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Inflammation and Atherosclerosis
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- Article
- Abstract
- The Scientific Basis of Inflammation in Atherogenesis
- Triggers for Inflammation in Atherogenesis
- Inflammation and the ACS
- Correlation of Elevated Inflammatory Markers With Adverse Prognosis
- Inflammation and Myocardial Necrosis and Ischemia
- Prevalence of Inflammation in the ACS and Interindividual Variability
- Inflammatory Biomarkers and Risk of First Cardiovascular Events: Implications for Prevention
- Conclusion
- Acknowledgments
- References
- Figures & Tables
- Info & Metrics
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Atherosclerosis, formerly considered a bland lipid storage disease, actually involves an ongoing inflammatory response. Recent advances in basic science have established a fundamental role for inflammation in mediating all stages of this disease from initiation through progression and, ultimately, the thrombotic complications of atherosclerosis. These new findings provide important links between risk factors and the mechanisms of atherogenesis. Clinical studies have shown that this emerging biology of inflammation in atherosclerosis applies directly to human patients. Elevation in markers of inflammation predicts outcomes of patients with acute coronary syndromes, independently of myocardial damage. In addition, low-grade chronic inflammation, as indicated by levels of the inflammatory marker C-reactive protein, prospectively defines risk of atherosclerotic complications, thus adding to prognostic information provided by traditional risk factors. Moreover, certain treatments that reduce coronary risk also limit inflammation. In the case of lipid lowering with statins, this anti-inflammatory effect does not appear to correlate with reduction in low-density lipoprotein levels. These new insights into inflammation in atherosclerosis not only increase our understanding of this disease, but also have practical clinical applications in risk stratification and targeting of therapy for this scourge of growing worldwide importance.
Over the last dozen years, appreciation of the role of inflammation in atherosclerosis has burgeoned. Although it was formerly considered a bland lipid storage disease, substantial advances in basic and experimental science have illuminated the role of inflammation and the underlying cellular and molecular mechanisms that contribute to atherogenesis. Compelling evidence for the importance of inflammation and atherosclerosis at both the basic and clinical level has evolved in parallel. Accumulating data indicate that insights gained from the link between inflammation and atherosclerosis can yield predictive and prognostic information of considerable clinical utility. This review summarizes the experimental and clinical evidence for inflammation in atherosclerosis, and assesses the current state of knowledge regarding the triggers for inflammation in this disease. We will evaluate the participation of inflammation in the acute coronary syndromes (ACS) and review the data supporting the use of inflammatory markers as prognostic and predictive instruments in the context both of ACS and of prediction of risk for various complications of atherosclerosis. Finally, we will consider how new insights into inflammation in atherosclerosis may identify innovative therapeutic strategies to improve outcomes of individuals at risk for or affected by this scourge of growing worldwide importance.
The Scientific Basis of Inflammation in Atherogenesis
In a variety of animal models of atherosclerosis, signs of inflammation occur hand-in-hand with incipient lipid accumulation in the artery wall. For example, blood leukocytes, mediators of host defenses and inflammation, localize in the earliest lesions of atherosclerosis, not only in experimental animals but in humans as well. The basic science of inflammation biology applied to atherosclerosis has afforded considerable new insight into the mechanisms underlying this recruitment of leukocytes. The normal endothelium does not in general support binding of white blood cells. However, early after initiation of an atherogenic diet, patches of arterial endothelial cells begin to express on their surface selective adhesion molecules that bind to various classes of leukocytes (Figure 1A). In particular, vascular cell adhesion molecule-1 (VCAM-1) binds precisely the types of leukocytes found in early human and experimental atheroma, the monocyte and T lymphocyte. Not only does VCAM-1 expression increase on endothelial cells overlying nascent atheroma,1 but mice genetically engineered to express defective VCAM-1 show interrupted lesion development.2
Interestingly, the foci of increased adhesion molecule expression overlap with sites in the arterial tree particularly prone to develop atheroma. Considerable evidence suggests that impaired endogenous atheroprotective mechanisms occur at branch points in arteries, where the endothelial cells experience disturbed flow.3 For example, absence of normal laminar shear stress may reduce local production of endothelium-derived NO. This endogenous vasodilator molecule also has anti-inflammatory properties and can limit expression of VCAM-1.4 In addition to inhibiting natural protective mechanisms, disturbed flow can augment the production of certain leukocyte adhesion molecules (eg, intercellular adhesion molecule-1 [ICAM-1]).5 Augmented wall stresses may also promote the production by arterial smooth muscle cells (SMCs) of proteoglycans that can bind and retain lipoprotein particles, facilitating their oxidative modification and thus promoting an inflammatory response at sites of lesion formation.6
Once adherent to the endothelium, the leukocytes penetrate into the intima (Figure 1A). Recent research has identified candidate chemoattractant molecules responsible for this transmigration. For example, monocyte chemoattractant protein-1 (MCP-1) appears responsible for the direct migration of monocytes into the intima at sites of lesion formation.7,8⇓ A family of T-cell chemoattractants may likewise call lymphocytes into the intima.9 Once resident in the arterial wall, the blood-derived inflammatory cells participate in and perpetuate a local inflammatory response (Figure 1B). The macrophages express scavenger receptors for modified lipoproteins, permitting them to ingest lipid and become foam cells. In addition to MCP-1, macrophage colony-stimulating factor (M-CSF) contributes to the differentiation of the blood monocyte into the macrophage foam cell.10,11⇓ T cells likewise encounter signals that cause them to elaborate inflammatory cytokines such as γ-interferon and lymphotoxin (tumor necrosis factor [TNF]–β) that in turn can stimulate macrophages as well as vascular endothelial cells and SMCs.12 As this inflammatory process continues, the activated leukocytes and intrinsic arterial cells can release fibrogenic mediators, including a variety of peptide growth factors that can promote replication of SMCs and contribute to elaboration by these cells of a dense extracellular matrix characteristic of the more advanced atherosclerosis lesion.13
Inflammatory processes not only promote initiation and evolution of atheroma, but also contribute decisively to precipitating acute thrombotic complications of atheroma (Figure 1C). Most coronary arterial thrombi that cause fatal acute myocardial infarction arise because of a physical disruption of the atherosclerotic plaque. The activated macrophage abundant in atheroma can produce proteolytic enzymes capable of degrading the collagen that lends strength to the plaque's protective fibrous cap, rendering that cap thin, weak, and susceptible to rupture. γ-Interferon arising from the activated T lymphocytes in the plaque can halt collagen synthesis by SMCs, limiting its capacity to renew the collagen that reinforces the plaque.14,15⇓ Macrophages also produce tissue factor, the major procoagulant and trigger to thrombosis found in plaques. Inflammatory mediators regulate tissue factor expression by plaque macrophages, demonstrating an essential link between arterial inflammation and thrombosis.16
Triggers for Inflammation in Atherogenesis
Oxidized Lipoproteins and Inflammation
For almost a century, many have regarded lipids as the sine qua non of atherosclerosis. Over the last few decades, a plausible model linking lipids and inflammation to atherogenesis has emerged. According to the oxidation hypothesis, low-density lipoprotein (LDL) retained in the intima, in part by binding to proteoglycan, undergoes oxidative modification.17,18⇓ Lipid hydroperoxides, lysophospholipids, carbonyl compounds, and other biologically active moieties localize in the lipid fraction of atheroma.19 These modified lipids can induce the expression of adhesion molecules, chemokines, proinflammatory cytokines, and other mediators of inflammation in macrophages and vascular wall cells. The apoprotein moieties of the lipoprotein particles can also undergo modification in the artery wall, rendering them antigenic and capable of inciting T-cell responses, thus activating the antigen-specific adaptive limb of the immune response.20 In some experimental situations, administration of antioxidants can retard the progression of atherosclerotic lesions that develop in the face of hyperlipidemia.
Although attractive, theoretically compelling, and supported by a considerable body of experimental evidence, the relevance of the LDL oxidation hypothesis to human atherosclerosis remains unproven. Chemical analysis of the types of modified lipids and proteins extracted from human atheroma do not necessarily correspond to the compounds derived from lipoproteins oxidized in vitro that have furnished much of the evidence linking oxidized lipoproteins to inflammation. Most cell culture studies of the biological effects of oxidized LDL have used material generated by transition metal–mediated oxidation, conditions that some find of dubious in vivo relevance. Hypochlorous acid–mediated derivation of lipoprotein constituents may bear closer relationship to human atherosclerosis than oxidative modification catalyzed by transition metals.21,22⇓ The leukocyte enzyme myeloperoxidase produces hypochlorous acid within the atheroma. Clinical trials have repeatedly failed to validate the concept that antioxidant vitamin therapy can improve clinical outcomes. Thus, "the jury is still out" on the applicability of the LDL oxidation hypothesis to patients.
Dyslipidemia and Inflammation
Other lipoprotein particles such as very low–density lipoprotein (VLDL) and intermediate-density lipoprotein also have considerable atherogenic potential. These lipoprotein particles can undergo oxidative modification like that of LDL. In addition, some evidence suggests that beta VLDL particles may themselves activate inflammatory functions of vascular endothelial cells.23,24⇓ High-density lipoprotein (HDL) protects against atherosclerosis. Reverse cholesterol transport effected by HDL likely accounts for some its atheroprotective function. However, HDL particles also can transport antioxidant enzymes such as platelet-activating factor acetylhydrolase and paraoxonase, which can break down oxidized lipids and neutralize their proinflammatory effects.
Hypertension and Inflammation
Hypertension follows closely behind lipids on a list of classical risk factors for atherosclerosis. Increasing evidence supports the view that, like atherosclerosis itself, inflammation may participate in hypertension providing a pathophysiological link between these two diseases. Angiotensin II (AII), in addition to its vasoconstrictor properties, can instigate intimal inflammation. For example, AII elicits the production of superoxide anion, a reactive oxygen species, from arterial endothelial cells and SMCs.25 AII can also increase the expression by arterial SMCs of proinflammatory cytokines such as interleukin (IL)–6 and MCP-1 and of the leukocyte adhesion molecule VCAM-1 on endothelial cells.26–28⇓⇓ Some of the clinical benefits of angiotensin-converting enzyme inhibitor therapy may derive from interrupting such proinflammatory pathways.
Diabetes and Inflammation
Diabetes is yet another risk factor for atherosclerosis of growing importance. The hyperglycemia associated with diabetes can lead to modification of macromolecules, for example, by forming advance glycation end products (AGE).29 By binding surface receptors such as RAGE (receptor for AGE), these AGE-modified proteins can augment the production of proinflammatory cytokines and other inflammatory pathways in vascular endothelial cells. Beyond the hyperglycemia, the diabetic state promotes oxidative stress mediated by reactive oxygen species and carbonyl groups.30 As in the case of hypertension, inflammation links diabetes to atherosclerosis.
Obesity and Inflammation
Obesity not only predisposes to insulin resistance and diabetes, but also contributes to atherogenic dyslipidemia. High levels of free fatty acids originating from visceral fat reach the liver through the portal circulation and stimulate synthesis of the triglyceride-rich lipoprotein VLDL by hepatocytes. The resulting elevation in VLDL can lower HDL cholesterol by augmenting exchange from HDL to VLDL by cholesteryl ester transfer protein. Adipose tissue can also synthesize cytokines such as TNF-α and IL-6.31 In this way obesity itself promotes inflammation and potentiates atherogenesis independent of effects on insulin resistance or lipoproteins.
Infectious agents might also conceivably furnish inflammatory stimuli that accentuate atherogenesis.32,33⇓ Acute infections can alter hemodynamics and the clotting and fibrinolytic systems in ways that can precipitate ischemic events. Chronic extravascular infections (eg, gingivitis, prostatitis, bronchitis, etc) can augment extravascular production of inflammatory cytokines that may accelerate the evolution of remote atherosclerotic lesions. Intravascular infection might also provide a local inflammatory stimulus that could accelerate atherogenesis. Many human plaques show signs of infection by microbial agents such Chlamydia pneumoniae. Chlamydiae, when present in the arterial plaque, may release lipopolysaccharide (endotoxin) and heat shock proteins that can stimulate the production of proinflammatory mediators by vascular endothelial cells and SMCs and infiltrating leukocytes alike.34 Epidemiological studies of infection, however, have yielded mixed results, with little prospective evidence that antibodies directed against Chlamydia pneumoniae, Helicobacter pylori, herpes simplex virus, or cytomegalovirus predict vascular risk.
Inflammation and the ACS
The mechanisms of ACS encompass elements of thrombosis and vasoconstriction superimposed on atherosclerotic lesions. Thrombosis frequently persists, detectable by angiography, by angioscopy, or at autopsy. In contrast, vasospasm presents challenges to quantification because of its transient nature. Reduction of stenoses by administration of nitrates35 or use of provocative maneuvers36,37⇓ provides evidence for arterial spasm. Indeed, thrombosis may beget vasospasm. Local thrombus formation generates serotonin, thromboxane A2, and thrombin. Each of these thrombosis-associated mediators can cause vasoconstriction not only at the site of thrombosis, but also downstream. In this manner, a proximal thrombus in an epicardial conduit coronary artery might propagate spasm to the distal smaller vessels. Thrombi present a more tractable therapeutic target than vasoconstriction, as vasodilator drugs, when given systemically, seldom overcome the effect of locally produced constrictor substances.35
Yet, even with aggressive thrombolytic, anticoagulant, and/or antiplatelet agents or interventional therapy, patients with ACS still have a 12% to 16% incidence of major cardiac events at 4 to 6 months after hospital discharge.38,39⇓ Novel treatments based on increased understanding of the underlying mechanisms of plaque instability should yield further improvements in outcomes. Growing evidence indicates that in ACS, elevated circulating inflammatory markers, in particular C-reactive protein (CRP), predict an unfavorable course, independent of the severity of the atherosclerotic or ischemic burden. Thus, inflammation represents one potential novel pathophysiological mechanism of the ACS that may furnish such a new target for therapy.
Correlation of Elevated Inflammatory Markers With Adverse Prognosis
Elevated values of circulating inflammatory markers such as CRP, serum amyloid A, IL-6, and IL-1 receptor antagonist commonly accompany ACS. Such elevations correlate with in-hospital and short-term adverse prognosis40–47⇓⇓⇓⇓⇓⇓⇓ and may reflect not only a high prevalence of myocardial necrosis, ischemia-reperfusion damage, or severe coronary atherosclerosis but also a primary inflammatory instigator of coronary instability. The contribution of each of the inflammatory processes mentioned above to prognosis may vary in different groups of patients according to the criteria used for their selection. In turn, the short-term prognostic role of elevated CRP values in ACS may correlate at least in part with the long-term prognostic role of CRP values within the normal range in normal individuals48,49⇓ and of elevated values in chronic coronary disease.50,51⇓ Of note, the degree of elevation in CRP discussed here in the context of the ACS exceeds the relative increases within the normal range measured by the high-sensitivity assay discussed below in relation to prospective coronary risk stratification.
Inflammation and Myocardial Necrosis and Ischemia
Liuzzo et al41 demonstrated early on that elevated CRP correlates with adverse short-term prognosis in selected patients with unstable angina, Braunwald class IIIb, who lacked evidence of myocardial necrosis and had an ischemic burden similar to that of patients without CRP elevation. Half of patients with ACS have persistently elevated CRP after discharge, a finding associated with recurrent episodes of instability and infarction.47 Patients with variant angina and large ischemic burden, or stable angina pectoris and severe coronary artery disease, have a very low incidence of elevated CRP, affirming the specificity of systemically detectable inflammation in ACS.52 Indeed, the elevation of CRP in unstable patients does not appear to relate merely to the extent and severity of atherosclerosis, as only about 20% of patients with chronic stable angina and a high prevalence of multivessel disease have elevated CRP values compared with 70% of patients with unstable angina.41 Moreover, CRP values in patients with peripheral vascular disease severe enough to require revascularization do not differ significantly from those observed in unstable angina and single-vessel disease53 (E. Rossi et al, unpublished data, 2001).
Not all patients with unstable angina and elevated CRP develop infarction. But practically all patients with infarctions preceded by unstable angina have elevated CRP on admission. The final sustained coronary occlusion leading to infarction may result from a coexistent prothrombic diathesis or from enhanced coronary vasoreactivity.54 Inflammation might not only mark increased risk of infarction, but also participate in precipitating occlusive events. In addition, aspects of the acute-phase inflammatory response may directly influence thrombosis. Although CRP serves as a convenient marker of inflammation, the other proteins augmented during the acute-phase response include fibrinogen and plasminogen activator inhibitor-1. Thus, inflammation can promote thrombus formation and can enhance clot stability by inhibiting endogenous fibrinolysis.
Prevalence of Inflammation in the ACS and Interindividual Variability
In patients with ACS, the prevalence of a primary inflammatory pathogenic component of coronary instability, as detectable by elevated CRP, varies considerably. Elevated CRP (>3 mg/L) is found in <10% of normals, in <20% of patients with chronic stable or variant angina, but in >65% of patients with unstable angina, Braunwald class IIIb, and in >90% of patients with acute infarction preceded by unstable angina, but in <50% of those in whom the infarction was totally unheralded (in samples taken before elevation of markers of necrosis).41,47,55⇓⇓
The absence of elevated CRP in >30% of patients with severe unstable angina and in >50% of those with acute MI not preceded by unstable angina suggests an important heterogeneity of the role of inflammatory triggers of the clinical syndromes of coronary instability.56 Individuals may vary in their response to inflammatory stimuli. The increase in CRP and IL-6 observed in response to the vascular trauma caused by coronary angioplasty or by uncomplicated cardiac catheterization51 and that observed after acute infarction57 correlates linearly with baseline CRP and IL-6 levels. In vitro, the IL-6 production by isolated monocytes from unstable patients with elevated CRP and IL-6 significantly exceeds that produced by monocytes from patients with normal values.47 These individual differences in the degree of response to given inflammatory stimuli may have a genetic basis. For example, certain haplotypes in the IL-1/IL-1 receptor agonist gene complex correlate with heightened inflammatory responses and incidence of ACS.58
Inflammatory Biomarkers and Risk of First Cardiovascular Events: Implications for Prevention
The above discussion reviewed the role of inflammatory mediators and markers in ACS. However, inflammation contributes across the spectrum of cardiovascular disease, including the earliest steps in atherogenesis. This recognition has had a profound impact on our understanding of atherothrombosis as more than a disease of lipid accumulation, but rather as a disorder characterized by low-grade vascular inflammation. Practically, we can use this concept to predict future cardiovascular risk.
The best human data relating inflammation to the prospective development of vascular events have come from large-scale, population-based studies. To date, elevated levels of several inflammatory mediators among apparently healthy men and women have proven to have predictive value for future vascular events. In particular, prospective epidemiological studies have found increased vascular risk in association with increased basal levels of cytokines such as IL-6 and TNF-α49,59–61⇓⇓⇓; cell adhesion molecules such as soluble ICAM-1, P selectin, and E selectin62–64⇓⇓; and downstream acute-phase reactants such as CRP, fibrinogen, and serum amyloid A.48,49,65–70a⇓⇓⇓⇓⇓⇓⇓ Several traditional cardiovascular risk factors track with these inflammatory biomarkers, in particular central obesity and body mass index. These observations have considerable importance because, as discussed above, adipocytes can produce inflammatory cytokines, and a common underlying disorder of innate immunity may well link obesity, accelerated atherosclerosis, and insulin resistance.71b In support of this hypothesis, very recent observations show that elevated levels of both IL-6 and CRP associate not only with the subsequent development of atherosclerosis, but also with the development of type II diabetes, even among individuals with no current evidence of insulin resistance.72
For clinical purposes, the most promising inflammatory biomarker appears to be CRP, a classical acute-phase marker and a member of the pentraxin family of innate immune response proteins.73 The clinical appeal of CRP stems from several analytic properties. Unlike upstream cytokines, CRP has a long half-life, affording stability of levels with no observable circadian variation.74 Further, CRP is easily measured in usual outpatient settings, and standardized high-sensitivity assays commercially available provide similar results in fresh, stored, and frozen plasma.75 Functionally, in addition to providing a downstream integration of overall cytokine activation, CRP has several direct effects that may affect vascular disease progression. These reported functions include an ability to bind and activate complement, induce expression of several cell adhesion molecules as well as tissue factor, mediate LDL uptake by endothelial macrophages, induce monocyte recruitment into the arterial wall, and enhance production of MCP-1.76–80⇓⇓⇓⇓
More than a dozen population-based studies have demonstrated that baseline CRP levels predict future cardiovascular events. CRP testing may thus have a major adjunctive role in the global assessment of cardiovascular risk.81 Available prospective epidemiological studies have included elderly as well as middle-aged individuals, and show consistency for the endpoints of first-ever myocardial infarction or stroke as well as for the development of symptomatic peripheral arterial disease53 (Figure 2). In one recent overview analysis that included 2557 cases with an average follow-up of 8 years, individuals with basal CRP levels in the top third exhibited a 2-fold increase in future vascular events even after adjustment for all other available vascular risk factors.69 Perhaps of equal clinical impact, both men and women with elevated levels of CRP consistently show high vascular risk, even in the absence of hyperlidipidemia.49,82⇓ Algorithms that combine CRP and lipid screening to improve risk assessment may have clinical utility for outpatient use81 (Figure 3).
In addition to providing a simple method to assess low-grade inflammation and improve global risk prediction, CRP screening may also provide a novel method of targeting statin therapy, particularly in the primary prevention of myocardial infarction and stroke. Both experimental and clinical outcome data now support the hypothesis that statins, in addition to being potent LDL-lowering agents, also attenuate plaque inflammation and influence plaque stability. Both pravastatin and cerivastatin can reduce macrophage content within experimental atherosclerotic plaques,83–85⇓⇓ whereas simvastatin, fluvastatin, and atorvastatin appear to reduce intimal inflammation86 and suppress the expression of tissue factor and matrix metalloproteinases both in vivo and in vitro.87,88⇓ Statins may also inhibit expression of adhesion molecules critical for monocyte attachment and adhesion to the vascular endothelium.89
The first data to link the utility of CRP as a marker of inflammation with potential utility in targeting statin therapy emerged from the Cholesterol and Recurrent Events (CARE) trial, a secondary prevention study in which elevated CRP levels correlated with significantly increased risk of recurrent coronary events.50,90⇓ In a series of hypothesis-generating studies, the CARE investigators then demonstrated that the magnitude of risk reduction attributable to pravastatin was substantially greater among those with evidence of inflammation compared with those without evidence of inflammation. The CARE investigators also reported that random allocation to pravastatin lowered CRP levels in a manner unrelated to the effect of pravastatin on LDL or HDL cholesterol, data that provided strong evidence that statins may have important anti-inflammatory effects.90
Although initially controversial, clinical studies with cerivastatin, lovastatin, simvastatin, and atorvastatin have since replicated the reduction in CRP first described in the CARE trial for pravastatin.91–94⇓⇓⇓ Of these confirmatory studies, the Pravastatin Inflammation CRP Evaluation (PRINCE) was by far the largest, enrolling 2884 patients into two parallel study arms: a secondary prevention cohort (N=1182), which received open-label pravastatin 40 mg daily, and a primary prevention cohort (N=1702), which was randomly allocated to either pravastatin 40 mg daily or to matching placebo.93 Forty percent of the PRINCE participants were women, and 28% took prophylactic aspirin, a regimen previously shown to attenuate the effect of CRP on vascular risk.48
Overall, random allocation to pravastatin in PRINCE reduced median CRP levels by 16.9% compared with placebo (P<0.001). This effect was seen as early as 12 weeks (median reduction in CRP with pravastatin 14.7%, P<0.001) and was present among all prespecified subgroups by gender, age, smoking status, body mass index, baseline lipid levels, or the presence of diabetes. This study showed no association between baseline CRP and baseline LDL cholesterol levels or between end-of-study CRP and end-of-study LDL cholesterol levels, such that <2% of the variance in CRP could be explained by lipid levels. As observed in prior hypothesis-generating studies, there was minimal evidence of association between change in LDL cholesterol and change in CRP, data again demonstrating the independent nature of these two effects.93
Although provocative, data describing CRP reduction with statins does not in itself establish a role for CRP testing as an adjunct to lipid screening, or as a tool to improve targeting of statin therapy. However, data from the recently released Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) CRP substudy addresses this issue directly.92 In brief, CRP levels were assessed at baseline among 5742 participants in AFCAPS/TexCAPS, a primary prevention study of lovastatin carried out among low- to moderate-risk individuals. This study showed an overall reduction in primary acute coronary events of 37%.95 In the inflammation analysis, participants were divided into four groups of equal size on the basis of lipid and CRP levels above or below study median (Table).92 As expected, random allocation to lovastatin therapy was highly effective in reducing primary acute coronary events among those with baseline levels of LDL cholesterol above 149 mg/dL, the median LDL value in the cohort as a whole. However, lovastatin therapy also reduced coronary event rates among those with lower levels of LDL cholesterol and above-median levels of CRP. In fact, the event rate in the placebo group (as well as the magnitude of risk reduction associated with lovastatin use) for those with above-median CRP levels and below-median lipid levels was just as high as that observed among those with overt hyperlipidemia. In marked contrast, lovastatin therapy did not benefit participants in the AFCAPS/TexCAPS trial who had below-average LDL levels and below-average CRP levels.92
The CRP data from AFCAPS/TexCAPS are important for several reasons. First, they confirm that elevated CRP levels strongly predict future vascular risk and that the addition of CRP to lipid screening helps to predict global risk. Second, the AFCAPS/TexCAPS CRP data raise the possibility that statin therapy may prove highly effective even among apparently healthy individuals who do not have hyperlipidemia, but who have a propensity toward coronary events as detected by elevated levels of CRP. Because half of all heart attacks and strokes in the United States occur among individuals with normal cholesterol levels, these data provide novel biological insights about some patients who may be at higher risk because of elevated CRP levels, although ≈50% of patients who develop an infarction not preceded by unstable angina appear to have normal levels of CRP on admission. As nearly 25 000 000 Americans fit within this low-LDL/high-CRP category yet remain outside current preventive guidelines, more specific understanding of the predictive role of elevated CRP in the presence of low LDL is needed.
Our understanding of atherosclerosis has evolved beyond the view that these lesions consist of a lifeless collection of lipid debris. Current evidence supports a central role for inflammation in all phases of the atherosclerotic process. Substantial biological data implicate inflammatory pathways in early atherogenesis, in the progression of lesions, and finally in the thrombotic complications of this disease. Clinical studies affirm correlation of circulating markers of inflammation with propensity to develop ischemic events and with prognosis after ACS. Intralesional or extralesional inflammation may hasten atheroma evolution and precipitate acute events. Circulating acute-phase reactants elicited by inflammation may not only mark increased risk for vascular events, but in some cases may contribute to their pathogenesis. This new insight into the role of inflammation in the pathobiology of atherosclerosis has initiated important new areas of direct clinical relevance. We can use inflammatory markers today for risk stratification. Future studies will gauge their utility as guides to monitor therapy. Finally, the quest to identify proximal stimuli for inflammation, as one pathogenic process in atherogenesis or trigger to lesion complication, may yield novel therapeutic targets in years to come.
This work was supported in part by grants from the National Heart, Lung, and Blood Institute to Drs Libby (HL-34636, HL-48743, and HL-56985) and Ridker (HL-58755 and HL-63293), and by the Leducq Foundation (to Drs Libby and Ridker). Dr Ridker is also supported by a Distinguished Scientist Award from the Doris Duke Foundation. Dr Maseri is supported by a grant from Fondazione Internazionale di Ricerca Per il Cuore onlus.
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- Inflammation and AtherosclerosisPeter Libby, Paul M. Ridker and Attilio MaseriCirculation. 2002;105:1135-1143, originally published March 5, 2002http://dx.doi.org/10.1161/hc0902.104353
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Harrigan, Jane (1988) 'Alternative Concepts of Conditionality.' Manchester Papers on Development, 6 (4). pp. 451-471.
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text: On Washington's glorious Olympic Peninsula, nestled next to Lake Quinault's serene waters, guests will find a true retreat. The hotel, listed on the National Register of Historic Places, is the perfect place to leave the cares of the world of work behind. Travellers are welcomed at the hotel, which has a total of 92 rooms. A 24-hour check-out service is available at the reception area. The establishment features various services and facilities, including a restaurant, a dining area, a bar, a playroom, a conference room and a business centre, for a comfortable and relaxing stay. Guests can buy souvenirs at the gift shop. Children can have a great time playing in the playground. Those arriving in their own vehicles can leave them in the car park of the accommodation. A bicycle hire service gives guests the opportunity to explore the surrounding area independently. Each of the rooms is appointed with air conditioning, central heating and a bathroom. A balcony or terrace is among the standard amenities of most rooms. The carpeted accommodation units feature a sofabed. Guests will also find a tea/coffee station included as standard. An ironing set is also available for travellers' convenience. Little extras, including a telephone, a TV, a radio, an alarm clock and WiFi (no extra charge), contribute to a great stay. A shower and a bathtub can be found in the bathrooms. A hairdryer is also available. A refreshing dip in the indoor or outdoor pool is an enjoyable way to cool down on hot days. The terrace is a great place to while away the time. A range of options are available, including biking/mountain biking, canoeing, kayaking and a sauna. Copyright GIATA 2004 - 2016. All major credit cards, including VISA, AMEXCO, Diners Club and MasterCard, are accepted for payment.


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RIO DE JANEIRO (AP) - Chicago Bulls point guard Derrick Rose is sitting out a preseason game against the Washington Wizards because of a sore left knee, the same one that kept him out all last season after surgery.
Rose has played two preseason games without any sign of problems. The first NBA game in South America now will be missing its biggest star.
The matchup at the HSBC Arena was expected to be a sellout, with the top ticket selling for about $915. The venue will be used for gymnastics during the 2016 Rio de Janeiro Olympics.
Copyright 2016The Associated PressAll Rights Reserved


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Natural Resources
Native Tribes Protest Energy Transfer Partners North Dakota Oil Pipeline
Richard Smallteacher
October 3rd, 2016
Representatives of some 280 indigenous nations have joined a protest on the Standing Rock Sioux reservation in North Dakota to oppose the construction of an oil pipeline by Energy Transfer Partners. If completed, the Dakota Access Pipeline is expected to help move 570,000 barrels of crude daily to Illinois.
Dakota Access Pipeline protest in Minnesota. Photo: Fibonacci Blue. Used under Creative Commons license
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Physical Description
Type Information
Catalog Number: USNM 194310
Collection: Smithsonian Institution, National Museum of Natural History, Department of Vertebrate Zoology, Division of Mammals
Sex/Stage: Male; Adult
Preparation: Skin; Skull
Collector(s): E. Heller
Year Collected: 1915
Locality: Piscocucho, Rio Urubamba, Cusco, Peru, South America
Elevation (m): 2652
- Type: Nelson, E. W. & Goldman, E. A. 1929 Nov 11. Journal of Mammalogy. 10: 347.
Northern South American cougar
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The northern South American cougar (Puma concolor concolor) is a subspecies of the cougar that lives in the northern part of South America, from Colombia and Venezuela to Peru and northern Brazil. It is the nominate subspecies of Puma concolor. It preys on birds, deer, sloths, mice, frogs, agoutis, and lizards, as a result of coexisting with larger jaguars.[1] They rarely prey on domesticated animals.[2]
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We are responsible for our dreams. This is the ultimate lesson of psychoanalysis - and fiction cinema. The makers of THE PERVERT'S GUIDE TO CINEMA return with THE PERVERT'S GUIDE TO IDEOLOGY. Philosopher Slavoj Žižek and filmmaker Sophie Fiennes use their interpretation of moving pictures to present a compelling cinematic journey into the heart of ideology - the dreams and beliefs that shape our common practices.
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text:
King Drive gets a burst of new food
Restaurants on N. King Drive have been sparse, or tended to be chains rather than independently owned restaurants - until lately.
Over the past months, I've encountered not one but three restaurants that offer something fresh for Milwaukee diners: wholesome, filling soups and sandwiches at one, spice-rich Somali dishes at another and updated Southern fare in a polished setting at a third. »Read Full Article
On Tap Today: Start the Year Right
Congratulations, you've made it to 2013...and hopefully you're not too hungover, because today's your first chance to start this year off right.
So if your resolution is to be a little more cultured this year, there's no better place to hit up than the Milwaukee Art Museum, which is open on this first day of 2013...although the Rembrandt exhibit is in its final days. »Read Full Blog Post(2)


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Dr. Angermeier is a Hand, Upper Extremity, and Microvascular Surgeon at the Medical University of South Carolina. He is accepting new patients in his Mount Pleasant, West Ashley, and downtown Charleston offices. He offers comprehensive care for problems from the elbow to the finger tips. He completed his Orthopaedic Surgery training at the Medical University of South Carolina and Hand, Upper Extremity, and Microvascular Surgery Fellowship at Duke University Medical Center. Common Problems Treated: Nerves: Carpal Tunnel Syndrome, Cubital Tunnel Syndrome, Nerve Injuries, Hand Numbness and Tingling Fractures: Finger Fractures, Hand Fractures, Wrist Fractures, Boxer's Fracture, Scaphoid Fracture, Distal Radius Fracture, Forearm Fractures, Malunions, Nonunions Tendon: Trigger Finger, Tennis Elbow, Golfer's Elbow, Epicondylitis, Tendinitis, Tenosynovitis, Tendon Injuries, Flexor and Extensor Tendon Lacerations, de Quervain's Tenosynovitis, Biceps Rupture, Biceps Tendinitis, Tendon Transfers Arthritis: Hand and Wrist Osteoarthritis, Rheumatoid Arthritis, Thumb Arthritis, CMC Arthritis, SLAC Wrist Cysts and Tumors: Hand and Forearm Tumors, Ganglion Cyst, Mucous Cyst, Osteochondroma, Giant Cell Tumor, Dupuytren's Contracture Ligaments: Hand, Wrist and Elbow Ligament Injuries, Ulnar Collateral Ligament Injuries, Gamekeeper's Thumb, Skier's Thumb, Scapholunate Ligament Injuries, TFCC Tears, DRUJ instability, Sports Injuries Surgical Techniques Offered: Microsurgery, Wrist Arthroscopy, Minimally Invasive, Xiaflex Injections, PRP Injections (Platelet Rich Plasma), Vascularized Bone Grafting.


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A Liverpool man says his brother's son, a US citizen who's a medical student in Syria, has been imprisoned, as anti-government violence continues.
Sam Char tells us that his nephew, Abdel Kader Char, was born here but the family moved to Syria several years ago. The whole family, including his brother, a graduate of Albany College of Pharmacy, holds US citizenship, so Sam Char has asked US Senator Chuck Schumer to help find him. Schumer's office tells us they've contacted the State Department's Office of American Services, which is trying to track the 22 year old.
Abdel Kader is a medical student, and was due in this country next month, to do a six week's rotation at the Cleveland Clinic.


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realmagick.com The shrine of knowledge.
A selection of articles related to clearing.
Original articles from our library related to the Clearing. See Table of Contents for further available material (downloadable resources) on Clearing.
- A Treatise on Astral Projection, Part 2: Training
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Parapsychology >> Astral Projection
- Affirmations and Rethinking
- On your journey in Meditation it is important to understand first that it will not be easy if you are truly trying to do it and do it right As we mentioned, the ego-conscious is not gonna go down without a fight. This is the reason for this page. Along the...
Mind >> Meditation
- A Treatise on Astral Projection, Part 3: The Rope Techniques
- A key ingredient to the new projection techniques is an invisible, imaginary ROPE hanging from your ceiling. This ROPE will be used to exert dynamic pressure at a single point on your astral body to force its separation from the physical. The ROPE technique...
Parapsychology >> Astral Projection
- Obsidian
- Projective. Element: Fire. Solid/translucent black to smoky. (Incl. "Navaho/Apache Tears") Objectivity, dis-attachment, grounding. Protection, grounding, divination, peace. Reduces fantasy/escapism. Absorbs and dissolves anger, criticism, fear, etc....
Earth Mysteries >> Stones, Minerals & Metals
- Select Cross-Cultural and Historical Personifications of Death
- This extensive introduction includes some of the more well known, along with some lesser known Death "incarnations", and I use that term loosely, as in many cultures, the Angel of Death can be quite an adept shapeshifter. We have tried to cull...
Mystic Sciences >> Necromantic Studies
- Of Master and Discipline
- Part 1 | Part 2 | Part 3 | Part 4 | Part 5 | Commentary Part 1 The following is a fictional account of a spiritual awakening with a factual basis. This five part series is offered to promote and encourage the practices of the World Mind Society, making the...
Mind >> World Mind
- Survivalists' Guide for the New Millennium: Chapter 5
- WHERE I LAY MY HEAD IS HOME A foot and light-hearted I take to the open road, Healthy, free, and the world before me, The long brown path before me leading Wherever I choose. Henceforth I ask not for good fortune, I myself am good fortune, Henceforth I...
Philosophy >> Survivalists Guide for the New Millennium
Clearing is described in multiple online sources, as addition to our editors' articles, see section below for printable documents, Clearing books and related discussion.
Suggested News Resources
- BoE Concerned Over Access to Clearing
- The Bank of England is concerned that some small UK firms find it difficult to obtain cost-effective access to central clearing and may decide to cease hedging interest rate risk.
- Expect loud explosions, road closures near Dulles for rock-clearing work
- A view of rock clearing work on Route 606 and Old Ox Road near Mercure Circle, which may need to close for two to three minutes at a time for rock blasts occurring close to the road. (Courtesy Dulles Corridor Metrorail...
- Publisher's Clearing House Scam Alert
- BEDFORD COUNTY (WSLS10) – The Bedford County Sheriff's Office is warning area residents about a Publisher's Clearing House scam. Deputies say scammers are mailing false congratulatory letters, along with a check. The thieves ask recipients to send ...
- Rare air: Greenville's Morris clearing new heights
- Morris missed her first two attempts at 15-7 before finally clearing the bar on her third try. After missing her first vault at 15-11, she employed a different, albeit risky strategy – passing twice and moving on to the next height of 16-¾.
Great care has been taken to prepare the information on this page. Elements of the content come from factual and lexical knowledge databases, realmagick.com library and third-party sources. We appreciate your suggestions and comments on further improvements of the site.
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text:
|By Marketwired .
Article Rating:
|July 9, 2014 10:55 AM EDT
CANTON, MI -- (Marketwired) -- 07/09/14 -- SW North America, Inc., a leading manufacturer of precision metalworking production machines, today announced it has opened its new North American sales and technical center to better serve and support its customers. The new Canton Technical Center is located at 40615 Koppernick Road, Canton, Mich. 48187-4280.
Located in the Detroit metropolitan area, the new office allows SW North America, Inc. to expand its foothold in the growing automotive market while increasing its customer base in the industrial, aerospace and defense, alternative energy, transportation, consumer products, and medical sectors.
The office is being led by Mark Reichenbacher, president & CEO, a 20-year industry veteran with management positions at various manufacturing companies. Prior to joining SW North America, Inc., he held various senior management positions at Grede Holdings LLC, ThyssenKrupp Waupaca, and Metaldyne.
"We will provide our U.S. and Canadian customers with the same level of service and support that our European customers have enjoyed from our home office," said Reichenbacher. "The Canton Technical Center provides a total solutions approach to the North American market. That includes turnkey sales, service, spare parts and project engineering."
SW North America, Inc. Opens Canton Technical Center
In conjunction with the new office, the company hired James Campbell as vice president of sales. Campbell has more than 30 years of sales and management experience, including senior leadership positions at The Cross Company, Giddings & Lewis, Future Tool & Machine Company, and Tri-Way Manufacturing Technologies Corp.
"We plan to aggressively build up our sales and marketing presence in North America," said Campbell. "In fact, we have already established contracts with both American, Canadian, and other multinational companies."
About SW North America, Inc.
SW North America, Inc. is a wholly owned subsidiary of Schwäbische Werkzeugmaschinen GmbH, Schramberg-Waldmössingen, Germany. SW is a designer and manufacturer of high-precision multi-spindle horizontal machining centers and manufacturing solutions for the metalworking industry. The company specializes in providing solutions for machining high volume, prismatic components utilizing their 4 & 5 axis multi-spindle technologies. SW serves customers in the industrial, aerospace and defense, alternative energy, transportation, consumer products, and medical sectors. In addition to the main facility in Germany, the company operates two technical centers that include sales, engineering, service and spare parts. One location is in Canton, Michigan that serves the North American market; the other is the soon-to-open facility in Suzhou, China that will support the Asian market. Additionally, SW has sales offices in fifteen other countries worldwide. More than 2,250 SW machines and manufacturing solutions are running successfully in multi-shift operations in 40 countries around the world. For further information, see http://www.sw-machines.com/en/sw-worldwide/.
Image Available: http://www2.marketwire.com/mw/frame_mw?attachid=2634988
Mike Wilson
Wilson Communications
Phone: (248) 789-8972
Traditional on-premises data centers have long been the domain of modern data platforms like Apache Hadoop, meaning companies who build their business on public cloud were challenged to run Big Data processing and analytics at scale. But recent advancements in Hadoop performance, security, and most importantly cloud-native integrations, are giving organizations the ability to truly gain value from all their data. In his session at 19th Cloud Expo, David Tishgart, Director of Product Marketing ...
Oct. 25, 2016 12:00 PM EDT Reads: 2,655
The Internet of Things will challenge the status quo of how IT and development organizations operate. Or will it? Certainly the fog layer of IoT requires special insights about data ontology, security and transactional integrity. But the developmental challenges are the same: People, Process and Platform and how we integrate our thinking to solve complicated problems. In his session at 19th Cloud Expo, Craig Sproule, CEO of Metavine, will demonstrate how to move beyond today's coding paradigm ...
Oct. 25, 2016 11:45 AM EDT Reads: 3,784
Although it has gained significant traction in the consumer space, IoT is still in the early stages of adoption in enterprises environments. However, many companies are working on initiatives like Industry 4.0 that includes IoT as one of the key disruptive technologies expected to reshape businesses of tomorrow. The key challenges will be availability, robustness and reliability of networks that connect devices in a business environment. Software Defined Wide Area Network (SD-WAN) is expected to...
Oct. 25, 2016 11:45 AM EDT Reads: 2,044
SYS-CON Events announced today that StarNet Communications will exhibit at the 19th International Cloud Expo, which will take place on November 1–3, 2016, at the Santa Clara Convention Center in Santa Clara, CA. StarNet Communications' FastX is the industry first cloud-based remote X Windows emulator. Using standard Web browsers (FireFox, Chrome, Safari, etc.) users from around the world gain highly secure access to applications and data hosted on Linux-based servers in a central data center. ...
Oct. 25, 2016 11:45 AM EDT Reads: 2,151
OnProcess Technology has announced it will be a featured speaker at @ThingsExpo, taking place November 1 - 3, 2016, in Santa Clara, California. Dan Gettens, OnProcess' Chief Analytics Officer, will discuss how Internet of Things (IoT) data can be leveraged to predict product failures, improve uptime and slash costly inventory stock. @ThingsExpo is an annual gathering of IoT and cloud developers, practitioners and thought-leaders who exchange ideas and insights on topics ranging from Big Data in...
Oct. 25, 2016 11:42 AM EDT
Developing software for the Internet of Things (IoT) comes with its own set of challenges. Security, privacy, and unified standards are a few key issues. In addition, each IoT product is comprised of (at least) three separate application components: the software embedded in the device, the back-end service, and the mobile application for the end user's controls. Each component is developed by a different team, using different technologies and practices, and deployed to a different stack/target –...
Oct. 25, 2016 11:30 AM EDT Reads: 2,007
Virgil consists of an open-source encryption library, which implements Cryptographic Message Syntax (CMS) and Elliptic Curve Integrated Encryption Scheme (ECIES) (including RSA schema), a Key Management API, and a cloud-based Key Management Service (Virgil Keys). The Virgil Keys Service consists of a public key service and a private key escrow service.
Oct. 25, 2016 11:30 AM EDT Reads: 1,108
SYS-CON Events announced today that CDS Global Cloud, an Infrastructure as a Service provider, will exhibit at the 19th International Cloud Expo, which will take place on November 1–3, 2016, at the Santa Clara Convention Center in Santa Clara, CA. CDS Global Cloud is an IaaS (Infrastructure as a Service) provider specializing in solutions for e-commerce, internet gaming, online education and other internet applications. With a growing number of data centers and network points around the world, ...
Oct. 25, 2016 11:30 AM EDT Reads: 3,594
Big Data has been changing the world. IoT fuels the further transformation recently. How are Big Data and IoT related? In his session at @BigDataExpo, Tony Shan, a renowned visionary and thought leader, will explore the interplay of Big Data and IoT. He will anatomize Big Data and IoT separately in terms of what, which, why, where, when, who, how and how much. He will then analyze the relationship between IoT and Big Data, specifically the drilldown of how the 4Vs of Big Data (Volume, Variety,...
Oct. 25, 2016 11:15 AM EDT Reads: 1,516
SYS-CON Events announced today that Tintri Inc., a leading producer of VM-aware storage (VAS) for virtualization and cloud environments, will present at the 19th International Cloud Expo, which will take place on November 1–3, 2016, at the Santa Clara Convention Center in Santa Clara, CA. Tintri VM-aware storage is the simplest for virtualized applications and cloud. Organizations including GE, Toyota, United Healthcare, NASA and 6 of the Fortune 15 have said "No to LUNs." With Tintri they manag...
Oct. 25, 2016 11:15 AM EDT Reads: 3,641
Data is the fuel that drives the machine learning algorithmic engines and ultimately provides the business value. In his session at Cloud Expo, Ed Featherston, a director and senior enterprise architect at Collaborative Consulting, will discuss the key considerations around quality, volume, timeliness, and pedigree that must be dealt with in order to properly fuel that engine.
Oct. 25, 2016 11:15 AM EDT Reads: 3,915
From wearable activity trackers to fantasy e-sports, data and technology are transforming the way athletes train for the game and fans engage with their teams. In his session at @ThingsExpo, will present key data findings from leading sports organizations San Francisco 49ers, Orlando Magic NBA team. By utilizing data analytics these sports orgs have recognized new revenue streams, doubled its fan base and streamlined costs at its stadiums. John Paul is the CEO and Founder of VenueNext. Prior ...
Oct. 25, 2016 11:00 AM EDT Reads: 3,674
SYS-CON Events announced today that eCube Systems, the leading provider of modern development tools and best practices for Continuous Integration on OpenVMS, will exhibit at SYS-CON's @DevOpsSummit at Cloud Expo New York, which will take place on June 7-9, 2016, at the Javits Center in New York City, NY. eCube Systems offers a family of middleware products and development tools that maximize return on technology investment by leveraging existing technical equity to meet evolving business needs. ...
Oct. 25, 2016 11:00 AM EDT Reads: 4,533
P2P RTC will impact the landscape of communications, shifting from traditional telephony style communications models to OTT (Over-The-Top) cloud assisted & PaaS (Platform as a Service) communication services. The P2P shift will impact many areas of our lives, from mobile communication, human interactive web services, RTC and telephony infrastructure, user federation, security and privacy implications, business costs, and scalability. In his session at @ThingsExpo, Robin Raymond, Chief Architect...
Oct. 25, 2016 10:45 AM EDT Reads: 3,679
Ask someone to architect an Internet of Things (IoT) solution and you are guaranteed to see a reference to the cloud. This would lead you to believe that IoT requires the cloud to exist. However, there are many IoT use cases where the cloud is not feasible or desirable. In his session at @ThingsExpo, Dave McCarthy, Director of Products at Bsquare Corporation, will discuss the strategies that exist to extend intelligence directly to IoT devices and sensors, freeing them from the constraints of ...
Oct. 25, 2016 10:45 AM EDT Reads: 3,063


text:
Fernando Alonso believes Mercedes to be the surprise of the Formula One season - and now the benchmark for Ferrari to aspire to.
Come the start of the campaign, rumours implied Mercedes had adapted more to the new regulations compared to fellow power-train suppliers Ferrari and Renault.
But it is fair to assume no-one expected Mercedes to blow away their rivals as they have done this season and usurp Red Bull as the force to beat.
From the 11 grands prix over the first period of the season, Mercedes team-mates Nico Rosberg and Lewis Hamilton have claimed 10 poles and won nine races between them.
F1 Hungarian Grand Prix - In pictures
F1 Hungarian Grand Prix - In pictures
1/15 Race
Daniel Ricciardo celebrates after the race
2/15 Race
Red Bull Racing's Australian driver Daniel Ricciardo (C) celebrates with Scuderia Ferrari's Spanish driver Fernando Alonso (L) and Mercedes' British driver Lewis Hamilton
3/15 Race
Daniel Ricciardo on his way to victory in the Hungarian Grand Prix
4/15 Race
Daniel Ricciardo on his way to victory in Hungary
5/15 Race
Lewis Hamilton pictured ahead of Nico Rosberg
6/15 Race
Lewis Hamilton spins at the second corner of the opening lap
The Mercedes mechanics wheel Lewis Hamilton's burnt out Mercedes back to the pits
Getty Images
8/15 Qualifying
Kevin Magnussen hit the tyre barrier in a heavy accident at turn one during the third qualifying session after it started raining
9/15 Qualifying
Lewis Hamilton walks back to the pit lane with his Mercedes burning in the background
Getty Images
10/15 Qualifying
Lewis Hamilton's Mercedes catches fire
11/15 Practice 3
Marcus Ericcson spins out during practice as Sauber's Esteban Gutierrez flashes past
Getty Images
12/15 Practice 2
Lewis Hamilton finished the day top of the time-sheets for both practice sessions
Getty Images
13/15 Practice 2
Nico Rosberg shows of his footballing skills in the paddock in-between Friday's practice sessions
Getty Images
14/15 Practice 1
Daniel Ricciardo watches on from the cockpit of his Red Bull
Getty Images
15/15 Practice 1
Lewis Hamilton of Great Britain and Mercedes GP drives during practice ahead of the Hungarian Formula One Grand Prix at Hungaroring
With eight grands prix to run once F1 returns from its summer break later this month, it is simply a question of when and not if Mercedes will win the constructors' championship and one of their drivers the main prize.
"Mercedes have surprised everybody," said double world champion Alonso.
"Now we are getting used to seeing them dominate every weekend, but I remember when we were in Jerez and Bahrain testing these new cars with very complex technology.
"We were all struggling, but straight away they were okay, and now from 11 races they've won nine and nearly always been on the front row.
"I would say they have been the biggest surprise - a good surprise - this year."
By contrast, Alonso has again driven beyond the capabilities of his car, hauling himself on to the podium twice in the 11 events.
Consequently, both he and Ferrari have nothing much to play for other than being the best of the rest, albeit with the determination to one day soon be battling Mercedes for honours.
"Mercedes are motivation for us," added Alonso.
"We know we can do a much better job as we haven't done a good one so far.
"We are making some progress, but the benchmark has changed - last year it was Red Bull, this year it's Mercedes.
"We simply have to get on top of our problems and try to arrive at their level."
PAReuse content


text: This shirt is made by the Brooklyn Circus in the USA, but I'm telling you to buy it from a store in London. Why? BECAUSE THAT'S JUST HOW THE INTERNET WORKS. I really like ticking stripes because, um, I just do. Why do I have to justify everything to you guys? It's, like, super exhausting if I'm being totally honest. Sometimes you just like something and you can't really explain why. If you've ever tried to justify a purchase to your friends and struggled to find a meaning or reason in your decisions, you now know what it's like for your significant other when they try to explain what they see in you.


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Makeup that compliments your skin care regimen.
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text:
And although all these recipe are more carb-conscious than traditional Thanksgiving fare, they're not all low-carb or gluten-free recipes, so if that's what you're looking for I've also done a round-up of my favorite 25+ Low-Carb and Gluten-Free Holiday Side Dishes, Appetizers, and Salads. Hope that's helpful!
Of course every year I have fun experimenting with new Thanksgiving recipes, so if you're someone who doesn't like to make the same thing every year, keep your eyes out for those coming during November. Now, let's talk about my healthy Thanksgiving favorites.
Low-Sugar (or Sugar-Free) Layered Pumpkin Cheesecake is something I've been making for Thanksgiving since 2006, and last year I finally took a better photo to show how good this is!
I can't skip this very old recipe for Broccoli Gratin with Swiss and Parmesan without protests from some of my family members, who think this is a must-have vegetable dish for Thanksgiving.
Roasted Brussels Sprouts with Balsamic, Parmesan, and Pine Nuts is the first brussels sprouts recipe I made for the blog and I still love this recipe!
Sweet Potato Appetizer Bites with Feta and Green Onion.
Ten Honorable Mention Thanksgiving Favorites:
Roasted Sweet Potatoes and Red Onions with Feta
Roasted Brussels Sprouts with Avocado and Pecans
Low-Sugar Fresh Cranberry Salsa with Cilantro, Lime, and Jalapeno
Thanksgiving Spinach Salad with Dried Cranberries, Almonds, and Goat Cheese
Roasted Butternut Squash with Rosemary, Pecans, and Gorgonzola Cheese
Twice-Baked Sweet Potatoes with Feta and Sumac
Green Apple, Celery, and Walnut Salad with Lemon-Mustard Vinaigrette
Arugula, Red Grape, and Shaved Manchego Salad
Roasted Brussels Sprouts with Pecans, with or without Gorgonzola Cheese
Apple-Jicama Slaw with Sweet and Spicy Sriracha Dressing
What Are Your Thanksgiving Favorites?


text:
Sweaty Betty
run looks | Sweaty Betty
Sweaty Betty Qualify Swimsuit
Sweaty Betty Offshore Training Bikini Top
Bonded jersey hooded jacket with neoprene feel. Statement styling includes a cropped front, dropback hem and reflective raglan seams. As functional as it is fashionable, it also features a chin guard, storm cuffs and external side zip pockets for rainy days.
Sweaty Betty Stability 3/4 Leggings
Sweaty Betty Barre Kit More
http://flybery.com/brands/sweaty-betty-81 Makarasana Barre Unitard…
Sweaty Betty yoga clothes. id totally wear this!
12 Health Goth Sports Bras by blackbettyblog on Polyvore featuring Wet Seal, Beth Richards, adidas, Lorna Jane, Leone 1947, Seafolly, Sweaty Betty, NIKE, Bodyism and Rebecca Minkoff
Propel Rash Guard - Black | Bikinis & Tankinis | Sweaty Betty


text:
Jun 28, 2013
A successful Asian foray for Coca-Cola Femsa provides a springboard for further expansion
To Mexico's Coca-Cola Femsa (KOF), the
opportunity was clear. Says its CFO Héctor
Treviño, when it comes to consuming soft drinks, no
other market in south east Asia looks as much like a Latin
American nation as the Philippines. "In other [Asian] countries
you see a much higher percentage of hot beverages and tea," he
Such dynamics were behind the company's...
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November 7, 2016 | Buenos Aires, Argentina
On the occasion of the 50th Annual Assembly, over 250 executives ... more
November 17, 2016 | Montego Bay, Jamaica
Caribbean economies are building momentum as efforts towards strengthening regional financial ... more
Which area will be most profitable for investment banks in LatAm in 2016?
All material is subject to strictly enforced copyright terms & conditions and cannot be repurposed or reproduced. © 2016 Latin American Financial Publications Inc.


text:
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Name: inovative toys and games.zip
Release: 2015
Type: WinZip
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Language: English
Last updated on: 01/28/2015 12:42:18
Supported OS: Windows 8, Windows 7, Windows Vista, Windows XP
Keys:01/28/2015 12:42:18
Hard-to-find training, meeting, and presentation supplies including training games, buzzers, fidget toys, certificate frames, ice breakers, flip chart stuff, easels ...Madix understands the needs of toy and game stores. A leading innovator in the store fixture industry, Madix has a history of successfully helping retailers solve ...Building Toys [Back to Top] K'NEX (Hatfield, PA): plastic construction toys made in U.S. (though motor components and other special parts made in China)Educational toys can be great tools for learning! Find information and reviews about the best educational toys and games for learning and development.Contain the chaos of your child's toys. Our expert-approved quick tips and smart solutions will finally get your playroom in order.Large selection of Toys and Therapy Products for special needs children with sensory or aspergers. Vests, Fidgets, swings, interactive learning and mobility tools ...Welcome to Mulberry Bush online toy shop. Buy quality traditional toys, games, wooden toys and gifts for children of all ages. Free delivery on orders over £75Suppliers of a range of educational toys, games, wooden puzzles, cardboard puzzles, knob puzzles, posters, flash cards, mind teasers .... South AfricaBabyFirstTV is The Place Where Babies & Toddlers can Learn & Play Online with Videos, Toys and Games ! Watch Baby First TV Online & Play BabyFirst TV Games.Light up early writing skills! Scribble & Write provides stroke-by-stroke guidance and has a NEW mode that provides instant accuracy feedback. Children trace the ...
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