Associação da atividade da Lp-PLA2 e de antioxidantes lipossolúveis com marcadores cardiometabólicos em adolescentes / Association of Lp-PLA activity and fat-soluble antioxidants with cardiometabolic markers in adolescents

Introdução: A obesidade se caracteriza como um processo oxidativo e inflamatório, que predispõe adolescentes, de modo precoce, a eventos até recentemente pouco frequentes nessa faixa etária. Assim, a ação da enzima Fosfolipase A associada às lipoproteínas (Lp-PLA ), que reduz fosfolipídios oxidados e gera lisofosfolipídios, bem como a disponibilidade de antioxidantes plasmáticos, representam um importante tema de pesquisa no contexto cardiovascular. Objetivo: Verificar se a atividade da LP-PLA 2 2 e a concentração de antioxidantes lipossolúveis se associam com os principais marcadores de risco cardiovascular em adolescentes. Métodos: Duzentos e quarenta e dois adolescentes (10 a 19 anos), de ambos os sexos foram distribuídos, segundo o índice de massa corporal (IMC), em três grupos: Eutróficos (n=77), Sobrepeso (n=82) e Obesos (n=83). A amostra foi caracterizada através de parâmetros sócio-econômicos, estado de saúde, uso de medicamentos, antedecentes familiares de doenças crônicas e prática de atividade física. Foram avaliados ainda os dados antropométricos (peso, altura e composição corporal - bioimpedância), e o consumo alimentar por meio de três recordatórios 24 h. A partir de uma amostra de sangue coletada após jejum (12h), realizaram-se as análises da atividade da Lp-PLA , LDL(-) e seus auto-anticorpos, perfil lipídico (colesterol total, LDL-C, HDL-C e triglicerídeos), tamanho da HDL, proteína transportadora de éster de colesterol (CETP), ácidos graxos não esterificados (NEFAs), adipocitocinas, assim como antioxidantes (retinol, licopeno, -tocoferol e -caroteno) no plasma. Resultados: Artigo 1: Lp-PLA maybe an important cardiovascular biomarker in obese adolescents. Verificou-se que o perfil lipídico, insulina, HOMA-IR (resistência à insulina) e LDL(-) evidenciaram um maior risco cardiovascular nos adolescentes obesos. A atividade da enzima Lp-PLA 2 mostrou uma variação proporcional ao IMC, circunferência da cintura e porcentagem de gordura.

Effects of selective COX-2 inhibition on prostanoids and platelet physiology in young healthy volunteers.

BACKGROUND: Selective inhibitors of cyclooxygenase-2 (COX-2) called coxibs, are effective anti-inflammatory and analgesic drugs. Recently, these drugs were associated with an increased risk for myocardial infarction and atherothrombotic events. The hypothesis of thromboxane-prostacyclin imbalance has been preferred to explain these unwanted effects. METHODS: We studied the effects of 14 days intake of rofecoxib (25 mg q.d.), celecoxib (200 mg b.i.d.), naproxen (500 mg b.i.d.) and placebo in a randomized, blinded, placebo-controlled study in young healthy volunteers (median age 25-30 years, each group n = 10). We assessed prostanoid metabolite excretion (PGE-M, TXB(2), 6-keto-PGF(1alpha), 11-dehydro-TXB(2), 2,3-dinor-TXB(2), and dinor-6-keto-PGF(1alpha)), the expression of platelet activation markers (CD62P, PAC-1, fibrinogen), platelet-leukocyte formation, the endogenous thrombin potential, platelet cAMP content and plasma thrombomodulin level. RESULTS: Naproxen suppressed biosynthesis of PGE-M, prostacyclin metabolites and thromboxane metabolites and thrombomodulin levels. In contrast, both coxibs had an inhibitory effect only on PGE-M, 6-keto-PGF(1alpha), and on dinor-6-keto-PGF(1alpha), whereas TXB(2), 2,3-dinor-TXB(2) and 11-dehydro-TXB(2) excretion were unaffected. None of the coxibs exerted significant effects on the expression of platelet activation markers, cAMP generation, platelet-leukocyte formation, or on thrombomodulin plasma levels. Interestingly, platelet TXB(2) release during aggregation was enhanced after coxib treatment following arachidonic acid or collagen stimulation. CONCLUSION: In young healthy volunteers coxibs inhibit systemic PGE(2) and PGI(2) synthesis. Platelet function and expression of platelet aggregation markers are not affected; however, coxibs can stimulate TXB(2) release from activated platelets. Combined decrease in vasodilatory PGE(2) and PGI(2) together with increased TXA(2) in proaggregatory conditions may contribute to coxib side effects.

Preparation method of an ideal model of multiple organ injury of rat with severe acute pancreatitis.

AIM: To establish an ideal model of multiple organ injury of rats with severe acute pancreatitis (SAP). METHODS: SAP models were induced by retrograde injection of 0.1 mL/100 g 3.5% sodium taurocholate into the biliopancreatic duct of Sprague-Dawley rats. The plasma and samples of multiple organ tissues of rats were collected at 3, 6 and 12 h after modeling. The ascites volume, ascites/body weight ratio, and contents of amylase, endotoxin, endothelin-1 (ET-1), nitrogen monoxidum (NO), phospholipase A(2) (PLA(2)), tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6) in plasma were determined. The histological changes of multiple organs were observed under light microscope. RESULTS: The ascites volume, ascites/body weight ratio, and contents of various inflammatory mediators in blood were higher in the model group than in the sham operation group at all time points [2.38 (1.10), 2.58 (0.70), 2.54 (0.71) vs 0.20 (0.04), 0.30 (0.30), 0.22 (0.10) at 3, 6 and 12 h in ascites/body weight ratio; 1582 (284), 1769 (362), 1618 (302) (U/L) vs 5303 (1373), 6276 (1029), 7538 (2934) (U/L) at 3, 6 and 12 h in Amylase; 0.016 (0.005), 0.016 (0.010), 0.014 (0.015) (EU/mL) vs 0.053 (0.029), 0.059 (0.037), 0.060 (0.022) (EU/mL) at 3, 6 and 12 h in Endotoxin; 3.900 (3.200), 4.000 (1.700), 5.300 (3.000) (ng/L) vs 41.438 (37.721), 92.151 (23.119), 65.016 (26.806) (ng/L) at 3, 6 and 12 h in TNF-alpha, all P < 0.01]. Visible congestion, edema and lamellar necrosis and massive leukocytic infiltration were found in the pancreas of rats of model group. There were also pathological changes of lung, liver, kidney, spleen, ileum, lymphonode, thymus, myocardium and brain. CONCLUSION: This rat model features reliability, convenience and a high achievement ratio. Complicated with multiple organ injury, it is an ideal animal model of SAP.

Plasma adhesion and inflammation markers: asymmetrical dimethyl-L-arginine and secretory phospholipase A2 concentrations before and after laparoscopic gastric banding in morbidly obese patients.

BACKGROUND: The aim of this study was to examine the relationship between subclinical inflammation and weight loss by laparoscopic adjustable gastric banding (LAGB). METHODS: Plasma concentrations of intercellular adhesion molecule-1 (ICAM-1), vascular adhesion molecule-1 (VCAM-1), sensitive C-Reactive Protein (sCRP), asymmetrical dimethyl-L-arginine (ADMA), Secretory Phospholipase A2 (sPLA2), and metabolic markers, such as homeostatic model assessment insulin resistance (HOMA-IR) and body mass index (BMI) were determined in morbidly obese patients (n=18, BMI 48.6 +/- 1.7 kg/m2) at baseline and 1 month after operations. Baseline levels in patients were also compared with age-matched controls (n=20, BMI 21.3 +/- 1.8 kg/m2). Plasma ICAM-1, VCAM, sCRP and ADMA, and sPLA2 concentrations were determined by enzyme-linked immunoassay methods and colorimetric method, respectively. RESULTS: Plasma sCRP, ICAM-1, ADMA and sPLA2 concentrations and HOMA-IR were significantly higher in morbidly obese patients than in controls (for each, P<0.01). Plasma VCAM-1 concentration was not changed in obese patients. HOMA-IR was significantly correlated with ICAM-1, ADMA and sPLA2 in the obese group at baseline (for each, P<0.01). There was a significant correlation between plasma sCRP and plasma glucose, VCAM-1, ICAM-1, ADMA and sPLA2 concentrations (for each, P<0.01). 1 month after LAGB, mean body weight loss was 13.2 +/- 6.3 kg, and plasma sCRP and ADMA concentrations and HOMA-IR and BMI were significantly decreased (for each, P<0.01). However, these levels cannot be decreased to the levels of the controls. CONCLUSION: Obesity and insulin resistance appear to be associated with low-grade inflammation and endothelial dysfunction. Insulin resistance and endothelial dysfunction were improved by weight loss after LAGB.

Tagging SNP haplotype analysis of the secretory PLA2-V gene, PLA2G5, shows strong association with LDL and oxLDL levels, suggesting functional distinction from sPLA2-IIA: results from the UDACS study.

Animal and human studies suggest that both secretory PLA2 (sPLA2)-V and sPLA2-IIA (encoded, respectively, by the neighbouring PLA2G5 and PLA2G2A genes) contribute to atherogenesis. Elevated plasma sPLA2-IIA predicts coronary heart disease (CHD) risk, but no mass assay for sPLA2-V is available. We previously reported that tagging single nucleotide polymorphism (tSNP) haplotypes of PLA2G2A are strongly associated with sPLA2-IIA mass, but not lipid levels. Here, we use tSNPs of the sPLA2-V gene to investigate the association of PLA2G5 with CHD risk markers. Seven PLA2G5 tSNPs genotypes, explaining >92% of the locus genetic variability, were determined in 519 patients with Type II diabetes (in whom PLA2G2A tSNP data was available), and defined seven common haplotypes (frequencies >5%). PLA2G5 and PLA2G2A tSNPs showed linkage disequilibrium (LD). Compared to the common PLA2G5 haplotype, H1 (frequency 34.9%), haplotypes H2-7 were associated with overall higher plasma LDL (P < 0.00004) and total cholesterol (P < 0.00003) levels yet lower oxLDL/LDL (P = 0.006) and sPLA2-IIA mass (P = 0.04), probably reflecting LD with PLA2G2A. Intronic tSNP (rs11573248), unlikely itself to be functional, distinguished H1 from LDL-raising haplotypes and may mark a functional site. In conclusion, PLA2G5 tSNP haplotypes demonstrate an association with total and LDL cholesterol and oxLDL/LDL, not seen with PLA2G2A, thus confirming distinct functional roles for these two sPLA2s.

Kinetics of group IB and IIA phospholipase A2 during low-volume continuous hemodiafiltration in severe acute pancreatitis.

Continuous hemodiafiltration (CHDF) has been performed for the treatment of severe acute pancreatitis. Phospholipase A2 (PLA2) is one of the important mediators which exacerbate acute pancreatitis, but whether PLA2 can be removed by CHDF is unclear. In this study, the kinetics of group IB and group IIA PLA2 was examined at the first session of low-volume CHDF in eight patients with severe acute pancreatitis. CHDF was performed using polysulfone hemofilters (surface area: 0.7 m(2)) at a blood flow rate of 100 mL/min and a filtration and dialysate flow rate of 10 mL/min each. The plasma concentrations of group IB and IIA PLA2 before the start of CHDF were 47.4 +/- 52.0 microg/L and 352 +/- 390 microg/L, respectively, and did not change significantly. The clearances of group IB and IIA PLA2 achieved by the CHDF circuit 1 h after the start of CHDF were 20.7 +/- 11.6 mL/min and 16.7 +/- 4.4 mL/min, respectively, with both clearances decreasing significantly with time. The clearance of group IB PLA2 into the waste fluid tended to increase with time; however, the concentrations of group IIA PLA2 in the waste fluid were less than the measurable sensitivity. These results indicate that group IB PLA2 is adsorbed on the hemofilter membrane in preference to being removed into the waste fluid, while group IIA PLA2 is mainly removed by adsorption. However, low-volume CHDF is not effective at eliminating the group IB and IIA PLA2 plasma concentration.

Clinical and pathological features of fat embolism with acute respiratory distress syndrome.

FES (fat embolism syndrome) is a clinical problem, and, although ARDS (acute respiratory distress syndrome) has been considered as a serious complication of FES, the pathogenesis of ARDS associated with FES remains unclear. In the present study, we investigated the clinical manifestations, and biochemical and pathophysiological changes, in subjects associated with FES and ARDS, to elucidate the possible mechanisms involved in this disorder. A total of eight patients with FES were studied, and arterial blood pH, PaO(2) (arterial partial pressure of O(2)), PaCO(2) (arterial partial pressure of CO(2)), biochemical and pathophysiological data were obtained. These subjects suffered from crash injuries and developed FES associated with ARDS, and each died within 2 h after admission. In the subjects, chest radiography revealed that the lungs were clear on admission, and pulmonary infiltration was observed within 2 h of admission. Arterial blood pH and PaO(2) declined, whereas PaCO(2) increased. Plasma PLA(2) (phospholipase A(2)), nitrate/nitrite, methylguanidine, TNF-alpha (tumour necrosis factor-alpha), IL-1beta (interleukin-1beta) and IL-10 (interleukin-10) were significantly elevated. Pathological examinations revealed alveolar oedema and haemorrhage with multiple fat droplet depositions and fibrin thrombi. Fat droplets were also found in the arterioles and/or capillaries in the lung, kidney and brain. Immunohistochemical staining identified iNOS (inducible nitric oxide synthase) in alveolar macrophages. In conclusion, our clinical analysis suggests that PLA(2), NO, free radicals and pro-inflammatory cytokines are involved in the pathogenesis of ARDS associated with FES. The major source of NO is the alveolar macrophages.

Secretory phospholipase A(2) activity and release kinetics of vascular tissue remodelling biomarkers after coronary artery bypass grafting with and without cardiopulmonary bypass.

BACKGROUND: Cardiopulmonary bypass (CPB) has long been recognised as a main cause of a postoperative complex systemic inflammatory response after coronary artery bypass grafting (CABG). METHODS: We determined the kinetics of peripheral blood release of the novel inflammatory biomarkers secretory phospholipase A(2) (sPLA(2)), matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) during the first 6 days following surgery in 16 patients undergoing CABG with (on-pump, n=9) or without (off-pump, n=7) CPB. Kinetic curves for these markers were compared to those of the well-known inflammatory parameters C-reactive protein (CRP) and fibrinogen. RESULTS: sPLA(2) activity exhibited a maximum value on day 2, then decreased until day 6 for both groups and in a similar manner as CRP levels. On the other hand, elevation of plasma levels of both MMP-9 and TIMP-1 occurred as early as on day 1 and remained at this level until day 6. No significant difference in kinetic characteristics (peak value, area under the curve, initial slope) between CABG with and without CPB was observed. CONCLUSIONS: These data show that the off- and on-pump groups did not show significantly different kinetics for the releases of all biomarkers studied, including sPLA(2) and biomarkers of the MMP-TIMP network. The off-pump procedure may therefore lead to global surgical trauma as important as CPB in terms of the systemic inflammatory process and matrix proteolysis pathway activation.

Circulating secretory phospholipase A2 activity and risk of incident coronary events in healthy men and women: the EPIC-Norfolk study.

OBJECTIVE: To assess the association between secretory phospholipase A2 (sPLA2) activity, which encompasses several types of sPLA2, and cardiovascular disease (CAD) in healthy individuals. METHODS AND RESULTS: We investigated this association in a nested case-control study among the 25,663 participants in EPIC-Norfolk cohort. Cases (n=991) were subjects in whom CAD developed during the 6 years of mean follow-up. Controls (n=1806) matched by age, sex, and enrollment time remained free of any CAD during follow-up. The risk of incident CAD was associated with increasing quartiles of sPLA2 activity (P<0.001). After adjustment for risk factors, C-reactive protein and sPLA2 type IIA concentration, the odds ratios of incident CAD in the second, third, and fourth quartiles of sPLA2 activity were 1.41, 1.33, and 1.56 (P=0.003), compared with the lowest quartile. sPLA2 activity and CRP were poorly correlated (r=0.15), and their combined values were more informative for incident risk of CAD than either biomarker alone. Subjects in the highest quartiles of sPLA2 activity and CRP had an adjusted odds ratio of 2.89 (95% confidence interval, 1.78 to 4.68; P<0.001) for CAD compared with those with the lowest quartiles of both markers. CONCLUSIONS: Measurement of serum sPLA2 activity provides additive prognostic value to traditional risk factors and CRP levels, and identifies a subgroup of individuals at high risk for incident CAD. Measurement of sPLA2 type II concentration had little added prognostic utility.

Glycoprotein Ibalpha polymorphism T145M, elevated lipoprotein-associated phospholipase A2, and hypertriglyceridemia predict risk for recurrent coronary events in diabetic postinfarction patients.

To explore altered platelet function in recurrent coronary event risk among diabetic postinfarction patients, we investigated a function-altering genetic polymorphism (T145M) in the von Willebrand factor binding region of the platelet glycoprotein Ibalpha (GPIbalpha) subunit. The study comprised diabetic and nondiabetic patients of the Thrombogenic Factors and Recurrent Coronary Events postinfarction study. Cox proportional hazards multivariable modeling, adjusted for significant clinical covariates, was performed using the polymorphism and metabolic, inflammatory, and thrombogenic blood markers. Nondiabetic patients demonstrated risk for elevated lipoprotein-associated phospholipase A(2) (Lp-PLA(2)). In contrast, diabetic patients demonstrated significant and independent risk for the M allele of the T145M polymorphism (MT plus MM versus TT, hazard ratio [HR] 3.73, 95% CI 1.90-7.33, P < 0.001), hypertriglyceridemia (2.91, 1.52-5.56, P = 0.001), and elevated Lp-PLA(2) (2.78, 1.45-5.35, P = 0.002). Joint risk (one, two, or three risk factors) expressed as relative outcome rates (compared with no risk factors) were 2.4, 4.0, and 8.2, respectively. We conclude that the M allele of the T145M polymorphism of the GPIbalpha subunit predicts risk for recurrent coronary events in diabetic postinfarction patients, but not in nondiabetic postinfarction patients, supportive of an important role for platelet hyperactivation in diabetic coronary heart disease.

Major biological effects induced by the skin secretion of the tree frog Phyllomedusa hypochondrialis.

Amphibian skin secretions contain several bioactive compounds such as biogenic amines, alkaloids, steroids, proteins and peptides; being peptides a continuously growing field of interest. This work aims to describe the main physiopathological properties of the tree frog Phyllomedusa hypochondrialis skin secretion, obtained by manual stimulation of the dorsal skin surface. Intravenous skin secretion administration provoked lethal effect in mice after 5min. Low doses induced significant systemic and local effects like edema and nociception in mice and topic administration induced myonecrosis in the endothelium of cremaster mice. The presence of phospholipase A(2) activity, proteolytic activity and creatine kinase activity (in the plasma of treated mice) are reported and are very likely to be related to the physiopathological (edematic and myotoxic) activities observed. These data provide in vivo evidence of the complex toxic effects of the P. hypochondrialis skin secretion as well as possible mechanisms of action for these effects.

A continuous fluorescence assay for the determination of calcium-dependent secretory phospholipase A2 activity in serum.

BACKGROUND: Calcium-dependent secretory phospholipase A(2)-IIA (sPLA(2)-IIA) in the circulation is a marker of inflammation, associated with acute and chronic disease processes. We describe a quick, sensitive and reliable microplate continuous fluorescence assay for determining sPLA(2) activity in serum. METHODS: Liposomes composed of a fluorescent probe and varying amounts of L-alpha-phosphatidylglycerol (PG) and 1,2-dioleoyl-L-alpha-phosphatidylcholine (DOPC) were used as substrates to determine the optimal protocol for sPLA(2) activity determination without interference from serum albumin and lipoproteins. RESULTS: Hydrolysis of the labeled substrate by sPLA(2)-IIA, characterized by increase in fluorescence intensity (FI) and confirmed by end-product analysis, occurred in a time-, calcium-, and protein-dependent manner. Liposomes containing 100% PG were most suitable for measurement of sPLA(2) activity without interference from serum components; LDL produced a Ca(2+)-independent increase in FI when liposomes containing DOPC were used. The assay determined that sPLA(2) activity in serum spiked with sPLA(2)-IIA and illustrated that endogenous sPLA(2) activity was markedly higher in sera from patients with sepsis than in healthy subjects. Intra-assay and inter-assay CVs were in the ranges of 1.6-8.8% and 3.0-11.5%, respectively. CONCLUSIONS: The described method has potential for rapid and sensitive screening of sPLA(2) activity in both clinical and research settings.

Phospholipase A2-catalyzed hydrolysis of plasmalogen phospholipids in thrombin-stimulated human platelets.

In the present study, phospholipase A(2) (PLA(2))-catalyzed hydrolysis of platelet membrane phospholipids was investigated by measuring PLA(2) activity, phospholipid hydrolysis, arachidonic acid release and choline lysophospholipid production in thrombin-stimulated human platelets. Thrombin-stimulated platelets demonstrated selective hydrolysis of arachidonylated plasmenylcholine and plasmenylethanolamine, with little change in diacyl phospholipids. Accelerated plasmalogen hydrolysis was accompanied by increased arachidonic acid and thromboxane B(2) release and increased lysoplasmenylcholine production. Thrombin stimulation caused an increase in PLA(2) activity measured in the cytosolic fraction with plasmenylcholine only; no increase in activity was measured with phosphatidylcholine. No change in membrane-associated PLA(2) activity was observed with either substrate tested. Pretreatment with the Ca(2+)-independent PLA(2)-selective inhibitor, bromoenol lactone, inhibited completely any thrombin-stimulated phospholipid hydrolysis. Thus, thrombin stimulation of human platelets activates a cytosolic PLA(2) that selectively hydrolyzes arachidonylated plasmalogen phospholipids.

Lipoprotein-associated phospholipase A2 A379V variant is associated with body composition changes in response to exercise training.

Lipoprotein-associated PLA2 (Lp-PLA2) hydrolyses the sn-2 position of glycerophospholipids, in particular platelet activating factor (PAF), generating significant amounts of Lyso-PAF which in turn, via a remodelling pathway, can generate arachidonic acid (AA) from alkyl-acyl-glycerophosphorylcholine. AA is a precursor for prostaglandin synthesis, which regulates adipogenesis through the peroxisome proliferator-activated receptor subfamily. AA may also modulate skeletal muscle growth. We investigated the association of the PLA2G7 A379V variant with changes in body composition in a longitudinal study of 123 male Caucasian army recruits over 10 weeks of intensive physical training. There was no effect of genotype on baseline measures. However, after exercise training, homozygosity for the 379V allele was associated with a decrease in percentage adipose tissue mass (-3.61+/-1.14%), compared to AV (-1.67+/-0.38%) and AA (-1.09+/-0.24%) genotypes (p=0.01), and a significant mean increase (3.51+/-1.17%) in percentage lean mass, compared to AV (1.64+/-0.38%) and AA (1.10+/-0.24%) recruits (p=0.02). The association of this genotype with changes in body composition after training suggests a novel role for Lp-PLA2.

Transfusion prevents acute chest syndrome predicted by elevated secretory phospholipase A2.

Acute pulmonary injury is known as acute chest syndrome (ACS) in patients with sickle cell disease (SCD). Secretory phospholipase A2 (sPLA2) was found to predict those at risk for ACS and a trial was designed to determine if red blood cell transfusion can be used to prevent ACS. Patients with an elevated sPLA2 were randomised to either receive a single transfusion or standard care. Five of the eight patients (63%) randomised to standard care developed ACS versus none of the seven patients randomised to the transfusion arm (P = 0.026, Odds ratio = 23.6, 95% confidence interval 1, 557). This study suggests that transfusion may prevent ACS.

Effect of a selective thromboxane A2 synthetase inhibitor on the systemic changes induced by circulating pancreatic phospholipase A2.

BACKGROUND: In acute pancreatitis, pancreatic phospholipase A(2) (PLA2) in the circulating blood hydrolyzes phospholipids contained in plasma lipoproteins, liberating eicosanoid precursors that are subsequently converted to various eicosanoids. The pathophysiological significance of eicosanoid synthesis via this pathway is unknown. The aim of this study was to clarify the role of thromboxane A(2) (TXA(2)) synthesis by circulating pancreatic PLA(2) in the pathogenesis of the systemic complications of acute pancreatitis. METHODS: Guinea pigs were divided into two groups: a control group and an ozagrel group, which received intravenous administration of ozagrel, a selective TXA(2) synthetase inhibitor. Pancreatic PLA(2) was infused intravenously in both groups for 30 min, and systemic changes during the infusion were examined. RESULTS: In the control group, there was an increase in plasma thromboxane B(2) (TXB(2)) concentration, a decrease in mean arterial pressure and heart rate, a decrease in arterial base excess (BE), bicarbonate concentration (HCO(3) (-)), and pH, a decrease in platelet count and plasma fibrinogen concentration, and a shortened prothrombin time during the infusion of pancreatic PLA(2). In the ozagrel-treated group, changes in plasma TXB(2) concentration, BE, HCO(3) (-), and platelet count were significantly inhibited. CONCLUSIONS: TXA(2) synthesis by circulating pancreatic PLA(2) contributes to metabolic acidosis and thrombocytopenia during acute pancreatitis.

Short-term lifestyle modification alters circulating biomarkers of endothelial health in sedentary, overweight adults.

Obesity and inactivity are associated with endothelial dysfunction that may contribute to the development of atherosclerosis. We examined the effects of a short-term lifestyle intervention on circulating biomarkers of endothelial health. Nineteen overweight or obese (mean body mass index (BMI): 28.9 +/- 0.7 kg/m2) men and women underwent 6 weeks of body mass reduction induced by moderate energy restriction (approximately 750 kcal/d; 1 kcal = 4.184 kJ) and aerobic training (approximately 400 kcal/d). Fasting serum samples were collected at baseline and after reduction in body mass (week 6) to assess concentrations of nitrotyrosine (NT), secretory phospholipase A2 (sPLA2), and soluble intracellular adhesion molecule-1 (sICAM-1). Body mass was significantly reduced from 81.3 +/- 2.8 to 77.3 +/- 2.6 kg (p < 0.05). Circulating concentrations of NT and sICAM-1 were significantly reduced with treatment (approximately 25% and approximately 10%, respectively), whereas sPLA2 levels were significantly elevated (approximately 45%). Elevations in sPLA2 were negatively correlated with changes in NT (r = -0.58, p = 0.047); reductions in NT did not correlate significantly with reductions in sICAM-1. It appears that circulating markers of endothelial health are susceptible to short-term exercise interventions with modest reduction in body mass, and such a lifestyle modification may improve endothelial health by reducing protein nitration products and cellular adhesion.

Value of blood tests including serum group IIA phospholipase A2 and bactericidal/permeability-increasing protein in Crohn's disease.

OBJECTIVE: Determination of the activity of Crohn's disease at a defined time-point is a challenging task since only endoscopy guidelines are given and secondary clinical findings, subjective symptoms and non-specific laboratory tests have therefore to be relied on. The purpose of the current study was to investigate the ability of blood tests to differentiate patient groups with different clinical disease activity and different clinical outcomes during follow-up in Crohn's disease. MATERIAL AND METHODS: During a visit to hospital, 73 outpatients with Crohn's disease were examined, a clinical score was calculated and blood samples were collected for 22 laboratory tests. The patients were also grouped according to clinical outcome during a 6-year follow-up. RESULTS: Serum group IIA phospholipase A2 and alpha-1-antitrypsin values were outside the reference interval more frequently (62% and 42%, respectively) than the other tests in active Crohn's disease. Only weak correlations were found between the clinical score and the test values, and the best correlation was found with serum lysozyme (r = 0.40). In a logistic regression model, the best prediction of disease activity at entry to the study was reached with a model including serum orosomucoid and serum lysozyme and the best prediction of clinical outcome during follow-up was reached using a model including serum albumin. CONCLUSIONS: Serum group IIA phospholipase A2 appeared to be the most sensitive marker of inflammation in Crohn's disease among the 22 blood tests compared. No reliable predictions of disease activity at the time of blood sampling or clinical outcome later during follow-up could be made from the blood tests studied.

Lipoprotein-associated phospholipase A2 independently predicts the angiographic diagnosis of coronary artery disease and coronary death.

BACKGROUND: Whereas C-reactive protein (CRP) is a nonspecific marker of coronary artery disease (CAD) and cardiovascular (CV) events, Lp-PLA2 may be a nonvariable inflammatory biomarker. We evaluated the independent association of lipoprotein-associated phospholipase A2 (Lp-PLA2) to angiographic CAD and CV events adjusting for standard factors, lipids, and CRP. METHODS: Lipoprotein-associated phospholipase A2 (PLAC test, diaDexus, Inc, San Francisco, CA) and CRP were measured from samples donated by consecutive consenting patients (N = 1493) enrolled in the registry of the Intermountain Heart Collaborative Study. All patients underwent coronary angiography (1996-1998) for CAD determination and were followed for 6.7 +/- 0.5 years (range 5.7-7.9 years) for CV events (death [including all-cause, CAD, and non-CAD CV death], myocardial infarction, and cerebrovascular accident). RESULTS: Lipoprotein-associated phospholipase A2 weakly correlated with lipids (low-density lipoprotein: r = 0.22, P < .001; high-density lipoprotein: r = -0.13, P < .001), but not CRP (r = 0.03, P = .26). Increasing quartile (Q) of Lp-PLA2 predicted greater the presence of CAD (vs Q1) for Q2 (adjusted odds ratio [OR] 1.15, 95% CI 0.78-1.71, P = .48), for Q3 (OR 1.53, 95% CI 1.02-2.31, P = .042), and for Q4 (OR 2.44, 95% CI 1.58-3.79, P < .001), although CRP was also predictive (vs Q1, Q2: OR 1.47, P = .057; Q3: OR 1.93, P = .002; Q4: OR 3.43, P < .001). In Cox regression, Lp-PLA2 predicted CAD death (vs Q1; Q2: adjusted hazard ratio [HR] 1.27, 95% CI 0.58-2.78, P = .55; Q3: HR 2.18, 95% CI 1.04-4.57, P = .04; Q4: HR 1.73, 95% CI 0.84-3.61, P = .14). CONCLUSION: Lipoprotein-associated phospholipase A2 was confirmed to predict the presence of CAD, even among patients undergoing coronary angiography. Uniquely, Lp-PLA2 predicted the risk of CAD death, but not all-cause death, myocardial infarction, or cerebrovascular accident.