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Osteopontin (OPN) is an extracellular matrix glycoprotein that plays a role in a variety of cellular activities associated with inflammatory and fibrotic responses. Increased OPN levels in myocardium and plasma have been demonstrated in patients with dilated cardiomyopathy (DCM). However, nothing is known about OPN levels in patients with hypertrophic cardiomyopathy (HCM). Therefore, the aim of our study was to compare plasma OPN levels in patients with these two most common cardiomyopathies. We examined plasma OPN as well as creatinine, C‑reactive protein (CRP), brain-type natriuretic peptide (BNP), and troponin I levels in 64 patients with DCM, 43 patients with HCM, and 75 control subjects. Transthoracic echocardiography was also performed on all cardiomyopathy patients. Plasma OPN levels were significantly elevated in patients with DCM compared with HCM patients (95 ± 43 vs. 57 ± 21 ng/ml; p < 0.001) and control subjects (54 ± 19 ng/ml; p < 0.001); however, there was no difference between HCM patients and control subjects. New York Heart Association (NYHA) class III or IV disease was more frequently present in DCM patients than in HCM subjects (44 % vs. 2 %, p < 0.0001). In multivariate analysis, BNP and CRP levels together with NYHA class were found to be significant predictors of plasma OPN levels in DCM patients (p = 0.002, p = 0.029, and p < 0.001 for BNP, CRP, and NYHA, respectively). Plasma OPN levels were associated with overall heart failure severity rather than with specific cardiomyopathy subtype in patients suffering from DCM or HCM, respectively.

INTRODUCTION: We analyzed concentrations of osteopontin (OPN) in patients with pancreatic ductal adenocarcinoma (PDAC) in order to determine firstly whether it is useful to distinguish between PDAC patients and those with chronic nonhereditary pancreatitis (CP) and type 2 diabetes mellitus (T2DM), and secondly whether OPN concentrations depend on the PDAC stage. METHODS: Groups consisting of 64 patients with PDAC, 71 with CP, 67 with T2DM and 48 healthy controls (CON) were enrolled in the study. Controls were compared with regard to levels of OPN, oxidative stress markers, conventional tumor markers and other biochemical parameters. RESULTS: Levels of OPN were higher in patients with PDAC compared with CP patients ( P< 0.001), T2DM ( P< 0.001) and CON ( P< 0.001). There were increased OPN levels in CP patients in comparison with T2DM ( P< 0.001) and CON ( P< 0.001). Patients with PDAC in stage IV had higher OPN levels than PDAC patients in stage III ( P< 0.01). There was no difference in OPN levels of PDAC patients in stage III compared to patients in stage II. CONCLUSION: Our pilot study demonstrates the usefulness of estimating OPN levels to differentiate between pancreatic cancer and chronic pancreatitis. Higher OPN levels over 102 ng/ml could be a potential diagnostic biomarker for pancreatic cancer.

Elevated levels of the extracellular matrix glycoprotein osteopontin (OPN) may be detected in both myocardium and plasma under various pathological conditions affecting the heart. Several studies demonstrated increased plasma OPN levels in patients with heart failure due to dilated cardiomyopathy (DCM), while other studies showed high OPN expression levels in the myocardium of such patients. However, very little is known about OPN levels in both plasma and myocardium of the same individual with DCM. Therefore, we aimed to compare plasma OPN levels and levels of myocardial OPN expression in patients with recent-onset DCM (Ro-DCM). We examined plasma OPN as well as creatinine, C‑reactive protein (CRP), brain natriuretic peptide (BNP), and troponin I levels in 25 patients with Ro-DCM. Furthermore, all subjects underwent transthoracic echocardiography, selective coronary angiography, and endomyocardial biopsy (EMB) for the assessment of myocardial OPN expression. No significant correlation between myocardial OPN expression and clinical, biochemical, or echocardiographic parameters was found. In log transformation analysis, plasma OPN levels correlated significantly with BNP levels (r = 0.46, p = 0.031), with CRP levels (r = 0.52, p = 0.015), and with early diastolic mitral annular velocity (r = −0.57, p = 0.009). There was a borderline association between the plasma OPN log value and New York Heart Association class (p = 0.053). Plasma OPN levels reflect heart failure severity in patients with Ro-DCM. Myocardial OPN expression is not associated with either plasma OPN levels or markers of heart failure in these individuals.

Objective: Cirrhosis is a final stage of chronic liver disease. High morbidity and mortality are mostly related to complications of portal hypertension. Remodelling of liver fibrotic tissue by matrix metalloproteinases (MMPs) is a permanent process leading to cirrhotic scar formation. The aim was to study the significance of functional metalloproteinase MMP-1 and MMP-7 gene variants in cirrhotic patients and their relationship to portal hypertension. Patients and Methods: 179 patients with liver cirrhosis (mean age 55.2±11.6 years) were examined for functional variants of MMP-1 (-A; rs1799750 ) and MMP-7 (G/A; rs17884789 ) genes. Measurement of hepatic venous pressure gradient, laboratory and ultrasound examination were performed in all patients. Literary data from healthy population were used for comparison of allele frequencies with our cirrhotic patients. Results: The frequency of rs1799750 (1G-1G 25%, 1G-2G 56%, 2G-2G 22%) genotypes in cirrhotic patients does not differ from the healthy population (p>0.05). In MMP-7 gene, one genotype (wild type GG) was found in our patients uniformly for rs17884789 variant. No relationship was found between the frequency of examined genotypes and either the severity of portal hypertension or Child-Pugh or MELD score. Conclusions: Functional variants of MMP-1 and MMP-7 have no relationship to portal hypertension in liver cirrhosis.

The receptor for advanced glycation end products (RAGE) and its ligands are involved in the pathogenesis of cancer. Glyoxalase I (GLO1) is an enzyme which detoxifies advanced glycation end product (AGE) precursors. The aim of the study was to find out the relationship between four polymorphisms (single nucleotide polymorphism, SNP) of the RAGE gene (AGER) and one SNP of the GLO1 gene and clear cell renal cancer (ccRCC). All polymorphisms (rs1800625 RAGE -429T/C, rs1800624 -374T/A, rs3134940 2184A/G, rs2070600 557G/A (G82S), and GLO1 rs4746 419A/C(E111A)) were determined by PCR-RFLP in 214 patients with ccRCC. A group of 154 healthy subjects was used as control. We found significant differences in the allelic and genotype frequencies of GLO1 E111A (419A/C) SNP between patients and controls—higher frequency of the C allele in ccRCC—58.6 vs. 44.5 % in controls, OR (95 % CI) 1.77 (1.32–2.38), p = 0.0002 (corrected p = 0.001); OR (95 % CI) CC vs. AA 2.76 (1.5–4.80), p = 0.0004 (corrected p = 0.002); and AC+CC vs. AA 2.03 (1.23–3.30), p = 0.0034 (corrected p = 0.017). High aggressiveness of the tumor (grade 4) was associated with the presence of C allele RAGE -429T/C SNP (original p = 0.001, corrected p = 0.005) and G allele RAGE 2184A/G SNP (p

Objectives PAPP-A is an independent mortality predictor of long term hemodialysis patients and a prognostic marker of acute coronary syndrome in general population. Cys327Cys PAPP-A polymorphism (SNP) (rs12375498) was found to be of significance in preeclampsia and the C allele of the PAPP-A C/G SNP (rs13290387) was defined as an independent risk factor for acute myocardial infarction. The aim of the study was to test the role of these PAPP-A SNPs in long term hemodialysis patients. Design and methods The studied group consisted of 464 subjects — 319 long term hemodialysis patients (183 men, 136 women, 62 ± 14 years) and 145 controls (65 men, 80 women, 49 ± 14 years). A subgroup of 211 hemodialysis patients (118 men, 93 women, 63 ± 13 years) was prospectively followed up for 4.5 years. During the follow up, 111 patients died, 51 of them due to cardiovascular events. PAPP-A SNPs were analyzed by DNA sequencing and serum PAPP-A was measured by TRACE. Results Both SNPs were in Hardy–Weinberg equilibrium. Allelic and genotype frequencies did not differ between patients and controls and were not related to serum PAPP-A concentrations. Cys327Cys SNP was significant for patients' survival (HR (95% CI): 1.616 (1.110–2.353), nominal p = 0.012, corrected p = 0.036) while C/G SNP was not. Conclusions Our study shows for the first time the significance of Cys327Cys PAPP-A SNP (rs12375498) for overall mortality of long term hemodialysis patients. Although it does not influence the concentration of PAPP-A it still could affect the correct function of this enzyme which has to be clarified in further studies.

Nitric oxide is an important vasoactive mediator. Changes in NO production, caused by functional variants of both endothelial and inducible NO synthase (eNOS, iNOS), might play a role in portal hypertension. The aim was to study the significance of functional eNOS and iNOS gene variants in cirrhotic patients and their interrelationship to both inflammatory and endothelial activation parameters.One hundred and thirty-two patients with liver cirrhosis (age 36-72 years) and 101 controls were examined for functional variants of eNOS (E298D, 27bpintr4, 786T/C) and iNOS (R221W, S608L) genes. Inflammatory (IL6, IL8, IL10) and vasoactive (sVCAM-1, E-selectin) cytokines were measured using ELISA kits.The frequency of E298D (GG 12%, GT 41%, TT 47%), 28bpintr4 (AA 6%, AB 28%, BB 66%), 786T/C genotypes (CC 17%, CT 45%, TT 38%), as well as R221W (CC 93%, CT 7%, TT 0%), and S608L (CC 65%, CT 32%, TT 3%) genotypes in cirrhotic patients did not differ from the controls (p0.05 for all comparisons). No relationship was found between the frequency of these genotypes and the severity of portal hypertension, or either inflammatory or vasoactive cytokines. A positive correlation was found between hepatic venous pressure gradient and cytokine concentration: sVCAM-1, IL6, IL8, IL10.Examined eNOS and iNOS variants have no relationship to pathogenesis of liver cirrhosis. Severity of portal hypertension was associated with the changes in endothelial activation.

States associated with insulin resistance, as overweight/obesity, type 2 diabetes mellitus (DM2), cardiovascular diseases (CVD), some cancers and neuropsychiatric diseases are characterized with a decrease of long-chain polyunsaturated fatty acids (LC-PUFA) levels. Amounts of LC-PUFA depend on the exogenous intake of their precursors [linoleic (LA) and α-linolenic acid (ALA)] and by rate of their metabolism, which is influenced by activities of enzymes, such as Δ6-desaturase (D6D, FADS2), D5D, FADS1, elongases (Elovl2, -5, 6).Altered activities of D5D/D6D were described in plenty of diseases, e.g. neuropsychiatric (depressive disorders, bipolar disorder, dementia), metabolic (obesity, metabolic syndrome, DM2) and cardiovascular diseases (arterial hypertension, coronary heart disease), inflammatory states and allergy (Crohns disease, atopic eczema) or some malignancies. Similar results were obtained in studies dealing with the associations between genotypes/haplotypes of FADS1/FADS2 and above mentioned diseases, or interactions of dietary intake of LA and ALA on one hand and of the polymorphisms of minor allels of FADS1/FADS2, usually characterized by lower activities, on the other hand.The decrease of the desaturases activities leads to decreased concentrations of products with concomitant increased concentrations of substrates. Associations of some SNP FADS with coronary heart disease, concentrations of plasma lipids, oxidative stress, glucose homeostasis, and inflammatory reaction, were described. Experimental studies on animal models and occurrence of rare diseases, associated with missing or with marked fall activities of D5D/D6D emphasized the significance of desaturases for healthy development of organism as well as for pathogenesis of some disease.

To investigate the relationship between osteopontin plasma concentrations and the severity of portal hypertension and to assess osteopontin prognostic value.A cohort of 154 patients with confirmed liver cirrhosis (112 ethylic, 108 men, age 34-72 years) were enrolled in the study. Hepatic venous pressure gradient (HVPG) measurement and laboratory and ultrasound examinations were carried out for all patients. HVPG was measured using a standard catheterization method with the balloon wedge technique. Osteopontin was measured using the enzyme-linked immunosorbent assay (ELISA) method in plasma. Patients were followed up with a specific focus on mortality. The control group consisted of 137 healthy age- and sex- matched individuals.The mean value of HVPG was 16.18 ± 5.6 mmHg. Compared to controls, the plasma levels of osteopontin in cirrhotic patients were significantly higher (P0.001). The plasma levels of osteopontin were positively related to HVPG (P = 0.0022, r = 0.25) and differed among the individual Child-Pugh groups of patients. The cut-off value of 80 ng/mL osteopontin distinguished patients with significant portal hypertension (HVPG above 10 mmHg) at 75% sensitivity and 63% specificity. The mean follow-up of patients was 3.7 ± 2.6 years. The probability of cumulative survival was 39% for patients with HVPG10 mmHg and 65% for those with HVPG ≤ 10 mmHg (P = 0.0086, odds ratio (OR), 2.92, 95% confidence interval (CI): 1.09-7.76). Osteopontin showed a similar prognostic value to HVPG. Patients with osteopontin values above 80 ng/mL had significantly lower cumulative survival compared to those with osteopontin ≤ 80 ng/mL (37% vs 56%, P = 0.00035; OR = 2.23, 95%CI: 1.06-4.68).Osteopontin is a non-invasive parameter of portal hypertension that distinguishes patients with clinically significant portal hypertension. It is a strong prognostic factor for survival.

The aim of the study was to investigate genetic and biochemical background of PAPP-A (pregnancy-associated plasma protein A) in patients with risk pregnancies.Five PAPP-A gene polymorphisms and PAPP-A maternal serum levels were studied together in 165 women in third trimester pregnancies complicated with threatening preterm labor (n=98), preeclampsia (n=35), intrauterine growth restriction (n=34) and ICP (intrahepatic cholestasis of pregnancy) (n=15). 114 healthy pregnant women served as controls.Preeclamptic patients had significantly higher frequency of TT genotype of Cys327Cys polymorphism compared to controls (p0.01). Patients with ICP had increased serum levels of PAPP-A compared to controls and correlation analysis showed significant relationship between PAPP-A and CRP (C-reactive protein) in the patients with intrauterine growth restriction (r=0.49, p=0.007).Our study indicates the association of TT genotype of Cys327Cys polymorphism of the PAPP-A gene with preeclampsia. However, further study with larger groups of preeclamptic patients is needed to confirm our results.

Rett syndrome is a neurodevelopmental disorder mainly caused by de novo mutations in the MECP2 (methyl-CpG-binding protein 2) gene. There is considerable variation in the severity of clinical features among Rett syndrome patients, even among patients with the same MECP2 mutation. In addition to X-chromosome inactivation pattern, the genetic background of the affected individual might also have a role in determining the severity of the disorder. We suggest that APOE is one of the genetic modulating factors. We analyzed clinical phenotypes of 46 patients with Rett syndrome, with confirmed MECP2 mutation. We discovered that among ε4 carriers, some clinical features were more severe, and the developmental regression occurred 4 months earlier on average than in those without the ε4 allele. Earlier onset of regression suggests a possible trend; however, it did not achieve distinctive statistical significance. Nevertheless, the ε4 allele of APOE may serve as a candidate modulation factor for the Rett syndrome phenotype.

Background: Advanced glycation end products (AGEs) belong to uremic toxins and some pathological effects of AGEs are linked to RAGE (receptor for AGEs). Their precursors are detoxified by the glyoxalase (GLO) system. The A419C (E111A) polymorphism of the GLO I gene is associated with vascular disease in hemodialysis (HD) patients and some RAGE gene polymorphisms are implicated in various pathological states. Aim: To study the relationship of A419C GLO I and four RAGE polymorphisms (–429T/C, –374T/A, 2184A/G and Gly82Ser) in the prognosis of HD patients. Methods: The group studied consisted of 214 chronic HD patients prospectively followed up for 43 months. 100 patients died, 48 due to cardiovascular causes. Results: The Kaplan-Meier analysis showed a higher mortality rate in patient-mutated homozygotes for RAGE –429CC, RAGE 2184GG and GLO I 419CC. A higher hazard risk was confirmed by the Cox proportional hazards model when wild-type homozygotes were taken as reference: RAGE –429CC 2.28 (95% CI 1.04–4.99), RAGE 2184GG 3.16 (95% CI 1.44–6.93), and GLO I 419CC 1.75 (95% CI 1.08–2.86). Both RAGE polymorphisms were also associated with cardiovascular mortality: RAGE –429CC 3.54 (95% CI 1.37–9.14) and RAGE 2184GG 5.04 (95% CI 1.93–13.11). Conclusion: In summary, our study shows for the first time a link between RAGE and GLO polymorphisms in the prognosis of HD patients.

The aldosterone synthase gene (CYP11B2) is an important candidate gene region in essential hypertension. We therefore studied the association of -344T/C polymorphism of the CYP11B2 gene with the presence and severity of hypertension in a case-control study. We studied 369 individuals, of whom 213 were hypertensive patients (139 controlled hypertensive, 74 resistant hypertensive) and 156 were healthy normotensive subjects. The -344T/C polymorphism of the CYP11B2 gene was determined using polymerase chain reaction - restriction fragment length polymorphism analysis. The distribution of genotypes in normotensive controls and hypertensive subjects were: TT 25.6 vs. 31.9 %, TC 51.9 vs. 57.3 % and CC 22.4 vs. 10.8 %. The -344T/C variant was associated with hypertension. Subjects carrying the -344T allele had a greater risk of hypertension compared to those having C allele (χ2 =5.89, p

The aim of this study was to investigate the effect of the microsomal triglyceride transfer protein (MTP) −493G/T polymorphism on clinical and biochemical parameters in relation to the presence of metabolic syndrome (MS). A group of 270 participants, 143 men and 127 women [50 men/36 women fulfilled the International Diabetes Federation (IDF) criteria of MS], was categorized on the basis of the MTP −493G/T polymorphism: GG homozygotes (Group GG) and carriers of the T allele (Group TT+TG). In men with MS, the presence of the T allele was associated with elevated concentrations of plasma insulin (by 48%, P

Advanced glycation end products (AGEs) take part in the pathogenesis of vascular, diabetic, and uremic complications. Their precursors are detoxified by the glyoxalase system. Our aim was to study A419C (E111A) single nucleotide polymorphism (SNP) of the glyoxalase I gene in hemodialysis (HD) patients. A419C SNP, several laboratory parameters including soluble receptor for AGEs (sRAGE), and clinical data were studied in 214 HD patients and 89 controls. Allelic and genotypic frequencies did not differ between HD patients and controls. A419C SNP was significantly linked with serum sRAGE, which sensitively reflects the AGE burden of the organism (3986 +/- 1638 pg/mL in the CC variant versus 3277 +/- 1398 pg/mL in the AC variant and 3297 +/- 1445 pg/mL in the AA variant, P < 0.01). In the CC variant, significantly higher prevalence of cardiovascular disease and peripheral vascular disease was found, while the prevalence of hypertension, diabetes mellitus, and dyslipidemia did not differ between genotypes. In summary, in this study we demonstrate for the first time the association of A419C polymorphism of the glyoxalase I gene with sRAGE levels and show the genetic predisposition to vascular complications in HD patients.

Receptor for advanced glycation end products (RAGE) may be involved in the pathogenesis of the cancer progression and metastasis. Pathological effects mediated via RAGE are physiologically inhibited by soluble RAGE (sRAGE), so the higher sRAGE levels may confer the patients with cancer with better outcome. The aim was to study sRAGE and RAGE gene polymorphisms in patients with breast cancer. The authors studied sRAGE and RAGE polymorphisms in 120 patients with breast cancer (subdivided based on the clinical stage, histologic grading, expression of hormonal and Her2/neu receptors) and in 92 healthy controls. Despite higher serum concentrations of AGEs, serum concentrations of sRAGE were lower in patients with breast cancer compared to healthy controls (1581 +/- 777 versus 1803 +/- 632 ng/mL, p < 0.05). Serum levels of sRAGE were higher in patients with advanced breast cancer (stage III), lower grade and positive estrogen receptors, and intermediate positivity of Her2/neu receptors and were also influenced genetically (Gly82Ser and 2184 AG polymorphisms of the RAGE gene). Decreased sRAGE levels in patients with breast cancer may contribute to the progression of the disease. Patients with better outcome (low grade and positive estrogen receptors) have higher sRAGE levels. Progression of the disease, may, however, increase sRAGE levels, possibly as a compensatory mechanism to counteract further progression.

Chromium(VI) is a recognized toxicant whose effects have been linked to its reduction to lower oxidation states. Although Cr(VI) is reduced by several systems, it is anticipated that its reduction by nitric oxide synthase (NOS) could have significant effects in endothelial and brain cells that express high constitutive levels of the enzyme. This possibility was examined by electron paramagnetic resonance that showed the formation of a stable Cr(V) species from NOS/Cr(VI). The formation of Cr(V) was calcium/calmodulin-independent indicating that Cr(VI) to Cr(V) reduction occurs at the flavin-containing domain of NOS. Accordingly, Cr(VI) reduction by the reductase domain of NOS and the chimera protein cytochrome-P450-reductase+tail-nNOS also generated Cr(V). Activation of tetrahydrobiopterin (BH(4))-free NOS with calcium/calmodulin diminished Cr(V) steady-state levels while increasing superoxide formation. Since SOD restored Cr(V) to control levels, this result was taken as evidence for a reaction between Cr(V) and superoxide. Supplementation of NOS with BH(4) cofactor not only failed to increase Cr(V) yields but generated superoxide and hydroxyl radical. Since the holoenzyme does not generate superoxide, this reaction indicated that Cr(V) mediates the oxidation of BH(4)-bound to the enzyme. In the presence of L-arginine, however, Cr(VI) neither enhances superoxide release nor inhibits NO formation from fully active NOS. This suggests that L-arginine protects BH(4) from Cr(V)-mediated oxidation. While Cr(V) was inactive toward NO, spin trapping experiments with 5-tert-butoxycarbonyl 5-methyl-1-pyrroline N-oxide and oxygen consumption measurements showed that Cr(V) reacts with superoxide by a one-electron-transfer mechanism to generate oxygen and Cr(IV). Thus, reduction of Cr(VI) to Cr(V) by NOS occurs in resting and fully active states. It is likely that the reaction between Cr(V) and superoxide influences the cytotoxic mechanisms of Cr(VI) in cells.

The aim of the study was to examine whether the circulating cell adhesion molecules, von Willebrand factor (vWf) and endothelin-1, are elevated in patients with essential hypertension with no other risk factors for atherosclerosis and thus may serve as a markers of endothelial dysfunction in uncomplicated hypertension. Furthermore, the effect of treatment with the ACE inhibitor, quinapril, on levels of endothelial dysfunction markers were studied. The levels of adhesion molecules (intercellular cell adhesion molecule-1 [ICAM-1], E-selectin, P-selectin), von Willebrand factor (vWf) and endothelin-1 were measured in patients with hypertension without any other risk factors of atherosclerosis before and after treatment with quinapril (n = 22) and in normotensive controls (n = 22). Compared with normotensive subjects, the hypertensive patients had significantly higher levels of ICAM-1 (238 vs 208 ng/ml, P = 0.02), vWf (119 vs 105 IU/dl, P < 0.05) and endothelin-1 (5.76 vs 5.14 fmol/ml, P < 0.05). Three-month treatment of hypertensive patients with quinapril led to a significant decrease in the levels of endothelin-1 (5.76 vs 5.28 fmol/ml, P < 0.01). We did not observe significant changes in the levels of adhesion molecules and vWf after ACE inhibitor treatment, although a trend toward a decrease was apparent with all these parameters. Patients with uncomplicated hypertension with no other risk factors of atherosclerosis had significantly elevated levels of ICAM-1, vWf, and endothelin-1. Our data suggest that these factors may serve as markers of endothelial damage even in uncomplicated hypertension. In hypertensive patients, treatment with the ACE inhibitor quinapril resulted in a significant decrease in endothelin-1 levels. These findings indicate a beneficial effect of ACE inhibitors on endothelial dysfunction in hypertensive patients.

Since beta2-adrenergic receptors (beta2AR) can influence blood pressure not only by vasodilation, but also participate in noradrenaline release from sympathetic nerve endings, we have studied whether Arg16Gly polymorphism of the beta2AR gene is associated with predisposition to essential hypertension and increased plasma noradrenaline concentration in offspring from normotensive (SN) and hypertensive parents (SH).The study population consisted of 105 young SN and 101 SH subjects matched for age and body mass index. Arg16Gly polymorphism of the beta2AR gene was determined by polymerase chain reaction (PCR) technique and subsequent incubation with NcoI restriction enzyme. Resulting fragments were separated using electrophoresis on a 4.2% Metaphor agarose gel.SH already had significantly higher systolic BP, and a tendency to higher diastolic BP than the SN group. The frequency of Arg/Arg homozygotes was significantly increased in SH when compared to SN (25% vs 15%). Results of logistic regression analysis showed the highest relative risk for the Arg/Arg genotype and suggested a recessive action of the Arg16 variant. There was an increased diastolic BP in Arg/Arg homozygotes of the SN group (p = 0.029). This genotype also had a tendency to increased heart rate in both groups (p = 0.049). There was no relationship of this polymorphism with plasma noradrenaline concentration.Our findings suggest that genetic variability of the beta2AR gene is implicated in predisposition to essential hypertension. However, the contradictory results between individual studies indicate that the action of the beta2AR gene is indirect, through multiple intermediate phenotypes and gene interactions.

Tyrosine hydroxylase (TH) is a rate-limiting enzyme for catecholamine biosynthesis. Increased sympathetic activity is associated with an increased left ventricular (LV) mass. However, the influence of TH gene polymorphisms on LV structure and function has yet to be investigated. Here, we analyse the association of Val-81-Met and tetranucleotide TCAT repeat TH polymorphisms with LV structure and function (assessed by echocardiography) in 108 normotensive men aged < or = 35 years (mean age: 25+/-4 years) with body mass index (BMI) < or = 30 kg/m2 (mean BMI: 23+/-3 kg/m2). The distribution of genotypes was VV homozygotes (n=42), VM heterozygotes (n=49) and MM homozygotes (n=17). The Val-81-Met polymorphism showed significant linkage disequilibrium with the TCAT polymorphism (P

Endothelial nitric oxide synthase (eNOS) produces nitric oxide (NO) which, after diffusing into vascular smooth muscle cells, activates guanylate cyclase leading to vasodilatation. A polymorphism (894G to T) in exon 7 of the eNOS gene causes the conversion of Glu to Asp in position 298. The recently described crystal structure of the heme domain of eNOS protein shows that Glu298 is fully solvent accessible and distant from regions integral to enzyme function. Searching for phenotypic expression of eNOS gene variants, we genotyped a group of patients with essential hypertension (H, n = 119) for the Glu298Asp polymorphism and compared them with age- and sex-matched healthy normals (N, n = 85). To specify phenotypic expression further, the hypertensive patients were subdivided into one group that responded well to regular antihypertensive therapy (CH, n = 45) and one group that was resistant to the therapy (RH, n = 74). Patients with BP higher than 140/90 mmHg when on adequate lifestyle modification and triple-combination therapy (including diuretics) were considered resistant. In RH and H groups, a significantly higher frequency of T alleles (P = 0.022 and P = 0.046, respectively) was found compared to normotonics (N). In well-controlled hypertonics, the same tendency was found, but did not reach statistical significance. The Glu298Asp polymorphism may contribute to the complex pathogenesis of essential hypertension and may be a factor in the resistance of these patients to conventional antihypertensive therapy. The presence of this allele may thus be predictive of the patients' therapeutic response.

Abstract —Previous studies with chromosome-Y consomic strains of spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats suggest that a quantitative trait locus for blood pressure regulation exists on chromosome Y. To test this hypothesis in the SHR–Brown Norway (BN) model and to study the effects of chromosome Y on lipid and carbohydrate metabolism, we produced a new consomic strain of SHR carrying the Y chromosome transferred from the BN rat. We found that replacing the SHR Y chromosome with the BN Y chromosome resulted in significant decreases in systolic and diastolic blood pressures in the SHR.BN-Y consomic strain ( P

An elevated plasma level of endothelin-1 was reported in several cardiovascular conditions including unstable angina pectoris and myocardial infarction. The present study was designed to evaluate the time course of the endothelin-1 release in unstable angina pectoris and to assess its relationship to the development of myocardial infarction and coronary vessel occlusion. The cohort studied included 32 patients with the clinical diagnosis of unstable angina pectoris who had been admitted to the coronary care unit and subsequently underwent coronary angiography (group A). Fourteen patients with chronic stable angina pectoris referred to routine diagnostic coronary angiography served as the control group (group B). A significant difference in the endothelin-1 plasma level was found between both groups, the values being 10.2 ± 5.3 and 6.0 ± 3.1 pg/ml (p < 0.01), respectively. There were, however, no significant differences between the following subdivisions of group A: patients with and without subsequent myocardial infarction; those with angiographically documented occlusion of at least one major branch of the coronary artery and no occlusion; and finally, those with persisting symptoms of angina pectoris and with favorable response to treatment. Neither was there any difference found among the subgroups differing in the time interval between the onset of chest pain and blood sampling. The time course of endothelin plasma concentrations showed elevated values lasting for more than 96 h after the index episode of prolonged chest pain. No correlation with the subsequent clinical course could be inferred. Thus, plasma endothelin level was elevated in patients with unstable angina pectoris and myocardial infarction and the increase persisted for several days after the onset of symptoms.

Endothelin plays an important role in cardiovascular pathology. As one of the most important endothelium-derived vasoconstrictor substances, endothelin together with endothelium-derived vasodilating factor control vascular tone and contribute to the vasoconstrictory response if the production of endothelium-derived vasodilating factor is impaired. The aim of the study was to assess the changes of the local endothelin level in coronary circulation immediately after percutaneous transluminal coronary angioplasty (PTCA). Plasma endothelin levels were measured in blood samples from the peripheral vein and ostium of the coronary artery before the angioplasty, and from the distal coronary artery just beyond the dilated segment and the peripheral vein immediately after the procedure. The plasma endothelin level was significantly higher in the ostium of the coronary artery already prior to PTCA as compared to the peripheral vein (10.9 +/- 3.4 vs. 7.2 +/- 2.1 pg/ml, p < 0.005). There was no change in the endothelin level in the coronary artery distal to the dilated segment immediately after the procedure as compared to the initial level, although this level was higher than the postangioplasty venous level (9.8 +/- 2.9 vs. 7.7 +/- 2.0 pg/ml, p < 0.005). Individual changes in coronary-artery plasma endothelin levels as a response to coronary angioplasty were disparate. An increase and a decrease in coronary artery plasma endothelin levels by more than 2 pg/ml after coronary angioplasty were observed in 3 and 6 subjects, respectively. In conclusion, increased plasma endothelin levels were found in blood samples drawn from the coronary artery as compared to the peripheral vein. There was no further change in the plasma endothelin level in the coronary artery distal to the dilated segment after angioplasty; however, the individual responses were disparate.

To investigate the possible role of endothelin in coronary vasoconstriction contributing to the development of myocardial ischemia, plasma endothelin concentrations at rest and during atrial pacing-induced myocardial ischemia have been measured in blood samples drawn from the aorta and coronary sinus in 12 patients with significant narrowing of the left anterior descending coronary artery. The plasma endothelin concentrations at rest were similar in the aorta (AO/R) and coronary sinus (CS/R) (4.8 +/- 2.4 and 4.5 +/- 1.7 pg/ml, respectively), the difference between coronary sinus and aorta plasma endothelin concentration (CS/R-AO/R) being -0.3 +/- 1.7 pg/ml. During atrial pacing-induced myocardial ischemia aortic plasma endothelin concentration (AO/P) did not change (4.6 +/- 2.6 pg/ml) and only an insignificant increase in the plasma endothelin concentration in the coronary sinus (CS/P) was observed (5.3 +/- 2.8 pg/ml). The difference between coronary sinus and aortic endothelin plasma concentration (CS/P-AO/P) was 0.6 +/- 2.5 pg/ml. Finally, the difference in endothelin concentrations between coronary sinus and aorta rose only insignificantly during pacing as compared to the resting values ([CS/P-AO/P]-[CS/R-AP/R] being 0.9 +/- 3.2 pg/ml). Thus, atrial pacing-induced myocardial ischemia in patients with significant left anterior descending coronary artery stenosis was not accompanied by significant changes in coronary sinus plasma endothelin concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)

Objectives The aim of the study was to analyze polymorphisms of receptor for advanced glycation end products (RAGE) gene, and glyoxalase I gene and soluble RAGE, sRAGE, in physiological and pathological pregnancy. Design and methods Polymorphisms of RAGE gene (− 429 T/C, − 374 T/A, 557 G/A, 2184 A/G) and glyoxalase I gene (A419C) and sRAGE serum levels were determined in 284 women with pathological and physiological pregnancy. Results No differences in distribution of genotype and allelic frequencies of studied polymorphisms were found. GA genotype of RAGE 557 G/A polymorphism (known as Gly82Ser) is associated with lower sRAGE serum levels in healthy pregnant women compared to GG genotype (483 ± 104 vs. 692 ± 262 pg/mL, p = 0.008). sRAGE correlates negatively with ALT in patients with pregnancy intrahepatic cholestasis (r = − 0.536, p = 0.05). Conclusions We did not show any association of RAGE and glyoxalase I gene polymorphisms with pathological pregnancy, however further studies are needed to confirm the results.

Prognosis of patients with pancreas cancer is very poor. The aim of the study was to test the significance of laboratory parameters in the prognosis of patients with pancreas cancer. The studied group included 57 patients (31 men, 26 women, mean age 65 ± 9 years). Blood was collected at the time of diagnosis of pancreas cancer and basic laboratory parameters, including nutritional and inflammatory markers and tumour markers were measured. Patients were followed up until death (median survival 147 days). Ferritin, iron, albumin, prealbumin, cholinesterase, haemoglobin, C-reactive protein, alkaline phosphatase and carcinoembryonic antigen were significant for patients' prognosis in univariate analysis while CA 19-9, bilirubin, liver, pancreas and kidney tests and lipids were not. Multivariate Cox regression demonstrated ferritin, iron and albumin as independent mortality predictors (RR (95%CI), per standard deviation: ferritin 1.497(1.215-2.241), p = 0.002; albumin, 0.716(0.521-0.977), p = 0.035; iron, 0.678(0.504-0.915), p = 0.010). Iron correlated significantly with albumin (r = 0.397, p = 0.002) but neither iron nor albumin correlated with ferritin. Patients who survived 100 days had significantly lower ferritin (median 239 μg/l vs. non-survivors 435 μg/l, p = 0.014), significantly higher albumin but the difference in serum iron was not quite significant. ROC analysis for ferritin revealed AUC for 100 days survival of 0.710, p = 0.007 (and 0.725, p = 0.004 for 200 days survival). AUC for albumin for 100 days survival was not significant (p = 0.073). This study points out ferritin as an independent mortality predictor in patients with pancreas cancer. High serum levels of ferritin at the time of diagnosis of pancreas cancer indicate bad prognosis of the patient.

UNLABELLED The aim of this study was to analyze the relationship of serum leptin as well as adiponectin and the manifestation of pancreatic cancer (PC). Serum leptin, adiponectin, glucose homeostasis and insulin resistance (expressed as HOMA-IR) were investigated in 64 patients with newly diagnosed PC and compared with 64 healthy controls (CON group) and 75 patients with type 2 diabetes (DM2). Seventy percent of newly diagnosed PC patients had DM2. The levels of leptin were lower, whilst adiponectin/leptin ratio was higher in PC patients (both with and without DM2), in comparison with CON and DM2 groups (P < 0.001) independently of age, BMI and waist circumference. Newly diagnosed PC is characterized with lower leptin concentrations and higher adiponectin/leptin ratio in comparison with CON or DM2 individuals. Analysis of these parameters could help in the screening of persons in high risk for PC, especially in those with DM2. KEYWORDS adiponectin, leptin, pancreatic cancer, type 2 diabetes mellitus.

Despite the introduction of new imaging methods, the prognosis of pancreatic carcinoma (PC) remains hopeless. Therefore, there has been exerted much effort to elucidate the risk factor enabling the diagnosis of PC in the "preclinical state". At the time of PC diagnosis, more than 30% of patients suffer from diabetes mellitus, much more often than in the rest of the population. It is not clear whether DM is a risk factor for PC onset or DM appears secondary to the destruction of the gland by the tumor progression or by the effect of unknown factors produced by the cancer cells.We enrolled 204 individuals into the study, 69 of them were controls, 70 patients had type 2 diabetes mellitus and 65 cases had newly diagnosed PC. The patients with PC had in 68% of cases disturbed glucose homeostasis and significantly higher values of insulin resistance index (HOMA-IR) in comparison with the control group. The presence of glucose homeostasis disturbances does not influence tumor staging and localization.Results of our pilot study confirmed the so far unsatisfactory state of PC diagnostics (majority of cases fall to stages III and IV) and corroborated the close relation to DM. The early markers for the risk of pancreatic carcinoma development should be searched among the factors participating in the regulation of the glucose homeostasis and insulin sensitivity.

The receptor for advanced glycation end-products (RAGE) takes part in the pathogenesis of many diseases, including diabetes mellitus and cancer. AGE-precursors are detoxified by glyoxalase (GLO). sRAGE, soluble RAGE, is an inhibitor of pathological effects mediated via RAGE. The aim was to study sRAGE and polymorphisms of RAGE (AGER) and GLO genes in patients with pancreas cancer (PC).The studied group consisted of 51 patients with PC (34 with impaired glucose tolerance-IGT, 17 without IGT), 34 type 2 DM and 154 controls. For genetic analysis, the number of patients was increased to 170. Serum sRAGE was measured by ELISA and all polymorphisms (RAGE -429T/C, -374T/A, 2184A/G, Gly82Ser and GLO A419C) were determined by PCR-RFLP and confirmed by sequencing.Soluble RAGE is decreased in patients with PC compared to patients with DM and controls (975+/-532 vs. 1416+/-868 vs. 1723+/-643pg/mL, p0.001). Patients with PC and IGT have lower sRAGE levels compared to patients with PC without IGT (886+/-470 vs. 1153+/-616pg/mL, p0.05). No relationship of sRAGE to the stage was found. We did not show any difference in allelic and genotype frequencies in all RAGE and GLO polymorphisms among the studied groups.This is the first study demonstrating decreased sRAGE in patients with pancreas cancer. Its levels are even lower than in diabetics and are lowest in patients with PC and IGT. Our study supports the role of glucose metabolism disorder in cancerogenesis. Further studies are clearly warranted, especially with respect to potential preventive and therapeutic implications.

Effect of advanced glycation end products (AGEs) in the pathogenesis of cancer could be diminished by interaction with soluble RAGE or by reducing AGE-precursors via glyoxalase I. Glu111Ala polymorphism of glyoxalase I gene, AGEs, and sRAGE serum levels were studied in 113 breast cancer patients and in 58 controls. Higher frequency of the mutated C allele was found in patients with negative estrogen receptors and in patients in clinical stage III compared to controls (P< 0.05). The presence of the C allele could represent a negative prognostic factor; however, further studies are needed to confirm this hypothesis.

Objectives RAGE (receptor for advanced glycation end products) is involved in pathogenesis of many diseases. The aim of the study was to test whether polymorphisms of RAGE gene are associated with the outcome of kidney transplantation. Design and methods Four polymorphisms of the RAGE gene (− 429T/C, − 374T/A, Gly82Ser and 2184A/G) were assessed in 145 renal transplant recipients and their relationship to histological changes in 12 months protocol kidney graft biopsy and renal function was examined. Results Genotype frequencies of each polymorphism corresponded to expected frequencies according to Hardy–Weinberg equilibrium. No differences between allelic and genotype frequencies among patients with normal histological findings, chronic allograft nephropathy and subclinical rejection were observed. Conclusion This is the first study on polymorphisms of the RAGE gene in patients with the transplanted kidney. No association of RAGE selected gene polymorphisms with 12-months outcome of renal transplants was shown in study.

Metabolic syndrome (MS) is defined by the clustering of several components (MSC), which include abdominal fat accumulation, impaired glucose homeostasis, hypertriglyceridemia, lowered high-density lipoprotein cholesterol, increased blood pressure, and hyperuricemia. Metabolic syndrome is also accompanied by increased oxidative stress and inflammation as well as by altered composition of esterified fatty acids (FA). Therefore, we have investigated 210 men (categorized into six groups with increasing number of MSC) to find trends in the extent of oxidative stress, FA pattern and frequency of pathological alleles of the selected candidate genes for lipid metabolism. Increasing number of MSC was connected with the raised serum glucose and insulin, increased concentrations of conjugated dienes in low-density lipoprotein (all p < 0.0001), and high frequency of e2 and e4 alleles of the apolipoprotein E gene (p < 0.005). However, the last significance was lost after the adjustment for age. The incidence of 54Thr allele for intestinal isoform of the fatty acid-binding protein (FABP-2) gene was comparable in all groups. The most important findings were the raised content of saturated FA and the increased activities of Delta9 and Delta6 desaturases (all p < 0.0001), and the decreased content of polyunsaturated FA n-6 family and the decreased activity of Delta5 desaturase (both p < 0.001) in connection with increasing number of MSC. In conclusion, the severity of MS is connected with the progression of oxidative stress and the unfavorable changes in the FA composition. These changes are independent of the studied gene polymorphisms.

Background. The receptor for advanced glycation end products (RAGE) is involved in the pathogenesis of vascular and inflammatory diseases. The pathological effects mediated via RAGE are physiologically inhibited by soluble RAGE (sRAGE). Our aim was to study sRAGE and RAGE gene polymorphisms in haemodialysis (HD) patients. Methods. A total of 261 stable HD patients were enrolled in the study and prospectively followed up for 30 months. At the begining of the study, sRAGE inflammatory and nutritional parameters were determined. RAGE polymorphisms were determined in a subgroup of 214 HD patients. A group of 100 healthy controls was used for comparison. Results. In HD patients, sRAGE is elevated in comparison with healthy controls (3427 � 1508 vs 1758 � 637 pg/ml, P < 0.001). It correlates negatively with residual diuresis (r ¼� 0.193, P < 0.05), with the acute phase reactants fibrinogen (r ¼� 0.174, P < 0.05) and orosomucoid (r ¼� 0.135, P < 0.05) and with the leucocyte count (r ¼� 0.158, P < 0.05). On the other hand, it is not related to the presence of diabetes mellitus, cardiovascular disease, nutritional status and mortality. The highest sRAGE levels are found in � 429 CC and 2184 GG polymorphisms of the RAGE gene. The same results as for sRAGE were obtained for endogenous secretory RAGE (esRAGE), which correlated significantly with sRAGE (r ¼ 0.88, P < 0.001). Conclusion. We conclude that in HD patients, sRAGE is increased due to decreased renal function, which is a very strong determinant of sRAGE levels, and is inversely related to inflammation. The highest sRAGE levels are influenced genetically. In our study, sRAGE levels were not related to mortality of HD patients.

Bleeding from esophageal varices is a major complication of liver cirrhosis. Non-selective beta-blockers exert an influence on the functional part of portal hypertension, thereby reducing the risk of bleeding. Direct measurement of this functional part is not possible; nevertheless, pro-inflammatory markers as well as parameters of endothelial dysfunction might serve as surrogate markers. The aim of study was to assess the correlation between the therapeutic efficacy of carvedilol and markers of endothelial dysfunction and systemic inflammation in patients with liver cirrhosis and portal hypertension.Thirty-six patients with cirrhosis and portal hypertension were given carvedilol, 25 mg q.i.d. for 30 days. Hepatic venous pressure gradient (HVPG) and biochemical determinations were performed prior to and after the treatment. Eight healthy individuals served as controls for comparison of biochemical markers.In the whole group of cirrhotic patients, HVPG decreased from 17.7+/-3.8 to 14.9+/-4.8 mmHg (p0.001). Complete response was seen in 15 patients (42%). Baseline serum levels of E-selectin were significantly higher in responders than in non-responders (119.8+/-70.6 versus 52.6+/-25.7 ng/ml; p=0.023) and in controls (28.8+/-22.2 ng/ml; p=0.004). Furthermore, baseline TNF-alpha levels were significantly higher in responders than in non-responders (22.8+/-15.7 versus 7+/-8.9; p=0.047) and in controls (5.5+/-5.9 pg/ml; p=0.005). Serum levels of ICAM-1 showed the same trend (4360+/-2870 versus 2861+/-1577 versus 651+/-196 ng/ml), although differences did not reach statistical significance.Markers of systemic inflammation and endothelial dysfunction seem to predict the hypotensive effect of carvedilol on portal hypertension in patients with liver cirrhosis and may be useful in the assessment of the efficacy of the therapy.

Aldosterone plays an important role in development of left ventricular (LV) hypertrophy and myocardial fibrosis. We assessed the influence of the T-344C polymorphism of aldosterone synthase - the rate-limiting enzyme in aldosterone biosynthesis - on the structure of the left ventricle in young normotensive men.The population included 113 normotensive mid-European Caucasian men aged 18-40 years (mean 27 +/- 5 years). The genotype was assessed using polymerase chain reaction with subsequent cleavage with restriction enzyme HAEIII (restriction fragment length polymorphism method) and visualization with ethidium bromide. Plasma renin activity (PRA) and plasma aldosterone were measured. All subjects were examined by echocardiography and LV mass was assessed by using M-mode based ASE formula.The distribution of the genotypes was TT 23%:TC 55%:CC 22%. There were no differences in blood pressure among the groups. Men with the TT genotype had significantly higher levels of PRA (2.7 +/- 1.7 vs 1.8 +/- 1.0 vs 1.8 +/- 1.1 ng/ml/h, p0.01) and slightly higher plasma levels of aldosterone (113 +/- 64 vs 93 +/- 43 vs 87 +/- 39 pg/ml, p = 0,12). In the whole population, LV mass index (LVMI) did not differ significantly among the genotypes (92 +/- 16 vs 86 +/- 18 vs 84 +/- 16 g/m, p=0.20). In the population divided according to PRA, subjects with high renin had significantly higher LVMI in presence of the TT genotype (95 +/- 17 vs 84 +/- 16 vs 81 +/- 15 g/m, p0.05).In agreement with previous studies, we found that the TT genotype of T-344C polymorphism of aldosterone synthase gene was associated with significantly higher levels of PRA in normotensive men. In subjects with high PRA, the TT genotype was associated with higher values of the LVMI.

Abnormalities in carbohydrate and lipid metabolism are common in patients with essential hypertension and in the spontaneously hypertensive rat (SHR). To identify chromosome regions contributing to this clustering of cardiovascular risk factors in the SHR, we searched for quantitative trait loci (QTL) associated with insulin resistance, glucose intolerance, and dyslipidemia by using the HXB/BXH recombinant inbred (RI) strains. Analysis of variance in RI strains suggested significant effects of genetic factors. A genome screening of the RI strains with more than 700 markers revealed QTL significantly associated with insulin resistance on Chromosomes (Chrs) 3 and 19. The Chr 19 QTL was confirmed by testing a previously derived SHR-19 congenic strain: transfer of a Chr 19 segment delineated by markers D19Rat57 and D19Mit7 from the Brown Norway (BN/Cr) strain onto the genetic background of the SHR/Ola was associated with decreased insulin and glucose concentrations and ameliorated insulin resistance at the tissue level. These findings suggest that closely linked genes on Chr 19, or perhaps even a single gene with pleiotropic effects, influence the clustering of metabolic disturbances in the SHR-BN model.

Left ventricular (LV) hypertrophy is a strong predictive factor for cardiovascular morbidity and mortality. LV structure and function are influenced by many variables, including genetic background. The potential role of gene polymorphisms of different components of the renin angiotensin system remains controversial. The aim of this study was to determine the influence of deletion/insertion (D/I) polymorphism of the angiotensin-converting enzyme (ACE) gene and M235--T polymorphism of the angiotensinogen (AG) gene on left ventricular morphology and function in young normotensive men. The study included 110 normotensive healthy males (mean age 24 +/- 4 years, age range 18 to 34 years) who were assessed by echocardiography for LV structure and function. In all subjects ACE D/I polymorphism was evaluated using a polymerase chain reaction (PCR) method. M235--T polymorphism assessment was available in 98 individuals. Significant differences between groups according to ACE I/D or AG M235--T polymorphisms were not found for parameters of LV morphology or for parameters of systolic and diastolic function. When subjects with DD or ID genotypes were grouped, their LV mass index was higher than that in subjects with II genotypes (86 +/- 14 vs 79 +/- 15, r = 0.033, p = 0.05). There were no significant differences among other variables. In a population of young normotensive men where the influence of confounding variables such as age, gender and associated pathological conditions is minimized, the gene polymorphisms of ACE I/D and AG M235--T are not important determinants of LV structure and function.

Disorders of carbohydrate and lipid metabolism have been reported to cluster in patients with essential hypertension and in spontaneously hypertensive rats (SHRs). A deletion in the Cd36 gene on chromosome 4 has recently been implicated in defective carbohydrate and lipid metabolism in isolated adipocytes from SHRs. However, the role of Cd36 and chromosome 4 in the control of blood pressure and systemic cardiovascular risk factors in SHRs is unknown. In the SHR. BN-Il6/Npy congenic strain, we have found that transfer of a segment of chromosome 4 (including Cd36) from the Brown Norway (BN) rat onto the SHR background induces reductions in blood pressure and ameliorates dietary-induced glucose intolerance, hyperinsulinemia, and hypertriglyceridemia. These results demonstrate that a single chromosome region can influence a broad spectrum of cardiovascular risk factors involved in the hypertension metabolic syndrome. However, analysis of Cd36 genotypes in the SHR and stroke-prone SHR strains indicates that the deletion variant of Cd36 was not critical to the initial selection for hypertension in the SHR model. Thus, the ability of chromosome 4 to influence multiple cardiovascular risk factors, including hypertension, may depend on linkage of Cd36 to other genes trapped within the differential segment of the SHR. BN-Il6/Npy strain.

21113 Background: Receptor for advanced glycation end products (RAGE) may be involved in the pathogenesis of the cancer progression and metastasis. Pathological effects mediated via RAGE are physiologically inhibited by soluble RAGE (sRAGE), so the higher sRAGE levels may confer the patients with cancer with better outcome.. Our aim was to study sRAGE and RAGE gene polymorphisms in patients with breast cancer. Methods: We studied sRAGE and RAGE polymorphisms in 120 patients with breast cancer (subdivided based on the clinical stage, histologic grading, expression of hormonal and C-erb B2 receptors) and in 92 healthy controls. Results: Despite higher serum concentrations of AGEs, serum concentrations of sRAGE were lower in patients with breast cancer compared to healthy controls (1581 ± 777 vs. 1803 ± 632 ng/ml, p < 0.05). Serum levels of sRAGE were higher in patients with advanced breast cancer (stage III), lower grade and positive estrogen receptors and intermediate positivity of C-erb B2 (Her-neu) receptors and were also influenced genetically (G82S and 2184 AG polymorphisms of the RAGE gene). Conclusions: Decreased sRAGE levels in patients with breast cancer may contribute to the progression of the disease. Patients with better outcome (with low grade and positive estrogen receptors) have higher sRAGE levels. Progression of the disease, may, however, increase sRAGE levels, possibly as a compensatory mechanism to counteract further progression. No significant financial relationships to disclose.