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Circulating levels of interleukin-17 and cardiovascular outcomes in patients with acute myocardial infarction
Aim Interleukin (IL)-17 pathway is being clinically targeted in immune-mediated diseases, most of which are associated with a significant cardiovascular risk. We investigated the relationship between serum levels of IL-17 and the risk of cardiovascular events in patients with acute myocardial infarction.
Methods and results We used data from 981 patients enrolled in the prospective, multicentre French registry of Acute ST elevation, or non-ST-elevation Myocardial Infarction (Fast-MI, NCT00673036). Serum levels of IL-17 were associated with the risk of all-cause death and recurrent MI at 2 years, with levels of IL-17 below the median indicative of a worse outcome. The impact of IL-17 remained significant after adjustment for known cardiovascular risk factors, C-reactive protein, and treatments including statins: hazard ratio (HR) = 1.40 (1.03–1.91); P = 0.03. IL-17 inhibited mononuclear cell adhesion to endothelium and reduced endothelial vascular cell adhesion molecule (VCAM-1) expression. Patients with low (below the median) IL-17 levels and high (above the median) soluble VCAM-1 (sVCAM-1) levels were at particularly increased risk of death and MI: adjusted HR = 2.22 (1.32–3.75) compared with the high IL-17/low sVCAM-1 group (P = 0.002).
Conclusions Low serum levels of IL-17 are associated with a higher risk of major cardiovascular events in Caucasian patients with acute MI. Our results raise possible concern about the use of inhibitors of the IL-17 pathway in clinical settings associated with a high cardiovascular risk.
Clinical trials registration: NCT00673036.
- Myocardial infarction
- Inflammation
- IL17 pathway
- Immune-mediated diseases
- Pharmacovigilance
- Prognosis
See page 556 for the editorial comment on this article (doi:10.1093/eurheartj/ehs399)
Atherosclerosis is a complex disease of the arterial wall initiated in response to a variety of pro-atherogenic stimuli, among which modified lipids play an important role.1,2 The latter induce innate and adaptive immune responses with both deleterious and protective components. A breakdown in this balance leads to uncontrolled disease progression and precipitates severe complications.3,4 The current understanding is that the deleterious component of the adaptive immune response is driven by T helper type 1 (Th1)-related mediators, mainly interferon (IFN)-γ, which play central roles in promoting vascular inflammation, artery wall remodelling, and plaque progression.3,4
The protective component is still poorly understood. However, several studies have shown that three cytokines, interleukin (IL)-5, IL-10, and transforming growth factor (TGF)-β, play critical counter-regulatory roles in atherosclerosis.3,5–11
Recently, a new lineage of CD4+ T cells, called Th17, has been identified and characterized.12 The Th17 subset is driven by specific transcription factors and produces IL-17A (hereafter referred to as IL-17), IL-17F, IL-21, IL-6, and IL-22.12 The discovery of Th17 lineage has revived a great interest in the potential roles of IL-17 in health and disease.13 Several studies have shown a non-redundant role for IL-17 in the clearance of specific pathogens that are not adequately controlled by Th1 or Th2 immunity, particularly extracellular bacteria and fungi.12 Beyond this role in host defence, several researchers have implicated Th17 cells and cytokines in the pathophysiology of immune-mediated diseases, such as rheumatoid arthritis, psoriasis, colitis, or asthma,12,13 even though definite proof of a pathogenic role is still lacking in humans.
On the basis of these data, several investigators hypothesized a deleterious role for IL-17 in atherosclerosis. Their results showed that IL-17 was expressed in human coronary and symptomatic carotid atherosclerotic lesions14–17 and reported enhanced production of pro-inflammatory mediators by vascular smooth muscle cells in response to IL-17, with or without help from IFN-γ.15,18 Other experimental data showed elevated expression of IL-17 at the early stages of lesion development compared with non-atherosclerotic animals,19 and reported reduction in the atherosclerosis burden20,21–23 or inflammation24 or reduction of ischaemia/reperfusion injury25 after inhibition of IL-17 signalling.
However, another set of data suggests a regulatory role for IL-17 in atherosclerosis. We have recently shown that mice with T cells deficient for suppressor of cytokine signalling (SOCS)3 displayed elevated levels of IL-17, associated with the reduced atherosclerotic lesion size.26 The systemic blockade of IL-17 signalling abrogated atheroprotection and promoted vascular inflammation.26 The results were related to the role of IL-17 in the regulation of endothelial vascular cell adhesion molecule (VCAM)-1 and to the control of both Th1 and Th2 responses. In addition, we found that an elevated expression of IL-17 in human carotid lesions was associated with signs of plaque stability.26 Another group recently reported accelerated progression of atherosclerosis in IL17A-deficient mice, which was prevented after supplementation with recombinant IL-17A.27
Overall, the relevance of IL-17 to human atherosclerosis remains poorly defined, and more importantly, its relevance to cardiovascular outcomes remains unexplored. This is an important issue given the current clinical testing of inhibitors of IL-17 signalling in immune-mediated diseases associated with a high cardiovascular risk. Therefore, the aim of the present study was to evaluate the relationship between circulating IL-17 levels and cardiovascular events, a composite of all-cause death and non-fatal myocardial infarction (MI), in patients who suffered from acute MI. In addition, since IL-17 has been shown to regulate VCAM-1 expression in mice,26 we examined the role of IL-17 in mononuclear cell adhesion to endothelial cells and explored the relationship between IL-17, VCAM-1 measured at acute stage and cardiovascular events at 2 years.
Study population
The population and methods of the French registry of Acute ST-elevation and non-ST-elevation Myocardial Infarction (FAST-MI) have been described in detail in previous publications.28,29 Briefly, all patients ≥18 years of age were included in the registry if they had elevated serum markers of myocardial necrosis higher than twice the upper limit of normal for creatine kinase, creatine kinase-MB, or elevated troponins, and either symptoms compatible with acute MI and/or electrocardiographic changes on at least two contiguous leads with pathologic Q waves (≥0.04 s) and/or persisting ST-elevation or depression >0.1 mV. The time from symptom onset to intensive care unit admission had to be <48 h. Patients were managed according to usual practice; treatment was not affected by participation in the registry. Of the 374 centres in France that treated patients with acute MI at that time, 223 (60%) participated in the registry. Among these, 100 centres recruited 1029 patients who contributed to a serum bank. Their baseline characteristics were comparable with the overall population of the registry. Written informed consent was provided by each patient. More than 99% of patients were Caucasians. The follow-up was collected through contacts with the patients' physicians, the patients themselves, or their family, and registry offices of their birthplace. The two-year follow-up was >98% complete. The outcome events were assessed blinded to the results of IL17, IL6, and sVCAM1 measurements. The study was reviewed by the Committee for the Protection of Human Subjects in Biomedical Research of Saint Antoine University Hospital and the data file was declared to the Commission Nationale Informatique et Liberté.
Blood sampling and measurements
Blood samples used for this study were recovered at the time of admission to the intensive care unit (<48 h from symptom onset). Blood samples were stored at –80°C at the Department of Clinical Pharmacology, University of Pierre et Marie Curie. All samples were identified by number only and were analysed in random order. Serum concentrations of IL-17 were measured using the flow cytomix assay (Bender Med Systems) with a detection limit at 2.5 pg/mL. Soluble VCAM-1 was measured using an ELISA assay (Bender Med Systems). The measurement of C-reactive protein and IL6 levels was also centralized. The limit of detection for sVCAM-1 was 0.6 ng/mL. Among the 1029 patients who contributed to a serum bank, results for IL-17, sVCAM-1, and IL6 levels were obtained for 981, 966, and 962 patients, respectively (missing measures or haemolysis). All measurements were performed in a blinded fashion.
Cell adhesion assay
Human peripheral blood mononuclear cells (PBMCs) were isolated on a PANCOLL gradient (Biotech GmbH). After a washout with PBS, cells were stained with the use of a fluorescent probe (0.5 μM; CellTracker Orange CMTMR; Molecular Probes). Briefly, the cells were incubated with the fluorescent probe during 30 min in RPMI and resuspended in culture medium after a 30 min washout for an adhesion assay. Human umbilical cord endothelial cells (HUVECs) (Pomocell) were plated in 48-well plates and stimulated for 24 h with 10 ng/mL tumour necrosis factor (TNF)-α (R&D Systems) in the absence or in the presence of recombinant IL-17 (R&D Systems) at 10 ng/mL or 100 ng/mL prior to a cell adhesion assay. After washout, fluorescent PBMC cells were made to adhere to HUVECs for 1 h. After two more washouts, adherent cells were fixed in 4% paraformaldehyde and counted in five different fields per condition under fluorescence microscope (Zeiss microscope).
ELISA assay
Human umbilical cord endothelial cells were stimulated with 100 ng/mL of TNF-α in the presence or not of either 10 or 100 ng/mL of recombinant IL-17 during 48 h. Then supernatants were collected for the ELISA assay of sVCAM-1 (Bender Med Systems) and IL-6 (BD Biosciences). The limit of detection for VCAM-1 was 0.6 ng/mL, and the lowest concentration of the standard sample for IL-6 was 4.7 pg/mL. The coefficients of variation of IL-17 and sVCAM-1 were 3.4 and 3.1% for the mean intra-assay and 4.9 and 5.2% for the mean inter-assay, respectively.
Statistical analysis
An outcome event was defined as all-cause death or non-fatal MI during the 2-year follow-up period. The primary endpoint, a composite of all-cause death and non-fatal MI defined as the episode index at inclusion, and was adjudicated by a committee whose members were unaware of patients' medications, and blood measurements. Continuous variables are described as mean ± SD and categorical variables as frequencies and percentages. Serum levels of IL-17, C-reactive protein, IL6, and sVCAM were log-transformed to remove positive skewness, before being used as continuous variables. Baseline demographic and clinical characteristics, treatment factors, and therapeutic management during hospitalization were compared as pre-specified among the median range of IL-17 levels using χ2 or Fisher' s exact tests for discrete variables, and by unpaired t-tests, Wilcoxon sign-rank tests for continuous variables. Median level IL-17 and sVCAM1 were based on the distribution of their baseline levels among the entire population. Survival curves according to the median IL17 level and sVCAM1 are estimated using the Kaplan–Meier estimator. We used a multivariable Cox proportional hazards model to assess the independent prognostic value of variables with the primary endpoint during the 2-year follow-up period. The multivariable model comprised sex, age, previous or current smoking, body mass index, family history of coronary disease, history of hypertension, acute MI, heart failure, renal failure, diabetes, heart rate at admission, Killip class, left ventricular ejection fraction, hospital management (including reperfusion therapy, statins, beta-blockers, clopidogrel, diuretics, digitalis, heparin), and log C-reactive protein levels. The statistical interaction between IL-17 and sVCAM-1 was tested by adding an interaction term with both variables in the Cox model. The results are expressed as hazard ratios for Cox models with 95% confidence intervals (CIs). All statistical tests were two-sided and performed using the SAS software version 9.1. For analysis of the cell adhesion and in vitro cytokines assays, we performed multiple comparisons using ANOVA and the Bonferroni/Dunn test.
Baseline demographics and clinical presentation
Of the 981 patients enrolled, 176 patients (18%) died or had an MI during the 2-year follow-up period. Patients who died or had an MI during the follow-up were older (75 ± 12 vs. 64 ± 13 years) with a higher proportion of females (43 vs. 27%), than those without an outcome event (see Supplementary material online, Table S1). They also had a higher rate of hypertension (80 vs. 58%), diabetes (51 vs. 28%), prior heart failure (15 vs. 3%), prior MI (30 vs. 15%), prior stroke or transient ischaemic event (14 vs. 6%), and chronic renal failure (14 vs. 3%) (all P < 0.001). They were less likely to be on statin therapy (68 vs. 81%), beta-blockers (51 vs. 76%), clopidogrel, heparin, but more likely to be on diuretics, or digoxin (all P < 0.004) compared with patients without an outcome event during the follow-up (Supplementary material online, Table S1). Patients who had an event were at higher risk of hospital death according to the GRACE (Global Registry of Acute Coronary Events) risk score (185 ± 34 vs. 158 ± 36) and fewer patients had undergone coronary angioplasty PCI (44 vs. 72%) or thrombolysis (10 vs. 18%) during hospitalization (all P < 0.009). The median of IL17 and sVCAM1 for the entire sample was 6.26 pg/mL (0–22.8) and 695.47 ng/mL (528–977), respectively. Patients who had an event had a significantly lower median of IL17 and higher sVCAM1 and IL6 at baseline (Supplementary material online, Table S1). However as shown in Table 1, the baseline characteristics of patients according to the median of IL-17 levels did not differ with the exception of a higher rate of previous or current smokers in those with baseline IL-17 levels <6.26 pg/mL (58 vs. 51% in patients with baseline IL-17 ≥6.26 pg/mL, P = 0.03). No significant correlation was observed between IL-17 and C-reactive protein (Pearson coefficient = −2%, P = 0.47). A weak positive correlation of IL-17 was observed with VCAM-1, Pearson coefficient = 0.13, P < 0.001).
|IL17A (pg/mL)
|<6.26 (n = 490)
|≥6.26 (n = 491)
|Demographic and risk factors
|Male sex (%)
|341 (70)
|343 (70)
|Age, year
|66 ± 14
|66 ± 14
|Hypertension (%)
|300 (61)
|306 (62)
|Hypercholesterolaemia (%)
|247 (50)
|268 (55)
|Diabetes mellitus (%)
|165 (34)
|149 (30)
|Family history of CAD (%)
|109 (22)
|127 (27)
|Previous or current smokers (%)
|285 (58)
|252 (51)
|Prior myocardial infarction (%)
|77 (16)
|92 (19)
|Prior PCI or CABG (%)
|85 (17)
|85 (17)
|Prior stroke or TIA (%)
|43 (9)
|32 (7)
|Prior heart failure (%)
|25 (5)
|23 (5)
|Chronic renal failure (%)
|26 (5)
|22 (4)
|Clinical presentation
|Body mass index (kg/m2)
|27 ± 5
|27 ± 4
|Systolic blood pressure at admission
|140 ± 30
|140 ± 27
|Diastolic blood pressure at admission
|80 ± 17
|80 ± 16
|Heart rate at admission
|80 ± 21
|79 ± 19
|STEMI, n (%)
|260 (53)
|250 (51)
|Killip entree class = 2 or more (%)
|138 (29)
|119 (25)
|GRACE score
|163 ± 38
|162 ± 36
|Left ventricular ejection fraction
|53 ± 12
|53 ± 13
|Baseline biological exams
|C-reactive protein (mg/L)a
|5.2 (1.86–18.36)
|4.92 (1.89–15.43)
|VCAM-1 (ng/mL)a
|675.8 (509–940.5)
|727.2 (550.8–1023.8)
|IL6 (pg/mL)a
|4.1 (2.3–9.6)
|3.8 (2.1–8.3)
|Medication previous admission
|Statins (%)
|142 (29)
|142 (29)
|Aspirin (%)
|168 (34)
|163 (33)
|In-hospital management
|PCI, n (%)
|320 (65)
|340 (69)
|Thrombolysis, n (%)
|77 (16)
|83 (17)
|Coronary artery bypass surgery, n (%)
|21 (4)
|14 (3)
|Statins (%)
|389 (79)
|383 (78)
|350 (71)
|347 (71)
|Calcium channel blockers (%)
|109 (22)
|93 (19)
|ACE inhibitors or ARB (%)
|251 (51)
|275 (56)
|Nitrated derivatives (%)
|261 (53)
|250 (51)
|Aspirin (%)
|454 (93)
|442 (90)
|Clopidogrel (%)
|435 (89)
|431 (88)
|Heparin (%)
|405 (83)
|405 (82)
|Low molecular weight heparin (%)
|323 (66)
|290 (59)
|Diuretics (%)
|169 (34)
|160 (33)
|Glycoprotein IIb/IIIa inhibitor (%)
|189 (39)
|198 (40)
|Digitalis glycosides (%)
|10 (2)
|9 (2)
ACE, angiotensin-converting enzyme inhibitors; ARB, angiotensin receptor blockers; PCI, percutanoeus coronary angioplasty; CABG, coronary artery bypass surgery. aBased on the median of baseline values from the entire population. bP is given by Wilcoxon rank-sum or Kruskal–Wallis (continuous variables) and an exact Pearson χ2 or Fisher test (categorical variables), ‡mean ± SD, *median, Q1, Q3.
Interleukin-17 and clinical outcomes at 2 years
The probability of outcome events as a function of the baseline IL-17 level is presented in Figure 1. At 2 years, event rates for death and MI was higher in patients with IL-17 levels <6.26 pg/mL (21%) compared with those with levels above the median (15%). The corresponding hazard ratio for event rates was 1.44 (95% CI = 1.07–1.95) (P = 0.02). After adjustment for known cardiovascular risk factors, C-reactive protein, and treatments including statins, low IL-17 levels remained an independent correlate of the risk of death or MI, HR 1.40 (1.03–1.91) (P = 0.03).
The adjusted HRs of death and recurrent MI associated with an increase of 1 pg/mL of IL-17 were 0.88 (0.79–0.99; P = 0.03), and 1.20 (1.05 to 1.37) for an increase of 1 pg/mL of IL-6, P = 0.007. We also tested for trend over tertiles of IL-17 and IL-6 to examine the association over a wider range of IL-17 and IL-6 levels. Compared with tertile 1, chosen as a reference, adjusted HRs were 0.66 (0.45–0.96) and 0.68 (0.47–0.99) for tertile 2 and tertile 3, respectively, for IL-17 (P = 0.03). The Cochran-Armitage trend test was significant (P = 0.021). Similarly, the adjusted HRs for tertiles 2 and 3 of IL6 were 1.09 (0.68–1.75) and 1.60 (1.04–2.45), respectively, compared with tertile 1 (P = 0.04).
The results were consistent with similar trends when examining separately the risk of death or MI, for IL17 and IL6, although statistical significance was not achieved due to fewer events.
Soluble vascular cell adhesion molecule-1 and clinical outcomes at 2 years
At 2 years, 25.7% of patients among those with sVCAM-1 levels above the median (≥695.47 ng/mL) died or had a non-fatal MI compared with 9.5% in those with levels below the median (<695.47 ng/mL). The adjusted HR of death and recurrent MI associated with log sVCAM was 1.85 (1.31–2.60; P = 0.0005). Soluble VCAM-1 levels above the median were associated with an increased risk of death or recurrent MI at 2 years (HR = 2.69, 95% CI = 2.11–4.16 compared with sVCAM-1 below the median, P < 0.0001). After adjustment for known cardiovascular risk factors, C-reactive protein, IL-17 levels, and treatments including statins, high sVCAM-1 levels remained an independent correlate of outcome events (HR = 1.75, 95% CI = 1.21–2.52, P = 0.003). The results remained significant with sVCAM categorized on tertiles. The results were consistent with similar trends when examining separately the risk of death or MI.
Combined assessment of Interleukin-17 and soluble vascular cell adhesion molecule-1 and clinical outcomes
At 2 years, 43% of death and MI occurred in patients with low (below the median) baseline IL-17 and high (above the median) baseline sVCAM-1 levels compared with 12% in those patients with high baseline IL-17 and low baseline sVCAM-1. The corresponding hazard ratio for event rates was 4.03 (95% CI = 2.48–6.55, P < 0.0001) and remained highly significant in the Cox multivariate analysis (adjusted HR = 2.22, 95% CI = 1.32–3.75, P = 0.002) (Figure 2). There was no statistically significant interaction between IL-17 and sVCAM-1 (P = 0.15).
Interleukin-17 reduces adherence of mononuclear cells and endothelial soluble vascular cell adhesion molecule-1 production
In the light of these results and our previous finding that the IL-17 protective role in a mouse model of atherosclerosis was associated with reduced endothelial sVCAM-1 expression, we tested the hypothesis that IL-17 modulates human mononuclear cell adhesion on endothelial cells. We observed a significant reduction in PBMC adhesion to TNFα-activated HUVECs in the presence of IL-17, which was associated with a significant reduction in sVCAM-1 expression (Supplementary material online, Figure). As a control, IL-17 enhanced IL-6 production in the same supernatants (Supplementary material online, Figure).
The major finding of this study is that elevated levels of IL-17 are associated with a better outcome in patients with acute MI, supporting a protective regulatory role of IL-17 in coronary heart disease. Moreover, the highest risk of death and recurrent MI was observed in patients with low levels of IL-17 and high levels of sVCAM-1, suggesting an important modulatory role of IL-17 on vascular inflammation.
Only a few studies have previously reported measurements of circulating IL-17 levels in patients with coronary heart disease. The first published investigations, performed in populations with <26 Chinese patients, suggested increased levels of IL-17 and Th17 subset in patients with coronary artery disease, more particularly in patients with acute coronary syndromes.30,31 However, these results were not replicated in Caucasians.15,32 Eid et al.15 found no difference in IL-17 levels between patients with coronary artery disease (n = 108) and referent outpatients without a diagnosis of coronary atherosclerosis (n = 59). In addition, IL-17 levels did not differ between patients with stable and those with unstable coronary syndromes.15 Our present results are in agreement with those of Eid et al. in that the median levels of IL-17 that we detect in a Caucasian population are far below the levels reported in Chinese patients. This issue would merit further investigation.
Importantly, the previous clinical studies have generated assumption about the role of IL-17 in coronary artery disease but none had assessed the relationship between IL-17 levels and cardiovascular outcomes. Our study is the first to tackle this issue and shows that the detection of elevated levels of IL-17 in patients with acute MI is associated with a better cardiovascular outcome, i.e. reduced mortality and recurrent MI after 1 year of the follow-up. Thus, the currently held dogma that IL-17 promotes coronary artery disease requires reconsideration.
Some experimental studies have proposed a pro-atherogenic role of IL-17 in atherosclerosis.20–23 However, as discussed recently,26 the evidence for the efficient and sustained blockade of IL-17 signalling was relatively weak in some of the previous work. Our experimental studies led us to different conclusions. We found that mice with increased IL-17 expression displayed significantly smaller atherosclerotic lesions, and the protection was abrogated after IL-17 neutralization.26 Moreover, the administration of recombinant IL-17 to Ldlr−/− mice significantly inhibited lesion development.26 This regulatory role of IL-17 in atherosclerosis has also been supported by a recent study showing that IL-17A deficiency enhances lesion development in the Apoe−/− model.27 Interestingly, IL-17 expression in human carotid lesions was associated with a lower macrophage but a higher smooth muscle cell content and a fibrous plaque phenotype, suggesting a role for IL-17 in promoting plaque stability.26 The atheroprotective role of IL-17 was associated with inhibition of Th1 responses,26 which is consistent with recent studies showing that IL-17 protects against Th1-mediated diseases like colitis, in part through the modulation of Th1 polarization.33
The role of IL-17 in the modulation of endothelial cell activation is still poorly understood. In a previous study, we showed a down-regulation of mouse endothelial VCAM-1 expression in vitro and in vivo in response to IL-17, in part through the modulation of NF-κB activation.26 Here, we have extended these findings to human cells and showed that IL-17 inhibits mononuclear cell adherence to pre-activated HUVECs in culture. Our results are consistent with other reports showing down-regulation of VCAM-1 expression in other cell types in response to IL-17.34,35 Further studies are required to fully delineate the mechanisms by which IL-17 alters endothelial cell activation and mononuclear cell adherence, and to identify the determinants and the cell subsets that produce IL-17 in the setting of acute ischaemic injury.
The modulation of VCAM-1 expression by IL-17 prompted us to look at the interaction between IL-17 and VCAM-1 in vivo with relation to cardiovascular outcomes. Previous studies have reported independent association between circulating levels of sVCAM-1 and future cardiovascular outcomes, particularly in patients with stable coronary artery disease,36 and in patients with diabetes.37 Such association could not be established in apparently healthy individuals.38–41 In acute ischaemic settings, sVCAM-1 levels show sustained elevation for up to 6 months following the index event.42 However, the prognostic value of elevated sVCAM-1 levels in patients with acute coronary syndromes remains relatively unexplored. Only very small studies that included a majority of patients with unstable angina have been published in this setting with contrasting conclusions.43–45 Our present study is the largest one to report on the relationship between sVCAM-1 levels and cardiovascular outcomes in patients with acute MI. The results clearly show that elevated levels of sVCAM-1 at the time of admission for acute MI are associated with a 2.6-fold increase in the risk of death and recurrent MI during the first year of the follow-up. Interestingly, IL-17 levels were associated with outcome events in these patients, the worst prognosis being for patients with both high sVCAM-1 and low IL-17 levels. These findings are consistent with the modulatory role of IL-17 on endothelial VCAM-1 expression and adhesion of mononuclear cells, and suggest an important role for IL-17 in the control of atherosclerosis-related vascular inflammation. It is important to note that in the same study sample, we found that IL-6 (known to induce IL-17 and vice versa) was associated with the worse outcome. This emphasizes the complexity of the system and the need for targeting very specific pathways to ensure both efficacy and safety.
It should be noted that blood sampling for the measurement of IL-17 and sVCAM-1 was performed at the time of admission to the intensive care unit before or concomitantly with the onset of treatment, <48 h after symptom onset. Cytokine levels may fluctuate during the first 48 h after acute MI. However, the available data indicate that IL-17 levels are not increased in patients with acute coronary syndromes compared with chronic stable patients,15 suggesting no major fluctuations during the acute setting. In addition, we believe that fluctuations in IL-17 levels, if any, might have reduced the probability of detecting a significant association between IL-17 and cardiovascular events. Another limitation is the observational nature of this registry-type study, which does not allow a cause–effect demonstration. However, it should be noted that the study was a prospective nationwide registry that closely represents everyday up-to-date current clinical practice. The monitoring of the data by clinical research assistants, the multivariable analyses, the centralized measurement of the biomarkers, blinded to the phenotype data including outcomes, limit, although they do not preclude, the risk of bias.
In conclusion, we show that low levels of IL-17 are independently associated with 1-year mortality and recurrent MI in a Caucasian population of patients admitted for acute MI. These results need confirmation in larger studies and in different patient populations. However, we believe that they may have immediate clinical implications. Clinical trials are currently investigating the efficacy of therapeutic strategies aimed at the inhibition of IL-17 pathway in different clinical settings, including diseases associated with a high cardiovascular risk. Although our study did not assess the direct relationship inhibition of IL17 and cardiovascular events, our findings suggest that patients included in trials using IL17 inhibitors, particularly those with identifiable cardiovascular risk factors, may be at potentially higher risk of serious cardiovascular events and should therefore be closely monitored. In this regard, it is noteworthy that major adverse cardiovascular events have been reported in psoriatic patients assigned to Ustekinumab46 or Briakinumab, two blockers of IL-12 and IL-23 that reduce both Th1 and Th17 pathways, which was not the case for patients assigned to placebo or treated with etanercept, an inhibitor of tumour necrosis factor-α.46,47
Supplementary material
Supplementary material is available at European Heart Journal online.
Fast-MI is a registry if the French Society of Cardiology, supported by unrestricted grants from Pfizer and Servier and a research grant from the French Caisse Nationale d'Assurance Maladie. This work on IL17 was also supported by Inserm, by Agence Nationale de la Recherche (ANR), by the transatlantic Leducq Network LINK, the European Union Seven Framework programme TOLERAGE. S.T. was supported by a post-doctoral fellowship from Fondation Lefoulon Delalande. Neither of these sponsors had a role in the management, analysis, and interpretation of data; drafting or approval of the manuscript.
Conflict of interest: none declared.
We thank the physicians who cared for the patients at the participating institutions, the International Clinical Trials Association Contract Research Organization (Fontaine-lès-Dijon, France), Elodie Drouet and the Clinical Research Assistant team of Unité de Recherche Clinique de l'Est Parisien (Assistance Publique–Hôpitaux de Paris and UPMC Paris 06), Benoît Pace, Vincent Bataille and Geneviève Mulak (French Society of Cardiology) for their assistance in designing the electronic case-record form and data management during the follow-up period. We are indebted to Carla Sebella-Arguelles and Paula Doceur (Aterovax, Paris, France) for help in IL-17 measurements.
- Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2012. For permissions please email: email@example.com


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This was sent to me by an old friend, Doug Turnbull, podcaster and writer of science fiction. He writes of his observations as an American watching the games in Rio, but also as a critical thinker, able to stand apart from patriotic or even nationalistic inclinations.
I like his thoughts here, I hope others do, too. I'll add a place Doug can be contacted, in the Comment section.
Dark Thursday
On Wednesday during one of the women's foot races, the runners from New Zeeland and USA, inadvertently collided. The American girl was first up and was about to continue the race when she noticed the other runner was still down. She stopped and helped her to her feet and they both were about to continue with the race when the American girl came up lame, with a bad knee injury. The runner from New Zeeland then stopped and helped her to continue to finish the race. To me, and I think to most who saw the events unfold, their actions were emblematic of humanity at its very best. I was truly proud of both of them.
If the event Wednesday was a proud moment, what happened in the women's 400 meter relay Thursday was not so much. A less dramatic and almost undetectable, "collision" occurred when (according to the contemporaneous video), the elbow of the Brazilian runner crossed the line (not against the rules) into the adjacent lane where the USA runner was approaching her hand-off to the next runner. The Brazilian runner appeared (again according to the video) not to be aware of the collision as she was busy running her own piece of the race, executing reception of the relay, the harder of the two jobs, flawlessly. However, the American runner, apparently as a result of the contact (as she said shortly after the event), momentarily lost her composure, slowed down, and fumbled the hand-off, thus ending the team's race. However, after several seconds, that same runner, retrieved the baton and handed it to her relay partner, who by all appearances had rightly given up the race as fairly lost, telling her to finish. She and the remaining runner did indeed finish, but a distant last. At this point, the American team immediately filed a challenge to the judges citing interference by the Brazilian runner as grounds. Both Tom Hammond and Ato Bolden, the NBC commentators, agreed with my assessment at the time: the protest was spurious, without merit, and would therefore fail. How wrong we were.
Until Thursday morning, I was enjoying an almost flawless Olympics. My only concern was the jingoistic "faux patriotic" chant that our huge contingent of USA fans insisted on howling every-time an American was doing well: "USA-USA." Their actions were embarrassing, as was the suitcase full of medals we were racking up. Our team was far too large and well-funded, reminding me of the Cold War Days when the Olympics were hopelessly politicized. I was annoyed, but still enjoying things until our Women's Relay team succeeded in getting a do-over in the 400 M relay. They dropped their baton and were rightfully out of the competition. The judges had made a political (Olympic politics) decision to give this to them. In the end, it was far easier to give it to us, and bump Brazil, who had done nothing wrong, but were already out of the running based on time. They took a chance that the super-fast USA team would blow their cakewalk do-over. It was the path of least resistance for them (the judges). Never mind that the right thing to do was to disqualify the USA team. They (USA) didn't foul up the do-over and bumped the Chinese team, who had won their place in the finals, fair and square. I nearly got physically sick. The judges were simply afraid of the shit-storm that would follow the denial of the protest. Being perennial sore losers (see last several elections), the USA would have been bitching in the ear of anyone who would listen that we were "cheated"– for the next 4 years. The whole affair made us (Team USA) look like a pretty sorry bunch.
To add insult to injury, NBC, who had covered the event and correctly judged it to be a simple relay error, after several hours, and very likely some angry calls from the producers in New York, reminding them who was paying the bills, they had changed their tune and fallen into lockstep with judgement, stating during their evening broadcast that "it was a fair and right decision." That was a lie and they knew it. NBC produced a transparently doctored video, which evening viewers saw, that made it appear that the Brazilian runner was at fault. Having seen the actual event that morning, I knew it to be a fake. I do radio and know how easy it is to edit a narrative to sound like something it is not. Listen to NBC's doctored 911 call of the Travon Martin killing, if you don't believe me. Despite the Network's claims, the bad decision was unfair to all the other competitors and was further compounded when the USA Relay team won the Gold medal, in a race they were not entitled to run.
Then the Lochte affair also broke on Thursday afternoon, and I realized our whole team was effectively being disgraced and dishonored by our stupid fans, unsportsmanlike behavior on and off the field, and odious public behavior in our host's beautiful city. Everyone on the planet (outside the USA), whether for right or wrong, has generalized (I do talk to my own international followers) that Americans are boorish, over rich bullies, and louts. Consider this: The people of Rio invited us to visit their home, and our swim team quite literally, not figuratively, peed all over the furniture. Nice going guys! Needless to say, you won't be hearing the "USA" chant coming out of me anytime soon. It was a Dark Thursday for me.
Lest the reader think I am merely badmouthing our entire team, I am not. Many other American athletes have conducted themselves with honor and humility in victory, and dignity in defeat. Our Decathlon champion, Ashton Eaton, the great young swimmer, Katie Ledecki, our Gymnastics team, and many more than I can name here, have deported themselves honorably. To me, the fruits of their efforts far outweigh that of the rotten apples.
I am reminded by these events, of the great Jesse Owens, who despite the terrible handicaps of poverty, bigotry, and prejudice, was able to do what many considered impossible: to earn a place on the Olympic team and then win several medals. Ignoring derisive public comments about the inferiority of his race, he had the character and courage to do the impossible, exhibiting grace, humility, and style in victory: no chanting, no fists in the air, no bragging on himself; and deported himself with equal poise and grace when defeated. He was emblematic of the country he lived in, one that dreamed great dreams and did great deeds. Most Americans still try to believe this, despite a growing mountain of countervailing evidence. There is a price on this "winning is everything" attitude that dominates US sports and other endeavors these days, and it is a high price to pay: We surrender our honor and decency.
Since this seems to be the week for public apologies, let me make this one: and it is not a fake one filled with phony alibis and prevarications, but heartfelt. As an American, I sincerely apologize to all my many friends across this world for the reprehensible behavior of the individuals who purport to represent the best of America. They do not. We have come out of these Games, looking like the stereotypical "Ugly Americans", that so many already judge us to be. Some of us truly are, but many more of us are not. Please believe that my friends.
So there it is, one man's opinion. To my many international friends, please share this commentary with YOUR friends. Indeed, whether you agree with mine or not, and please feel free to include your own opinions. Thank you.


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World of Warcraft
So... List of things to do at level 90 puh-lease!!
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- So... List of things to do at level 90 puh-lease!!
Loyal Royal 4 years ago#1
To clarify, this isn't an "I'm bored, gimme something to do" topic. More of a "this game is huuuuuuuuge and I may be missing out on something cool that I'm totally oblivious to!"
Sent from my iPhone via PowerFAQs 1.9
CallmeSoren 4 years ago#2
PSN: Selxis, Gamertag: Sornic, Wii Friendcode: To be updated.
Loyal Royal (Topic Creator)4 years ago#3
Ah sorry. I guess the DISCUSSION board for WoW on GameF(Frequently)A(Asked)Qs(Questions) was the wrong place to ASK and possibly DISCUSS this. My bad.
XBL GAMERTAG - loyal royal jay
dejavu1982 4 years ago#4
the wow board is just full of people who only respond to troll threads, gamefaqs isnt the best for asking question, should go to wow's main forums, BUT to answer your question one thing to do is hunt for the extremily rare monsters for mounts:), love it
Ness0123456789 4 years ago#5
Depends on your ilvl, but the basic gist of it is:
Fresh 90 - Sub ilvl 425: Continue doing the quests through Pandaria until you complete the Dread Wastes (I'd advise you to do this anyways if it's your first 90 simply to get a better undrestanding of the storyline and to fill out the rest of your gear slots). You can also start the various daily hubs throughout Pandaria now as well:
-Golden Lotus in the Vale of Eternal Blossoms
-Klaxxi in the Dread Wastes (after you've completed it)
-Operation Shieldwall (you may wanna wait a bit on this until you get better gear) in Krasarang Wilds after getting the breadcrumb in Shrine of the Seven Stars
-Order of the Cloud Serpent in the Jade Forest
-The Tillers in Valley of the FouR Winds
-The Anglers in Krasarang Wilds
Also, once you get the Golden Lotus to Revered, you unlock the Shado-Pan dailies in Townlong Steppes and the August Celestial Dailies at each of the four Temples of the Celestials in Pandaria.
Ilvl 425: You may now queue for Scenarios, 3-man instances that take around 10-15 minutes to complete, award 40 Valor Points (used to buy epic gear) for the first complete, 20 Valor Points for every subsequent completion, and award a loot box at the end that may or may not contain ilvl 463 blues or a 476 epic.
Ilvl 435: You may now queue for Heroics, 5-man dungeons geared for level 90s. Completing your first Heroic will award you with 80 VP, and every subsequent clear will give you 40 VP, along with a handful of Justice Points (used to buy mostly useless blue gear) for every boss that's killed.
ilvl 460: You may now queue for Mogu'Shan Vaults in Raid Finder, a 25-man raid that's an easier version of the raid's Normal Mode (with the added bonus of having 25 people instead of 10). Each clear gives 90 VP for the first clear of each wing, and every subsequent clear gives 45 VP. You also have a chance at getting a piece of 476 Epic loot from the bosses when they die.
ilvl 470: You may now queue for Heart of Fear in Raid Finder. Same deal with the VP, but you now get a chance at 483 Epics after each boss kill. After completing both wings of Heart of Fear, you unlock the Terrace of Endless Springs for Raid Finder, which concludes 5.0's storyline and offers a few more bosses with more shiny epics.
Also, in answer to the Brawler's Guild thing, it's an invite only (You can pick up an intie for about 1-5K gold now on the Black Market Auction House in the Veiled Stair). Once you get the invite, and use it, you can go to the Brawler's Guild in either Ogrimmar or Stormwind (located in the Deeprun Tram) depending on your faction, and go do some solo boss fights for kicks. There's no real reward for doing it, but it is pretty fun.
There's also Battle Grounds to be run as well, and the two World Bosses (Sha of Anger in Kun-Lai and Galleon in Valley of the Four Winds) that you can kill as well. There's also the legendary quest line that begins with Wrathion in the Tavern of the Mists in the Vield Stair. Lastly, should you have the desire or urge you can join a raiding guild and run the three raids in 5.0 on Normal and eventually Heroic for higher ilvl loot. And of course the aweomness that is Pet Battles.
Each person might see a rose with a different shade of red, but the fact that we can all agree on is beauty -- that is a miracle.
-Michea, FFXI
Loyal Royal posted...
Ah sorry. I guess the DISCUSSION board for WoW on GameF(Frequently)A(Asked)Qs(Questions) was the wrong place to ASK and possibly DISCUSS this. My bad.
Technically he did answer your question.
i5 3570k | Asrock b75 pro3 |9800 gt | 8 GB DDR3 1600MHz | Antec EA-650W | 1 TB HDD | Cooler Master elite 431+
mrplanktom 4 years ago#7
You can play with Jack Black's kung fu pandas or some pokemon!
There's no group of people more delusional than blizz fanboys. Including scientologists.
Loyal Royal (Topic Creator)4 years ago#8
Ness that's awesome thanks :D
XBL GAMERTAG - loyal royal jay
Lightning Bolt 4 years ago#9
From: Loyal Royal | #003
Ah sorry. I guess the DISCUSSION board for WoW on GameF(Frequently)A(Asked)Qs(Questions) was the wrong place to ASK and possibly DISCUSS this. My bad.
FAQs are thataway ->
One day dude, I'm just gonna get off the bus, and I'm gonna run in the woods and never come back, and when I come back I'm gonna be the knife master!
-The Rev
Kanus_oq_Seruna 4 years ago#10
This is still a message board for game discussion, and asking questions regarding gameplay is expected. That, and WoW is one of those game types that it's a tad hard to write faqs for, as every few months/weeks, you'd have to scrap a portion of what you have. You might as well take the time to learn how to make addons that could be more helpful.
For topical discussions of the Source Mod remake of Half Life: http://www.gamefaqs.com/boards/683833-black-mesa
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Security is a top-of-mind concern for CIOs and data center managers. In environments where regulatory requirements play a role, it is critical to ensure that organizational data is safe and secure at every access point. Awareness isn't enough, though. Organizations must be able to gauge their security preparedness. That's why Logicalis, an international provider of integrated information and communications technology (ICT) solutions and services, has developed a checklist of seven key things to look for in a secure IT environment.
"The cornerstone when securing an IT environment is to classify the data that runs through that environment," explains Von Williams, director of information security, audits and compliance for Logicalis. "You have to know whether your data is private, confidential or public before you can assign security protocols and policies that will safeguard that data to the extent required for each level of classification."
According to Logicalis, there are seven key ways to know if an IT environment is operating under a "best practices" approach to data security. Using this checklist as a guide is a good start, but Williams warns that IT security is not a static process and controls must be employed to continually assess and reassess the companywide policies and strategies that keep security in check.
What Motivates Consumers to 'Like' Content and Brands on Facebook Ninety-three percent of Facebook users click the "Like" button at least monthly, but the meaning behind "Like" varies considerably by age and context.
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Five Core Tenets of the Social IntranetThe new intranet will be a heterogeneous environment of systems across the whole company.
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Future IT leaders will need to seek technologies that eliminate silos in order to deliver the right information to the right person within the right application environment at the right time. ... More >>


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Yamaha Absolute Birch Custom Nouveau Reviewed!
Yamaha Absolute Birch Custom Drums
What's Nouveau?
Yamaha's Absolute Custom Series drums are made from maple, birch, or beech and have been designed to allow drummers to mix and match shells to create drum sets featuring the sound characteristics they desire in a matching finish. This is a great idea. Maple is known for its even frequency distribution and long sustain, while birch is known for a good attack with an enhanced low end with shorter sustain and was preferred by recording drummers for years. Beech is sonically in the middle of these two woods. By simply choosing the shell material you want for each drum you can create a unique, customized kit without the delivery time more commonly associated with large mammal gestation.
While these drums have been available for a few years Yamaha has just upgraded the Absolute Custom line offering a plethora of new finishes and has created an entirely new version of the line named the Absolute Nouveau (that's French for "new"). It's named after the Nouveau Lug featured on these drums. You may be thinking, "New lug? Ho hum." Wrong! This is a unique and completely revolutionary lug. The idea for this lug came about when Yamaha tried to design a lug that made minimal contact with the shell while also making head changes easier. How'd they do this? Nouveau lugs attach at the shell's nodal point, which is its point of least vibration. This minimizes the resonance dampening effect of hardware attached to the shell. To make head replacements easier, Yamaha has done something very innovative. Loosening the Nouveau lugs' tension rods just halfway allows the entire lug to pop off the shell, speeding head changes while minimizing the chances of losing a tuning screw or a washer. This means the rim and lug, screws and washer all remain attached to each other when they're removed.
Because it's removable, this reminded me slightly of the lug found on Ayotte drums. However, the Yamaha Nouveau lug makes no direct contact with the drum shell and floats, hanging off its mounting bolt without impeding the shell's resonance. Brilliant! It's also much more attractive than the rather pedestrian Ayotte design.
How useful is a removable lug? The new lug design proved its value before I even got the kit home. Yamaha sent a 24" x 18" bass drum in a case, which wouldn't fit in the back seat of my car. I took the drum out of the case and still no luck. I put the passenger seat all the way back and the drum almost fit through the passenger door. By turning the bass drum tuning bolts three or four times I was able to slip a couple of lugs and claws off the posts that held them and was finally able to squeeze the drum into my car. Once in the car, replacing the lugs to the posts was accomplished just as easily. These drums are also available with the Absolute lugs featured on earlier models of these drums, but thank Zeus this drum didn't have them.
Up Close
I received a six-piece Birch Absolute Custom kit in a spectacular Blue Sparkle for review. This kit came with suspended Tom Toms in what Yamaha calls "universal sizes" of 10" x 8", 12" x 9", 15" x 14", and 18" x 16", and a 14" x 7" matching wood snare drum with a 24" x 18" bass drum. The bass drum features a 7-ply 7mm thick all-birch shell with no reinforcing rings and matching Blue Sparkle wood bass drum hoops. The snare and toms have 6-ply 6mm thick shells also without reinforcing rings. The Absolute Custom kits have always featured thinner shells than their other drum lines, sacrificing a touch of projection for increased tone and warmth. All of the toms feature Yamaha YESS mounts to increase sustain.
The first thing I noticed was that the finish of the drums was perfectly done and really caught my eye. Yamaha has never been known for an extensive selection of finish choices but I'm glad to report they've recently taken great strides to change that reputation. The finishes available include a selection of 33 custom colors and 12 "core" colors. The core colors include Cherry Wood, Sea Blue, Solid Black, Silver Sparkle, Black Sparkle, White Marine Pearl, Vintage Natural, Honey Yellow, White Mica, Red Pearl Natural, and Vintage Black.
The drums now also feature aluminum die-cast hoops on the snare and toms, which are designed to increase sustain while giving more reliable tuning. There are new die-cast claw hooks on the bass drum with protective rubber gaskets to prevent marring the hoops. The bearing edges were smooth and appeared to be cut to a standard 45-degree angle. I like the look of these new removable lugs too. They are very stylish and, as previously mentioned, extremely functional. All vent holes are drilled at the nodal points of the shells as well.


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realmagick.com The shrine of knowledge.
U G Krishnamurti London Period
A selection of articles related to u g krishnamurti london period.
Original articles from our library related to the U G Krishnamurti London Period. See Table of Contents for further available material (downloadable resources) on U G Krishnamurti London Period.
- History of the Egyptian Religion, part I: Early Dynastic Period
- I - Predynastic - Early Dynastic Period. The temples were in essence the *Home of the God* and thus a place where only Pharaoh as the Son of God and those he appointed as his deputies, could meet with the god. This goes all the way back to Archaic and...
Religions >> Egyptian
- Astrological Emphasis: Aquarius, 2001
- General | Love | Work | Health Aquarius: January, 21st- February, 19th. This article applies to Aquarians during 2001. General Those born under the sign of Aquarius are characterised by their great passion for mystery and prove to have a fighting spirit in...
Astrology >> Aquarius
- Astrological Emphasis: Pisces, 2001
- General | Love | Work | Health Pisces: February, 21st - March, 20th. This article applies to Pisceans during 2001. General Pisces is the twelfth sign of the Zodiac, astrologically dominated by Jupiter and Neptune, exalted by the Moon and with Mercury in exile....
Astrology >> Pisces
- Ostara - The Vernal Equimox
- ABOUT OSTARA | RITUAL | FOODS | REFERENCES ABOUT OSTARA Ostara (pronounced Oh-star-ah) is also called Eostre, Easter, Vernal Equinox, Spring Equinox, and the First Day of Spring. This is the time of year when day & night are equal, and heralds the return of...
Holidays >> Ostara
- Mabon, The Witch's Thanksgiving
- To Autumn O Autumn. Laden with fruit, and stained With the blood of the grape, pass not, but sit Beneath my shady roof, there thou may'st rest, And tune thy jolly voice to my fresh pipe; And all the daughters of the year shall dance, Sing now the lusty song...
Holidays >> Mabon
U G Krishnamurti London Period is described in multiple online sources, as addition to our editors' articles, see section below for printable documents, U G Krishnamurti London Period books and related discussion.
Suggested Pdf Resources
- A Life Sketch of U.G. Krishnamurti Body, Mind, And Soul — do they
- By then UG was in his twenties, a period of extreme restlessness and change. The study of ..... describe UG's phase in London as 'the dark night of the soul'.
- www.ugkrishnamurti.org
- Enlightenment, U.G. Krishnamurti took close aim .....
- www.ugkrishnamurti.org
- the build-up of sex and love nadbudowa seksu i - The Essential UG
- UG: Yes. That's a fact. We do not want to accept it because it destroys the myth that human ......
- www.ugkrishnamurti.org
- View PDF - Sabyasachi Guha
- route, and "The Mystique of Enlightenment" by U.G. Krishnamurti randomly popped ...
- www.guhasabyasachi.com
- An Instance of Dependent Origination: Are Krishnamurti's Teachings
- journals. over a period of years, forty-eight past lives were uncovered spanning a period from ..... resonances in the teachings of U.
- www.shin-ibs.edu
Suggested Web Resources
- U. G. Krishnamurti - Wikipedia, the free encyclopedia
- [edit]. He ultimately separated from his family and went to live in London. While sitting one day in Hyde Park, he was confronted ...
- en.wikipedia.org
- Essential UG--UG Passed Away March 22, 2007 - U.G. Krishnamurti
- Mar 22, 2007 During this period, UG also underwent a life-altering, mystical ... After his aimless wanderings in London and Paris, like a dry leaf blown here, ...
- www.ugkrishnamurti.org
- A Life Sketch of U.G. Krishnamurti Body, Mind, And Soul — do they
- By then UG was in his twenties, a period of extreme restlessness and change. The study of ..... describe UG's phase in London as 'the dark night of the soul'.
- www.ugkrishnamurti.org
- Ch. 5: Adrift in London - The Well
- In the year 1961, U.G. landed in London, alone and penniless.
- www.well.com
- The Teachings of Jiddu Krishnamurti - Top Documentary Films
- Jiddu Krishnamurti was born on 11 May 1895 in Madanapalle, a small town in south ... During this period, UG also underwent a life-altering, mystical experience, ... After his aimless wanderings in London and Paris, like a dry leaf blown here, ...
- topdocumentaryfilms.com
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.
U G Krishnamurti London Period Topics
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French educator and inventor, born 4 January 1809, at Coupvray, Seine-et-Marne, France ; died 6 January, 1852. He became blind when three years of age, and at the age of thirteen was sent to the Institution for the Blind at Paris. There he showed a talent for intellectual studies and for music; when his instruction had been completed he was appointed professor in that institution. It was then that he invented his system of writing in raised or relief points for the blind. Before him, Valentin Haüy, the founder of the Institution for the Blind, had invented the method of printing in raised letters which allowed the blind to read by touch; Charles Barbier had invented a sonographic point system as distinguished from Haüy's line or letter system and had devised a simple instrument by which the blind could emboss the words or print them in relief. But this system of writing, based on the sounds of the French language, was too conventional and did not furnish the signs necessary for punctuation and ciphers. Braille, keeping to Barbier's point system and the principle of relief writing, found the means of representing, by the various combinations of six dots, not of the sounds but the alphabetical letters and all the signs of punctuation, and even of music. This invention, being alphabetic instead of sonographic, was a great advance in the education of the blind, and though it has been modified, at times, as to the combinations of dots (American, English, and English revised systems), the system is still, in most countries, the basis of methods for the education of the blind. The inventor set forth the principles of his system in his work: "Procédé pour écrire les paroles, la musique, et la plein-chant, à l'usage des aveugles", printed in raised letters in 1829. Though this system cannot be said to be the definitive method of education and writing for the blind, the name of Braille will always remain associated with one of the greatest and most beneficent devices ever invented.
The Catholic Encyclopedia is the most comprehensive resource on Catholic teaching, history, and information ever gathered in all of human history. This easy-to-search online version was originally printed between 1907 and 1912 in fifteen hard copy volumes.
Designed to present its readers with the full body of Catholic teaching, the Encyclopedia contains not only precise statements of what the Church has defined, but also an impartial record of different views of acknowledged authority on all disputed questions, national, political or factional. In the determination of the truth the most recent and acknowledged scientific methods are employed, and the results of the latest research in theology, philosophy, history, apologetics, archaeology, and other sciences are given careful consideration.
No one who is interested in human history, past and present, can ignore the Catholic Church, either as an institution which has been the central figure in the civilized world for nearly two thousand years, decisively affecting its destinies, religious, literary, scientific, social and political, or as an existing power whose influence and activity extend to every part of the globe. In the past century the Church has grown both extensively and intensively among English-speaking peoples. Their living interests demand that they should have the means of informing themselves about this vast institution, which, whether they are Catholics or not, affects their fortunes and their destiny.
Copyright © Catholic Encyclopedia. Robert Appleton Company New York, NY. Volume 1: 1907; Volume 2: 1907; Volume 3: 1908; Volume 4: 1908; Volume 5: 1909; Volume 6: 1909; Volume 7: 1910; Volume 8: 1910; Volume 9: 1910; Volume 10: 1911; Volume 11: - 1911; Volume 12: - 1911; Volume 13: - 1912; Volume 14: 1912; Volume 15: 1912
Catholic Online Catholic Encyclopedia Digital version Compiled and Copyright © Catholic Online


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With just a few days before the March 15 trade deadline, it's a perfect time for a fresh batch of NBA power rankings to assess where all 30 teams stand.
Some teams are beyond help regardless of how active the front office is in making deals, but there are a handful of teams that could be heavily impacted by any deals constructed this week.
Miami remains out of the top spot, Philadelphia is showing everyone why they should be taken seriously and the hype around Los Angeles becoming a Clippers town has died down considerably.


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GeForce GTX 780 EX OC 3072MB PCI-Express Graphics Card (78XNH5DN8MSU)
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A flank marker used during the Civil War by a Saratoga County regiment came out of storage for a grand unveiling Wednesday. The 77th Infantry Regiment, or Bemis Heights Regiment, was organized at Saratoga Springs in 1861, and more than 150 years later one of its artifacts was prepared for display by Saratoga museum curators. In fact, a large portion of New York's military history is now featured at the state Capitol, thanks to work ...
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Sagarika RaoLatest answers
Follow and Ask me 5 Question. And I'll do the same :) @Jaswinder3444
doha wali :P
Yo bruh :P
Ao HAru Ride?
What do you look forward to most this year?
Idk. University.
Who're your favorite internet friends?
Did you just insert an apostrophe in the word whore? XDDDD just kidding mate xD
Hm, there's quite a few. Ask me on facebook?
Favorite Anime ?
Prince of Tennis, Ace of Diamond, Shingeki no Kyojin, Skip Beat, Kuroko no Basuke.
Hit my ask box with a list of anime and I'll pick out from them cuz I have too many favorites :P
Favorite pickup line?
Hit my ask box with Physics/Math pick up lines and I'll answer the one I like xD
First liker gets 25 likes + 1 question rest gets 2 likes? ♡♡
Why does the Easter bunny hide eggs?
I still don't get why.
If you were candy, what would you be?
WONKA'S GOBSTOPPERS hehehehehehehehehehe
Wait, if you're gonna rule the world, don't you have to know how to dance? There are those royal ballroom dancing things yeah?
Fuck it. I have two left feet, you lil shit.
What are some things that make you really happy?
Tezuka Kunimitsu is not a thing.
Neither is Miyuki Kazuya,
Neither is food.
World domination plan? Pray tell, where will you get the money for your funding???
...........secret xD
What's the best prank you've ever played on somebody?
Today! Poured pink hair dye into mum's shampoo. Her reaction when she screamed was fabulous! XDDDD
I told her it could be washed off, so she went back in and washed it off. Sorry, no pic :P
What would you do for a Klondike bar? :D
*insert Ryan Higa video about what he would do for a Klondike bar*
Do you ever feel...like a plastic bag...drifting through the wind...wanting to start again? *James Franco voice*
Anon, whoever you are, you're awesome. XD


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ok if you are making a new vampire team -which cullens do you want to be on the team ?????
Alice ,Jasper and Emmett :D
source: Twilight - FB
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Reishi Mushroom & Walnut Super Dark Chocolate Bar, Prosciutto & Buffalo Mozzarella Panini Recipe
This savory Chocolate recipe is perfect for meat and cheese and lovers. It calls for the freshest (2 days old or younger) Mozzarella di Bufala you can find, to which you combine nicoise olives, prosciutto, basil leaves, olive oil, and our Vosges® Reishi Mushroom & Walnut Super Dark Chocolate Bar. An easy recipe for a quick afternoon lunch, perfect for a picnic.
Prep Time: 12 Mins | Cook Time: 5 mins
- 1 3oz. Reishi Mushroom & Walnut Super Dark Chocolate Bar (need 3 squares)
- 1 ½ oz buffalo mozzarella
- 2 slices thick Italian country bread, about 1/2 inch thick and 4-5 inches wide
- 2 tbsp olive oil
- a sprinkle Murray River Pink Salt
- 3 slices prosciutto, La Quercia (new prosciutto sulfite free from Iowa)
- 2 basil leaves
- 5 nicoise olives, pitted and sliced
Katrina's Inspiration"I cannot describe my love of the real McCoy, fresh (meaning 2 days old or younger) Mozzarella di Bufala. It is not easy to find in the U.S. or should I say close to impossible, but this stringy, elastic and I would say a bit rubbery, fresh cheese is ..."
DirectionsEquipment needed: Panini press, waffle iron, clothes iron or cast iron pan.
1. Cut mozzarella into slices and place between sheets of cloth towels for at least 10 minutes to help eliminate the excess water in the cheese and prevent your panini from becoming soggy.
2. Brush olive oil on all sides of the bread. Place olives, Reishi Mushroom & Walnut Super Dark Chocolate Bar and salt on one side followed by the mozzarella, basil and prosciutto.
3. Press to golden brown and serve immediately.
Yields One Panino
Pairing tip: This recipe goes perfectly with a bottle of Italian Barbaresco.
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Balch Springs Visual and Performing Arts Alliance
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NetBSD 7.0.2 Operating System Officially Released, Available for Download Now
On October 27, 2016, NetBSD Project, through Soren Jacobsen, proudly announced the release and general availability of the second maintenance update to the NetBSD 7.0 operating system.
AMD Rolls Out AMDGPU-PRO 16.40 Driver for Ubuntu and Red Hat Enterprise Linux
AMD released a new version of its new AMDGPU-PRO graphics driver for GNU/Linux distribution, bringing support for the Red Hat Enterprise Linux (RHEL) operating system, besides Ubuntu.
Ubuntu Vs. Linux Mint - Which Is Better in 2016?
Ubuntu and Linux Mint are currently arguably 2 of the most popular Linux distros (with Debian) around. They are both quite user-friendly and for the Linux newbie, you couldn't be wrong choosing either. For a very long time, Ubuntu was considered the distro of choice by most Linux enthusiasts, but it has currently been surpassed by Linux Mint (and Debian) as the distro with most hits.
Docker 1.12.3 App Container Engine Updates Buildtags for Ubuntu 14.04 LTS ARMhf
Last week, we reported on the release of the second maintenance update to the stable Docker 1.12 series of the open source app container engine, and it now looks like Docker 1.12.3 has been released with more improvements and bug fixes.
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8 posts tagged with slugs.
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Let's go sunning / It's so good for you
Leafy, verdant Elysia chlorotica (the Eastern Emerald Elysia) is a sea slug with a secret: they photosynthesize. These marauding mollusks slurp up chloroplasts from their favorite algal snack, Vaucheria litorea, incorporating them into their own digestive cells and putting them to work soaking up sunshine (and, incidentally, acquiring a healthy green glow). But how? [more inside]
Slug Solos
Saturday Morning Cartoons/Breakfast Danish
The Story of Animation is a tongue-in-cheek educational film about the process of animation, aimed primarily at potential animation clients who are more clueless than most about how these toons get made (and how long it's gonna take and how much it's gonna cost). Made by-and-for graduates of the The Animation Workshop, an animation school in Viborg, Denmark, which has posted A LOT of impressive student works on YouTube... [more inside]
What are nudibranchs? Jewels of the sea. Page after page of photographs of these squishy hermaphrodites.
Life in the Undergrowth
Mating Leopard Slugs entwine - one of the untold wonders of the animal kingdom captured on video.... The BBC gets up close and personal with Life in the Undergrowth in their new wildlife documentary. A must see for any animal, insect or David Attenborough fan... (If the main vid link doesn't work for you try it from here - realplayer needed)
For the gardener who has everything, a slug eating robot
For the gardener who has everything, a slug eating robot will seek and destroy those slimy gastropods destroying the garden. The only downside is having to admit the crappy beer you buy is for yourself and not for your slug traps!
Hey this marshmallow is a little chewier than I like...eeeeuuuwww!!
Hey this marshmallow is a little chewier than I like...eeeeuuuwww!! Girl finds large garden slug in her Rice Krispy Treat...complete with requisite gross-out pic!
Apophallation and you
Apophallation and you - The ex Mrs. Bobbit has nothing on the garden slug, who sometimes must preform apophallation to end the reproduction ritual. Movies like 'Lair of the White Worm' used the imagery of apophallation to scare the crap out of me when I was 14.
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Sexy Katya returns as a blonde and shows us how delicious her pussy looks.
would love to taste that sweet pussy and suck on those great little tits
Pretty face!Beautiful eyes!
Great body!Delicious ass for anal sex!Tight and delicious asshole!
She likes and makes anal sex? JUICY and delicious shaved pussy !TASTY and MEATY clit, pussy lips! Delicious small tities!
wow hot!!
Very hot, ty
Yummy. A delicious babe.


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Whitefish Bay orchestra to put on 'Jungle Jam' children's concert
The Whitefish Bay High School Orchestra will present "Jungle Jam," its annual Music for Munchkins children's concert, Feb. 10 at Whitefish Bay High School, 1200 E. Fairmount Ave., Whitefish Bay.
During the preconcert petting zoo from 12:30 to 1:15 p.m., children of all ages can touch and play stringed instruments. The concert begins at 1:30 p.m., with music from "The Lion King" and the "Pink Panther" theme on the program. »Read Full Article
Video: The Concert Corner - Recapping the Grammys and Matchbox Twenty
So the Grammy recap, the photo gallery and a five memorable Grammy moments blog post weren't the last word on this year's awards. During the Concert Corner this week with CineStars Brittany Umar, we talked about the show's strongest performers. Also discussed: Matchbox Twenty and Phillip Phillips sets at a sold-out Riverside Theater Saturday, and a look at concerts this week.
Banner weeks ahead for Wisconsin books, including the Scott Walker vs. unions faceoff
In the next few weeks, a bounty of nonfiction books by Wisconsin writers will be published, including an account by two Journal Sentinel reporters of the kerfuffle that began in Madison in March 2011, when Gov. Scott Walker and public employe unions battled over changes in state law that ultimately scuttled public employee bargaining rights.
"More than They Bargained For: Scott Walker, Unions, and the Fight for Wisconsin," by Jason Stein and Patrick Marley, will go on sale circa March 22 at local bookstores and online book vendors. Published by the University of Wisconsin Press, "More Than They Bargained For" offers a detailed play-by-play account of the Madison drama, including the Capitol occupation by protestors and the runaway Democratic legislators. Stein and Marley, who work out of the Journal Sentinel's Madison bureau, have added fresh reporting and interviewing to the work they did on the spot. The reporters will have a book launch event 7 p.m. March 26 at Boswell Book Co., 2559 N. Downer Ave. »Read Full Blog Post(14)
Esquire magazine reports bin Laden's slayer offered new identity in Milwaukee
Did the American military offer the man who shot and killed Osama bin Laden a new identity "driving beer truck in Milwaukee"?
Here's what a story from the March issue of Esquire is saying. »Read Full Article(6)
Charles Allis Art Museum serves tea with the Mad Hatter
Tails are optional, but hats are a must at The Charles Allis Art Museum's Mad Hatter Tea on March 9 from 3 p.m. to 5 p.m.
Guests can join "Alice in Wonderland" characters The Mad Hatter, The March Hare, Alice, and The Red Queen for tea, tea sandwiches and sweets, featuring Rishi Tea and Lee John's Catering. »Read Full Article
Big Sean, Rufus Wainwright, Fountains of Wayne among new Milwaukee show announcements
Milwaukee venues kicked off Monday morning announcing a diverse array of concerts for this spring, ranging from a solo performance from torch singer Rufus Wainwright to a show with rapper Big Sean.
On Tap for Today: The Bucks, identity problems and more
Welcome back, Monday. Hope you had a great weekend.
We offer a few waves to keep that weekend spirit. For instance, the Milwaukee Bucks take on the Washington Wizards at 7 p.m. at the BMO Harris Bradley Center. »Read Full Blog Post