The role of interleukin-18 in the metabolic syndrome

The metabolic syndrome is thought to be associated with a chronic low-grade inflammation, and a growing body of evidence suggests that interleukin-18 (IL-18) might be closely related to the metabolic syndrome and its consequences. Circulating levels of IL-18 have been reported to be elevated in subjects with the metabolic syndrome, to be closely associated with the components of the syndrome, to predict cardiovascular events and mortality in populations with the metabolic syndrome and to precede the development of type 2 diabetes. IL-18 is found in the unstable atherosclerotic plaque, in adipose tissue and in muscle tissue, and is subject to several regulatory steps including cleavage by caspase-1, inactivation by IL-18 binding protein and the influence of other cytokines in modulating its interaction with the IL-18 receptor. The purpose of this review is to outline the role of IL-18 in the metabolic syndrome, with particular emphasis on cardiovascular risk and the potential effect of life style interventions

Circulating levels of IL-18 are significantly influenced by the IL-18 +183 A/G polymorphism in coronary artery disease patients with diabetes type 2 and the metabolic syndrome: an Observational Study

<p>Abstract</p> <p>Background</p> <p>Increased IL-18 serum levels have been associated with diabetes type 2, metabolic syndrome and the severity of atherosclerosis. The present study investigated the presence and influence of IL-18 genetic variants on gene- and protein expression in stable coronary artery disease (CAD) patients.</p> <p>Methods</p> <p>The +183 A/G (rs 5744292), -137 G/C (rs 187238) and -607 C/A (rs 1946518) polymorphisms were determined in 1001 patients with angiographically verified stable CAD, and in 204 healthy controls. IL-18 gene-expression was measured in circulating leukocytes in 240 randomly selected patients. Circulating IL-18 and IL-18 binding protein levels were measured immunologically in all patients.</p> <p>Results</p> <p>The +183 G-allele associated significantly with lower serum levels of IL-18 (<it>p </it>= 0.002, adjusted for age, glucose, body mass index and gender) and a 1.13- fold higher IL-18 gene-expression (<it>p </it>= 0.010). No influence was observed for the -137 G/C and -607 C/A polymorphisms. The IL-18 binding protein levels were not influenced by IL-18 genotypes. IL-18 levels were significantly higher in men as compared to women, and in patients with diabetes type 2 and metabolic syndrome compared to those without (<it>p </it>≤ 0.001, all). The reduction in IL-18 levels according to the +183 G-allele was 3-4 fold more pronounced in diabetes and metabolic syndrome as compared to unaffected patients.</p> <p>Finally, the +183 AA genotype was more frequent in patients with hypertension (<it>p </it>= 0.042, adjusted for age, body mass index and gender).</p> <p>Conclusion</p> <p>The reduction in serum IL-18 levels across increasing numbers of +183G-alleles was especially apparent in patient with diabetes type 2 and metabolic syndrome, suggesting a beneficial GG genotype in relation to cardiovascular outcome in these patients.</p> <p>Clinical Trial Registration Number</p> <p>ClinicalTrials.gov: <a href="http://www.clinicaltrials.gov/ct2/show/NCT00222261">NCT00222261</a></p

The influence of CYP 2C19*2 polymorphism on platelet function testing during single antiplatelet treatment with clopidogrel

<p>Abstract</p> <p>Background</p> <p>Different platelet function tests can be used to evaluate the degree of achieved platelet inhibition in patients treated with clopidogrel. The presence of CYP 2C19*2 polymorphism can reduce the formation of the active metabolite of clopidogrel, resulting in less platelet inhibition.</p> <p>Patients and Methods</p> <p>Patients with symptomatic coronary artery disease, all on chronic single aspirin treatment were randomized to continue on aspirin or change to clopidogrel. In 219 randomly selected clopidogrel treated patients, platelet reactivity was evaluated by VASP-PRI determination and by use of VerifyNow P2Y12-PRU. The CYP 2C19*2 G/A polymorphism was further determined.</p> <p>Results</p> <p>The total frequency of clopidogrel resistance was 29.0% by VASP-PRI and 31.6% by VerifyNow-PRU. The number of patients being hetero- and homozygous combined for the CYP 2C19*2 polymorphism (GA/AA) was 64 (29%). Platelet reactivity was significantly higher in patients with the polymorphism compared to wild-type patients (GG). VASP-PRI was 50.9% (SD19) in patients having the polymorphism compared to 38.3% (SD21) in patients with the GG genotype (p = 0.001). Correspondingly, the mean PRU was 165 (SD67) compared to 124 (SD69) (p < 0.001). The frequency of clopidogrel resistance in patients with the polymorphism was 32% compared to 16% in wild-type patients when defined by VASP-PRI (p = 0.006). When defined by PRU (VerifyNow), the corresponding frequencies were 53% and 22% (p < 0.001).</p> <p>Conclusions</p> <p>Clopidogrel treated patients with the CYP 2C19*2 polymorphism have significantly increased platelet reactivity compared to patients with the wild-type, evaluated with the VASP determination, and even more pronounced with the VerifyNow P2Y12 method.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov: <a href="http://www.clinicaltrials.gov/ct2/show/NCT00222261">NCT00222261</a></p

Making it real: exploring the potential of Augmented Reality for teaching primary school science

The use of Augmented Reality (AR) in formal education could prove a key component in future learning environments that are richly populated with a blend of hardware and software applications. However, relatively little is known about the potential of this technology to support teaching and learning with groups of young children in the classroom. Analysis of teacher-child dialogue in a comparative study between use of an AR virtual mirror interface and more traditional science teaching methods for 10-year-old children, revealed that the children using AR were less engaged than those using traditional resources. We suggest four design requirements that need to be considered if AR is to be successfully adopted into classroom practice. These requirements are: flexible content that teachers can adapt to the needs of their children, guided exploration so learning opportunities can be maximised, in a limited time, and attention to the needs of institutional and curricular requirements

Gender differences of polymorphisms in the TF and TFPI genes, as related to phenotypes in patients with coronary heart disease and type-2 diabetes

<p>Abstract</p> <p>Background</p> <p>Tissue factor (TF) and its inhibitor tissue factor pathway inhibitor (TFPI) are the main regulators of the initiation of the coagulation process, important in atherothrombosis. In this study we have investigated the frequency of six known TF and TFPI single nucleotide polymorphisms (SNPs) in CHD patients as compared to healthy individuals. These genotypes and the phenotypes (TF, TFPI free and total antigen) were evaluated with special reference to gender and diabetes in the CHD population.</p> <p>Methods</p> <p>Patients with angiographically verified CHD (n = 1001; 22% women, 20% diabetics), and 204 healthy controls (28% women), were included. The investigated SNPs were: TF -1812C/T and TF -603A/G in the 5'upstream region, TF 5466A/G in intron 2, TFPI -399C/T and TFPI -287T/C in the 5'upstream region and the TFPI -33T/C in intron 7.</p> <p>Results</p> <p>No significant differences in frequencies between the CHD population and the controls of any polymorphisms were observed. In the CHD population, the TF 5466 A/G SNP were significantly more frequent in women as compared to men (p < 0.001). The TF-1812C/T and the TF-603A/G SNPs were significantly more frequent in women without type-2 diabetes compared to those with diabetes (p < 0.018, both), and the heterozygous genotypes were associated with significantly lower TF plasma levels compared to the homozygous genotypes (p < 0.02, both).</p> <p>The TFPI-399C/T and the TFPI-33T/C SNPs were associated with lower and higher TFPI total antigen levels, respectively (p < 0.001, both).</p> <p>Conclusion</p> <p>Genetic variations in the TF and TFPI genes seem to be associated with gender and type-2 diabetes, partly affecting their respective phenotypes.</p

Effect of diet and omega-3 fatty acid intervention on asymmetric dimethylarginine

BACKGROUND AND AIM: Impaired vasodilatation has been suggested to be caused by inhibition of nitric oxide generation by the recently described asymmetric dimethylarginine (ADMA). In the present study we wanted to explore whether n-3 polyunsaturated fatty acid (PUFA) supplementation and/or diet intervention have beneficial influence on endothelial function assessed as plasma levels of ADMA and L-arginine. METHODS: A male population (n = 563, age 70 ± 6 yrs) with long-standing hyperlipidemia, characterized as high risk individuals in 1970–72, was included, randomly allocated to receive placebo n-3 PUFA capsules (corn oil) and no dietary advice (control group), dietary advice (Mediterranean type), n-3 PUFA capsules, or dietary advice and n-3 PUFA combined and followed for 3 years. Fasting blood samples were drawn at baseline and the end of the study. RESULTS: Compliance with both intervention regimens were demonstrated by changes in serum fatty acids and by recordings from a food frequency questionnaire. No influence of either regimens on ADMA levels were obtained. However, n-3 PUFA supplementation was accompanied by a significant increase in L-arginine levels, different from the decrease observed in the placebo group (p < 0.05). In individuals with low body mass index (<26 kg/m(2)), the decrease in L-arginine on placebo was strengthened (p = 0.01), and the L-arginine/ADMA ratio was also significantly reduced (p = 0.04). CONCLUSION: In this rather large randomized intervention study, ADMA levels were not influenced by n-3 PUFA supplementation or dietary counselling. n-3 PUFA did, however, counteract the age-related reduction in L-arginine seen on placebo, especially in lean individuals, which might be discussed as an improvement of endothelial function

Serum Levels of Dihomo-Gamma (γ)-Linolenic Acid (DGLA) Are Inversely Associated with Linoleic Acid and Total Death in Elderly Patients with a Recent Myocardial Infarction

Dihomo-gamma-linolenic acid (DGLA) is an n-6 polyunsaturated fatty acid (PUFA) derived from linoleic acid (LA). The LA:DGLA ratio reflects conversion from LA to DGLA. Low levels of DGLA in serum have been related to poor outcome in myocardial infarction (MI) patients. Aims: To assess the association of DGLA and LA:DGLA with total death as a primary aim and incident cardiovascular events as a secondary objective. Methods: Baseline samples from 1002 patients, aged 70 to 82 years, included 2–8 weeks after an MI and followed for 2 years, were used. Major adverse clinical events (MACE) consisted of nonfatal MI, unscheduled coronary revascularization, stroke, hospitalization for heart failure or all-cause death. Cox regression analysis was used to relate serum n-6 PUFA phospholipid levels (%wt) to the risk of MACE, adjusting for the following: (1) age, sex and body mass index (BMI); (2) adding baseline cod liver oil supplementation; (3) adding prevalent hypertension, chronic kidney disease and diabetes mellitus. Results: Median DGLA level in serum phospholipids was 2.89 (Q1–Q3 2.43–3.38) %wt. DGLA was inversely related to LA and LA:DGLA ratio. There were 208 incident cases of MACE and 55 deaths. In the multivariable analysis, the hazard ratio (HR) for the total death in the three higher quartiles (Q2–4) of DGLA as compared to Q1 was 0.54 (0.31–0.95), with p = 0.03 (Model-1), 0.50 (0.28–0.91), with p = 0.02 (Model-2), and 0.47 (0.26–0.84), with p = 0.012 (Model-3), and non-significant for MACE. Risk of MACE (Model 3) approached borderline significance for LA:DGLA in Q2–4 vs. Q1 [HR 1.42 (1.00–2.04), p = 0.052]. Conclusions: Low levels of DGLA were related to a high LA:DGLA ratio and risk of total death in elderly patients with recent MI.publishedVersio

Abnormal glucose regulation in patients with acute ST- elevation myocardial infarction-a cohort study on 224 patients

<p>Abstract</p> <p>Background</p> <p>A high prevalence of impaired glucose tolerance and unknown type 2-diabetes in patients with coronary heart disease and no previous diagnosis of diabetes have been reported. The aims of the present study were to investigate the prevalence of abnormal glucose regulation (AGR) 3 months after an acute ST-elevation myocardial infarction (STEMI) in patients without known glucometabolic disturbance, to evaluate the reliability of a 75-g oral glucose tolerance test (OGTT) performed very early after an acute STEMI to predict the presence of AGR at 3 months, and to study other potential predictors measured in-hospital for AGR at 3 months.</p> <p>Methods</p> <p>This was an observational cohort study prospectively enrolling 224 STEMI patients treated with primary PCI. An OGTT was performed very early after an acute STEMI and was repeated in 200 patients after 3 months. We summarised the exact agreement observed, and assessed the observed reproducibility of the OGTTs performed in-hospital and at follow up. The patients were classified into glucometabolic categories defined according to the World Health Organisation criteria. AGR was defined as the sum of impaired fasting glucose, impaired glucose tolerance and type 2-diabetes.</p> <p>Results</p> <p>The prevalence of AGR at three months was 24.9% (95% CI 19.1, 31.4%), reduced from 46.9% (95% CI 40.2, 53.6) when measured in-hospital. Only, 108 of 201 (54%) patients remained in the same glucometabolic category after a repeated OGTT. High levels of HbA1c and admission plasma glucose in-hospital significantly predicted AGR at 3 months (p < 0.001, p = 0.040, respectively), and fasting plasma glucose was predictive when patients with large myocardial infarction were excluded (p < 0.001).</p> <p>Conclusion</p> <p>The prevalence of AGR in STEMI patients was lower than expected. HbA1c, admission plasma glucose and fasting plasma glucose measured in-hospital seem to be useful as early markers of longstanding glucometabolic disturbance. An OGTT performed very early after a STEMI did not provide reliable information on long-term glucometabolic state and should probably not be recommended.</p

Increased levels of CRP and MCP-1 are associated with previously unknown abnormal glucose regulation in patients with acute STEMI: a cohort study

<p>Abstract</p> <p>Background</p> <p>Inflammation plays an important role in the pathophysiology of both atherosclerosis and type 2 diabetes and some inflammatory markers may also predict the risk of developing type 2 diabetes. The aims of the present study were to assess a potential association between circulating levels of inflammatory markers and hyperglycaemia measured during an acute ST-elevation myocardial infarction (STEMI) in patients without known diabetes, and to determine whether circulating levels of inflammatory markers measured early after an acute STEMI, were associated with the presence of abnormal glucose regulation classified by an oral glucose tolerance test (OGTT) at three-month follow-up in the same cohort.</p> <p>Methods</p> <p>Inflammatory markers were measured in fasting blood samples from 201 stable patients at a median time of 16.5 hours after a primary percutanous coronary intervention (PCI). Three months later the patients performed a standardised OGTT. The term abnormal glucose regulation was defined as the sum of the three pathological glucose categories classified according to the WHO criteria (patients with abnormal glucose regulation, n = 50).</p> <p>Results</p> <p>No association was found between inflammatory markers and hyperglycaemia measured during the acute STEMI. However, the levels of C-reactive protein (CRP) and monocyte chemoattractant protein-1 (MCP-1) measured in-hospital were higher in patients classified three months later as having abnormal compared to normal glucose regulation (p = 0.031 and p = 0.016, respectively). High levels of CRP (≥ 75 percentiles (33.13 mg/L)) and MCP-1 (≥ 25 percentiles (190 ug/mL)) were associated with abnormal glucose regulation with an adjusted OR of 3.2 (95% CI 1.5, 6.8) and 7.6 (95% CI 1.7, 34.2), respectively.</p> <p>Conclusion</p> <p>Elevated levels of CRP and MCP-1 measured in patients early after an acute STEMI were associated with abnormal glucose regulation classified by an OGTT at three-month follow-up. No significant associations were observed between inflammatory markers and hyperglycaemia measured during the acute STEMI.</p

High adherence to the nordic diet is associated with lower levels of total and platelet-derived circulating microvesicles in a norwegian population

Circulating microvesicles (cMV) are small phospholipid-rich blebs shed from the membrane of activated vascular cells that contribute to vascular disease progression. We aimed to investigate whether the quality of the Nordic diet is associated with the degree of blood and vascular cell activation measured by MV shedding in elderly patients after an acute myocardial infarction (AMI). One-hundred and seventy-four patients aged 70-82 years were included in this cross-sectional study. Fasting blood samples were taken within 2 to 8 weeks after an AMI. Annexin V (AV) cMV derived from blood and vascular cells were measured through flow cytometry. A patient's usual diet was recorded with the SmartDiet® questionnaire. Patients with higher adherence to the Nordic diet (highest diet score) had lower levels of total AV and platelet-derived (CD61/AV and CD31/AV) cMV. Dietary habits influence cellular activation. A high adherence to the Nordic diet (assessed by the SmartDiet® score) in elderly post-AMI patients was associated with lower levels of platelet activation, which was reflected by a lesser release of MV carrying platelet-derived epitopes, potentially contributing to an explanation of the cardioprotective effects of the Nordic diet