APOE Genotype-Function Relationship: Evidence of −491 A/T Promoter Polymorphism Modifying Transcription Control but Not Type 2 Diabetes Risk

BACKGROUND: The apolipoprotein E gene (APOE) coding polymorphism modifies the risks of Alzheimer's disease, type 2 diabetes, and coronary heart disease. Aside from the coding variants, single nucleotide polymorphism (SNP) of the APOE promoter has also been shown to modify the risk of Alzheimer's disease. METHODOLOGY/PRINCIPAL FINDINGS: In this study we investigate the genotype-function relationship of APOE promoter polymorphism at molecular level and at physiological level: i.e., in transcription control of the gene and in the risk of type 2 diabetes. In molecular studies, the effect of the APOE -491A/T (rs449647) polymorphism on gene transcription was accessed by dual-luciferase reporter gene assays. The -491 A to T substitution decreased the activity (p<0.05) of the cloned APOE promoter (-1017 to +406). Using the -501 to -481 nucleotide sequence of the APOE promoter as a 'bait' to screen the human brain cDNA library by yeast one-hybrid system yielded ATF4, an endoplasmic reticulum stress response gene, as one of the interacting factors. Electrophoretic-mobility-shift assays (EMSA) and chromatin immuno-precipitation (ChIP) analyses further substantiated the physical interaction between ATF4 and the APOE promoter. Over-expression of ATF4 stimulated APOE expression whereas siRNA against ATF4 suppressed the expression of the gene. However, interaction between APOE promoter and ATF4 was not -491A/T-specific. At physiological level, the genotype-function relationship of APOE promoter polymorphism was studied in type 2 diabetes. In 630 cases and 595 controls, three APOE promoter SNPs -491A/T, -219G/T (rs405509), and +113G/C (rs440446) were genotyped and tested for association with type 2 diabetes in Hong Kong Chinese. No SNP or haplotype association with type 2 diabetes was detected. CONCLUSIONS/SIGNIFICANCE: At molecular level, polymorphism -491A/T and ATF4 elicit independent control of APOE gene expression. At physiological level, no genotype-risk association was detected between the studied APOE promoter SNPs and type 2 diabetes in Hong Kong Chinese

Fluid challenges in intensive care: the FENICE study A global inception cohort study

Fluid challenges (FCs) are one of the most commonly used therapies in critically ill patients and represent the cornerstone of hemodynamic management in intensive care units. There are clear benefits and harms from fluid therapy. Limited data on the indication, type, amount and rate of an FC in critically ill patients exist in the literature. The primary aim was to evaluate how physicians conduct FCs in terms of type, volume, and rate of given fluid; the secondary aim was to evaluate variables used to trigger an FC and to compare the proportion of patients receiving further fluid administration based on the response to the FC.This was an observational study conducted in ICUs around the world. Each participating unit entered a maximum of 20 patients with one FC.2213 patients were enrolled and analyzed in the study. The median [interquartile range] amount of fluid given during an FC was 500 ml (500-1000). The median time was 24 min (40-60 min), and the median rate of FC was 1000 [500-1333] ml/h. The main indication for FC was hypotension in 1211 (59 %, CI 57-61 %). In 43 % (CI 41-45 %) of the cases no hemodynamic variable was used. Static markers of preload were used in 785 of 2213 cases (36 %, CI 34-37 %). Dynamic indices of preload responsiveness were used in 483 of 2213 cases (22 %, CI 20-24 %). No safety variable for the FC was used in 72 % (CI 70-74 %) of the cases. There was no statistically significant difference in the proportion of patients who received further fluids after the FC between those with a positive, with an uncertain or with a negatively judged response.The current practice and evaluation of FC in critically ill patients are highly variable. Prediction of fluid responsiveness is not used routinely, safety limits are rarely used, and information from previous failed FCs is not always taken into account

EFFECT OF ACUTE CHANGES IN AORTIC PRESSURE ON THE CORONARY RESERVE

Study objective - The aim was to evaluate the effect of acute changes in aortic pressure on the coronary reserve and hyperaemic response. Design - Aortic pressure changes were induced either by intra-aortic balloon pumping or by the production of acute aortic regurgitation. A transient 20 s occlusion of the left anterior descending coronary artery was used as the hyperaemic stimulus Experimental subjects - The experiments were performed on 19 open chest anaesthetised dogs, weight 13-32 kg. Measurements and main results - During intra-aortic balloon pumping the mean diastolic aortic pressure increased by 24.7(SEM 2.9) mm Hg (p &lt; 0.001), while in aortic regurgitation it decreased by 47.7(11.1) mm Hg (p &lt; 0.01). At the peak hyperaemic response the driving coronary pressure was 121.4(2.8) mm Hg during intra-aortic balloon pumping and 59.8(11.5) mm Hg during aortic regurgitation. The peak hyperaemic flow increased by 12.0(3.8) ml.min-1 (p &lt; 0.01) during intra-aortic balloon pumping, compared to the values before pumping and decreased by 14.9(4.2) ml.min-1 (p &lt; 0.01) during aortic regurgitation, compared to the values before aortic regurgitation. The coronary reserve, expressed as the ratio of the hyperaemic to the resting flow, increased by 0.7(0.1) (p &lt; 0.001) during intra-aortic balloon pumping and decreased by 0.4(0.2) (p &lt; 0.05) during aortic regurgitation. A positive significant correlation coefficient was found at the peak hyperaemic response between the mean aortic pressure and the total forward effective coronary flow, and between the mean diastolic aortic pressure and the diastolic component of the coronary flow, during both intra-aortic balloon pumping and aortic regurgitation. Conclusions - The results suggest that coronary reserve increases during intra-aortic balloon pumping and decreases during aortic regurgitation; these changes could be attributed to the effect of the pressure changes on the hyperaemic flow

ON LINE ECHOCARDIOGRAPHY IN EVALUATING LEFT ATRIAL CHANGES IN ACUTE MITRAL REGURGITATION AND IN MONITORING A CATHETER-MOUNTED BALLOON FOR ITS CORRECTION

The purpose of this study was to evaluate changes in the left atrial size in acute mitral regurgitation (AMR) and monitor its correction by a catheter-mounted balloon (B). In 16 dogs, pressure changes in the left atrium (LA) were related to LA size and regurgitant mitral flow after the production of AMR by severing the mitral cusps. TEE was used for evaluating LA area (ALA) and the mitral regurgitation flow area (AMRF). TEE was also used in monitoring the position of a catheter-mounted B inserted through the LV apex and positioned on the mitral ring to relieve AMR. The B was inflated during systole and deflated during diastole. The ALA increased by 4.89 +/- 1.21 cm(2) (mean +/- 1 SD) (p &lt; 0.001) after AMR, the AMRF increased by 3.01 +/- 0.85 cm(2) (p &lt; 0.001) and the mean atrial pressure (LAP) by 9.38 +/- 2.43 mmHg (p &lt; 0.001). In all experiments the position of the B could be confirmed in the 2D image and in 4 the reduction of AMRF by the function of the B was documented by the colour flow Doppler. It is concluded that after AMR the size of the LA increases along with the increase in LA pressure and a phasically inflated balloon and its effect on AMR can be easily identified and monitored by TEE

Alzheimer's disease and type 2 diabetes: the association study of polymorphisms in tumor necrosis factor-alpha and apolipoprotein E genes

Type 2 diabetes (T2D) and Alzheimer's disease (AD) are two progressive disorders with high prevalence worldwide. Polymorphisms in tumor necrosis factor-alpha (TNF-?) and apolipoprotein E (ApoE) genes might be associated with both T2D and AD, representing possible genetic markers for the development of the AD in subjects with T2D. The aim was to determine ApoE and G-308A TNF-? gene polymorphisms in unrelated Croatian Caucasians: 207 patients with sporadic AD, 196 T2D patients and 456 healthy controls. Patients with AD had higher frequency of ApoE4 allele compared to T2D patients and controls. The significant association, observed between ApoE2 allele and T2D, disappeared after the data were adjusted for age and sex. The genotype or allele frequencies of G-308A TNF-? gene polymorphism were similar among the patients with AD, T2D and healthy controls. In conclusion, these results do not support the hypothesis that the A allele of G-308A TNF-? gene polymorphism is associated either with AD or T2D. Our data confirm the association between the ApoE4 allele and AD, and point out the E2 allele of ApoE gene as the possible risk factor for T2D

One-Year Mortality for Bivalirudin vs Heparins Plus Optional Glycoprotein IIb/IIIa Inhibitor Treatment Started in the Ambulance for ST-Segment Elevation Myocardial Infarction: A Secondary Analysis of the EUROMAX Randomized Clinical Trial.

Importance: Uncertainty exists regarding potential survival benefits of bivalirudin compared with heparin with routine or optional use of glycoprotein IIb/IIIa inhibitors (GPIs) in patients with ST-segment elevation myocardial infarction (STEMI). Few data are available regarding long-term mortality in the context of contemporary practice with frequent use of radial access and novel platelet adenosine diphosphate P2Y12 receptor inhibitors. Objective: To assess the effect of bivalirudin monotherapy compared with unfractionated or low-molecular-weight heparin plus optional GPIs on 1-year mortality. Design, Setting, and Participants: This international, randomized, open-label clinical trial (EUROMAX [European Ambulance Acute Coronary Syndrome Angiography]) included 2198 patients with STEMI undergoing transport for primary percutaneous coronary intervention from March 10, 2010, through June 20, 2013, and followed up for 1 year. Patients were randomized (1:1) in ambulance to bivalirudin monotherapy vs unfractionated or low-molecular-weight heparin plus optional GPIs (control group). Analysis was based on intention to treat. Main Outcomes and Measures: The primary outcome of this prespecified analysis was 1-year mortality. All deaths were adjudicated as cardiac or noncardiac by an independent, blinded clinical events committee. One-year mortality was assessed and examined across multiple prespecified subgroups. Results: Of the 2198 patients enrolled (1675 men [76.2%] and 523 women [23.8%]; median [interquartile range] age, 62 [52-72] years), complete 1-year follow-up data were available for 2164 (98.5%). All-cause 1-year mortality occurred in 118 patients (5.4%). The number of all-cause deaths was the same for both treatment groups (59 deaths; relative risk [RR], 1.02; 95% CI, 0.72-1.45; P = .92). No differences were noted in the rates of 1-year cardiac death (44 [4.0%] for the bivalirudin group vs 48 [4.3%] for the control group; RR, 0.93; 95% CI, 0.63-1.39; P = .74) or noncardiac death (15 [1.4%] for the bivalirudin group vs 11 [1.0%] for the control group; RR, 1.39; 95% CI, 0.64-3.01; P = .40). Results were consistent across the prespecified patient subgroups. The rate of deaths occurring from 30 days to 1 year was also similar (27 [2.5%] in the bivalirudin group vs 25 [2.3%] in the control group; RR, 1.10; 95% CI, 0.64-1.88; P = .73). Conclusions and Relevance: In patients with STEMI who were being transported for primary percutaneous coronary intervention, treatment with bivalirudin or with heparin with optional use of GPI resulted in similar 1-year mortality. The reduced composite end point of death and/or major bleeding at 30 days in the bivalirudin arm of the EUROMAX trial did not translate into reduced cardiovascular or all-cause death at 1 year. Trial Registration: clinicaltrials.gov Identifier: NCT01087723

The association between apolipoprotein E gene polymorphisms and essential hypertension: a meta-analysis of 45 studies including 13 940 cases and 16 364 controls

The apolipoprotein E single-nucleotide polymorphisms are among the potential candidate genes that may serve as modulators in susceptibility to essential hypertension. In an effort to clarify earlier inconclusive results, we performed a meta-analysis of population-based case-control genetic association studies. Random-effects methods were applied on summary data in order to combine the results of the individual studies. We identified in total 45 studies, including 13 940 hypertensive cases and 16 364 controls. The contrast of E4 carriers versus non-carriers yielded an overall odds ratio (OR) of 1.16 (95% confidence interval (CI): 1.02, 1.31), whereas the contrast of E4 allele versus the others in a subtotal of 6617 cases and 7330 controls, yielded an OR of 1.39 (95% CI: 1.12, 1.72). There was moderate evidence of publication bias in both contrasts, which was eliminated after excluding studies not in Hardy-Weinberg equilibrium. Subgroup analyses revealed that significant estimates arose from studies on Asian populations, as opposed to the Caucasian ones. Furthermore, no evidence of publication bias was demonstrated in the comparisons within this subgroup. Our results are consistent with recent meta-analyses but show that the association is weaker than that has been previously demonstrated. Further studies are needed in order to fully address questions about the etiological mechanism of the particular association, as well as to study the effect in populations of African descent