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Pathophysiology| October 16 2012
High Glucose Inhibits the Aspirin-Induced Activation of the Nitric Oxide/cGMP/cGMP-Dependent Protein Kinase Pathway and Does Not Affect the Aspirin-Induced Inhibition of Thromboxane Synthesis in Human Platelets
Isabella Russo;
Isabella Russo
Internal Medicine and Metabolic Disease Unit, San Luigi Gonzaga Hospital, Department of Clinical and Biological Sciences, San Luigi Gonzaga School of Medicine, University of Turin, Turin, Italy
Michela Viretto;
Michela Viretto
Cristina Barale;
Cristina Barale
Luigi Mattiello;
Luigi Mattiello
Gabriella Doronzo;
Gabriella Doronzo
Andrea Pagliarino;
Andrea Pagliarino
Franco Cavalot;
Franco Cavalot
Mariella Trovati;
Mariella Trovati
Corresponding author: Mariella Trovati, mariella.trovati@unito.it.
Giovanni Anfossi
Deceased.
Diabetes 2012;61(11):2913–2921
Isabella Russo, Michela Viretto, Cristina Barale, Luigi Mattiello, Gabriella Doronzo, Andrea Pagliarino, Franco Cavalot, Mariella Trovati, Giovanni Anfossi; High Glucose Inhibits the Aspirin-Induced Activation of the Nitric Oxide/cGMP/cGMP-Dependent Protein Kinase Pathway and Does Not Affect the Aspirin-Induced Inhibition of Thromboxane Synthesis in Human Platelets. Diabetes 1 November 2012; 61 (11): 2913–2921. https://doi.org/10.2337/db12-0040
Since hyperglycemia is involved in the "aspirin resistance" occurring in diabetes, we aimed at evaluating whether high glucose interferes with the aspirin-induced inhibition of thromboxane synthesis and/or activation of the nitric oxide (NO)/cGMP/cGMP-dependent protein kinase (PKG) pathway in platelets. For this purpose, in platelets from 60 healthy volunteers incubated for 60 min with 5–25 mmol/L d-glucose or iso-osmolar mannitol, we evaluated the influence of a 30-min incubation with lysine acetylsalicylate (L-ASA; 1–300 μmol/L) on 1) platelet function under shear stress; 2) aggregation induced by sodium arachidonate or ADP; 3) agonist-induced thromboxane production; and 4) NO production, cGMP synthesis, and PKG-induced vasodilator-stimulated phosphoprotein phosphorylation. Experiments were repeated in the presence of the antioxidant agent amifostine. We observed that platelet exposure to 25 mmol/L d-glucose, but not to iso-osmolar mannitol, 1) reduced the ability of L-ASA to inhibit platelet responses to agonists; 2) did not modify the L-ASA–induced inhibition of thromboxane synthesis; and 3) prevented the L-ASA–induced activation of the NO/cGMP/PKG pathway. Preincubation with amifostine reversed the high-glucose effects. Thus, high glucose acutely reduces the antiaggregating effect of aspirin, does not modify the aspirin-induced inhibition of thromboxane synthesis, and inhibits the aspirin-induced activation of the NO/cGMP/PKG pathway. These results identify a mechanism by which high glucose interferes with the aspirin action.
Atherothrombotic cardiovascular events are the leading cause of morbidity and mortality in type 2 diabetes (1). Platelet hyperactivity, a critical factor in the pathogenesis of atherothrombosis (2), plays a major role in this phenomenon (3). Thus, an aggressive antiaggregating treatment with aspirin is strongly recommended for diabetic patients (4). The aspirin-induced prevention of cardiovascular events, however, is lower in diabetes than in the general population (5–7). Among the mechanisms involved in aspirin resistance are the accelerated half-life of circulating platelets, the occurrence of a proinflammatory and prothrombotic status, the presence of an increased oxidative stress responsible for platelet activation through isoprostanes, and the use of inadequate aspirin doses (8–10).
Type 2 diabetes is frequently associated with obesity and insulin resistance; the role of these two conditions on platelet dysfunction and on aspirin resistance has been reviewed (9,11,12). The main feature of diabetes, however, is hyperglycemia, which is involved in the pathogenesis of vascular complications (13); the direct role played by high glucose on platelet sensitivity to aspirin has not been fully investigated thus far. Experimental and clinical investigations have mainly focused on chronic hyperglycemia (14–16); a few studies have evaluated the effects of acute platelet exposure to high glucose in in vitro models (17–19).
Since viability of platelets in vitro is limited to a few hours, studies in vitro are designed only to evaluate whether acute increases in glucose concentrations influence platelet responses to aspirin. This is a relevant topic because the so-called "stress hyperglycemia" worsens the prognosis of acute coronary syndromes (20), and postprandial glycemic excursions are considered a strong cardiovascular risk factor (21); among the pathophysiologic mechanisms involved, the role of oxidative stress has been underlined (21). In type 2 diabetes, postprandial hyperglycemia predicts cardiovascular morbidity and all-cause mortality even when glycated hemoglobin is taken into account (22).
The classic mechanism by which aspirin interferes with platelet responses is the prevention of thromboxane A2 (TXA2) formation by an irreversible acetylation of the catalytic site of cyclooxygenase-1 (23,24). Besides this pivotal action, aspirin increases platelet bioavailability and synthesis of nitric oxide (NO) (25–27) via acetylation of the constitutive nitric oxide synthase (cNOS) (28). As previously reviewed (29), NO is deeply involved in platelet antiaggregation through the synthesis of cGMP and the consequent activation of the cGMP-dependent protein kinase (PKG); the cGMP/PKG system modulates basic mechanisms of platelet activation, such as agonist-induced increases of cytosolic calcium and cytoskeleton protein contraction. A relevant target of PKG is the focal adhesion protein vasodilator-stimulated phosphoprotein (VASP), which PKG preferentially activates via phosphorylation at serine 239 (30); thus, VASP is a mediator of cGMP action involved in platelet inhibitory pathways. Impaired NO synthesis and/or sensitivity plays a crucial role in the platelet dysfunction described in diabetic patients (31).
Short-term incubations of platelets with high glucose in vitro decrease the effects of aspirin on platelet GPIIb-IIIa and P-selectin expression (18) and reduce the aspirin-induced inhibition of platelet aggregation (17,19). It has not been evaluated thus far, however, whether high glucose impairs the ability of aspirin to inhibit thromboxane synthesis or activate the NO pathway; the second phenomenon could be hypothesized because NOS inhibition prevents the effects of high glucose on the aspirin antiaggregating properties (19).
The aims of this study are therefore to investigate whether a short-term platelet exposure to high glucose in vitro modifies the aspirin effects on thromboxane synthesis and/or on the NO/cGMP/PKG pathway activation.
Chemicals.
ADP, amifostine, sodium arachidonate (NaA), trisodium citrate, d-glucose, l-monomethylarginine (l-NMMA), methylene blue (MB), HEPES-Na, PBS, Tween-20, indomethacin, and mannitol were obtained from Sigma-Aldrich (St. Louis, MO). l-[2,3,4,5-3H]Arginine monohydrochloride was obtained from GE Healthcare Europe GmbH (Milan, Italy). The source of the specific antibodies for Western blotting is shown in the section concerning Western blot analysis. Lysine acetylsalicylate (L-ASA) was provided by sanofi-aventis (Milan, Italy). We preferred L-ASA to ASA because it is soluble in water instead of in DMSO or ethanol, which influence platelet function; L-ASA is a soluble salt of acetylsalicylic acid (ASA) that is converted to ASA and is widely used in clinical practice because it presents the powerful antiplatelet effect of ASA with fewer gastrointestinal side effects (32).
Subjects and platelet preparation.
After overnight fasting, we studied 60 healthy volunteers (34 men and 26 women; age = 23.8 ± 0.7 years; BMI = 22.4 ± 0.4 kg/m2), nonsmokers, who denied taking drugs in the previous 2 weeks and had normal fasting and 2-h plasma glucose concentrations after an oral glucose tolerance test, normal insulin sensitivity (HOMA IR = 1.7 ± 0.05), and arterial blood pressure values <140/90 mmHg. They gave informed consent before investigation, and the ethics committee of our hospital approved the study. Venous blood samples were withdrawn without stasis and anticoagulated with 3.8% trisodium citrate, pH 7.4 (volume for volume [v/v], 1/9), for aggregation studies or with citrate-dextrose solution (ACD; v/v, 1/6) for experiments on washed platelets (WPs). Platelet counts were performed on a hematology system of the Bayer Corporation (Tarrytown, NY). Platelet-rich plasma (PRP) was obtained by using the Platelet Function Centrifuge (BioData Corporation, Horsham, PA), designed to provide a rapid separation of PRP by a centrifugation for 30 s and of platelet-poor plasma by a further centrifugation for 120 s. To prepare WPs, ACD-anticoagulated PRP was submitted to further centrifugation at 2,000 g for 10 min. The pellet was washed two times with HEPES-Na buffer (10 mmol/L HEPES Na, 140 mmol/L NaCl, 2.1 mmol/L, MgSO4, 5 mmol/L glucose, pH 7.4). WPs are usually used to measure the NO/cGMP/PKG signaling in platelets (33). They present some degree of activation; actually, the concentrations of the platelet activation marker sP-selectin (ELISA kit; Bender MedSystems GmbH, Vienna, Austria) were similar in PRP and in surnatants of WPs (24.2 ± 1.9 and 25.7 ± 1.7 ng/108 platelets; n = 7; P = NS), indicating that WPs still release P-selectin after removal of the protein contained in the plasma fraction of PRP.
Study design.
Whole blood and platelet samples (PRP and/or WPs) were exposed for 60 min to different d-glucose concentrations (5, 15, and 25 mmol/L) and then incubated for 30 min with L-ASA (1–300 μmol/L). Some experiments have been repeated with 20-min preincubations with the antioxidant agent amifostine (200 μmol/L), the NOS inhibitor l-NMMA (100 μmol/L), or the guanylate cyclase inhibitor MB (50 μmol/L). Some experiments have been carried out with the iso-osmolar control mannitol instead of glucose.
In the different samples, we measured 1) platelet reactivity in high shear-stress conditions in WB; 2) platelet aggregation in PRP in response to NaA (1 mmol/L) or ADP (10 μmol/L); 3) TXB2 concentrations in response to NaA (1 mmol/L) or ADP (10 μmol/L) both in PRP at the end of each aggregation test and in resting WPs; 4) NOS activity in resting WPs; and 5) cGMP production in unstirred PRP and VASP phosphorylated at serine 239 in WPs.
Platelet reactivity in high shear-stress conditions.
Platelet responses were evaluated in whole blood by a Platelet Function Analyzer (PFA-100; Siemens Healthcare Diagnostic Products GmbH, Marburg, Germany), which measures platelet responses under standardized high-shear conditions as a function of the time needed to form a platelet plug, named "closure time" (seconds), within an aperture cut into a platelet-reactive membrane coated with collagen and epinephrine (CEPI) (34).
Platelet aggregation studies.
Platelet aggregation studies were carried out in PRP by following light-scattering changes as described by Born (35) using an eight-channel aggregation system (Platelet Aggregation Profiler, Model PAP-8; BioData Corporation). Platelet aggregation in response to agonists was reported as maximal aggregation. Each aggregation test was recorded for 5 min after the addition of the agonist.
TXB2 synthesis.
In PRP, TXB2 levels were measured at the end of the aggregation tests (i.e., 5 min after the addition of agonists) after blocking platelet responses with indomethacin (10 μmol/L) and 100 μL of ACD; each sample was then spun at 8,000 g for 2 min, and supernatants were stored and frozen at −80°C.
TXB2 was also measured in WPs resuspended in HEPES buffer containing 0.38 mg/mL fibrinogen in the presence of a 60-min preincubation with 5 or 25 mmol/L glucose. WPs were then exposed to L-ASA (300 μmol/L for 30 min) and stimulated by 1 mmol/L NaA, or by 10 μmol/L ADP for 5 min at 37°C. The reaction was stopped by centrifugation at 2,300 g for 5 min at 4°C, and the supernatants were stored and frozen at −80°C. TXB2 was measured by using the EIA kit (Cayman Chemical Company, Ann Arbor, MI).
Platelet NOS activity.
NOS activity was measured by evaluating the conversion of l-[3H]arginine to l-[3H]citrulline (36). Actually, NOS induces the conversion of l-arginine to l-citrulline and to NO with a 1:1 stoichiometry (36). In brief, WPs were resuspended for 60 min in HEPES buffer in the presence of 5 and 25 mmol/L glucose and then exposed to L-ASA (300 μmol/L for 30 min) together with 1 μCi l-[3H]arginine (in HEPES-Na containing CaCl2); platelet reactions were stopped by centrifugation at 2,000 g for 10 min; platelet lysates were mixed with Dowex cation exchange resin (Na+ form) to absorb l-arginine. l-[3H]citrulline in the supernatant was measured by liquid scintillation counting. Results were expressed as pmol l-citrulline/min/mg protein.
cGMP production.
cGMP was measured in unstirred PRP samples (500 μL) incubated at 37°C for 60 min with 5 and 25 mmol/L glucose and then exposed to L-ASA (300 μmol/L for 30 min). Platelet reactions were stopped with 30% trichloroacetic acid (100 μL). Precipitated proteins were removed by 20-min centrifugation at 2,000 g at 4°C. After the addition of 1 mol/L of HCl (100 μL), the supernatant was submitted to 10 extractions with ethylic ether to remove trichloroacetic acid. Samples were then lyophilized and kept at −80°C until determination. cGMP measurement was carried out using a radioimmunoassay kit (Immuno Biological Laboratories, Hamburg, Germany). Data are expressed as pmol/109 platelets.
VASP phosphorylation at serine 239.
For detection of VASP phosphorylated at serine 239, WPs were incubated with 300 μmol/L L-ASA for 30 min in the presence of a 60-min preincubation with 5 and 25 mmol/L glucose and processed as previously described (37). After Western blot, membranes were incubated with a monoclonal antibody recognizing VASP phosphorylated at serine 239 (1:1,000; Merck KGaA, Darmstadt, Germany) and then with horseradish peroxidase–conjugated rabbit anti-mouse IgG (1:3,000; Santa Cruz Biotechnology, Santa Cruz, CA). After additional washes, membranes were submitted to chemiluminescence (GE Healthcare Europe GmbH), and the density of bands was analyzed with Kodak 1D Image Analysis software.
Values in the text and figures are means ± SEM. Statistical analysis was performed with different approaches in the different protocols according to the scale type of data: 1) when only two measures had to be compared, we used Student t test for paired data when appropriate; 2) results concerning PFA-100 have been evaluated with the nonparametric Wilcoxon signed rank test because closure time is a harmonic variable with a maximum of 300 s, which does not fluctuate proportionally within the scale; 3) results concerning platelet aggregation responses and agonist-induced thromboxane synthesis have been evaluated with a parametric generalized linear model two-factor within subject ANOVA for repeated measures (n glucose concentration × m L-ASA concentration). All data analyses were performed using SPSS Statistics version 17.0 (SPSS 2008).
Platelet function evaluated by PFA-100.
Figure 1 shows the L-ASA effects on PFA-100 CEPI closure time in the presence of three different glucose concentrations (n = 34). L-ASA increased time closure (Wilcoxon signed rank test P < 0.0001 between every L-ASA concentration), but glucose levels did not modify closure time responses in the presence of the different L-ASA concentrations.
Effect of platelet exposure to different L-ASA concentrations on closure time of PFA-100 CEPI in the presence of different glucose concentrations. Box plots range from the first to the third quartile; bold line in the boxes represents the median. Wiskers range from the minimum to the maximum of the measured values in the absence of outliers. Dots represent outliers with values between 1.5 and 3 (interquartile range); asterisks represent extreme outliers. Statistical analysis, carried out by Wilcoxon signed rank test, shows that glucose (5, 15, and 25 mmol/L; n = 34) did not modify closure time responses in the presence of the different L-ASA concentrations.
In response to NaA.
Glucose 25 mmol/L attenuated the inhibitory effect of L-ASA on NaA-induced platelet aggregation (n = 24). In particular, a two-factor within subject ANOVA 3 × 5 (glucose concentration [5, 15, and 25 mmol/L] × L-ASA concentration [0, 1, 5, 50, and 100 μmol/L]) shows that 1) in the absence of L-ASA, high glucose did not modify platelet aggregation; 2) the main effect (i.e., on the whole sample) of L-ASA was significant starting from the concentration of 5 μmol/L (P < 0.0001 for all the concentrations vs. baseline); 3) the inhibitory effect of L-ASA was significant starting from the concentration of 1 μmol/L in the presence of 5 mmol/L glucose (the worst P value =0.009 vs. baseline) and starting from 5 μmol/L L-ASA in the presence of 15 and 25 mmol/L glucose (P < 0.0001 for all concentrations vs. baseline); and 4) the inhibitory effects of 5 and of 50 μmol/L L-ASA did not differ in the presence of 5 vs. 15 mmol/L glucose, whereas it differed in the presence of 5 vs. 25 mmol/L glucose (P < 0.0001) and 15 vs. 25 mmol/L glucose (P < 0.0001) (Fig. 2A).
Effect of platelet exposure to different glucose concentrations on the L-ASA–induced inhibition of platelet aggregation responses to NaA and ADP. Statistical analysis, carried out by two-factor within subject ANOVA for repeated measures, shows that the response to L-ASA on platelet aggregation induced by NaA (A) and ADP (B) did not differ between 5 and 15 mmol/L glucose, whereas it differed between 5 and 25 mmol/L glucose (P < 0.0001 for both agonists) and between 15 and 25 mmol/L glucose (P < 0.0001 for both agonists; n = 24).
In the presence of 20 mmol/L mannitol, the inhibitory effect of L-ASA on NaA-induced platelet aggregation was not different from that observed in the presence of 5 mmol/L glucose (n = 8; P = NS for all L-ASA concentrations). In particular, the inhibition exerted by 50 μmol/L L-ASA was 52.44 ± 2.85% with 20 mmol/L mannitol vs. 54.25 ± 1.42% with 5 mmol/L glucose.
In response to ADP.
Glucose (25 mmol/L) attenuated the inhibitory effect of L-ASA on ADP-induced platelet aggregation (n = 24). In particular, a two-factor within subject ANOVA 3 × 4 (glucose concentration [5, 15, and 25 mmol/L] × L-ASA concentration [0, 75, 150, and 300 μmol/L]) shows that 1) in the absence of L-ASA, high glucose did not modify platelet aggregation; 2) the concentration-dependent inhibitory main effect (i.e., on the whole sample) of L-ASA on ADP-induced aggregation was significant starting from the concentration of 75 μmol/L (P < 0.0001 for all the concentrations vs. baseline); 3) the inhibitory effect of L-ASA was significant starting from the concentration of 75 μmol/L in the presence of 5 and 15 mmol/L glucose (P < 0.0001 for all concentrations vs. baseline) but only from 150 μmol/L in the presence of 25 mmol/L glucose (P < 0.0001 for 150 and 300 μmol/L L-ASA vs. baseline); and 4) the inhibitory effects of 75, 150, and 300 μmol/L L-ASA did not differ in the presence of 5 vs. 15 mmol/L glucose, whereas they differed in the presence of 5 vs. 25 mmol/L glucose (P < 0.0001) and 15 vs. 25 mmol/L glucose (P < 0.0001) (Fig. 2B).
In the presence of 20 mmol/L mannitol, the inhibitory effect of L-ASA on ADP-induced platelet aggregation was not different from that observed in the presence of 5 mmol/L glucose (n = 8; P = NS for all L-ASA concentrations). In particular, the inhibition exerted by 150 μmol/L L-ASA was 35.10 ± 1.98% with 20 mmol/L mannitol vs. 36.25 ± 2.42% with 5 mmol/L glucose.
The influence of amifostine.
The results are shown in Fig. 3. In the presence of the radical oxygen scavenger amifostine, the L-ASA–induced inhibition on platelet aggregation of NaA and ADP did not differ in experiments performed at 5 vs. 25 mmol/L glucose (n = 9). Amifostine, therefore, reversed the inhibitory effect exerted by 25 mmol/L glucose on the L-ASA effects, without modifying platelet aggregation in the absence of L-ASA or the L-ASA effect in the presence of 5 mmol/L glucose.
Effect of preincubation with amifostine on the L-ASA–induced inhibition of platelet aggregation in response to NaA and ADP in the presence of different glucose concentrations. At 5 mmol/L glucose (n = 9): amifostine vs. baseline and amifostine + L-ASA vs. L-ASA alone, P = NS for platelet aggregation induced by both NaA (A) and ADP (B). At 25 mmol/L glucose (n = 9): amifostine vs. baseline, P = NS for platelet aggregation induced by both NaA (A) and ADP (B); amifostine + L-ASA vs. L-ASA alone, P = 0.002 (Student paired t test) for platelet aggregation induced by NaA (A) and P < 0.0001 (Student paired t test) for platelet aggregation induced by ADP (B).
Thromboxane synthesis
In PRP.
As shown in Fig. 4A and B, L-ASA induced a concentration-dependent reduction of TXB2 measured at the end of both NaA- and ADP-elicited aggregation (n = 24, main effect of L-ASA; P < 0.0001 for both agonists); TXB2 values did not differ between 5 and 25 mmol/L glucose either in the absence of L-ASA or in the presence of each L-ASA concentration.
Effect of platelet exposure to different glucose concentrations on the L-ASA–induced inhibition of thromboxane synthesis in response to NaA and to ADP. Statistical analysis, carried out by two-factor within subject ANOVA for repeated measures, shows that TXB2 values did not differ between 5 and 25 mmol/L glucose either in the absence of L-ASA or in the presence of each L-ASA concentration for both NaA (n = 24) (A) and ADP (n = 24) (B).
In WPs.
In unstirred WPs (n = 8), baseline TXB2 concentrations were 27.9 ± 0.9 and 27.03 ± 0.31 ng/mL in the presence of 5 and 25 mmol/L glucose, respectively (P = NS); high glucose failed to modify the TXB2 response to NaA and ADP, both in the presence and in the absence of L-ASA. In particular, 1) after NaA stimulation, TXB2 concentrations in the presence of 5 and 25 mmol/L glucose were 56.8 ± 3.9 and 56.9 ± 3.3 ng/mL without L-ASA (P = NS), 27.9 ± 2.8 and 29.8 ± 2.5 ng/mL with L-ASA (P = NS); 2) after ADP stimulation, TXB2 concentrations in the presence of 5 and 25 mmol/L glucose were 31.9 ± 2.5 and 31.7 ± 2.7 ng/mL without L-ASA (P = NS), 17.5 ± 1.4 and 17.1 ± 1.7 ng/mL with L-ASA (P = NS).
Activation of the NO/cGMP/PKG pathway
The effect of L-ASA on platelet NOS activity in the presence of 5 and 25 mmol/L glucose is shown in Fig. 5 (n = 12). In experiments carried out at 5 mmol/L glucose, 300 μmol/L L-ASA increased platelet synthesis of NO (P < 0.0001), whereas in experiments carried out at 25 mmol/L glucose, the NO values without and with 300 μmol/L L-ASA did not differ. Amifostine restored the L-ASA ability to increase NO synthesis in experiments carried out at 25 mmol/L glucose (P < 0.04 vs. amifostine alone), without modifying NO synthesis in the absence of L-ASA or the L-ASA effect at 5 mmol/L glucose.
Effect of L-ASA on platelet NOS activity in the presence of different glucose concentrations with and without preincubation with amifostine. At 5 mmol/L glucose (n = 12): L-ASA vs. baseline, P < 0.0001; amifostine vs. baseline and amifostine + L-ASA vs. L-ASA alone, P = NS (Student paired t test). At 25 mmol/L glucose (n = 12): L-ASA vs. baseline, P = NS; amifostine vs. baseline, P = NS; amifostine + L-ASA vs. L-ASA alone, P < 0.05; amifostine + L-ASA vs. amifostine alone, P < 0.04 (Student paired t test).
In experiments carried out at 5 mmol/L glucose in the presence of the NOS inhibitor l-NMMA, NO values without and with 300 μmol/L L-ASA did not differ (12.5 ± 1.3 and 14.4 ± 1.4 fmol [3H]citrulline/min/mg protein, respectively) (n = 12).
Finally, in experiments carried out in the presence of 20 mmol/L mannitol, 300 μmol/L L-ASA increased NO synthesis from 11.8 ± 2.8 to 25.3 ± 3.10 [3H]citrulline/min/mg protein (P < 0.0001), reaching values that did not differ from those measured at 5 mmol/L glucose, which were higher than those measured at 25 mmol/L glucose (n = 12; P < 0.0001).
Data are shown in Fig. 6. In the presence of 5 mmol/L glucose, 300 μmol/L L-ASA increased intraplatelet cGMP (n = 12; P < 0.003); this effect is attributable to the NO-induced activation of guanylate cyclase, as it was completely prevented by both l-NMMA and MB.
Effect of L-ASA on platelet cGMP in the presence of different glucose concentrations without and with the guanylate cyclase inhibitor MB and the NOS inhibitor l-NMMA. At 5 mmol/L glucose (n = 12): L-ASA vs. baseline, P < 0.003; MB + L-ASA vs. baseline, P = NS; l-NMMA + L-ASA vs. baseline, P = NS (Student paired t test). At 25 mmol/L glucose (n = 12): L-ASA vs. baseline, without or with MB or l-NMMA, P = NS (Student paired t test).
The L-ASA effect on cGMP was absent in experiments carried out at 25 mmol/L glucose (n = 12). The inhibitory effect of high glucose was independent of its osmotic action because in the presence of 20 mmol/L mannitol L-ASA induced a significant increase of cGMP from 13.1 ± 2.5 to 27.5 ± 2.4 pmol/109 platelets (P < 0.0001); the cGMP values reached after L-ASA incubation in the presence of 20 mmol/L mannitol did not differ from those reached in the presence of 5 mmol/L glucose and were significantly higher than those reached in the presence of 25 mmol/L glucose (P < 0.0001).
As shown in Fig. 7, in the presence of 5 mmol/L glucose, a 30-min platelet exposure to 300 μmol/L L-ASA caused a significant increase of VASP phosphorylated at serine 239 (n = 6; P < 0.001); this effect was absent in the presence of 25 mmol/L glucose (n = 6; P = NS vs. without L-ASA).
Effect of L-ASA on platelet VASP phosphorylation at serine 239 in the presence of different glucose concentrations. At 5 mmol/L glucose (n = 6): L-ASA vs. baseline, P < 0.001 (Student paired t test). At 25 mmol/L glucose (n = 6): L-ASA vs. baseline, P = NS (Student paired t test).
This study shows that in vitro exposure to high glucose (i.e., 25 mmol/L) of platelets from healthy subjects reduces the antiaggregating action of aspirin, an effect blunted by the antioxidant agent amifostine. It also shows that high glucose does not affect the ability of aspirin to inhibit thromboxane synthesis but impairs the ability of aspirin to activate the NO/cGMP/PKG pathway. Furthermore, it demonstrates that high glucose per se does not influence platelet aggregation in response to agonists, thromboxane synthesis, and the NO/cGMP/PKG pathway.
Thus, high glucose reduces the antiaggregating properties of aspirin only at very high concentrations; the extent of inhibition, although significant, is modest. In our experimental conditions, we did not observe the dramatic dose-dependent inhibition of platelet sensitivity to aspirin described by other authors (17,19).
Is it possible to translate results obtained in vitro to in vivo conditions? It is interesting to observe that the lack of effects on platelet aggregation and platelet sensitivity to aspirin exerted by a 15 mmol/L glucose incubation in our in vitro study is in agreement with the results of studies carried out in vivo; actually, when acute hyperglycemia (∼14 mmol/L) was induced by the hyperglycemic clamp in type 2 diabetic patients, glucose did not affect platelet sensitivity to agonists and did not modify the antiaggregating effects of aspirin (38).
In our study, however, in vitro exposure to high glucose failed to increase the shear stress–induced platelet activation evaluated by PFA-100 even at 25 mmol/L, whereas acute hyperglycemia induced in vivo by the hyperglycemic clamp at ∼14 mmol/L increased the shear stress–induced platelet activation (39); this discrepancy is likely attributable to the fact that the results obtained by the hyperglycemic clamp correlated with the increase of circulating levels of von Willebrand factor, which reflects the effects of high glucose on vascular endothelium in vivo (38).
Thus, the translation of results obtained with glucose incubated in vitro to in vivo conditions of acute hyperglycemia is not immediate. Actually, the so-called "hyperglycemic spikes" may affect other cells in vivo (such as endothelial cells and leukocytes), which can influence platelet function.
In our study, glucose impairs the L-ASA effects at 25 mmol/L. We observed that when PRP from aspirin-sensitive nondiabetic subjects on a chronic aspirin treatment is incubated in vitro with this glucose concentration, there is an increase of platelet responses to agonists, showing that high glucose reduces the aspirin action also when the drug is assumed in vivo (40). No in vivo study, however, has thus far evaluated the influence on platelets of a short-term increase of glucose, reaching the concentration of 25 mmol/L. This phenomenon occurs in clinical practice in type 1 and, more rarely, type 2 diabetes in high-stress conditions (infections, acute coronary syndromes, etc.), and therefore in states of severe insulin deficiency and resistance, and is accompanied by profound hormonal and metabolic abnormalities that can influence platelets and other cells in addition to high glucose. Further studies are needed to explore the changes in aspirin sensitivity occurring in these in vivo settings. The contribution of our in vitro investigation is to show the effects of high glucose isolated from those of other metabolic and hormonal molecules altered in acute hyperglycemic conditions and the effects on platelets isolated from those occurring in other cells able to influence platelet function.
From the biochemical point of view, our study originally shows that platelet exposure to high glucose does not modify either baseline thromboxane production or the ability of aspirin to inhibit agonist-induced thromboxane synthesis but blunts the aspirin-induced activation of the NO/cGMP/PKG pathway.
Furthermore, our study provides the first demonstration that in human platelets aspirin increases not only NO synthesis and cGMP concentrations but also VASP phosphorylation at serine 239, and that high glucose inhibits the activating phosphorylation of VASP induced by aspirin.
The inhibitory effect of high glucose on the aspirin-induced activation of the NO pathway is not due to an osmotic mechanism, because it is not reproduced by iso-osmolar mannitol. On the other hand, the ability of the antioxidant agent amifostine to restore the aspirin-induced increase of NO production in the presence of high glucose strongly supports the role of oxidative stress, which is deeply involved in the reduction of NO synthesis/bioavailability in platelets (41). Amifostine, as is well known, is an organic thiophosphate prodrug that acts as a potent intracellular scavenger of free radicals (42). Since in our study high glucose does not influence the NO/cGMP/PKG pathway per se, in keeping with a previous observation (43), these results indicate that, by oxidative stress, it interplays with the mechanism by which aspirin activates the same pathway. Because aspirin activates cNOS by acetylation (28), it could be hypothesized that reactive oxygen species interfere with this acetylation process.
In conclusion, the current study demonstrates that a short-term platelet exposure to very high glucose concentrations modestly inhibits platelet responses to agonists by a mechanism likely attributable to oxidative stress; furthermore, it shows for the first time that high glucose does not modify the ability of aspirin to reduce thromboxane synthesis but inhibits the ability of aspirin to activate the antiaggregating pathway NO/cGMP/PKG. The short-term viability of platelets for in vitro studies does not allow long-term incubations; thus, our results provide information concerning mechanisms involved in the effects of "stress hyperglycemia" (20) or "postprandial spikes" (21), without excluding that smaller glucose concentrations could chronically affect platelet function playing a role in the "aspirin resistance" described in diabetes, a condition in which an effective platelet antiaggregation is of crucial importance (44).
This study was supported by a grant to M.T. from the European Foundation for the Study of Diabetes/sanofi-aventis European Programme (2008) entitled "Macrovascular Complications and Blood Glucose Abnormalities."
No potential conflicts of interest relevant to this article were reported.
I.R., M.T., and G.A. conceived and designed the study, collected and interpreted data, and wrote the manuscript. M.V., C.B., L.M., and G.D. contributed to data collection and results interpretation. A.P. contributed to results interpretation and statistical analysis. F.C. contributed to results interpretation and discussion. M.T. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Stamler
Vaccaro
Neaton
Diabetes, other risk factors, and 12-yr cardiovascular mortality for men screened in the Multiple Risk Factor Intervention Trial
Davì
Platelet activation and atherothrombosis
Vinik
Erbas
Pittenger
Platelet dysfunction in type 2 diabetes
Standards of medical care in diabetes—2011
Ajjan
Aspirin resistance and diabetes mellitus
Angiolillo
Antiplatelet therapy in diabetes: efficacy and limitations of current treatment strategies and future directions
De Berardis
Strippoli
Aspirin for primary prevention of cardiovascular events in people with diabetes: meta-analysis of randomised controlled trials
Aspirin: promise and resistance in the new millennium
Arterioscler Thromb Vasc Biol
Anfossi
Resistance to aspirin and thienopyridines in diabetes mellitus and metabolic syndrome
Curr Vasc Pharmacol
Sweeny
Gorog
Fuster
Antiplatelet drug 'resistance'. Part 1: mechanisms and clinical measurements
Nat Rev Cardiol
Platelet dysfunction in central obesity
Nutr Metab Cardiovasc Dis
Santilli
Vazzana
Platelet activation in obesity and metabolic syndrome
Obes Rev
;13:27–42
Brownlee
The pathobiology of diabetic complications: a unifying mechanism
Watala
Golanski
Pluta
Reduced sensitivity of platelets from type 2 diabetic patients to acetylsalicylic acid (aspirin)-its relation to metabolic control
Thromb Res
Ulicna
High glucose contributes to aspirin insensitivity in streptozotocin-diabetic rats: a multiparametric aggregation study
Blood Coagul Fibrinolysis
Hailpern
Billett
Aspirin resistance associated with HbA1c and obesity in diabetic patients
J Diabetes Complications
De La Cruz
Arrebola
Influence of glucose concentration on the effects of aspirin, ticlopidine and clopidogrel on platelet function and platelet-subendothelium interaction
Eur J Pharmacol
Le Guyader
Davis-Gorman
McDonagh
Inhibition of platelet GPIIb-IIIa and P-selectin expression by aspirin is impaired by stress hyperglycemia
Kobzar
Mardla
Samel
Short-term exposure of platelets to glucose impairs inhibition of platelet aggregation by cyclooxygenase inhibitors
Malmberg
Gerstein
Stress hyperglycaemia and increased risk of death after myocardial infarction in patients with and without diabetes: a systematic overview
Ceriello
Colagiuri
International Diabetes Federation guideline for management of postmeal glucose: a review of recommendations
Cavalot
Pagliarino
Postprandial blood glucose predicts cardiovascular events and all-cause mortality in type 2 diabetes in a 14-year follow-up: lessons from the San Luigi Gonzaga Diabetes Study
Awtry
Loscalzo
Platelet-active drugs : the relationships among dose, effectiveness, and side effects
O'Kane
Aspirin modifies nitric oxide synthase activity in platelets: effects of acute versus chronic aspirin treatment
Cardiovasc Res
Chakraborty
Banerjee
Inhibition of human blood platelet aggregation and the stimulation of nitric oxide synthesis by aspirin
Madajka
Malinski
Effect of aspirin on constitutive nitric oxide synthase and the biovailability of NO
Xie
Aspirin acetylates nitric oxide synthase type 3 in platelets thereby increasing its activity
Gkaliagkousi
Platelet-derived nitric oxide signaling and regulation
Circ Res
cAMP- and cGMP-dependent protein kinase in vitro and in intact human platelets
J Biol Chem
Mularoni
Burzacca
Platelet resistance to nitrates in obesity and obese NIDDM, and normal platelet sensitivity to both insulin and nitrates in lean NIDDM
Majluf-Cruz
Chavez-Ochoa
Effect of combined administration of clopidogrel and lysine acetylsalicylate versus clopidogrel and aspirin on platelet aggregation and activated GPIIb/IIIa expression in healthy volunteers
Kobsar
Koessler
Kehrer
Gambaryan
The thrombin inhibitors hirudin and Refludan(®) activate the soluble guanylyl cyclase and the cGMP pathway in washed human platelets
Thromb Haemost
Favaloro
Clinical utility of the PFA-100
Semin Thromb Hemost
GVR
Aggregation of blood platelets by adenosine diphosphate and its reversal
Horinouchi
β(2)-adrenoceptors activate nitric oxide synthase in human platelets
Doronzo
Platelet resistance to the antiaggregatory cyclic nucleotides in central obesity involves reduced phosphorylation of vasodilator-stimulated phosphoprotein
Clin Chem
Gresele
Marzotti
Guglielmini
Hyperglycemia-induced platelet activation in type 2 diabetes is resistant to aspirin but not to a nitric oxide-donating agent
Acute, short-term hyperglycemia enhances shear stress-induced platelet activation in patients with type II diabetes mellitus
J Am Coll Cardiol
Frascaroli
Mattiello
Aspirin resistant subjects present a proinflammatory milieu with an increased oxidative stress: in these conditions, high glucose fails to influence platelet responses to agonists
[Abstract]
Platelet resistance to the antiaggregating effect of N-acetyl-L-cysteine in obese, insulin-resistant subjects
Marzatico
In vitro antioxidant properties of amifostine (WR-2721, Ethyol)
Cancer Chemother Pharmacol
High glucose rapidly activates the nitric oxide/cyclic nucleotide pathway in human platelets via an osmotic mechanism
Colwell
The platelet in diabetes: focus on prevention of ischemic events
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License .


text:
Ditech sells Reverse Mortgage Solutions to Mortgage Assets Management
Struggling nonbank completes sale of reverse mortgage business
October 1, 2019, 4:03 pm By Ben Lane
When the federal judge overseeing the bankruptcy of Ditech Holding approved the struggling nonbank's sale of its forward and reverse mortgage businesses to New Residential Investment and Mortgage Assets Management, it was only a matter of time until those deals were completed.
As it turns out, that "matter of time" ended up being only a few days.
Earlier this year, Ditech agreed to sell its forward mortgage originations and servicing businesses to New Residential and the stock and assets of its reverse mortgage business, Reverse Mortgage Solutions, to Mortgage Assets Management.
Late last week, the United States Bankruptcy Court for the Southern District of New York approved the sale of both companies, and Monday, Ditech completed the sale of Reverse Mortgage Solutions to Mortgage Assets Management.
Under the terms of the agreement, Mortgage Assets acquired "certain stock and assets" associated with Reverse Mortgage Solutions, and agreed to maintain the current operations of RMS as a wholly-owned subsidiary.
According to Ditech, RMS is "continuing to serve its customers in the ordinary course."
Ditech also said that it expects to close on the sale of its forward mortgage business to New Residential "in the coming days."
Thomas Marano, Ditech Holding's chairman of the board and CEO, said the company is "pleased" to complete the sale.
"We are pleased to complete this sale, which we believe maximizes the value of the RMS business and ensures that customers will continue to receive the comprehensive suite of services they expect from RMS," Marano said. "We have worked closely with the team at Mortgage Assets to ensure a smooth transition for customers. I would like to thank the employees of RMS for their contributions and we wish them well as part of Mortgage Assets."
The sale comes after years of financial trouble for Ditech, the nonbank formerly known as Walter Investment Management.
The company suffered years of financial losses, culminating in the company filing for bankruptcy. The company then completed a restructuring plan that eliminated $800 million in corporate debt, changed its name, and emerged from bankruptcy a year later.
But that wasn't enough to salvage the company, as Ditech filed for Chapter 11 again just 14 months later. This time, it included its subsidiaries, Ditech Financial and Reverse Mortgage Solutions, in its restructuring plan.
And now, the company has sold off one of its main subsidiaries and will complete the sale of the other in a matter of days.

redpajama_set_name: RedPajamaCommonCrawl


text:
DominzyLoaded Tech Hacks Phone Tech Tech News Technology Apple Is Offering One Million Dollars To Anyone That Can Hack an iPhone
Apple Is Offering One Million Dollars To Anyone That Can Hack an iPhone
Dominzy 2:09 am Hacks Phone Tech Tech News Technology
Apple is making some major changes to the bug-bounty program it introduced in 2016, including the introduction of a new million-dollar reward.
Apple has massively increased the amount it's offering hackers for finding vulnerabilities in iPhones and Macs, up to $1 million. It's by far the highest bug bounty on offer from any major tech company.
The company says it will pay out $1 million to security researchers who can carry out what is known as a zero-click full chain kernel execution attack with persistence. That means anyone who can get to the core of Apple's iOS operating system and gain control of an iPhone in a way that wouldn't require any user interaction would be eligible for the payout, as Forbes and TechCrunch explain.
That's a substantial difference from the $200,000 maximum it paid out to researchers when the program launched. It's also the biggest bug-bounty reward offered by a major technology company, according to Forbes. Those who spot a vulnerability in a beta version of Apple's software before it launches can also receive a 50% bonus.
Apple announced the changes to its bug-bounty program during the Black Hat cybersecurity conference in Las Vegas alongside other critical updates.
ALSO READ: How To Create And Monetize A Blog For Free
In addition to the new $1 million reward, Apple also revealed that it's expanding the program to its other platforms such as macOS, tvOS, and watchOS, the software that powers its Mac, Apple TV, and Apple Watch products. The company is also nixing the program's invite-only requirement and is opening it to all researchers who wish to participate.
Simple Tips On How To Get Real Instagram Followers...
List Of Countries Where Whatsapp Has Been Banned
Apple Is Offering One Million Dollars To Anyone Th...
JUMIA Agent Seminar Registeration
A New Operating System Has Been Launched To Battle...
How To Create A Single Page Website Without Any Co...


text:
Q: Magento Contact Form - been receiving email from myself For some reason, when a customer submit the contact form, it appears in my gmail that the email was sent from myself, not from my customer.
Please check out the pictures so you know what I am talking about.
http://i.stack.imgur.com/QsACc.jpg
This image shows the email came from myself
http://i.stack.imgur.com/nghG2.jpg
Look at the arrow, this is what I see every email that comes from the contact from. Same name, same title.
This is really annoying because when many people use this, there is no way I can tell which one is which.
This is my contact page: meome.vn/lien-he
There might be some code to put in the email template that I don't know. Anyway if anyone knows how to fix this, please help me. I really appreciate it.

A: Did you check your email configuration in the backend.
Admin -> System -> configuration -> Store Email Addressess and
Admin -> System -> configuration -> Contacts -> Email options

A: Technically, this is a duplicate of Change 'From' field of magento contact form email to the sender but I put a complete and thorough answer here. A simple core hack is one answer provided there.
I am determined to not hack core files, so I solved this problem by making a custom controller. I read up and it seemed easy enough... and also no extensions on the market offer the goals I set out to accomplish: 1) have customer email & name on the From; 2) simple human input for anti spam; and 3) a couple custom fields, 3 of which are actually product attributes.
The files to accomplish this are:
$ find -type f
./Cycleworks/Cycleworks_ContactExtended.xml
./Cycleworks/ContactExtended/controllers/IndexController.php
./Cycleworks/ContactExtended/Helper/Data.php
./Cycleworks/ContactExtended/etc/config.xml

And now for the files themselves... The first XML file tells Magento about your custom override.
// copy this to app/etc/modules/
./Cycleworks/Cycleworks_ContactExtended.xml
<?xml version="1.0"?>
<config>
    <modules>
        <Cycleworks_ContactExtended>
            <active>true</active>
            <codePool>local</codePool>
        </Cycleworks_ContactExtended>
    </modules>
</config>

The remainder of the files go in app/code/local/. Below, I copied the postAction() function from the original controller and then added my code at the top and then made the one change in ->sendTransactional()
./Cycleworks/ContactExtended/controllers/IndexController.php
<?php
require_once 'Mage/Contacts/controllers/IndexController.php';
class Cycleworks_ContactExtended_IndexController extends Mage_Contacts_IndexController
{
    public function postAction()
    {
    $post = $this->getRequest()->getPost();
    if ( $post ) {
        if( stripos( $post["people"],"tires") ===FALSE ){
            Mage::getSingleton('customer/session')->addError("Please correctly answer the question to confirm you are human.
\"".$this->getRequest()->getPost("people")."\" is not correct.");
                $this->_redirect('*/*/');
                return;
        }
        $extras=Array( "bike_year","bike_make","bike_model","bike_model_ext" );
        foreach($extras as $field) {
            if( $post[$field] == "empty" )
                $post[$field]= "----";
        }
        $comment = $post['comment']."\nMage::getStoreConfig(self::XML_PATH_EMAIL_SENDER)=\n'".Mage::getStoreConfig(self::XML_PATH_EMAIL_SENDER)."'";
        $post['comment']= nl2br($comment);

        $translate = Mage::getSingleton('core/translate');
        /* @var $translate Mage_Core_Model_Translate */
        $translate->setTranslateInline(false);
        try {
            ...
            ...
            ...
            $mailTemplate->setDesignConfig(array('area' => 'frontend'))
                ->setReplyTo($post['email'])
                ->sendTransactional(
                    Mage::getStoreConfig(self::XML_PATH_EMAIL_TEMPLATE),
                    array( 'name'=>$post['name'],'email'=> $post['email'] ),        // Mage::getStoreConfig(self::XML_PATH_EMAIL_SENDER), //
                    Mage::getStoreConfig(self::XML_PATH_EMAIL_RECIPIENT),
                    null,
                    array('data' => $postObject)
                );
            ...
            ...
            ...
    }
}

Nice and empty shell. And yes, these all have opening <?php tags but not closing ones??
./Cycleworks/ContactExtended/Helper/Data.php
<?php
class Cycleworks_ContactExtended_Helper_Data extends Mage_Core_Helper_Abstract
{

}

And the XML in the custom module:
./Cycleworks/ContactExtended/etc/config.xml
<?xml version="1.0"?>
<config>
    <modules>
        <Cycleworks_ContactExtended>
            <version>0.0.01</version>
        </Cycleworks_ContactExtended>
    </modules>
    <frontend>
        <routers>
            <contacts>
                <args>
                    <modules>
                        <Cycleworks_ContactExtended before="Mage_Contacts">Cycleworks_ContactExtended</Cycleworks_ContactExtended>
                    </modules>
                </args>
            </contacts>
        </routers>
    </frontend>
    <global>
        <helpers>
            <contactextended>
                <class>Cycleworks_ContactExtended_Helper</class>
            </contactextended>
        </helpers>
    </global>
</config>

That's all the backend. As for the form itself, I added this code to form.phtml below the comments block and above the closing
 tag. For most people this file is in app/code/design/frontend/default/default/template/contacts. Since I have a TM template that I purchased, mine is in default/a034/template/contacts
<?php
$confirm_people_question="Motorcycles have two of these and rhymes with plires";    // CKCK form anti-spam
?>

    *<?php echo $confirm_people_question ?>

        <input name="people" id="people" title="Please confirm you are people" value="" class="required-entry input-text" type="text" />

<?php
// from http://www.sharpdotinc.com/mdost/2009/04/06/magento-getting-product-attributes-values-and-labels/
$wanted=Array("make","model","engine_size");    // note that each attribute needs to be searchable
$attributes = Mage::getModel('catalogsearch/advanced')->getAttributes();    // $productAttrs = Mage::getResourceModel('catalog/product_attribute_collection');
$attributeArray=array();
foreach($attributes as $a){
    if(  in_array( $a->getAttributeCode(), $wanted) ){
        foreach($a->getSource()->getAllOptions(false) as $option){
            $attributeArray[$a->getAttributeCode()][$option['value']] = $option['label'];
        }
    }
}

?>

    Year

        <select id="year" name="bike_year">
            <option value="empty"></option>
            <?  for( $idx=date("Y"); $idx >= 1985; $idx-- )
                    echo "                      <option value=\"$idx\">$idx</option>\n";
            ?>
        </select>

    Make

        <select id="make" name="bike_make">
            <option value="empty"></option>
            <?  foreach( $attributeArray['make'] as $id => $brand )
                    echo "                      <option value=\"$brand\">$brand</option>\n";
            ?>
        </select>

    Model

        <select id="model" name="bike_model">
            <option value="empty"></option>
            <?  foreach( $attributeArray['model'] as $id => $model )
                    echo "                      <option value=\"$model\">$model</option>\n";
            ?>
        </select>

        More

            <input type="text" size="15" value="" id="model_ext" name="bike_model_ext" class="input-text">

I almost forgot, the final key to the puzzle is the mail template in the admin area: System - Transactional Emails. Find your HTML contact template (or make a new one and do not convert it to plain text) and this is what I've got:

Name	{{var data.name}}

E-mail	{{var data.email}}

Telephone	{{var data.telephone}}

<fieldset><legend>Subject:   {{var data.subject}}</legend>
{{var data.comment}}
</fieldset>
Bike info: {{var data.bike_year}} {{var data.bike_make}} {{var data.bike_model}} {{var data.bike_model_ext}}

I never really thought I would have made my own custom module, but I followed the recipes I found on here and elsewhere and put this together. It also behaves correctly when the capcha  fails. I did try to research how to give the option to CC the customer with their own contact, but I couldn't find anything.
Later, I tried to make a custom module to allow an alternate admin notification email template for new orders but the knowledge I had learned from above wasn't enough. :P So my knowledge and comfort with Magento is perhaps above "dangerous hack", but I still have a long way to go.

redpajama_set_name: RedPajamaStackExchange


Cross The Roads Java Game for mobile phone. Cross The Roads free download.
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Smartphones jar Cross The Roads - free download for Java, Mobile Phone, and Tablet.


An innovative system for 100% waterproofing, a liquid-tight seal, and savings of more than 90% in labour costs.
One-of-a-kind concrete taper ties for tie rod protection: can be removed, reused and recycled.
Where can our products be used?


In Concert is a dazzling choral and instrumental music showcase featuring Australia's premier Public Schools Music Ensembles and the Combined Secondary Schools Choir at the beautiful Sydney Town Hall. The guest artists for 2018 are the highly acclaimed a cappella vocal ensemble The Idea of North. In this eClip series, The Arts Unit's Elizabeth Scott and The Idea of North's Naomi Crellin conduct the repertoire and share teaching tips for each of the songs to ensure teachers get the best out of their choirs in preparation for In Concert.


text:
In ingegneria del software, l'analisi del dominio (domain analysis nella letteratura di lingua inglese) è una delle attività che costituiscono l'analisi e concorrono alla definizione delle specifiche di un sistema o applicazione software o, più spesso, di una intera famiglia di applicazioni.

Descrizione
Lo scopo dell'analisi del dominio è quello di comprendere a fondo i concetti, le dinamiche, le regole generali che definiscono il dominio applicativo in cui il sistema software dovrà essere impiegato, ovvero il contesto in cui il software dovrà agire. Normalmente, l'analisi del dominio precede l'analisi dei requisiti, poiché solo avendo compreso a fondo il contesto in cui il sistema software dovrà operare è possibile stabilire quali siano le caratteristiche che il sistema deve esibire per integrarsi in quel contesto nel modo più efficace. L'analisi del dominio, come le altre fasi dell'analisi, deve quindi essere condotta congiuntamente da analisti ed esperti del dominio (per esempio, i clienti stessi che commissionano lo sviluppo del sistema, o i probabili utenti del sistema stesso).

L'analisi del dominio è spesso associata alla ingegnerizzazione del dominio (domain engineering): l'introduzione di un sistema software in un certo contesto produttivo potrebbe infatti portare alla ridefinizione o alla riorganizzazione di alcuni aspetti del contesto stesso, per cui lo stesso "dominio" potrebbe essere modificato. Per esempio, una procedura d'ufficio strutturata in un certo modo per essere applicabile da impiegati umani potrebbe essere ripensata in modo da sfruttare i punti di forza dell'automazione impiegando software di produttività personale o di produttività cooperativa come i sistemi di gestione del workflow.

L'ingegneria del software moderna attribuisce una grande importanza all'analisi del dominio anche rispetto all'obiettivo del massimo riuso del software. La comprensione del dominio può infatti portare alla realizzazione di moduli software che incorporano la conoscenza acquisita durante l'analisi, e che quindi potranno probabilmente essere riutilizzati in diverse applicazioni afferenti allo stesso dominio applicativo. Essi potrebbero per esempio essere raccolti in un framework di componenti riusabili.

Le tecniche di analisi orientata agli oggetti sono normalmente considerate fra le più adatte all'analisi del dominio. Concetti come quello di classe, ereditarietà, metodo e attributo si prestano a essere usati durante il dialogo fra analisti ed esperti del dominio (essendo comprensibili anche ai non tecnici) e al contempo forniscono un modello già adatto a essere raffinato in un progetto. L'analisi a oggetti del dominio utilizzerà quasi certamente la notazione standard UML o suoi derivati.

Voci correlate
Analisi (ingegneria del software)
Analisi dei requisiti
Famiglia di applicazioni
Framework
UML

Progettazione del software

redpajama_set_name: RedPajamaWikipedia


April 16 is a special day for Musikay and Maestro Potvin.
We present the final concert of its tenth year, while Maestro Potvin celebrates the life of his older son and remembers his second child who passed away ten years ago.
To celebrate our tenth anniversary of founding, we offer an intimate program of a cappella music written by the masters of the Franco-Flemish school; in other words, the wonderful compositions of Dufay, Josquin, Ockeghem, and Binchois.
For Maestro Potvin, this is the celebration of his older son's twelfth birthday. This also marks the tenth anniversary of the passing of his baby boy. In honour of his two children Maestro Potvin presents two new works. The first is a piano composition that earned his eldest a third place award in a provincial composition competition. The piece, "The swinging monkey", has been arranged especially for the formidable voices of Musikay. The second is a mystical work composed for his second son, set to the words Lux aeterna luceat ei, Domine (May everlasting light shine upon him, O Lord). The piece expresses the pain of the loss of a loved one, and explores the deep emotions that evolve over time as one tries to heal from such a life changing experience.
Join us for this special concert on April 16, 7:30 p.m. at St. John's United Church, in Oakville.
For those wanting to know more about the music, the group hosts a chat and tea at 6:30 p.m.
Pre-concert chat and tea at 6:30 p.m.
Email, or call 905.825.9740 for information.


In response to the growing popularity of fuel-efficient tires in the automotive industry, Evonik's Chester, Pa., site is expanding the precipitated silica capacity by 22,000 metric tons (MT) by 2014.
Chester's expansion is part of Evonik's initiative to increase world-wide capacities for precipitated silica by 30 percent between 2010 and 2014. As a market leader in silicas, the company has committed to a multi-million dollar investment for its completion. This project is the next phase in Evonik's global growth strategy as capacities at facilities in Europe and Asia have already been expanded.
Precipitated silica is also used as an ingredient in the food and animal feed industries, and in paints and coatings. Evonik's fumed silicas improve the surfaces and properties of various products such as enhancing the polish of silicone wafers in the chip industry and improving the scratch resistance of paints.
For additional information about Evonik in North America, please visit our website: www.evonik.com/north-america. Please visit us on Facebook at www.facebook.com/EvonikNorthAmerica link. Follow us on Twitter at http://twitter.com/EvonikN_America.


The goal of the Westfield Science Program is to foster students' curiosity about the natural world and provide them with the skill set to plan and carry out investigations about natural phenomena. This goal includes providing students with the foundational concept knowledge in the areas of Physical Science, Earth & Space Science, Life Science, and Engineering Practice that they will continue to build upon as they progress through their education in the sciences. Through authentic hands-on learning experiences students develop their ability to question, reason, argue, and communicate their findings.
Please see the side menu (to the right) for specific curriculum information.


Brilliant looking special effect with the basing, it really has a dynamic look to it. I also like how the color of the Nid blends in with its surroundings, but still pops with the stripes on its back. I'm sure it will destroy your enemies just like the Welsh destroyed the Scots in rugby.
Looking awesome mate. Really love the realistic paint job. There's too many brightly coloured nids running around! The base is just how I'd imagine them to look bursting our from underground.
Cheers dude! I had to leave out a large bit of the tail to accomodate the base, but its worth it! At least i'll have some spare 'Nid tail in the bits box!


I was a senior in high school when the stock market crashed in the crash that ended in the Great Depression .
The crash didn't affect my family directly, because we didn't have any stock.
We had one rule about money at our house: Save some, give some, spend some. My mother printed the rule out and hung it in a frame above the kitchen sink, where I saw it every day.
In grade school I had $1 a week allowance, and of this 10 cents went into the collection plate at church, 50 cents went into the savings bank downtown, and 40 cents was for me to spend any way I chose.
In high school I had $5 a week: 50 cents for church, 50 cents for street-car fare to school, $1.25 for lunches, $1.00 for the bank and $1.75 for spending money: cokes after school, tickets to the football games, plays at the Victory Theater.
My mother was a stay-at-home mother. My father was a commercial artist. They sent me all through the Depression to one of the best colleges in Ohio, and they paid all the bills with money they saved.
There were no scholarships in those days, and no student loans. I applied for a board job waiting tables in the dining room, thinking to help my parents with the bills. I was told that board jobs were for students who needed them more than I did.
When I graduated, I got a job teaching school and stuck at it for 31 years. With my first paycheck, which was $100 for a month's teaching, I gave $10 to the church, saved $50 and had $40 left for room rent and food and other expenses. Room rent in those Depression days was $2 a week.
I did the same later when I got a job at the newspaper. I even put some of the money I saved into the stock market.
When I married, my husband and I borrowed money from the bank to build a house. One month he made the payment, and the next month I made it.
One day my mother called us into her parlor. "You are both earning money," she said. "You should each make a house payment every month. That way you will get it paid off in half the time."
So that is what we did, and she was right.
If I wanted to make any large purchase - a car, say, or a harpsichord, I saved up the money until I had enough to pay cash for it.
That's the way people who grew up in the Depression did things.
Now I am the last leaf on my family tree, and I have moved to Bethany Retirement Village so I will be a burden to nobody so long as I can pay my bills.
The other day I received a letter that gave me a jolt.
The writer is a daughter of a cousin of mine. She is married and is a teacher. The letter said, "I would like to take off work - not work summer school. I got the notion in my head to ask if you would like to give me about $5,000 so I could do this in the care-free manner that I am seeking. It's really not so much about the money as it is about needing to feel supported, a way to take a break that I really need. If I had the money, I would not hesitate. I will have trouble granting myself permission otherwise."
I have not answered the letter. She will wonder whether I even got her letter.
But she sent her request to the wrong person, considering how I was educated about money at my house.
It seems to me that the way to grant yourself permission to take a summer off and not work is to save the money up beforehand.


When I was young my mother gave me a little red notebook. She included an article about the bygone phenomenon of the commonplace book. I loved the idea of a little place that I could keep all my random thoughts – my favorite quotes, a list of favorite mascaras, my favorite paint swatch. These topics are probably far from what Thomas Jefferson kept in his commonplace book, but still, these books were not meant to be in-depth scientific journals, just little places to keep little daily ideas. Commonplace books take their name from the Latin phrase locus communis, meaning "a theme or article of general application".
The use of the commonplace book began in England during the 17th century, and originated the gerund "commonplacing". I wish these little books were still part of our daily lives!
That is what I want with this blog. I am not a genius with an invention worth writing about, or a flashy celebrity whose hourly schedule is a profitable commodity. I don't even plan on boring you with stories of my trips to the dentist. I just want to write about ideas. Ideas that are worth sharing. Ideas that improve life. Ideas that I don't want to lose. This is my attempt to begin commonplacing. Welcome!


Uplifts the soul. It fills my soul to explore this wonderful world we have been blessed with. The beauty if her people, the natural artifacts as well as those created by her inhabitants. Traveling alone or with those we love, it is all first-rate for the soul.
Inspiration. Discovering the magic of the Rocky Mountains, the healing energy of the ocean and the waterfalls. Marvel at the majestic faces of Mount Rushmore and grasp the tumultuous history in our ancient civilizations. There are 195 official countries to discover in the world. We have choices to explore, adventures to delve into, amazing foods to taste, emotions to embrace.
Feel like a kid again. Blessed with new opportunities to explore our world brings the kid out in all of us. "Harry Potter World" here we come! We see through curious eyes and our attention is focused in the present moment. We can ride a wave, play in the sand, explore a castle, and get lost in Disney World. All this at any age. As a traveler it is okay to ride on the kiddy rides, eat caramel corn, and laugh until you cannot breathe.
Love and connection. Blessed with variety of nationalities on the planet each of us has gifts to share with one another. Every nation has a personality colored with the magnificence of its population. I have become comfortable striking up a conversation with a stranger and often end up with new friends. We grow as an individual when we see how others live, what they value, and the signature of their culture.
Improves my faith. Wherever you go, there you are. I have come to realize I don't need much to survive. A prayer, suitcase stuffed with clothes and some money; go a long way. Start the day with a prayer and some travel tips from the locals and the trip unfolds beautifully. Prayers seem especially useful when plans do not materialize and we are left to our resilient ability to adapt and improvise.
Improves self awareness. Learning to trust your decisions and intuition builds self-awareness and confidence. You come to realize how fantastic it is to be free to chose where you want to go, where to stay, whom to converse with, what food to eat, how to explore the unlimited choices. Your ability to discern what path to go on will come with clarity and the practice of trusting the guidance within.
My own time. No reason to rush! I can shop if I want, eat when I chose. I have ample reason to go shutter happy with my camera. I can enjoy silence while sitting by the ocean shore. People watch perch at a sidewalk café. I can satisfy my curiosity and discover what makes this world tick. Vacations and travel time can be so liberating.
Travel to a neighboring town, state, or country and enjoy the blessings of our diverse and magnificent world.
Beautifully written. An inspiration! Thank you!


* Copyright 2019 Google Inc. All Rights Reserved.
// since the model chunks up the melody in 16ths.
// iterations means the process is faster, but the results are less good.
// show that using a mask doesn't infill space.
note.pitch = 76 - 10 * v; // Different pitches for each voice.
// Optionally, treat any consecutive notes as merged.


text:
Q: Add Multiple Filters to SpringSecurity namespace FilterChain How can I add multiple custom implementations of standard Http Filter to a Spring Security namespace FilterChainProxy? I know I can add one filter to the chain by using the after, before or position attributes. But how can I add more than one filter?. Here is my security config file
<http pattern="/javax.faces.resource/**" security="none"/>
<http pattern="/resources/**" security="none"/>
<http pattern="/session_list.jsp" security="none"/>
<http pattern="/security/cas_logout.jsf" security="none"/>
<http pattern="/user/account_signup.jsf" security="none"/>
<http pattern="/user/company_user_association.jsf" security="none"/>
<http pattern="/user/account_signup_review.jsf" security="none"/>

<http auto-config="true" use-expressions="true" entry-point-ref="casEntryPoint" access-decision-manager-ref="accessDecisionManager">
    <intercept-url pattern="/**" access="hasRole('ROLE_USER')"/>
    <logout logout-success-url="/security/cas_logout.jsf" invalidate-session="true"/>
    <custom-filter position="CAS_FILTER" ref="casFilter"/>
    <custom-filter ref="requestSingleLogoutFilter" before="LOGOUT_FILTER"/>
    <custom-filter ref="singleLogoutFilter" before="CAS_FILTER"/>
</http>

     <beans:bean id="portalSessionFilter" class="org.x.web.security.PortalSessionInterceptor"/>
     <beans:bean id="requestUrlStackFilter" class="org.x.web.security.RequestUrlStackFilter"/>

I would like to add the portalSessionFilter and requestUrlStackFilter to the filter chain above. I can potentially do this
<custom-filter ref="portalSessionFilter" before="LAST"/>

But how do I add requestUrlStackFilter before LAST and right after portalSessionFilter BTW both of them are simple GenericFilterBean implementations.
I tried creating another FilterChainProxy bean with the above two filters in its chain list and add that bean as a custom-filter to the namespace configuration before LAST and the filters seem to work but my JSF navigation is broken, especially with commandLink (I think AJAX calls are failing when using this FilterChainProxy)
Can anyone suggest any ideas on how to add these two filters and possible other filters to the Spring Security Filter Chain?

A: I found a solution to the problem I was having. I solved it by implementing my own filter chain instead of using the spring security filter chain proxy to chain my filters. The problem with FilterChainProxy is that it uses reset method at the end of the filter chain which will cause problems if you inject it in between the main spring security filter chain proxy.
The custom filter chain just processes the required filters and hands back control to the main spring security filterchainproxy. Here is how the config looks after the changes
<http auto-config="false" use-expressions="true" entry-point-ref="casEntryPoint" access-decision-manager-ref="accessDecisionManager">
    <intercept-url pattern="/**" access="hasRole('ROLE_USER')"/>
    <logout logout-success-url="/security/cas_logout.jsf" invalidate-session="true"/>
    <custom-filter position="CAS_FILTER" ref="casFilter"/>
    <custom-filter ref="requestSingleLogoutFilter" before="LOGOUT_FILTER"/>
    <custom-filter ref="singleLogoutFilter" before="CAS_FILTER"/>
    <custom-filter ref="customFilterChain" before="LAST"/>
</http>

<beans:bean id="customFilterChain" class="org.x.web.security.CustomFilterChain">
<beans:constructor-arg>
    <beans:list>
        <filter-chain pattern="/javax.faces.resource/**" filters="none"/>
        <filter-chain pattern="/resources/**" filters="none"/>
        <filter-chain pattern="/**" filters="portalSessionFilter,requestUrlStackFilter"/>
    </beans:list>
</beans:constructor-arg>

Here CustomFilterChain extends GenericFilterBean but in the doFilter method chains the filters (matching the request pattern) and finally passes control back to the main spring security FilterChainProxy


text:
Q: Is it bad to inject controller class into a controller class? By trying to follow single responsibility principle, I decided that rendering form view I could move to another class. Also to render form I already am planning to use 5 dependencies. So the main controller which injects form will have less dependencies which is good.
I never injected controller classes into a controller class. What I usually do is I create the library. I have libraries folder made as sibling to controllers folder.
But now thinking - maybe better idea would be to have another controller injected into a controller?
Tried to search for this, but did not find any examples. But at the same time tried creating controller with just constructor function and echo a string. Then inject this controller into another. And string gets displayed.
So this means it is possible to inject controller into controller. So is it good? Or maybe this would be a must?
By default laravel do not even have libraries folder which is interesting, maybe creators assumes that it is not needed.

A: Yes it's bad. Controllers not only must have one single responsibility, but they are also a different kind of class that should have only one job: A controller is a proxy between the HTTP request and your application (models, repositories, views). So basically it should receive an HTTP request, get some data from your models and pass it away to a view.
Everything else should be done by your support classes (models, repositories, helpers, composers, etc.).
If you are in need to call a second controller class, it's probably because you need methods on that controller that should not be in that controller, because your controllers are doing more than what their job is.
This is one of my controllers:
class Connect extends BaseController {

    public function index()
    {
        $connections = $this->execute(GetConnectionsCommand::class);

        return View::make('connections.index')->with('connections', $connections);
    }

}

There's a lot happening behind the scenes in that GetConnectionsCommand to get the information to show all connections, and my controller should not know any about it all.
There are some subviews on that ´connections.index´ view, but calling subviews are a view responsibility, my controller doesn't have to know that a particular view needs subviews to be rendered. I can have a master view and some @ifs inside it to render them all properly.
A controller returns data (a rendered view, rendered by another class) back to the response object (behind scenes in Laravel), which is the guy responsible for effectively rendering the data which will be passed back to your browser. So a controller is right in the middle of something, doing very little orquestration, because, the more it knows about your business logic, the more you'll feel it needs to ´talk´ to another controller. You can think of it as MVP if you like, but this is pure MVP using the Single Responsibility Principle as it should be. But in this case the Controller is not decoupled from the view, because there is no Interface between them, so it's not really MVP.


text:
Nebesa (German: Himmelreich, formerly Egrisch Reuth) is a small village in Karlovy Vary Region, Czech Republic. It is one of the nine town districts of Aš. In 2001 the village had a population of 13.

In the village there is a chapel of Virgin Mary, a restaurant and bus stop.

Geography
Nebesa lies 3 kilometres southeast from Aš, on extensive area, but mostly covered by forests.

History
Nebesa is first mentioned in 1315. During the Seven Years' War  an entrenchment was built here by Austrian marshal Macquir. On May 8, 1759 a battle was fought here between armies of Austrian marshal Macquir and Prussian general von Finck.

Etymology
In Czech, Nebesa means heaven. The German name, Himmelreich, has a similar meaning: himmel means heaven and reich means empire.

Landmarks
 Catholic chapel of Virgin Mary from 1907
 iron crucifix from 1862.

References

Aš
Villages in Cheb District


I have been playing around with the SLEEK Original Palette and this is what I could come up with, and am wearing it out later this evening.
I used the darkest lilac(3rd shade) from the REVLON Illuminace as a base, followed by the Blue(1st row; 3rd shade) on inner half of my lids with Purple(1st frow; 5th shade occupied the other half. I made use of the Gold from L'OREAL HiP Duo in Flamboyant to blend any harsh edges. For the outer corner, I use the Dark Navy Blue(1st row; 4th shade) which is black-blue with bluish shimmers. I find this really chalky and had to be careful when building up the pigment. In the end I decided not to go for that intensive finish and blend it out for that soft smoky effect. Yeah, the Navy Blue look yucky in the photos. (lol) I use my fingers to apply on the eyeshadows, but blend with a brush.
Black(1st row; last shade) is highly-pigmented; I used it to line my upper eye but it kept "slipping" down to my inner waterline. I finished the look with LANCOME Le Stylo on my waterline; stopped halfway, and ELIZABETH ARDEN Ceramide Lash Extending Treatment Mascara.


text:
Tag: Merck & Co.
No. 17 | Merck & Co. | DiversityInc Top 50
Uncategorized April 14, 2016 Written by DiversityInc Staff
WHY THEY'RE ON THE LIST Merck & Co. has been a mainstay on this list for more than 10 years. Chairman and CEO Kenneth Frazier, who chairs the executive diversity council, is a visible supporter of Merck & Co.'s commitment to diversity. KEY RESULTS Blacks, Latinos and Asians in Senior…
Boy Scouts' President Says Gay Ban Not Sustainable; Girl Scouts Supporting Transgender Members
Uncategorized May 22, 2015 Written by DiversityInc Staff
The Girl Scouts of America and the Boy Scouts of America both made headlines this week as they stride toward embracing LGBT equality. First, in a progressive policy change, the Girl Scouts of America will now grant membership to transgender children. The GSUSA's frequently asked questions section on its website…
VIDEO: Culturally Competent CareWomen
Uncategorized October 28, 2014 Written by Featured Partner
Sheri Humphrey Global Marketing Leader, Women's Health Fertility Franchise Merck & Co. Sheri Humphrey is the Global Marketing Leader for the Fertility Franchise at Merck and Company. In this role, Sheri is responsible for collaborating with her commercial and clinical colleagues and leading development of short and long term market…
VIDEO: 2014 DiversityInc Special Awards
The 2014 DiversityInc Special Awards were handed out at a dinner ceremony on October 21, 2014 at the Marriott Marquis in New York City. CEOs from all seven recipient companies were on hand to accept their awards and share some insight into what their company does that sets them apart….
VIDEO: 2014 Top Company for Employee Resource Groups: Merck & Co.
Top Company for Employee Resource Groups: Merck & Co. Accepting award: Willie Deese, Executive Vice President and President, Merck Manufacturing Division Reasons for Honor: Merck has nine Employee Business Resource Groups with 60 chapters, including groups based on veteran status and religion. Each group has its own business plan, tied…
Award-Winning Actress S. Epatha Merkerson and Merck Challenge African Americans with Type 2 Diabetes to Get to Their Goals
Featured Partners News October 20, 2014 Written by Featured Partner
Award-Winning Actress S. Epatha Merkerson and Merck Challenge African Americans with Type 2 Diabetes to Get to Their Goals Merkerson Visits Washington, D.C. on June 26 With America's Diabetes Challenge: Get to Your Goals Program WHITEHOUSE STATION, N.J., June 26, 2014 /PRNewswire/ — Merck (NYSE: MRK), known as MSD outside…
Web Seminar: DiversityInc Top 50 Best Practices from Merck, EY
Uncategorized July 11, 2013 Written by Featured Partner
By Manuel McDonnell Smith If you've clicked on this article, then you want to know what impact an effective and well-executed plan for diversity and inclusion can have on a business and its bottom line. What strategies work best for engaging employees, leaders, suppliers and customers/clients Our most recent Web…
Boy Scouts Ends Ban on Gay Scouts, but Keep Ban on Gay Leaders
Uncategorized May 24, 2013 Written by Featured Partner
By Chris Hoenig In what was an expected decision, the Boy Scouts of America has lifted its ban on openly gay scouts in a nearly 2-to-1 vote. The measure was approved by 61 percent of the roughly 1,400 voting members of the BSA's National Council at its meeting Thursday in…
Boy Scouts to End Gay Ban for Members, Not Leaders
Uncategorized April 19, 2013 Written by Featured Partner
By Barbara Frankel Under pressure from corporate donors, the public and President Obama, the Boy Scouts of America today announced an end to its ban on gay members. But the policy would still not allow gay or lesbian scout leaders. The Boy Scouts' board, which includes the CEOs of AT&T…
Global Diversity Research Executive Summary: 203 Data Submissions in 46 Countries
Uncategorized February 6, 2013 Written by Featured Partner
By Barbara Frankel To evaluate the impact of global diversity efforts, we have investigated best practices that correlate to results, measured in increased human-capital diversity and business opportunity. Through 203 data submissions and extensive interviews with 25 companies, we have learned that diversity-and-inclusion initiatives have been mostly focused around gender,…
A federal court ordered the city of Horn Lake in #Mississippi to grant permission to build a #mosque after official… https://t.co/zG3rX3KWFr 4 hours ago
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If what you seek is a no frills accommodation for your Leyte escapade, then GV Hotel Ormoc fits the bill.
Tucked in Real corner Solidor Street in Ormoc City, GV Hotel Ormoc greets you with a friendly facade. Its reception area is open and cheery, wi... If what you seek is a no frills accommodation for your Leyte escapade, then GV Hotel Ormoc fits the bill.
Tucked in Real corner Solidor Street in Ormoc City, GV Hotel Ormoc greets you with a friendly facade. Its reception area is open and cheery, with a service-minded staff manning the 24-hour operational front desk. Just 7 kilometers away from Ormoc Airport, the hotel enjoys a convenient location near the city center and some of Ormoc's top tourist destinations.
The accommodation is part of a local chain of hotels with branches in select provinces all over the country. The GV Hotel brand is known for its comfortable rooms that will not break your budget. GV Hotel Ormoc is home to an array of clean and cozy rooms to suit your lodging needs. Each room features practical amenities to aid you in your stay, including air conditioning, cable TV, and an en suite toilet and bath with shower. Daily housekeeping is provided.
GV Hotel Ormoc features basic facilities for your worry-free stay. Stay connected online with the complimentary WiFi access in select areas within the property. This smoke-free hotel also has free parking spaces for the guests.
With 3 prominent lakes, namely Lake Danao, Lake Kasudsuran and Lake Janagdan, Ormoc is an ideal destination for nature lovers and adventure seekers. Foodies will also delight in Ormoc's culinary offerings, such as its famous queen pineapple and countless native delicacies. History buffs or not, tourists can reminisce the past and visit the city's landmarks which include Philippine-Japan Peace Memorial Park and WWII Veterans' & Centennial Park.


Bolivia - bolivia Pick-number: 164a uncirculated 1983 100 Pesos Boliv.
Banknotes bolivia Pick-number: 164a uncirculated 1983 100 Pesos Boliv.
issue reason: 1983 100 Pesos Boliv.
bolivia Pick-number: 164a used (III) 1983 100 Pesos Boliv.
bolivia Pick-number: 165a used (III) 1981 500 Pesos Boliv.
bolivia Pick-number: 164c used (III) 1983 100 Pesos Boliv.
bolivia Pick-number: 163a used (III) 1962 100 Pesos Boliv.
bolivia Pick-number: 164b used (III) 1983 100 Pesos Boliv.
bolivia Pick-number: 166a used (III) 1981 500 Pesos Boliv.


(2) purchase, sell or offer for sale an alcohol without liquid machine.
(c) As used in this section, "alcohol without liquid machine" means a device designed or marketed for the purpose of mixing alcohol with oxygen or another gas to produce a mist for inhalation for recreational purposes.
History: L. 2010, ch. 136, § 206; July 1, 2011.


 Which one of the following Mughal Emperors gave an important Farman to the English facilitating their trade in India ?
Which one of the following Mughal Emperors gave an important Farman to the English facilitating their trade in India ?
Where are the traces of Portuguese culture found in India ?
Who was the First Governor general of Bengal ?
Who were the first Europeans to reach India for trade ?
During the Mughal Period which one of the following traders first came to India ?


We are a Letterpress printing shop. We offer group and private workshops; custom stationery; wedding suites and event announcements.
Our letterpress shop features greeting and holiday cards, calendars, bookmarks, coasters, mini broadsides and art prints. Open from 10-4 Mon-Sat. We are also open every First and Third Friday from 6-10pm in addition to our daytime hours.
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