorphism of the factor (F) XIII A-subunit is unclear. Given that acetylation of fibrinogen by aspirin can alter its clotting properties and the presence of fibrin stimulates thrombin-mediated activation of FXIII, we have tested the hypothesis that treatment with aspirin differentially modulates the influence of the FXIII Val34Leu polymorphism on its activation in vivo. METHODS AND RESULTS: The rates of the disappearance of FXIIIA chain and the appearance of its activated form (FXIIIAa) in sequential 30-second blood samples collected at the site of microvascular injury were compared in 14 healthy carriers of the Leu34 allele and 23 Val34 homozygotes both before and after a 7-day aspirin ingestion (75 mg/d), with the use of quantitative Western blotting. The presence of the Leu34 allele was associated with a significant increase in the maximum rate of FXIII activation by thrombin. Although the Leu34-positive and -negative subjects were similar with respect to aspirin-related impairment of thrombin generation, aspirin led to a more pronounced inhibition of the activation of FXIII in the Leu34 carriers as compared with the Val34 homozygotes. CONCLUSIONS: Inhibition of FXIII activation by aspirin is enhanced in the Leu34 carriers in vivo, suggesting that these subjects might benefit more than the Leu34-negative subjects from the reduction in risk for myocardial infarction with low-dose aspirin.

Anti-thrombotic action of clopidogrel and P1(A1/A2) polymorphism of beta3 integrin in patients with coronary artery disease not being treated with aspirin.

Individual variability in response to clopidogrel is known but its mechanism is poorly understood. We examined the relationship between glycoprotein IIIa polymorphism P1(A1/A2) and anti-thrombotic actions of clopidogrel. Clopidogrel (75 mg/d; 2 weeks) was administered to 48 normolipemic patients with coronary artery disease. Bleeding time, thrombin generation at the site of microvascular injury, platelet function under high shear, using PFA-100 with ADP cartridge, and platelet surface activation markers (P-selectin and fibrinogen binding sites on GPIIb/IIIa complex detected by PAC-1 antibody), were studied both before and after clopidogrel treatment. Both unstimulated and low-dose (0.02 microM and 1 microM) in vitro ADP-stimulated platelets were examined. GP IIIa polymorphism was assessed by polymerase chain reaction and restriction fragment length polymorphism analysis. We identified 32 P1(A1/A1) homozygotes, 15 P1(A1/A2 heterozygotes and one P1(A2/A2) homozygote. Clopidogrel significantly prolonged bleeding time in all subjects, but this effect was greater in P1(A2 carriers (p < 0.01). Furthermore, clopidogrel only depressed thrombin generation at the site of microvascular injury (p < 0.01) in P1(A2) patients and prolonged closure time measured in vitro by PFA-100 (p < 0.05). At baseline spontaneous expression of PAC-1 and P-selectin was higher in P1(A2) subjects as compared to P1(A1) homozygotes (p < 0.05 for both antigens). Clopidogrel lowered the expression of both markers affecting more P1(A2) carriers, so that the difference in binding PAC-1 antibody between platelets from P1(A1) and P1(A2) carriers disappeared, while the difference in P-selectin expression slightly diminished. Anti-thrombotic effects of clopidogrel are more pronounced in CAD patients carrying the P1(A2) allele than in P1(A1) homozygotes.

Early antithrombotic and anti-inflammatory effects of simvastatin versus fenofibrate in patients with hypercholesterolemia.

The aim of the study was to determine whether a short-term treatment with simvastatin or fenofibrate may result in beneficial anti-inflammatory and antithrombotic effects in patients with high risk of coronary artery disease. In a randomized, double-blind study, we compared markers of inflammation, thrombin formation and platelet activation in patients with LDL cholesterol >130 mg/dl assigned to receive simvastatin (40 mg/d; n=20) or micronised fenofibrate (160 mg/d; n=22) for 28 days. Simvastatin, but not fenofibrate, lowered C-reactive protein (CRP) by 32% on day 3 (p<0.001), while both drugs reduced CRP significantly on day 28. Interleukin-6, soluble CD40 ligand, and monocyte chemoattractant protein-1 levels decreased significantly (by 20 to 50%) in both treatment groups on days 3 and 28. Soluble cell adhesion molecules remained unchanged in both groups. Simvastatin and fenofibrate significantly lowered plasma concentrations of thrombin-antithrombin complexes on days 3 and 28, but not platelet beta-thromboglobulin (betaTG) levels. Soluble P-selectin was lowered only in the simvastatin group. The total amount of thrombin generated at the site of microvascular injury also declined (by about 30%) as early as after 3 days of fenofibrate or simvastatin therapy, whereas beta TG release was reduced only in the simvastatin group on days 3 and 28. All the effects were independent of the changes in lipid profiles. Our results suggest that statins and fibrates can exert antithrombotic and anti-inflammatory effects as early as after 3 days of therapy. However, in contrast to statins, fibrates have no influence on platelet function within one month of therapy.

Genetic polymorphisms in chronic obstructive pulmonary disease.

Etiology of chronic obstructive pulmonary disease remains unknown but, despite some inconsistencies in reports on inflammatory cells, mediators and proteases involved in the pathogenesis of chronic obstructive pulmonary disease, genetic risk factors were proposed as a cause of susceptibility to the disease. Results of many studies suggested polygenic inheritance, with the genetic component consisting of several genes of a small effect each, rather than of single major gene. We are going to review the clinical importance of alpha-1 antitrypsin, glutathione S-transferase, microsomal epoxide hydrolase, matrix metalloproteinase, tumor necrosis factor-a, alpha-1 antichymotrypsin, alpha 2-macroglobulin, cytochrome P4501A1, heme oxygenase-1 genes polymorphisms associated with susceptibility and progression of the chronic obstructive pulmonary disease.