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BACKGROUND: The inflammatory biomarker interleukin-6 (IL-6) is associated with mortality in atrial fibrillation (AF). OBJECTIVE: To investigate if repeated IL-6 measurements improve the prognostication for stroke or systemic embolism, major bleeding, and mortality in anticoagulated patients with AF. METHODS: IL-6 levels by ELISA were measured at study entry and at 2 months in 4830 patients in the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial with 1.8 years median follow-up. In the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial, IL-6 was measured at study entry, 3, 6, and 12 months in 2559 patients with 2.0 years median follow-up. Associations between a second IL-6 measurement and outcomes, adjusted for baseline IL-6, clinical variables, and other cardiovascular biomarkers, were analyzed by Cox regression. RESULTS: Median IL-6 levels were 2.0 ng/L (interquartile range [IQR] 1.30-3.20) and 2.10 ng/L (IQR 1.40-3.40) at the two time-points in ARISTOTLE, and, in RE-LY, 2.5 ng/L (IQR 1.6-4.3), 2.5 ng/L (IQR 1.6-4.2), 2.4 ng/L (IQR 1.6, 3.9), and 2.4 ng/L (IQR 1.5, 3.9), respectively. IL-6 was associated with mortality; hazard ratios per 50% higher IL-6 at 2 or 3 months, respectively, were 1.32 (95% confidence interval, 1.23-1.41; P

Background There is little mechanistic information on factors predisposing atrial fibrillation (AF) patients to thromboembolism or bleeding, but generation of nitric oxide (NO) might theoretically contribute to both. Objectives The authors tested the hypothesis that plasma levels of the methylated arginine derivatives asymmetric and symmetric dimethylarginine (ADMA/SDMA), which inhibit NO generation, might be associated with outcomes in AF. Methods Plasma samples were obtained from 5,004 patients with AF at randomization to warfarin or apixaban in the ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial. ADMA and SDMA concentrations were measured by high-performance liquid chromatography. Relationships to clinical characteristics were evaluated by multivariable analyses. Associations with major outcomes, during a median of 1.9 years follow-up, were evaluated by adjusted Cox proportional hazards models. Results Both ADMA and SDMA plasma concentrations at study entry increased significantly with patients’ age, female sex, renal impairment, permanent AF, or congestive heart failure. ADMA and SDMA increased (p 2 DS 2 -VASc and HAS-BLED scores, but decreased in the presence of diabetes. On multivariable analysis adjusting for established risk factors and treatment, tertile groups of ADMA concentrations were significantly associated with stroke/systemic embolism (p = 0.034), and death (p 2 DS 2 -VASc or HAS-BLED predictive models improved C-indices for those outcomes. Neither ADMA nor SDMA predicted differential responses to warfarin or apixaban. Conclusions In anticoagulated patients with AF, elevated ADMA levels are weakly associated with thromboembolic events, elevated SDMA levels with bleeding events and both are strongly associated with increased mortality. These findings suggest that disturbances of NO function modulate both thrombotic and hemorrhagic risk in anticoagulated patients with AF. (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation [ARISTOTLE]; NCT00412984)

To evaluate and validate the prognostic value of growth-differentiation factor 15 (GDF-15) beyond clinical characteristics and other biomarkers concerning bleeding and stroke outcomes in patients with atrial fibrillation in the RE-LY trial.GDF-15 was measured in samples collected at randomization in 8,474 patients with a median follow-up time of 1.9 years. Patients were stratified based on predefined GDF-15 cutoffs: group 1,1,200 ng/L (the 90th percentile in healthy individuals); group 2, 1,200-1,800; and group 3,1,800 ng/L (high-risk individuals). Efficacy and safety outcomes were compared across groups of GDF-15 in Cox models adjusted for baseline characteristics, cardiac (N-terminal pro-b-type natriuretic peptide, high-sensitive troponin T), inflammatory (interleukin 6, C-reactive protein) and coagulation (D-dimer) biomarkers, and randomized treatment.GDF-15 concentrations were1,200 ng/L in 2,647 (31.2%), between 1,200 and 1,800 ng/L in 2,704 (31.9%), and1,800 ng/L in 3,123 (36.9%) participants, respectively. Annual rates of stroke, major bleeding, and mortality increased with higher GDF-15 levels. The prognostic value of GDF-15 was independent of clinical characteristics for these outcomes. In models also adjusted for biomarkers, GDF-15 remained significantly associated with major bleeding (hazard ratio [95% CI] group 3 vs group 1 1.76 [1.28-2.42], P.0005) and all-cause mortality (hazard ratio 1.72 [1.30-2.29], P.0005). GDF-15 improved the c index of both the HAS-BLED (0.62-0.69) and ORBIT (0.68-0.71) bleeding risk scores.In patients with atrial fibrillation, GDF-15 is an independent risk indicator for major bleeding and all-cause mortality, but not for stroke. Therefore, GDF-15 seems useful as a specific marker of bleeding in patients with AF on oral anticoagulant treatment.

Large quantities of water are required to produce the food for a nation, some of which is derived within the country and some associated with imported food commodities. In this study, we consider the spatially explicit potential impact of alternative healthier eating scenarios for the UK on global blue water scarcity using the concept of a water scarcity footprint. The water required to produce the food consumed by the UK was estimated at 52.6 Gm 3 /y of which 93% is from rainfall at the point where it falls and 7% is “blue” water withdrawn from surface and ground water resources. Five alternative healthier diets were considered and the impact on the blue water scarcity footprint was modest (ranging from −3% to +2% compared to baseline). However more significant impacts were projected on the geographical distribution of the blue water scarcity footprint. This study has shown that if current trade patterns continue, policies to promote healthier eating in the UK may contribute to increased blue water scarcity at home and in other parts of the world. The use of virtual water estimates and global datasets of water scarcity can help to understand the potential environmental impacts of alternative diets.

Background D-dimer is related to adverse outcomes in arterial and venous thromboembolic diseases. Objectives To evaluate the predictive value of D-dimer level for stroke, other cardiovascular events, and bleeds, in patients with atrial fibrillation (AF) treated with oral anticoagulation with apixaban or warfarin; and to evaluate the relationship between the D-dimer levels at baseline and the treatment effect of apixaban vs. warfarin. Methods In the ARISTOTLE trial, 18 201 patients with AF were randomized to apixaban or warfarin. D-dimer was analyzed in 14 878 patients at randomization. The cohort was separated into two groups; not receiving vitamin K antagonist (VKA) treatment and receiving VKA treatment at randomization. Results Higher D-dimer levels were associated with increased frequencies of stroke or systemic embolism (hazard ratio [HR] [Q4 vs. Q1] 1.72, 95% confidence interval [CI] 1.14–2.59, P = 0.003), death (HR [Q4 vs. Q1] 4.04, 95% CI 3.06–5.33) and major bleeding (HR [Q4 vs. Q1] 2.47, 95% CI 1.77–3.45, P

OBJECTIVE:This study sought to assess the prognostic value of N-terminal pro–B-type natriuretic peptide (NT-proBNP) in patients with atrial fibrillation (AF) enrolled in the ARISTOTLE (Apixaban for ...

MISER chromatography was evaluated to increase data processing speed for a rapid, miniaturized in vitro formulation screen. This approach permitted quick data interpretation by eliminating time-consuming steps such as integration, quantitation and report generation. Some flexibility in analytical methodology was lost due to limited instrument platforms capable of injecting multiple samples and acquiring all data in a single chromatogram. In our instrumental setup, an isocratic run was used to perform MISER chromatography, producing results comparable to our generic gradient methods while reducing processing times. This novel data format was easily interpreted and provides equivalent information to a formulation scientist as compared to traditional tabulated reports.

Objective A diet rich in whole grain cereals is suggested to protect against type 2 diabetes and facilitate body weight regulation. However, little is known about the impact of different cereals and the underlying mechanisms. The objective of this study was to compare the long-term metabolic effects of diets supplemented with whole grain wheat or whole grain rye in the C57BL/6J mouse. Methods Mice were fed the whole grain supplements in a low-fat background diet for 22 wk. Oral and intravenous glucose tolerance tests were performed during the study and in vitro insulin secretion assays were performed at the end of the study. Body weight, energy intake, body fat content, and plasma parameters were measured during the study. Results A dietary supplement of whole grain rye suppressed body weight gain and resulted in significantly decreased adiposity, plasma leptin, total plasma cholesterol, and triacylglycerols compared with a supplement of whole grain wheat. Also, a slight improvement in insulin sensitivity was observed in the rye group compared with the wheat group. The decreases in body weight and adiposity were observed in the absence of differences in energy intake. Conclusion Long-term administration of whole grain rye evokes a different metabolic profile compared with whole grain wheat in the C57BL/6J mouse, the primary difference being that whole grain rye reduces body weight and adiposity compared with whole grain wheat. In addition, whole grain rye slightly improves insulin sensitivity and lowers total plasma cholesterol.

Body Mass Index (BMI) is a risk factor for atrial fibrillation (AF). Few studies have examined the relations between BMI and outcomes in patients with AF treated with different types of oral anticoagulation. The ARISTOTLE trial randomized 18,201 patients with AF to median 1.8 years treatment with

AMP-activated protein kinase (AMPK) is the downstream component of a protein kinase cascade that acts as an intracellular energy sensor maintaining the energy balance within the cell. The finding that leptin and adiponectin activate AMPK to alter metabolic pathways in muscle and liver provides direct evidence for this role in peripheral tissues. The hypothalamus is a key regulator of food intake and energy balance, coordinating body adiposity and nutritional state in response to peripheral hormones, such as leptin, peptide YY-(3-36), and ghrelin. To date the hormonal regulation of AMPK in the hypothalamus, or its potential role in the control of food intake, have not been reported. Here we demonstrate that counter-regulatory hormones involved in appetite control regulate AMPK activity and that pharmacological activation of AMPK in the hypothalamus increases food intake. In vivo administration of leptin, which leads to a reduction in food intake, decreases hypothalamic AMPK activity. By contrast, injection of ghrelin in vivo, which increases food intake, stimulates AMPK activity in the hypothalamus. Consistent with the effect of ghrelin, injection of 5-amino-4-imidazole carboxamide riboside, a pharmacological activator of AMPK, into either the third cerebral ventricle or directly into the paraventricular nucleus of the hypothalamus significantly increased food intake. These results suggest that AMPK is regulated in the hypothalamus by hormones which regulate food intake. Furthermore, direct pharmacological activation of AMPK in the hypothalamus is sufficient to increase food intake. These findings demonstrate that AMPK plays a role in the regulation of feeding and identify AMPK as a novel target for anti-obesity drugs.

Lactococcus lactis splits phosphorylated trehalose by the action of inorganic phosphate-dependent trehalose-6-phosphate phosphorylase (TrePP) in a novel catabolic pathway. TrePP was found to catalyze the reversible conversion of trehalose 6-phosphate into beta-glucose 1-phosphate and glucose 6-phosphate by measuring intermediate sugar phosphates in cell extracts from trehalose-cultivated lactococci. According to native PAGE and SDS-PAGE, TrePP was shown to be a monomeric enzyme with a molecular mass of 94 kDa. Reaction kinetics suggested that the enzyme follows a ternary complex mechanism with optimal phosphorolysis at 35 degrees C and pH 6.3. The equilibrium constants were found to be 0.026 and 0.032 at pH 6.3 and 7.0, respectively, favoring the formation of trehalose 6-phosphate. The Michaelis-Menten constants of TrePP for trehalose 6-phosphate, inorganic phosphate, beta-glucose 1-phosphate, and glucose 6-phosphate were determined to be 6, 32, 0.9, and 4 mm, respectively. The TrePP-encoding gene, designated trePP, was localized in a putative trehalose operon of L. lactis. This operon includes the gene encoding beta-phosphoglucomutase in addition to three open reading frames believed to encode a transcriptional regulator and two trehalose-specific phosphotransferase system components. The identity of trePP was confirmed by determining the N-terminal amino acid sequence of TrePP and by its overexpression in Escherichia coli and L. lactis, as well as the construction of a lactococcal trePP knockout mutant. Furthermore, both TrePP and beta-phosphoglucomutase activity were detected in Enterococcus faecalis cell extract, indicating that this bacterium exhibits the same trehalose assimilation route as L. lactis.

Inflammation has been associated with cardiovascular disease and the burden of atrial fibrillation (AF). In this study we evaluate inflammatory biomarkers and future cardiovascular events in AF patients in the RE-LY study.Interleukin-6 (IL-6), C-reactive protein (CRP) (n = 6,187), and fibrinogen (n = 4,893) were analyzed at randomization; outcomes were evaluated by Cox models and C-statistics.Adjusted for clinical risk factors IL-6 was independently associated with stroke or systemic embolism (P = .0041), major bleedings (P = .0001), vascular death (P.0001), and a composite thromboembolic outcome (ischemic stroke, systemic embolism, myocardial infarction, pulmonary embolism and vascular death) (P.0001). CRP was independently related to myocardial infarction (P = .0047), vascular death (P = .0004), and the composite thromboembolic outcome (P = .0001). When further adjusted for cardiac (troponin and N-terminal fragment B-type natriuretic peptide [NT-proBNP]) and renal (cystatin-C) biomarkers on top of clinical risk factors IL-6 remained significantly related to vascular death (P.0001), major bleeding (P.0170) and the composite thromboembolic outcome (P.0001), and CRP to myocardial infarction (.0104). Fibrinogen was not associated with any outcome. C-index for stroke or systemic embolism increased from 0.615 to 0.642 (P = .0017) when adding IL-6 to the clinically used CHA2DS2-VASc risk score with net reclassification improvement of 28%.In patients with AF, IL-6 is related to higher risk of stroke and major bleeding, and both markers are related to higher risk of vascular death and the composite of thromboembolic events independent of clinical risk factors. Adjustment for cardiovascular biomarkers attenuated the prognostic value, although IL-6 remained related to mortality, the composite of thromboembolic events, and major bleeding, and CRP to myocardial infarction.

BACKGROUND: In the ARISTOTLE trial comparing apixaban with warfarin in pts with AF, apixaban 2.5mg was used in pts with 2 or more dose reduction (DR) criteria: age 80 years, creatinine 1.5mg/dL, weight 60kg. Pts assigned 2.5mg of apixaban vs. warfarin (n1⁄4831) had similar reductions in stroke/SE and major bleeding to pts assigned 5.0 mg of apixaban vs. warfarin (n1⁄417,370). METHODS: We compared pts assigned to apixaban 5.0mg or warfarin, with 1 of 3 DR criteria with pts with 0 of 3 criteria. Stroke/SE and major bleeding rates, hazard ratios and 95% CIs were evaluated, and interactions between treatment and the presence of 1 vs. 0 DR criteria were determined. RESULTS: Among pts assigned 5.0mg of apixaban or warfarin, 4046 (23%) had one DR criteria. These pts were older (77 vs. 68 years), of lighter weight (86 vs . 70 kg), and had worse renal function (creatinine 1.00 vs. 1.07 mL/min) than pts with no DR criteria. Pts with one DR criteria had more stroke/SE and major bleeding but had similar benefits of apixaban vs. warfarin on stroke/SE (p1⁄40.41) and major bleeding (p1⁄40.65). Similar patterns were seen for individual DR criteria. CONCLUSION: Pts with isolated advanced age ( 80 years), low body weight ( 60kg), or renal dysfunction (Cr 1.5mg/dL) had slightly more stroke/SE and significantly more major bleeding but similar benefits with apixaban 5.0mg BID compared with warfarin to pts with none of these characteristics. Apixaban 5.0mg BID is a safe and efficacious dose for these pts. BMS/Pfizer