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Low-Dose Nω-Nitro-l-Arginine Methyl Ester Treatment Improves Survival Rate and Decreases Myocardial Injury in a Murine Model of Viral Myocarditis Induced by Coxsackievirus B3
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Abstract Recent reports demonstrated the expression of inducible-type NO synthase in the heart of viral myocarditis. Since NO has multiple biological actions, a substantial amount of NO produced in the diseased heart may act either as a cytotoxic or as a cytoprotective molecule in the process of myocarditis. In the present study, we examined the effect of inhibition of NO synthesis on the mortality and the extent of myocardial injury in a murine model of coxsackievirus B3–induced myocarditis. We fed the infected mice drinking water containing a relatively low concentration (0.37 mmol/L) of Nω-nitro-l-arginine methyl ester (L-NAME) for 14 days after virus inoculation. This dose of L-NAME did not change virus titers in the heart. However, L-NAME–fed mice showed a significant reduction in mortality compared with those fed normal drinking water (nontreated mice). On the contrary, mice given a higher concentration of L-NAME (3.7 mmol/L) exhibited increased mortality. In addition, mice fed a low concentration of L-NAME showed reductions in the severity of heart failure and in the area of myocardial necrosis. Although systemic blood pressure was reduced in nontreated mice, in mice fed a low concentration of L-NAME, it was maintained at a level similar to that in uninfected control mice. L-NAME–treated mice also exhibited a reduction in the degree of inflammatory cell infiltration associated with decreased production of tissue prostaglandin E2 levels in the heart compared with nontreated mice. Therefore, NO is likely to be involved in the pathogenic mechanisms of myocardial injury and resultant cardiac dysfunction in a murine model of coxsackievirus B3–induced viral myocarditis.
Nitric oxide is a molecule with multiple biological actions and is known to be important in a variety of physiological and pathological processes.1 2 3 Besides acting as a vasodilatory substance and a neurotransmitter, NO participates in the immune and inflammatory systems. NO is synthesized by NOS from l-arginine in a variety of cell types. The biochemical and molecular studies identified three types of isoforms of NOS: constitutive endothelial, neuronal, and inducible.4 5 6 7 8 Recently, we have reported that iNOS mRNA and protein are expressed in the heart in the murine model of viral myocarditis induced by CVB3.9
In viral myocarditis, the myocytes are first damaged by the direct cytolytic effect of the virus after viral infection.10 Then, the cell-mediated immunological responses play a predominant role in the inflammatory process and subsequent myocardial damage. Natural killer cells and cytotoxic T cells are suggested to be involved in the mechanisms.11 12 However, biochemical mechanisms of cell-mediated immune responses are still not well understood. In addition to its action as a vasodilator to maintain tissue perfusion, NO has been reported to exert an inhibitory effect on viral replication. NO is also shown to act as a cytotoxic molecule, modulate cardiac contractility, and influence cardiac function.13 14 15 16 Because of these multiple actions, NO produced in the inflammatory tissue may play either a protective or a detrimental role in the pathogenesis of viral myocarditis. A recent report showed that inhibition of NOS enhanced viral replication and resulted in an increase in the mortality in the murine model of viral myocarditis.17 On the other hand, another report suggested the cytotoxic effect of NO in the murine model of viral myocarditis.18 In a model of autoimmune myocarditis in rats, NO contributed to the progression of myocardial damage.19 20
The present study was undertaken to evaluate the effect of long-term supplementation of a NOS inhibitor after virus infection on the extent of myocardial injury and on the mortality rate in a murine model of viral myocarditis induced by CVB3. For this purpose, we fed mice a relatively low concentration of the NOS inhibitor L-NAME in their drinking water to yield low-dose L-NAME treatment (0.37 mmol/L). The results of the present study demonstrated that low-dose L-NAME treatment improved the mortality and decreased myocardial injury, whereas high-dose L-NAME (3.7 mmol/L) increased mortality; the study also suggested that NO acts as an important modulating factor of myocardial inflammation and injury in viral myocarditis.
Materials and Methods
Virus Preparation
The method used was similar to that described in our previous report.9 CVB3 (Nancy strain), a gift from Dr Hara (National Institute of Hygienic Science, Tokyo, Japan), was grown in Vero cells in MEM containing fetal bovine serum. The virus preparation had a titer of 1×107 pfu/mL and was stored at −130°C until use.
Animals and Virus Inoculation
Three-week-old C3H/He male mice (Nippon Clea Co, Osaka, Japan) were inoculated intraperitoneally with either 1×105 or 5×106 pfu CVB3 in 0.5 mL PBS. For examining mortality rate after virus inoculation, we used 5×106 pfu, which was revealed to produce death in 50% of the animals in the preliminary study. For examinations of histopathological changes in the heart, systemic blood pressure, virus titers, and PGE2 levels, we inoculated mice with 1×105 pfu CVB3, which resulted in low mortality rate (≈5%). The day of inoculation was defined as day 0 in the following study.
Effect of L-NAME on Mortality After Viral Inoculation
We examined the effect of inhibiting NO production during the process of viral myocarditis on mortality. After receiving 5×106 pfu CVB3, mice were randomly classified into two groups, a nontreated group and a group treated with L-NAME. Feeding of L-NAME (0.37 mmol/L) was started on the day of virus inoculation and continued until the animals were killed on day 14. The first group of mice was fed untreated (without L-NAME) drinking water (nontreated group, n=42). In the other group, L-NAME was dissolved in the drinking water at a concentration of 100 mg/L (0.37 mmol/L), yielding a daily intake of ≈5 to 10 mg/kg of L-NAME in each mouse (low-dose L-NAME–fed group, n=43). In these two groups of animals, mortality on 14 days after virus inoculation (5×106 pfu) was compared. In addition, we examined the effect of a higher concentration of L-NAME on the mortality after virus inoculation. For this purpose, we fed a relatively high concentration of L-NAME (3.7 mmol/L) to another group of infected (5×106 pfu CVB3) mice (high-dose L-NAME–fed group, n=32).
Effects of L-NAME on Histopathological Changes
In another set of experiments, we studied the effects of NO synthesis inhibition on the extent of myocardial damage in viral myocarditis. As in the mortality protocol, either low-dose (0.37 mmol/L, n=50) or high-dose (3.7 mmol/L, n=90) L-NAME feeding was started on the day of virus inoculation (1×105 pfu) and was continued until the animals died or were killed for study. Nontreated infected mice (n=50) were also used for the examination. In addition, another group of mice (n=8) was given drinking water containing D-NAME (0.37 mmol/L) after virus inoculation. For comparison of body and heart weights and cardiac pathological changes, saline injection instead of virus inoculation was performed in 6 uninfected control mice that received distilled water, in 10 uninfected mice fed low-dose L-NAME (0.37 mmol/L), and in 10 uninfected mice fed high-dose L-NAME (3.7 mmol/L).
After the mice were killed, body weights were determined, the hearts were removed, and heart weights were determined. The hearts were fixed in 10% formalin and embedded in paraffin, and two 5-μm-thick slices were taken at the papillary muscle level. The myocardial sections were stained with hematoxylin and eosin and Masson's trichrome. Using these sections, two independent researchers operating in a blind manner examined the extent of inflammatory cell infiltration and the area of myocardial necrosis. Because the lesions of necrosis, inflammatory cell infiltration, and fibrosis overlapped each other and clear differentiation of each lesion was difficult, we measured the total area, including necrosis, inflammatory cell infiltration, and fibrosis, and defined it as the area of necrosis. For the determination of total myocardial area and the area of necrosis, we took pictures of each section, magnified its original size by ×40 using a computerized image analyzer, and then determined the margin of the area to trace. After obtaining each area by planimetry, percent necrotic area was calculated by dividing the sum of area of necrosis by the whole myocardial area of each section. The determination of the margin was sometimes difficult, but the interobserver difference in the measured area was <10%. The mean of two sections from one heart was used for statistical analysis.
We also semiquantitatively evaluated the degree of inflammatory cell infiltration in each section by using the pathological grade as described previously.21 Pathological grade was determined as follows: grade 1 (mild), one or two small foci in the whole myocardial area; grade 2 (slight), several small foci; grade 3 (moderate), multiple small foci or several large foci; grade 4 (severe), multiple large foci; and grade 5 (very severe), diffuse infiltration, necrosis, or calcification. If the grading score for each specimen differed between the two examiners, the third examiner decided the grading score. In each group, subsets of mice were killed on day 3 for examination of early pathological changes, on day 7 for pathological grading of cellular infiltration, and on day 14 for measurement of percent necrotic area and the pathological grade. D-NAME–fed and uninfected control mice were killed on day 14. In addition, histological examinations were also performed in some of the deceased mice used in "mortality protocol."
Effect of L-NAME Treatment on Systemic Blood Pressure During Myocarditis
We measured systemic blood pressure in both control and infected conscious mice (n=5 for each group). Mice were anesthetized with pentobarbital sodium (80 mg/kg). With the mouse supine, a 1-cm inguinal incision was made under a microscope, and the right femoral artery was isolated from surrounding structures. The polyethylene catheter (single lumen SP8, Natsume Japan) was then inserted into the artery. The catheter was advanced to a 0.5-cm depth and secured in place. The catheter was then flushed with heparinized saline (100 U/mL saline), sealed with cyanoacrylate glue, tunneled to the back of the mouse, and tucked into a subcutaneous pocket on the back. The incision was sutured with 6-0 surgical silk. The mice were then allowed to recover in a standard rodent cage with food and water available ad libitum for 24 hours. After removal from the subcutaneous pocket, the arterial catheter was connected to a pressure transducer (MLT1050, AD Instruments Japan). Blood pressure was analyzed with Mac Lab/4s (AD Instruments Japan). Baseline mean blood pressure measurement was started 24 hours after surgery and continued for a total of 3 hours when the mice were noted to be quietly resting and not sleeping or engaging in grooming or feeding activities. The average value of blood pressure obtained during this period was used for the assessment.22 23
Virus Titer in the Heart
For the infectivity assay, hearts of the infected mice (1×105 pfu) were removed aseptically on days 2, 3, 6, 10, and 14, and virus titers in the heart were measured in the nontreated and the low-dose L-NAME (0.37 mmol/L)–fed groups. We also examined virus titers in hearts from the high-dose L-NAME (3.7 mmol/L)–fed group. In each examination, 5 mice were used. The whole heart was weighed and homogenized in 1 mL of MEM. After centrifuging at 1500g for 10 minutes at 4°C, 0.1 mL of supernatant was inoculated into Vero cells for 60 minutes at 37°C in 5% CO2. Cells were then overlaid with 4 mL of medium containing MEM and 10% methylcellulose. After 4 days of incubation at 37°C in a humidified atmosphere containing 5% CO2, cells were stained with crystal violet, and plaques were counted with a microscope. The myocardial virus titer was expressed as log10 pfu/mg.
Effect of L-NAME Treatment on Prostaglandin Production in the Heart
Since proinflammatory prostaglandins play an important role in the early phase of inflammation and NO is reported to inhibit them,24 25 we measured tissue PGE2 levels in both nontreated and low-dose L-NAME–fed mice (1×105 pfu). In the L-NAME–fed group, L-NAME (0.37 mmol/L) feeding was started on the day of virus inoculation and was continued until death. On day 4 and day 7, 5 mice in each group were killed so that tissue PGE2 levels could be assessed. After excising the heart, the specimens were homogenized in 1 mL of PBS containing 1.8% indomethacin, frozen in liquid nitrogen, and stored at −80°C. The concentrations of PGE2 were determined by specific radioimmunoassay using the 125I-PGE2 assay system (Amersham). The cross-reactivity of other prostaglandins with the antisera was as follows: 6-ketoprostaglandin F1, 0.04%; thromboxane B2, 0.08%. The concentration was expressed as picograms per milligram tissue.
Statistical Analysis
Survival curves of infected mice were obtained by the Kaplan-Meier method. The survival curves were evaluated by Mantel-Cox log-rank test. χ2 analysis was used to compare the mortality rate between the groups. Statistical analysis of body weight, heart weight, heart weight–to–body weight ratio, the pathological grade and percent necrotic area, blood pressure, virus titers, and prostaglandin production was performed by one-way ANOVA (Bonferroni). Differences were considered statistically significant at P<.05. Results are expressed as mean±SEM.
Mortality of the Infected Mice
Nontreated and low-dose L-NAME–fed mice began to die on day 5 or 6 after virus inoculation, and the majority of deaths occurred from day 6 to day 10. This is in accordance to our previous observations.9 All of these deceased mice showed signs of congestive heart failure, such as coat ruffling, weakness, and irritability before death. Macroscopic examination revealed pleural effusion and congestion of the lung and liver, suggesting the presence of congestive heart failure, in the deceased mice. On day 14, mice fed L-NAME (0.37 mmol/L) in drinking water exhibited a significantly lower mortality ratio compared with the nontreated mice (23.3% versus 50.0%, P<.05; Fig 1⇓).
On the other hand, when the infected mice were treated with high-dose L-NAME (3.7 mmol/L), ≈60% of the mice died on day 3, 80% of the mice were lost before day 4, and almost all mice died by day 7. The postmortem pathological examination of the mice that died on day 3 (n=10) revealed no distinct microscopic findings of myocardial necrosis or cellular infiltration in the heart. In addition, macroscopic examination of the whole body revealed no distinct abnormalities, such as bleeding, in any organ.
Cardiac Histopathology
Ten nontreated, 10 low-dose L-NAME–fed, and 10 high-dose L-NAME–fed mice were killed on day 3; 15 nontreated, 13 low-dose L-NAME–fed, and all 6 surviving high-dose L-NAME–fed mice were killed on day 7; and 23 nontreated and 24 low-dose L-NAME–fed mice were killed on day 14. The inflammatory process of infected mice in these groups was in accordance with previous reports. On day 3, a few scattered small foci of myocyte necrosis were noted. The myocardial necrosis and cell infiltration were extensive on day 7. Infiltration of the inflammatory cells was decreased, and necrotic myocardium gradually changed to fibrosis and calcification on day 14, as was reported previously.26 27 Along with these histopathological changes, the infected mice decreased their body weight (infected mice [nontreated], 16.5±3.9 g; uninfected mice, 21.3±0.4 g; P<.05; on day 14). The heart weight of the infected mice showed a significant increase compared with that of the uninfected mice (infected mice, 0.11±0.02 g; uninfected mice, 0.09±0.04 g; P<.05; on day 14) (Table 1⇓). The infected hearts, with enlarged cardiac cavities, consisted of necrotic foci surrounded by infiltrating cells and interstitial edema.
As in the high virus titer–inoculated mice, mice inoculated with low virus titers (1×105 pfu) experienced high mortality after high-dose L-NAME treatment. Approximately 50% of the mice died by day 3, and only 10% of the mice survived on day 7. Examinations of 10 high-dose L-NAME–treated mice surviving on day 3 revealed the presence of small necrotic foci, but the area of necrosis was not different from that in the other two groups. There was no pulmonary congestion in any of three groups on day 3. The mice surviving on day 7 demonstrated the presence of necrosis and cell infiltration. The areas of necrosis and cell infiltration of the surviving mice were small compared with those in the other two groups (Fig 2⇓). However, because of the high mortality, it was not possible to collect sufficient data for quantitative histopathological analysis in high-dose L-NAME–fed mice; the use of surviving animals of limited number may bias the data analysis. Therefore, the quantitative analysis on day 7 was performed in only low-dose L-NAME–fed and nontreated mice. When the infected mice were treated with low-dose L-NAME (0.37 mol/L), the body weight was bigger and heart weight was smaller compared with the nontreated infected mice (Table 1⇑). In addition, macroscopic findings of heart failure, such as pleural effusion or congestion of the lung, were observed in 4 of the 23 nontreated mice, whereas none of the low-dose L-NAME–fed mice showed such findings.
Histopathological examination revealed a remarkable reduction in the percent necrotic area in the low-dose L-NAME–fed group compared with the nontreated infected group (no treatment, 22.4±6.8%; low-dose L-NAME, 11.9±4.6%; P<.05) (Figs 2⇑ and 3a⇓). Because the disease demonstrated the focal nature and because infiltrated cells were intermingled in the inflammatory lesions, the quantitative cell type identification in the inflammatory area in each animal was difficult. Therefore, we did not determine whether there was a change in the infiltrated cell types by low-dose L-NAME treatment. We evaluated the extent of inflammatory cell infiltration by semiquantitative analysis. The pathological grading revealed a significant reduction of the extent of cell infiltration on day 7 and on day 14 in low-dose L-NAME–fed mice (Fig 3b⇓).
There were no necrotic lesions or cell infiltration in the hearts of uninfected control mice. Likewise, neither necrosis, cell infiltration, nor fibrosis was detected in uninfected mice treated with low-dose or high-dose L-NAME. D-NAME treatment did not change the area of myocardial necrosis and the degree of cell infiltration. On the other hand, histopathological examination in the deceased mice in the "mortality protocol" revealed the presence of intensive myocardial necrosis and fibrosis in both low-dose L-NAME–fed and nontreated mice.
Blood Pressure in Mice
Blood pressure was low immediately after anesthesia and remained low for at least 2 hours compared with 24 hours later. Table 2⇓ shows the changes in mean blood pressure after virus inoculation and the effects of L-NAME treatment. High-dose L-NAME treatment for 14 days increased mean blood pressure in control (uninfected) mice (93±4 versus 122±4 mm Hg, P<.01), and low-dose L-NAME for 14 days also increased blood pressure significantly (93±4 versus 106±4 mm Hg, P<.01). In nontreated infected mice, blood pressure was decreased on days 7 and 14 after virus inoculation, probably because of myocardial damage and/or heart failure. Blood pressure of low-dose L-NAME–fed mice was significantly higher compared with that of nontreated mice on day 7 and day 14. On the other hand, on day 3, when high-dose L-NAME–fed mice began to die, there were no significant differences in blood pressure among three groups (nontreated, low-dose L-NAME–fed, and high-dose L-NAME–fed groups).
Myocardial Virus Titer
Virus content was not detected in the noninfected mice. No differences were found in the virus content on days 2, 3, 6, 10, and 14 between the nontreated and the low-dose L-NAME–fed groups. Even on day 6, when the virus replication in the heart is at its peak, there were no statistical differences in the virus titers between low-dose L-NAME–fed and nontreated mice (Table 3⇓). In the high-dose L-NAME–fed group, virus titers were examined only on day 3, because most of the animals died thereafter. On day 3, there were no statistical differences in virus titers between high-dose L-NAME–fed and nontreated groups. However, since we measured virus titers in mice surviving on day 3 (5 of 10 mice inoculated), we could not rule out the possibility that the titers might be increased in the deceased animals.
Tissue Prostaglandin Levels in the Heart
L-NAME treatment decreased the production of proinflammatory prostaglandins. We measured tissue PGE2 levels on day 4, the early stage of inflammation, and on day 7, when the inflammatory cell infiltration was most extensive. The tissue PGE2 levels in low-dose L-NAME–fed mice were significantly reduced compared with those in nontreated mice on days 4 and 7 (Fig 4⇓).
Recently, we and another group demonstrated the expression of iNOS in a murine model of CVB3-induced viral myocarditis.9 17 The histochemical study revealed that immunostaining for iNOS was present in the infiltrating cells, which were mainly macrophages and polymorphonuclear leukocytes. The induction of iNOS is likely due to proinflammatory cytokines in the process of viral myocarditis.26 We reported that the peak of iNOS expression in the heart was 8 days after virus inoculation, when myocardial necrosis and cell infiltration were most extensive. The prominent expression of iNOS suggests local production of NO in the heart with viral myocarditis. Because of its multiple biological actions, NO produced in the heart may exert either protective or detrimental action in the pathogenesis of viral myocarditis. In the present study, we found that the inhibition of NO synthesis by low-dose L-NAME markedly decreased the mortality rate in the murine model of CVB3-induced viral myocarditis. Along with the reduction of mortality rate, the area of myocardial necrosis and the degree of cell infiltration were significantly decreased in the hearts of mice treated with low-dose L-NAME.
As one of the mechanisms of myocardial destruction of viral myocarditis, the direct cytolytic effect of the virus on myocytes plays an important role in the early phase after virus inoculation.27 Viral replication causes myocardial necrosis with inflammation in the heart. Experimental studies in vitro have shown an inhibitory effect of NO on viral replication.28 The anti–viral-replication effect of NO is suggested to be mediated by its inhibitory action on viral ribonucleotide reductase.29 Therefore, it was possible that an inhibition of NO synthesis resulted in the worsening of myocardial damage. Indeed, the recent report of Lowenstein et al17 showed that mice with CVB3-induced viral myocarditis had increased myocardial virus titers and a higher mortality when treated with NOS inhibitors. However, in the present study, we found that low-dose L-NAME treatment had no effects on viral titers in the heart throughout the observation period of 2 weeks after virus inoculation. In accordance with the present study, Akaike et al30 reported that in mice with influenza virus–induced pneumonia, L-NMMA, a NOS inhibitor, significantly improved the survival rate without suppression of virus replications in the lung. The difference between the study of Lowenstein et al and ours seems at least in part due to the dose of NOS synthesis inhibitor given to the animal. In the study of Lowenstein et al, they fed mice relatively high concentrations of L-NAME (10 and 100 mmol/L), whereas we gave them a low concentration of L-NAME (0.37 mmol/L). Lowenstein et al found unchanged myocardial virus titers when the concentration of given L-NMMA was <10 mmol/L. In addition, a relatively high concentration of NO was shown to be required to inhibit viral replication.28 Therefore, although NO was produced in the heart, the concentration of NO produced in the heart might not be high enough to inhibit viral replication.
The difference in the dose also likely accounts for the discrepancy between the present study and that of Lowenstein et al17 involving the effect of L-NAME on the mortality of mice with viral myocarditis. Indeed, when we fed the infected mice high-dose L-NAME (3.7 mmol/L), almost all of them died by 7 days after virus inoculation. Although we found unchanged myocardial virus titers in high-dose L-NAME–treated mice on day 3 in spite of increased mortality, we could not rule out the possibility that there might occur increased viral replication between days 4 and 7.
There are several mechanisms that may contribute to the beneficial effects of low-dose L-NAME treatment on viral myocarditis in the present study. First, an improvement of tissue perfusion by NO synthesis inhibition must be taken into account. We found that even the low-dose L-NAME increased blood pressure. The nontreated infected mice showed reductions of blood pressure on days 7 and 14, which probably represented the hemodynamic deterioration due to myocardial damage and resultant heart failure. However, the low-dose L-NAME–fed infected mice exhibited significantly higher mean blood pressure than did the nontreated mice on days 7 and 14. Therefore, the low-dose L-NAME used in the present study likely served to improve tissue perfusion, particularly when the animals were in heart failure or shock state, and resulted in the improvement of survival rate.
Next, it is shown that NO produced in neutrophils or macrophages acts as a cytotoxic molecule in some circumstances. The induction of iNOS has been demonstrated in various types of autoimmune complex injury and inflammatory reactions.31 32 In those pathological conditions, NO may be involved in the production of tissue damage and edema.33 NO is shown to inhibit mitochondrial respiratory chain reaction, aconitase of the Krebs cycle, and synthesis of DNA by inactivating ribonucleotide reductase.34 Moreover, NO may combine with oxygen-derived free radicals to form peroxynitrite and further change to hydroxy radicals.35 These radicals are potent cytotoxic molecules and thereby may participate in the mechanisms of myocyte destruction.36 In the present study, L-NAME treatment decreased the area of myocardial necrosis and fibrosis. Therefore, it is possible that a large amount of NO produced in the heart plays a crucial role in myocardial destruction in viral myocarditis and that an inhibition of NO production results in the amelioration of myocardial damage.
In addition to the augmentation of the inflammatory and cytotoxic process, NO produced in the heart may decrease ventricular function and thus aggravate heart failure. Brady et al15 showed in isolated cardiac myocytes that endogenously produced NO from endothelium attenuated the contraction of myocytes. Moreover, NO produced by the cardiac myocyte itself has been shown to act as an autocrine factor to reduce myocardial contractility. Balligand et al37 reported an augmentation of inotropic response to β-adrenergic agonists by administration of the NO synthesis inhibitor L-NMMA. The improved survival rate by L-NAME observed in the present study may be partially related to the augmentation of cardiac function by this drug. Although we did not measure cardiac function in the present study, the preserved blood pressure in low-dose L-NAME–fed mice may indicate improved cardiac function, and the improved cardiac function may also be related to the reduced myocardial damage by NO synthesis inhibition.
On the other hand, NO has been demonstrated to augment the production of proinflammatory prostaglandins in the tissue with inflammation, and NOS inhibitors reduce them. NO may exaggerate the inflammatory process by the generation of additional proinflammatory prostaglandin, which enables inflammatory cells to reach the lesion of inflammation.24 25 In the present study, we found reduction in inflammatory cell infiltration in the inflammatory area and decreased tissue PGE2 levels by low-dose L-NAME treatment. Recently, Salvemini et al38 used the rat carrageenan-stimulated air pouch model and reported that the anti-inflammatory mechanisms of NO synthesis inhibitors are partly mediated by the inhibition of prostaglandin production and cellular infiltration. Although the reduced prostaglandin production may represent the result of decreased inflammation, it is possible that the beneficial anti-inflammatory effects of low-dose L-NAME treatment are in part mediated by the inhibition of proinflammatory prostaglandin.
Finally, we found increased mortality in high-dose L-NAME–fed mice. It seemed that NO synthesis inhibition resulted in biphasic effects depending on the dose used. We measured blood pressure in these animals on day 3, when they began to die, and found that blood pressure values were not different from those of control mice. Therefore, the high-dose L-NAME–treated mice were neither in excess hypertensive condition nor in shock state on day 3, nor did the high mortality seem to be the result of increased myocardial damage. Indeed, we found no pulmonary congestion and no lethal necrotic foci in mice treated with high-dose L-NAME on day 3. Thus, although we cannot completely exclude the possibility of increased viral replication, the high mortality may have resulted from either the toxic effect of this agent or yet-unknown mechanism(s). Further studies to clarify the mechanism of high mortality induced by high-dose L-NAME treatment are needed.
Our results suggest that NO can be regarded as a common important modulating factor of myocardial damage in various pathological conditions mediated by immune and inflammatory processes. Furthermore, recent clinical studies demonstrated induction of iNOS in the heart of patients with heart failure, and locally produced cytokines such as tumor necrosis factor-α are suggested to be responsible for the induction.39 NO produced in the heart may also be involved in pathophysiology other than viral myocarditis.
Selected Abbreviations and Acronyms
|coxsackievirus B3
|Nω-nitro-d-arginine methyl ester
|inducible-type NOS
|Nω-nitro-l-arginine methyl ester
|NO synthase
|plaque-forming units
|prostaglandin E2
This study was supported in part by a grant-in-aid for Scientific Research to Dr Kawashima (C 06670717) and to Dr Hayashi (B 07457050) from the Ministry of Education, Science, and Culture, Japan.
- Received June 23, 1997.
- Accepted July 5, 1997.
- © 1997 American Heart Association, Inc.
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Stuehr DJ, Nathan CF. Nitric oxide: a macrophage product responsible for cytostasis and respiratory inhibition in tumor target cells. J Exp Med. 1989;169:1543-1555.
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Beckman JS, Beckman TW, Chen J, Marshall PA, Freeman BA. Apparent hydroxyl radical production by peroxynitrite: implications for endothelial injury from nitric oxide and superoxide. Proc Natl Acad Sci U S A. 1990;87:1620-1624.
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Yang X, Chowdhury N, Cai B, Brett J, Marboe C, Sciacca RR, Michler RE, Cannon PJ. Induction of myocardial nitric oxide synthase by cardiac allograft rejection. J Clin Invest. 1994;94:714-721.
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Balligand JL, Ungureanu D, Kelly RA, Kobzik L, Pimental D, Michel T, Smith TW. Abnormal contractile function due to induction of nitric oxide synthesis in rat cardiac myocytes follows exposure to activated macrophage-conditioned medium. J Clin Invest. 1993;91:2314-2319.
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Salvemini D, Manning PT, Zweifel BS, Seibert K, Connor J, Currie MG, Needleman P, Masferrer JL. Dual inhibition of nitric oxide and prostaglandin production contributes to the antiinflammatory properties of nitric oxide synthase inhibitors. J Clin Invest. 1995;96:301-308.
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- Low-Dose Nω-Nitro-l-Arginine Methyl Ester Treatment Improves Survival Rate and Decreases Myocardial Injury in a Murine Model of Viral Myocarditis Induced by Coxsackievirus B3Shuji Mikami, Seinosuke Kawashima, Kenji Kanazawa, Ken-ichi Hirata, Hak Hotta, Yoshitake Hayashi, Hiroshi Itoh and Mitsuhiro YokoyamaCirculation Research. 1997;81:504-511, originally published October 19, 1997https://doi.org/10.1161/01.RES.81.4.504
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- Low-Dose Nω-Nitro-l-Arginine Methyl Ester Treatment Improves Survival Rate and Decreases Myocardial Injury in a Murine Model of Viral Myocarditis Induced by Coxsackievirus B3Shuji Mikami, Seinosuke Kawashima, Kenji Kanazawa, Ken-ichi Hirata, Hak Hotta, Yoshitake Hayashi, Hiroshi Itoh and Mitsuhiro YokoyamaCirculation Research. 1997;81:504-511, originally published October 19, 1997https://doi.org/10.1161/01.RES.81.4.504Permalink:


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Ooey Gooey Date Squares
(178) Ratings:
Prep Time:
Baking Time:
Makes:25 squares
Set a date to bake these delicious squares with your kids. They'll love the sweet taste and ooey gooey filling.
- Preheat oven to 350ºF (180ºC). Lightly oil and line a 9" x 9" (2.5 l) baking dish with parchment paper, overlapping 2 sides for easy removal.
- Filling: combine filling ingredients in a saucepan. Bring to a boil. Reduce heat and simmer, stirring often, until thickened, 10-15 minutes. Cool.
- Base and topping: Cream butter and brown sugar in large bowl with electric mixer. Add remaining dry ingredients. Mixture will be a bit crumbly. Reserve 1 cup (250ml) for topping.
- Pat remaining 3 cups onto bottom of prepared pan. Spread with date mixture. Sprinkle remaining cup (250ml) of oat mixture.
- Bake in preheated oven for 25 to 30 minutes, or until top is golden brown. Cool and cut into squares.
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ApparelnBags.com process puts you in the driving seat to assure high quality of decoration services are delivered to you. To place the order, steps are easy as 1 – 2 – 3.
Fill a simple form and have us provide you most competitive quote.
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You are in-charge at every stage of the process. You'll be informed and your order will not be produced unless we get a final approval from you.
As soon as we complete your order production, we'll send you tracking information and keep you appraised with delivery details


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Stock Graphic >> Pattern - Seamless pattern for fashion Design 58738 by Lian-art @ CreativeMarket
File Size: 10.18 MB; Tileable: Yes; Requirements: Adobe CS1+; Vector: Yes.
Seamless pattern for fashion Design - Silhouettes of glamor clothes and accessories - Black and white images on pink background.
Click on the preview to see what you get.
Zip includes.
- 1 EPS 8 + 1 Hi res JPEGs files
This image is a vector illustration and can be scaled to any size without loss of resolution. All parts of the image are editable. Watermarks will not appear on your purchased files.
Note: This images are NOT for sale and are NOT included in the sales package.
Best regards, Elena
Keywords: pink, wallpaper, glasses, tile, clothes, handbag, bikini, luxury, glamor, accessories, female, fashion, shoes, repeat, fabric, woman, objects, makeup, shop, shopping.


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The big day itself is exactly one week away, but if you're anything like me then you still haven't finalised your plans/outfit/TBR pile. So for this weeks Saturday Share, I thought I'd throw together all of the videos and blog posts and Pinterest DIYs I've been perusing recently!
♥ My little sister is constantly watching Halloween Costume DIYs on YouTube at the moment but one that particularly caught my eye was this video named 30 Last Minute DIY Halloween Costumes. If you still don't know what you're going as for Halloween then you're sure to make up your mind after watching this!
♥ Georgina from She Might Be Loved is the blogger to be following if you're in need of some Halloween make-up inspiration! My favourite look of hers last year was the Female Hades but my favourite this year (so far) is probably the Scary Vampire. Definitely check out her blog and scroll through all of her amazing tutorials.
♥ Have no plans for Halloween and intend on staying indoors surrounded by sweets and books? Join in with the Hallowreadathon! My girl Imogen created this fab read-a-thon last year and I joined in (I read The Curious Incident of the Dog in the Night-Time) and I'm looking forward to joining in again this year!
♥ If you're intending to go along with the suggestion above, I'd also recommend a Lush bath using one of the Halloween collection. Check out Victoria's review of the Lord of Misrule bath bomb - the photos are so beautiful!
♥ I'm half considering throwing a mini Halloween party for my sister and her school friends this year, so of course I've been pinning like crazy. Check out my Halloween Party Pinterest board for DIY decorations and food inspiration!
♥ If you've only just decided to throw a little party, this Buzzfeed article showing 31 Last Minute Halloween Hacks will be a total life-saver!
♥ Following on with all this party talk, allow me to introduce you to where I'll be getting my decorations from: Poundland. They have the most amazing Halloween decorations that are, obviously, just £1 each. I feel like there's no point in buying expensive decorations that I'm only going to use once a year, and they're actually really well made. (P.S my little ghost tea light holder as seen in this post is from there.)


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7th Circuit Decision: 'Ultimate Case'
Originally printed 4/13/2017 (Issue 2515 - Between The Lines News)
Two very important and significant court decisions impacting LGBT rights were issued last week. The first, Hively v. Ivy Tech Community College of Indiana, is a 7th Circuit Court of Appeals ruling that "discrimination on the basis of sexual orientation is a form of sex discrimination" prohibited by Title VII (the federal law that bars employment discrimination based on sex). The lawsuit was filed by Kimberly Hively, a lesbian who was working as an ajunct professor at Ivy Tech. Despite years of successful teaching, her attempts to secure a full-time tenure position were unsuccessful and finally her contract was not renewed under circumstances that led her to believe that it was because of her sexual orientation. Hively is the first federal appellate court decision to embrace this legal theory. The 7th Circuit covers the states of Indiana, Illinois, and Wisconsin, and this decision will especially help LGBT people in Indiana who have no specific protections against discrimination in their state civil rights laws.
What makes this decision especially authoritative is that it was decided upon rehearing of an appeal "en banc." En banc is a term in which an appeal is heard by all of the active judges on a federal Circuit Court of Appeals instead of by a three-judge panel that typically decides appeals. Of the 11 judges who heard this appeal, eight agreed that current federal law prohibiting sex discrimination also protects against sexual orientation discrimination. This decision was non-partisan in that five out of the eight majority judges were appointed by Republican Presidents.
While there have been a number of federal appellate decisions that have held that discrimination against LGBT people for failure to conform with gender stereotypes (as to how men and women should look, act, dress, love, etc) is illegal sex discrimination, the 7th Circuit decision says that not being heterosexual represents the "ultimate case" of not conforming to sex stereotypes because "it is based on assumptions about the proper behavior for someone of a given sex." In other words, LGBT people inherently will not conform to gender stereotypes and that fact more often than not is the impetus for
As the 7th Circuit further explained that "[a]ny discomfort, disapproval, or job decision based on the fact that the complainant- a woman or man- dresses different, speaks different, or date or marries a same-sex partner, is reaction purely based on sex."
The decision is consistent with federal agencies, such as the Departments of Education, Health and Human Services, Labor, HUD, as well the Equal Employment Opportunity Commission (EEOC), which enforces Title VII and investigates employment discrimination complaints. The decision is also consistent with numerous federal court decisions (including the 6th Circuit, which covers Michigan) that have held that gender identity discrimination against transgender persons is barred as a form of sex discrimination.
The 7th Circuit decision creates a split in the Circuit Court of Appeals that makes it increasingly likely that the U.S. Supreme Court will eventually have to weigh in on this issue to resolve it nationally.
While Ivy Tech College has announced it will not seek Supreme Court review, the 7th Circuit's decision makes it likely that other federal courts will follow their lead. Even if these appellate courts do not agree with the 7th Circuit, the losing LGBT plaintiff in another circuit would have a strong argument for the Supreme Court to hear an appeal, given the conflict that would be created between the 7th Circuit's decision and theirs.
The second important decision (Smith v. Avanti) came from a federal district court in Colorado, where Judge Raymond Moore held that a landlord discriminated against Tonya and Rachel Smith when she refused to rent to them because of their "uniqueness." The Smiths are a same-sex couple with two children. Rachel is transgender. The landlord told the couple that she had kept a low profile for 30 years, but that wouldn't be possible if she rented to the Smiths because of their "unique relationship".
The Court found that the landlord discriminated against the Smith family because they did not conform to traditional gender stereotypes in violation of the Fair Housing Act, which prohibits discrimination on the basis of sex in housing. Judge Moore's opinion marks that first time that a federal court has ruled that the Fair Housing Act's sex discrimination prohibitions apply to discrimination based on stereotypes about sexual orientation and gender identity.
Both case decisions are significant steps forwards towards LGBT equality. The Lambda Legal Defense and Education Fund are to be applauded for their work on both of these cases. The decisions also point out just how high the stakes are for our community in terms of the make-up of the federal judiciary. Like many other minority groups, the LGBT community often depends on courts to protect our equality and freedom, particularly when we live in a State like Michigan where the current legislative majority is hostile to our issues (and has consistently failed to amend our State civil rights laws to specifically include sexual orientation and gender identity). In finding that civil rights laws prohibiting sex discrimination protect LGBT people, federal (and some state) courts are taking in account societal change and holding that LGBT people deserve equal dignity and respect. Rather than seeing our constitution as frozen in time, they see it as a living breathing document that can and should address current issues in society. This is contrasted with approach of originalists, like the recently confirmed Supreme Court Justice Neil Gorsuch, who believes that courts should look "backward not forward."
Indeed Gorsuch has expressed expressed disapproval of civil rights impact litigation, writing in 2005 that "American liberals have become addicted to the courtroom ... as the primary means of effecting their social agenda on everything from gay marriage" to other issues. Candidate Trump announced his intention during the 2016 presidential campaign to appoint judges to the federal bench who are originalist and this could have a significant negative impact on our ability to move forward on LGBT civil rights, while other branches of government continue to stall.The ACLU of Michigan has been a champion for our equality for decades. Jay Kaplan, the organization's staff attorney of the LGBT Project, has for years provided us a thoughtful, serious and effective voice for LGBT equality. This week's column is yet another example of how the ACLU fights for us, and we must support them together. That's why BTL is offering to double your donation to the ACLU by April 17. To donate, visit the "BTL's Challenge Grant to the ACLU of Michigan" page. Make your gift and BTL will match your gift 100 percent.
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Tesla Model S Almost Perfect, but Not Recommended by Consumer Reports
Although the Tesla Model S scored a near-perfect 99 out of 100 in Consumer Reports latest test, the product testing outlet won't list the electric luxury car on its recommended list.
"Another concern is investing in a new car and startup company with no track record for reliability or resale value, and a skimpy (although growing) service network," says Consumer Reports in its full review. "So, yes, despite its stratospheric road-test score, we can't recommend the Model S until we have sufficient reliability data."
Basically, CR is saying that despite car being great, it is still dangerous to be an early adopter, especially when it comes to EV tech from a startup company
SEE ALSO: Tesla Model S Rated 99 out of 100 by Consumer Reports
Despite the words of caution, the rest of the the review is spent effusively praising the car. "Slipping behind the wheel of the Tesla Model S is like crossing into a promising zero-emissions future," says the review. The Model S is "brimming with innovation, delivers world-class performance, and is interwoven throughout with impressive attention to detail."
Discuss this story at Tesla-Buzz.com
[Source: Consumer Reports via Hybrid Cars]


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Caribbean Buzz has the unique capability of supporting yachts which are equipped for helicopter operations. With a strong background in naval ship landings, Caribbean Buzz Helicopters boasts a long pilot history of yacht support worldwide.
As part of its helicopter support package, CBZ manages the aircraft maintenance program, provides pilot services, and manages the day-to-day operations such as flight permits.


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Vintage Remington Fleet Wing Portable Typewriter Fleetwing Baby Blue w/Case Nice
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- Sold Date:
- Source: eBay
Very hard to find and in very nice condition. Remington Fleet Wing portable typewriter in baby blue along with the hard locking carrying case (made in Germany). Looks & works great, very little wear.The only thing I see is there is only one bumper cushion that sits underneath the unit but I will pack carefully and shouldn't have any problems.All the keys are cool, some minor scuff marks but otherwise a really sweet typewriter looking for a new home.Very heavy (22lbs) so shipping will be approprite Feel free to ask questions and thanks for looking.PS, We are in So. Cal (Covina) so if your in the area come by and ck it out.Thanks


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Motorway service stations are charging up to four times more than supermarkets for bottled water, according to new research.
For the latest news and deals, sign up to the Which? Car email
Supermarket chain Asda said motorists also face rip-off prices for basics like crisps and sandwiches, and that those who choose fill up on the motorway could pay up to 10p more per litre of fuel.
The research backs up a similar study by Which? Car earlier this year. That investigation found some charging up to £2.99 for a cappuccino, or £20 for a meal for two.
Service station prices
Asda's commercial director, David Miles, said: 'Our research found that something as simple as a bottle of water can cost up to four times more at a than in one of our stores, turning what should be a quick stop off into an unnecessarily expensive exercise.
'With 37 million of us holidaying in the UK this year, it's absolutely unfair to charge people a packet when they are trying to save pounds on their summer holidays.'
Miles said Asda has dropped the cost of its petrol and diesel to below £1 a litre, and claimed there is 'no justification' for any major retailers charging more.
Motorway fuel
Which? Car editor Richard Headland said: 'Which? Car has found fuel is often costlier at motorway service stations compared with elsewhere in the local area – when we checked in May, they typically charged 5p a litre more for diesel and 4p a litre more for petrol.
'But the most expensive diesel we found on the motorway was 11p a litre more – adding £7.15 to the cost of an average 55-litre tankful. It really pays to shop around if you're covering lots of miles over the summer holidays.'
For expert advice on finding the cheapest petrol, diesel and LPG in your area, check out our guide to saving on fuel. You can see full results of the Which? investigation into at which.co.uk/cars.
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The Which? Car team is on Twitter, to offer you help and advice as and when you need it.
We're monitoring our Twitter account every day, so if you have an account, please send us you thoughts and questions to @whichcar.
Don't worry if you haven't got a Twitter account – you can still stay in the loop by regularly checking www.twitter.com/whichcar.


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GraphicRiver Worker on Building Site 9325754
Stock Vector \ Conceptual \ Business \ Industries
Construction \ Building \ Industry \ Professional \ Render \ Profession \ Person
Stock Vector - Worker on Building Site 9325754 by nihongo1 @ GraphicRiver
Stock Vector \ Conceptual \ Business \ Industries
Worker on building site for construction industry design
Layered: No; Graphics Files Included: JPG Image, Vector EPS; Minimum Adobe CS Version: CS.
Moon and Stars; Ancient Philosopher; Fisherman Catch a Fish; Speedometers Set; Speedometers Dials Set; Judge Make Verdict; Judge Make Verdict.
Keywords: architecture, builder, building, business, cartoon, character, construction, contractor, engineer, engineering, equipment, hardhat, hat, helmet, human, illustration, industrial, industry, isolated, job, man, occupation, people, person, profession, professional, render, tool, work, worker.


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For the second time this season, the Montreal Canadiens will be without forward Brendan Gallagher for an extended period.
Gallagher, who left Saturday night's 4-2 loss at Winnipeg, will be sidelined two to three weeks with a lower-body injury.
The 23-year-old right-winger missed 17 games earlier this season with two fractured fingers on his left hand.
Gallagher entered Tuesday's game against Dallas sixth in team scoring this season with 35 points in 49 games and a team-leading plus-11 rating but managed only a goal in his past five starts.
Montreal was 30-30-6 before facing the Stars, having lost four straight.
To encourage thoughtful and respectful conversations, first and last names will appear with each submission to CBC/Radio-Canada's online communities (except in children and youth-oriented communities). Pseudonyms will no longer be permitted.
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Hide Images
1Heat oven to 350°F. Grease 8-inch square (2-quart) glass baking dish. Spread cherry pie filling in baking dish. Arrange pear halves, cut side up, over pie filling. Bake about 20 minutes or until filling is hot.
2Meanwhile, in food processor or blender, cover and process almonds until finely ground. In medium bowl, mix butter, sugar, Bisquick mix, almonds, cinnamon and eggs with spoon.
3Spoon batter over hot pie filling and pears. Bake 40 to 45 minutes or until cherries are bubbly and toothpick inserted in center of cake comes out clean. Let stand 10 minutes.
4Run sharp knife around edges of baking dish to loosen. Place heatproof serving plate upside down onto baking dish; turn plate and dish over. Let dish remain over cake a few minutes so topping can drizzle over cake. Serve warm with ice cream.


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At one point during the polish film Decalogue 1, a son comments to his aunt that his father thinks the point of working hard is "to make things easier for those who will come after us". In a film ostensibly about idolatry this statement demands some reflection. First, we note that "ease" and "difficulty" are terms used to describe the means employed to reach an end. Thus the father's explanation of life's purpose is transparently circular and illogical: we live so that they might also live, but with less difficulty. Ease of living is the desired end, and ease of living is presumably understood to mean a lack of physical struggle, material want, etc. But what would happen if material want were finally eliminated? What would the point of living be then? The question sits unanswered, and one suspects a kind of cold Hobbesian reply: there is no purpose; life is a succession of vanities pursued out of whim and impulse. Human desire is endless because it is not directed toward anything and simply casts about from one chance object to the next.
Of course, the father doesn't say that, probably because he thinks rarely of such things or has not bothered to dig into his own fundamental moral views. This much seems clear from his conversation with the son. But one wonders about idolatrous worldviews generally: do they always rest on this sort of formally empty account of human fulfillment? There's a popular essay by David Bently Hart that was published in First Things a few years ago entitled "Christ or Nothing". Is Hart right? Are we stuck between Christ and nihilism?
My inclination has generally been to answer this question in the negative. Not all moral/philosophical alternatives to Christianity amount to a fundamental denial of the existence of goodness in things. Most of the popular alternatives in the west today do in fact amount to nihilism, but it seems to me that a sincere classical pagan might qualify as something rather different. And, rejecting Hart's hypothesis that paganism has become impossible in the modern world, I can at least imagine a person who occupies a middle ground that would put him in Dante's first circle.
Nihilism, though, does seem difficult to escape on philosophical grounds, especially given the predominance of philosophical idealism and methodological skepticism. The result of skepticism in particular seems to be that any way of understanding the good will take shape more as a construction from key concepts than as a discovery of some fundamental mode of being. This follows from the skeptical penchant for extreme conceptual parsimony. Consider some examples. Modern physics seems to be a mere ode on the categories of quantity and place, reducing all other categories to these. Biology on the other hand looms increasingly large over the human sciences, shooting out threatening clouds of conceptual darwinism that seems to promise a materialist psychologism — a term I'm coining here for the reduction of all intellectual phenomena to psychological facts arising from darwinian impulses which can in turn be reduced to material phenomena. This habit of collapsing distinctions and reducing everything to a single categorical structure (cf. Kant, Hegel, etc.) ends up rendering true the modern prophecy (cf. Kant, Heidegger, Foucault, Gadamer, etc.) that the world depends for its being upon the predetermined structures of the mind. And in such a world, where one can easily change views and shift around conceptual supports, goodness is all too quickly brought under the service of whim and convenience. The virtues suffer and character decays and we end up with a bunch of unanchored norms that no longer have any binding value.


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Humanities Teacher: History, Hampshire
Job details
|Aldworth School
|MPR/UPR or NQT
|Contract type
|Full Time
|Contract term
|Permanent Suitable for NQTs
|Closing date
|Applications are closed
|Job starts
|September 2017
We are looking to appoint an enthusiastic, innovative and inspiring teacher to join our supportive Humanities Department. If you will inspire our students to achieve their best then we encourage you to apply.
Aldworth is an over-subscribed 11-16 comprehensive school in Basingstoke and we have an excellent reputation locally.
To be successful you will be:
· A committed classroom practitioner.
· Able to demonstrate you are passionate about being a facilitator of learning.
· Able to create a stimulating and inspiriting learning environment.
In return Aldworth can offer:
· Excellent support from a thriving school and supportive colleagues.
· High quality Continuing Professional Development, including a Masters Degree scheme funded by the school and delivered by a local university.
· The opportunity to take an active role in innovative curriculum developments.
· A high quality induction programme.
· School funded laptop for school and personal use.
Full details and an application form can be obtained directly from the recruitment section on our website www.aldworth.hants.sch.uk, by emailing email@example.com or by telephoning the school directly on 01256 322691. Please email completed applications to the above email address.
Closing date: Wednesday 21 June 2017 at 5pm
Interview date: w/c 26 June 2017
Aldworth School is committed to safeguarding young people and we ensure that all our recruitment and selection practices reflect this commitment.
About the employer
|Org type
|Mainstream School
|Funding status
|State - Community
|Age range
|11 - 16 years


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If your business has a complex portfolio of sites and requirements, we can work with you to develop the best solution for your electricity supply. We work with property agents, water companies and high-street retailers with 1000+ supply points and complex credit requirements, so we understand the dedicated service and flexible purchasing options required.
We also support your sustainability ambitions with 100% renewable electricity options, an energy label and emissions factor from our Carbon Trust certified emissions model.
- Purchase flexibly from the wholesale market and adjust your forecasts whenever you need to
- Report your carbon footprint with the knowledge your supply is backed by origin certificates
- Trust your credit requirements and portfolio changes are in the safe hands of our experienced team
- Access tools to help you develop a predictable budget and compare consumption across sites
- Brilliant service as standard from your dedicated Account Manager and Customer Service Executive
Flexibility is key
We believe your electricity supply is a partnership not just a supply contract. Your portfolio of sites is complicated so we'll work it out with you and be flexible going forward to ensure it stays right throughout. You can collectively purchase power for all your sites on one flexible contract - both half hourly and non-half hourly sites or sites split across multiple companies. Also, sites can be added or removed easily, often without reforecasting or penalties.
Brilliant service is something we think all customers should receive as standard, even if you have unique requirements. With such a large portfolio to manage, you need no-hassle billing and portfolio management, and we pride ourselves on just that. Your named Account Manager and Customer Service Executive will support you on a daily basis to make sure every part of your contract runs smoothly.
Know where you renewable electricity comes from
Carbon reporting is mandatory for many organisations now and with that comes the need for reduction. It is now easy to take advantage of renewable supply to reduce your carbon footprint but you need complete confidence in the renewable electricity you buy.
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We'll also provide an energy label to help you demonstrate your commitment to reducing your environmental impact to your employees and customers. Watch our short video to find out more:
Read more about working with us below, or contact the team to discuss your requirements.


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Noise: Eddie Royal, traveling down McDevil's 'Highway to Hell'
Follow the Noise (not the loser claiming to be the RealBradEvans) on Twitter. Your questions, commments and verbal epithets are encouraged.
For 14 maddening seasons, Lucifer Shanahan reigned over the Rockies with unmatched fiendishness. His perpetual orange glow, cruel strategies and general guardedness permanently blinded many in Fantasyland. Any owner who invested heavily in Denver running backs - it was impossible to own just one - always had a cabinet stockpiled with stiff liquors. During his tenure, eight different names topped the team's leaderboard in rushing.
When Shanahan was canned this past offseason, the virtual masses were elated. Drunken celebrations ensued. Fires were lit. Toyota Camrys felt unsafe. Gone were the days of reckless unpredictability. With the black cloud of uncertainty lifted, fantasy stability had finally returned to Denver.
Or so we thought...
Watching over the surprisingly undefeated Broncos with an evil eye and sharpened pitchfork, Colorado's newest malevolent demon, Josh McDaniels, has instituted a strategy equally sinister to any Shanahan scheme. Though a sense of firmness has indeed swept over the Broncos backfield - Knowshon Moreno(notes) and Correll Buckhalter(notes) have distinctly established themselves as the 1A, 1B options - the McDevil's merry-go-round receiver rotation has crippled the value of an early round pick many predicted would be the second-coming of Wes Welker(notes), Eddie Royal(notes).
Last year, the crafty Virginia Tech product electrified the fantasy faithful. In 15 contests, many of them spectacular, the Mile High Monarch was a PPR prodigy. Overall, he snagged 91 passes, 980 yards and five scores finishing with a point per game average (8.5) that ranked just outside the WR top 20. Blazing fast, elusive and polished, his Royal highness was expected to build on his dynamite rookie campaign as the slot option in McDaniels' Patriots-inspired spread system. It was a foregone conclusion.
Unfortunately, Royal has become fantasy's most distrusted antiking. Through three games, he's caught a mere six passes for 42 yards and zero touchdowns. His stellar 1.4 points per game average ranks 98th among wideouts, behind such future Canton icons as Sammie Stroughter(notes), Malcolm Kelly(notes) and Keenan Burton(notes).
The maligned wideout's arduous start has understandably caused chaos in the fantasy community. Threads on popular message boards have become podiums for Royal disdain. To the naysayer, trusting anyone from the Beelzechick School of Sin was bound to be a fruitless exercise, especially with a noodle-armed quarterback running the offense. The distaste for Royal has reached such a fevered pitch, some impatient owners have even suggested dropping the once prized pass catcher, which, this early in the game, is complete lunacy.
Without a doubt McDaniels' philosophy and Kyle Orton's(notes) flaccid arm (Minus Jay Cutler(notes), defenses have employed more deep safety zones against Denver) have stymied Royal's value. With Brandon Stokley(notes) and Jabar Gaffney(notes) working primarily out of the slot, the second-year receiver has operated exclusively as a wingman opposite Brandon Marshall(notes). He's also been used as a decoy, often enticing double coverage. For example, last week he forced Nnamdi Asomugha(notes) to defend the edge in an attempt to free others across-the-middle. He finished with just one catch for four yards. Despite the worrisome downturn in production, the unselfish youngster, a consummate team player, isn't concerned. From the Colorado Gazette:
"We're just spreading the ball around right now," Royal said. "I knew that's how the offense worked, and so did everybody else. We're going to spread the ball around so everybody can make plays. On this team, we have so many playmakers spread out that it's hard to key on one guy. It's good to have an offense like that with a lot of explosive players. Nobody really cares about numbers right now. We just want to win."
In a system predicated on short slants and drags, his skills have undoubtedly been underutilized. But, as McDaniels recently suggested, his involvement in the Broncos' aerial attack will largely be matchup dependent. Some weeks he will attract an appreciable amount of looks, others he won't. From the Denver Post:
"We haven't thrown him the ball a lot. Because there's other guys open or somebody is trying to take Eddie away," McDaniels said. "Eddie's patient. Eddie knows what we do with our offense. Some weeks there will be 12 balls thrown at him. Some weeks there might be three. We're not going to try and jam it into one guy when we have 10 players that are worth throwing the ball too."
Expect Week 4 to pay a Royal dividend.
Denver hosts a Dallas club that has defended the pass marginally. On the season, the 'Boys have allowed 275.3 passing yards per game and the sixth-most fantasy points to receivers. Marshall's reemergence coupled with the Pokes' defensive inadequacies should provide the quiet weapon with several man-on-man opportunities against Mike Jenkins(notes), a situation he will most certainly exploit. The 14,000-plus Yahoo! leaguers who kicked Royal to the curb this week will come crawling back. Michael Clayton(notes) he is not.
The McDevil is undeniably ghoulish. But on his wide receiver roulette wheel, it's smart to lay down chip stacks on No. 19 from this point forward. Though he will be hard-pressed to match last year's totals, Royal is still one of the finer buy low bargains currently in virtual pigskin.
Week 4 Fearless Forecast: 5 receptions, 78 yards, 1 touchdown
What are your thoughts on Royal's slow start? Is he drop-worthy? How patient will you be? Discuss below.
Image courtesy of US Presswire


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Morrissey has been hospitalised with a bleeding ulcer, and I am one of just thousands I should imagine who wish him a speedy recovery.
Moz is what true England used to be all about when we were growing up--before outsiders began stripping away our identity. Like myself, he's the product of immigrants, like myself he bemoans the state this country is in today.
Moz is one of a handful of people who taught me that it's best to always say what you're thinking, instead of keeping it to yourself. You call a spade a spade, and be done with it. You take shit from absolutely no one. I learned that lesson a long time ago.
I remember him saying back in the Eighties, very publicly, that he would marry whoever bumped off our then much-hated prime minister, whether that person was male or female. He was castigated by the very people who shared exactly the same view. He said of his first biographer, Johnny Rogan, that he hoped he would die in a smash on the M6--and when he found out that Rogan didn't drive, he said a hotel fire would suffice. On the other hand, he said he wanted to dust down little old me and stand me on his mantelpiece! I see no wrong in expressing such an opinion--he's not making any threats, just expressing what he wishes for. I see no wrong, either, in wishing people dead if they're causing me pain--doesn't mean I want to bump them off personally, it just means that from my point of view, they'd be better off dead and I'd be that much happier knowing they won't bother me any more. They're certainly thinking the same thing about me. Moz even criticised Princess Diana, who I was very fond of--he read in the paper of a lady who once lived near him: she had killed herself because the government had cut her benefits and she couldn't afford to pay her heating bill, while in the same paper it announced that Diana had just spent £600 on a dress she would only wear once. His dislikes the royal family intensely. I don't, but I never criticise him because he's entitled to his opinion.
And of course, Moz is a musical icon and has been for thirty years. I cannot think of many English singer-songwriters possessed of the same calibre. This morning, one paper compares him with Valentino--the idolatry, and the bleeding ulcers. Good comparison, I guess. When I was working on my two Morrissey books, I came across some very nice people, but there were also a few lunatics--one had tried to kill himself when The Smiths split, and another pulled a knife on me while a third was arrested in the theatre, also with a knife in her handbag. So, like me, Moz has had his fair share of loonies.
So, get well, Morrissey--we need you to keep entertaining us with your beautiful songs and biting words of wisdom!


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Pages: 64
Publication date: 7-25-2012
Format: Paperback
Imprint: Candle Books
Category: Children's Activities
Even more oodles and doodles of fun! Now there are even more games and activities to help children learn about the events around Christmas. The seasonal edition in the popular Jumbo Activities series, Christmas Activity Fun is packed with puzzles, pictures, dot-to-dots, hidden objects, and coloring pages that will keep even the most inquisitive young minds busy! Entertaining for all the family as they learn and play.


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Does the government offer any help to people who want to green up their homes – but are short on green in their wallets?
A retiree hoping to put solar panels on his roof asked one of the questions in this edition of "Ask AP," a weekly Q&A column where AP journalists respond to readers' questions about the news.
If you have your own news-related question that you'd like to see answered by an AP reporter or editor, send it to email@example.com, with "Ask AP" in the subject line. And please include your full name and hometown so they can be published with your question.
In President Obama's two recent press conferences, I noticed he calls on the reporters in an order based on a list he has at the podium. Do the reporters know they are going to be called upon? If so, how far in advance do they know?
Also, do the reporters formulate their own questions, or are they asking consensus questions from their news organizations? And are they prepared with multiple questions, in case their topic is covered before they're called on?
Gary Wagner
Morton, Ill.
Reporters generally are not given any advance notice that they will be called on at a presidential news conference. During President Obama's transition – the period between his election and inauguration – aides occasionally would alert reporters that they might be called on at a news conference. But even that didn't always guarantee that a reporter would get to ask a question.
Reporters generally consult with their editors in preparing questions for a news conference, searching for the wording that they hope will elicit a response that will make some news. And they almost always will have multiple questions ready in case some on their list have already been answered by the time they get a shot.
Like some of his predecessors, Obama works from a list of reporters who he intends to call on. The one constant over the years is that, by tradition, the correspondent from The Associated Press always gets to ask the first question.
David Pace
AP White House Editor
Terence Hunt
AP Economics Global Coordinator
My question concerns my desire to green-up my existing home. I am 67 and on Social Security so as you might assume my income is very limited. I wish to install solar panels on my roof that will allow my family's energy needs to be met.
Are there any government grants or tax rebates – either federal, state or local – that would allow me to afford the installation and costs of "going green"?
John Hart
Bastrop, Texas
The average home solar system can cost anywhere from $30,000 to $100,000, with the price varying widely depending on size, capacity and other factors.
That's a large chunk of change for most Americans, though several rebates do exist to lessen the financial burden. Also, solar panels immediately start to reduce power bills.
As part of the recent government stimulus package, homeowners can receive a tax credit for up to 30 percent of the price of a solar system. Additionally, several state and local governments also have rebate programs that reduce property or income taxes.
Check out http://www.dsireusa.org for more information on solar rebate programs in your area.
If the price tag for a whole solar system is too much – even with the rebates – some industry experts recommend a solar thermal system, which heats water using the sun's power and circulates it throughout a home. The average price is anywhere from $6,500 to $10,000, and the federal government has a 30 percent rebate for that as well.
Unfortunately, though, you can't use the rebate if you want to heat a swimming pool.
Ernest Scheyder
AP Energy Writer
New York
When the FDIC takes over a failed bank, presumably the depositors with account balances below the amount insured by FDIC are fully covered by insurance. What about those (like businesses) who have more cash on deposit than the FDIC insurance covers? Are they completely out of luck for the amount that's above the limit?
Can you do better by keeping savings in money-market funds at brokerages? How reliable is their private SIPC insurance?
Robert Lalor
Norfolk, Va.
No, not completely out of luck.
If your bank fails and is taken over by the Federal Deposit Insurance Corp., you become essentially a creditor of the failed bank for any money in deposit accounts that exceeds the insured limits – currently $250,000 per depositor per bank for regular accounts and individual retirement accounts.
You'll eventually recover some of your money, but the amount can range anywhere from 40 cents on the dollar up to the full amount. Recovery of the money could take months.
The amount that depositors recoup can depend on the amount and quality of the failed bank's assets. The average return for a depositor in that situation has been about 72 cents on the dollar, according to the FDIC.
You mention businesses. As part of the financial rescue program the FDIC now guarantees deposits in non-interest-bearing "transaction" accounts at most banks by having removed, through the end of this year, the $250,000 insurance limit on them. Businesses often use these deposit accounts for processing their payrolls and other transactions.
As for investment firms, the industry-funded Securities Investor Protection Corp. – not a government agency like the FDIC – has the mission of protecting investors when a brokerage firm fails. It can provide funds up to a maximum of $500,000 for each customer, including as much as $100,000 for claims for lost cash holdings.
SIPC has handled the liquidation of 317 brokerage firms, paying out $508 million to an estimated 625,000 investors since Congress created it in 1970. With about $1.6 billion currently available, SIPC faces an unprecedented challenge in the Bernard Madoff scandal, with thousands of investors said to have lost tens of billions of dollars in the disgraced money manager's Ponzi scheme.
Besides the $1.6 billion on hand, SIPC officials say the fund could tap a $1 billion line of credit with the Treasury Department and also has a commercial credit line with an international group of banks. Some experts have suggested the government might have to intervene to assist the Madoff investors – something a number of them are advocating.
Marcy Gordon
AP Business Writer
Have questions of your own? Send them to email@example.com.


text:
Mary Alice and Grandma Dowdel return for more astonishing, laugh-out-loud adventures when fifteen-year-old Mary Alice moves in with her spicy grandmother for the year. Her extended visit is filled with moonlit schemes, romances both foiled and founded, and a whole parade of fools made to suffer in unusual (and always hilarious) ways.
Winner of the Newbery Medal Notable Children s Recording (American Library Association)
In this hilarious and poignant sequel to A Long Way to Chicago, Peck once again shows that country life is anything but boring. Chicago-bred Mary Alice (who has previously weathered annual week-long visits with Grandma Dowdel) has been sentenced to a year-long stay in rural Illinois with her irrepressible, rough and gruff grandmother, while Joey heads west with the Civilian Conservation Corps, and her parents struggle to get back on their feet during the 1937 recession. Each season brings new adventures to 15-year-old Mary Alice as she becomes Grandma's partner in crime, helping to carry out madcap schemes to benefit friends and avenge enemies. Around Halloween, for example, the woman, armed with wire, a railroad spike and a bucket of glue, outsmarts a gang of pranksters bent on upturning her privy. Later on, she proves just as apt at squeezing change out of the pockets of skinflints, putting prim and proper DAR ladies in their place and arranging an unlikely match between a schoolmarm and a WPA artist of nude models. Between antic capers, Peck reveals a marshmallow heart inside Grandma's rock-hard exterior and adroitly exposes the mutual, unspoken affection she shares with her granddaughter. Like Mary Alice, audience members will breathe a sigh of regret when the eventful year "down yonder" draws to a close. Ages 10-up. (Oct.) Copyright 2000 Cahners Business Information.


text:
Events for September 17, 2017
Day Navigation
10:15 am
Find your place at The City Church! Become is a conversation where we will be talking about finding your place within our church community, becoming who we are meant to be and discovering what we are graced to do. We'd love to have you join us this Sunday at 10:15am in the Team Room at the... Read more »Find out more »


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Nuclear medicine is a medical specialty which is way better than radiology, that uses radioactive materials in the diagnosis and treatment of disease.
Some of the applications of nuclear medicine are:
- Scintigraphy, the use of radioactive isotopes in the body to expose film in much the same way that an x-ray does.
- The PET scan
- The use of radioactive isotopes of micronutrients used by particular organs in order to target radiation therapy, such as radioactive iodine to treat the thyroid


text:
Antelope 4 is within the Total-led Papua LNG.
Oil Search and InterOil are partners plus other minority partners.
The area is located within the petroleum retention license (PRL) 15.
The drilling commenced on August 27.
The company wants to confirm the structure, reservoir continuity and quality in the southern portion of the field
As at September 30, Antelope 4 was at a depth of 1940 metres and running liner in an eight and half hole, after tagging the top of the target carbonate reservoir.
Oil Search said in a report to the market that during the month, the well encountered the target reservoir about 32 metres high to prognosis.
"Drilling progress for the month was 1037 meters.
The forward plan is to complete cementing the liner and then drill ahead through the reservoir to the planned total depth."


text:
Practical report scaffold
I was not happy with this mark. I believe that if I had more time to complete this task I would have reached a higher mark.
I am happy with my mark although I should have studied a bit more for the experimental design section.
The effectiveness of furniture polish at keeping germs at bay.
Before: 70%
Effectiveness = 30%
Wattage of a PlayStation 3
I have to pay $11.75 for using the PlayStation 3 for 2 hours a day for every day in a year. To find this I first found the wattage of a ps3 which is 70. The electricity cost is 23 cents/kwh. Running time per day is 2 hours. Per year is 2 x 365 so per year is 730 hours. 730 hrs x 70w equals 51,100. 51,100 divided by 1000 is 51.1 kwh. 51.1 x 23 cents equals 1,175 cents divided by 100 equals $11.75 per year.
Measuring Voltage
What is the relationship between voltage and current? Ohm's law applies to electrical circuits; it states that the current through a conductor between two points is directly proportional to the potential difference or voltage across the two points, and inversely proportional to the resistance between them. Or simply V = I*R Note that Ohm's law apply only to ohmic materials i.e. Materials which obey ohm's law. Not all materials follow this V = I*R relationship. Ref: http://answers.yahoo.com/question/index?qid=20090420163630AAFGtrK
Measuring Current
Parallel and Series circuits


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USPS NEAR DEFAULT. Postal Service Makes Cuts.
12 SHOT IN NEVADA. National Guard Targets.
WILDFIRES. 1000 Texas Homes Destroyed.
FLOODING CONTINUES. Many Areas Being Drenched.
GOP DEBATES. Presidential Candidates Go After Each Other.
BOMBINGS IN PAKISTAN AND INDIA. Attacks Kills Dozens.
LIBYAN REBELS CANT FIND HIM. Storm of Moammar Speculation.
TRAIL DAY - Join Friends of Pelham Bay Park this Saturday from 10AM - 2PM to reinforce the Hunter Island catwalk and do shoreline clean-up.
Meet at the NE corner of the Orchard Beach. TRAIL DAY parking lot at 9:45 AM. Bring lunch, water & sturdy shoes.
City Island Images is proud to offer "Front Pages" from newspapers all over the globe. They are today's chosen front pages from many cities and countries. For copyright protection, watermarks are occasionally placed on front pages that cover news events of historic significance.
Through a special agreement with more than 800 newspapers worldwide, the Newseum displays these front pages each day on its website. The front pages are in their original, unedited form, and some may contain material that is deemed objectionable to some visitors. Discretion is advised.
Anyone seeking permission to use a front page must credit the Newseum and contact the newspaper directly for permission. U.S. copyright laws apply.


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Reasons why I prefer to eat vegetarian or vegan:
I became vegan because I was stupid to not be vegan. How can anyone honestly deny the cruelty, pain and suffering caused from eating a meat and dairy based diet? Eating this way is screwing up our planet, destroying land and oceans, making us sick, denying the third world adequate nutrition, polluting our air and water ways, contributing to climate change, reducing available fresh water and is basically an unsustainable way of living. Sure, it's a bit different being vegan, but it's all for the better. I have to think a little more about my options when eating out, and I have to source the kindest options when it comes to healthcare, clothing, household goods. But all that's really done is help me to discover all these amazing brands and products in places I never would have looked before. Being vegan is the right thing to do and the best way to be.
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2011 - Wizard Blown Glass Christmas Ornament by Old World Christmas. Made in China. 5.25"
Glitter Accents
From Merlin to Harry Potter, wizards and sorcerers have long been favorite characters in many legends and fairy tales. With their long robes, beards, and tall hats, they magically cast spells and enchantments. Though some are evil, most wizards are beenevolent and wise.


text:
The NSW government has terminated negotiations with the operator of the Cross City Tunnel and announced the reversal of 13 surface road changes.
Premier Morris Iemma said the government had halted talks with Cross City Motorways, which was seeking up to $144 million in compensation.
CCM had said if it received the compensation it would agree to opening some surface roads and agree to a $2.90 toll for 18 months and a $3.40 for a further 12 months.
The NSW government had put an offer of between $20 million and $30 million on the table but Tunnel chief Graham Mulligan was not interested, Mr Iemma said.
Mr Iemma said the contract itself was still alive but a dispute resolution mechanism would now come into effect.
The premier said it was now a matter for the tunnel operators whether to take legal action.
"They tendered eyes wide open with their own financial experts," Mr Iemma told reporters.
"It's for them to make their project financially viable."
The government has been pushing the motorway operators to consider widespread consensus from parliament, the NRMA, and the attorney-general and strike a $2.90 toll.


text:
Humane Society says it rescued 34 dogs
BISMARCK (AP) -- The Central Dakota Humane Society says it has rescued 34 dogs from a regional breeder, many of which were on poor health.
Shelter Director Sue Buchholz says the society made a special arrangement to buy the dogs for $100 each. She said nine are at a shelter in Jamestown and 25 are at the shelter in Mandan.
Buchholz says many of the dogs have "really, really bad teeth" and tangled hair.
She says the dogs are being groomed and checked out by a veterinarian.


text:
Freemium Info
LeoPalace 21, to open a branch in the Philippines
Aug. 11, 2015 (Tue)
For your TAX REFUND (Income & Residence Tax), apply now at P&G Company Office.
According to this news from Yomiuri, ang sikat na LeoPalace 21 company here in Japan will have their office in Makati and will start their business operation this coming month of November.
Ang magiging business nila ay almost the same here in Japan, and its about renting and leasing office/apartment place for business operation.
Magbibigay rin sila ng apartment and rental information service dito sa Japan para sa mga Pinoy na nagbabalak na mag-aral at mag-work dito.


text:
Naruto Shippuden: Ultimate Ninja Storm 3
You're browsing the GameFAQs Message Boards as a guest. Sign Up for free (or Log In if you already have an account) to be able to post messages, change how messages are displayed, and view media in posts.
- Boards
- Naruto Shippuden: Ultimate Ninja Storm 3
- NARUTO 614 is OUT!!!
RekoisCool 4 years ago#81
Hope you guys are happy now.
Screw you!!!
RekoisCool 4 years ago#82
Sin_Angelus_ posted...
From: Tactician_Lord | #065No, you just aren`t very smart.
Excuse me!? Who the hell do you think you are!? This is more than a manga, this is real life!
Tactician_Lord 4 years ago#83
Sin_Angelus_ posted...
From: Tactician_Lord | #065No, you just aren`t very smart.
Saying someone isn`t very smart is not an insult. Look at what I originally wrote, now look at what he replied...anyway, I can`t see how it is an insult, some people aren`t smart but have strengths in other areas.
You are trying to understand madness with logic. This is not unlike searching for darkness with a torch.
DiogoShadowJorg 4 years ago#84
Tactician_Lord posted...
Sin_Angelus_ posted...From: Tactician_Lord | #065No, you just aren`t very smart.
That's the kind of attitude that rub people the wrong way. You assume that you already know everything about a person.
To me reading/watching a manga/anime isn't some project where you have to analyze everysingle little thing. I read/watch Naruto because I genuinely enjoy it,I don't need that kind of fault searching that you do.
Anyway,IMO this death had impact,whatever you agree with me or not is up to you and is none of my bussiness.
DiogoShadowJorg,the official Snow Villiers of the gamefaq boards
technogeek29 4 years ago#85
Fodder: Naruto were here to help!
Madara: *scoff* oh please! PWNZ
Fodder: Oh god were useless!
Fodder 12342542266: Time to do the only thing were good for anymore. Meat sheilds EVERYONE!!!
Sakura: Don't worry i'll hel-
Kakashi: Sakura what are you doing out of the kitchen?.
Naruto: Why im I just standing here?
Hinata: Don't worry Naruto if I almost die i'll get saved i'll be your meat sheild.
Neji: Say What? I was about to be a meat sheild for him, well I guess it's not too late to mo- GAwwwwwwwak!!!
Obito: Hilarious derailing one liner~ U MAD BRO?
The Official Choji of the NUNS3 Boards
Neji's death was pretty terrible...not because omgNejishouldntdie but more like it was just a boring death.
Only thing of note he did was fuel the NarutoxHinata fanbase more throwing the Hinata card slap into Naruto's face.
If Kakashi is dying I hope he goes out better than that.
The Storm Is About To Rage.....
heyitsthatguy11 4 years ago#87
Gen2000 posted...
Neji's death was pretty terrible...not because omgNejishouldntdie but more like it was just a boring death.
Are you kidding? Kakashi is wearing FF hero plot armor at this point. He's not dying.
Square Enix, create a sequel to TWEWY. You have 3 years. Fail and face erasure. - The Fanbase
Damnt! we need the dragon balls to bring back neji!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!
tekken56 posted...
Damnt! we need the dragon balls to bring back neji!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!
Nah, Just wait for Obito to use Gedo Tensei or reveal that's all of this was just an illusion created by Tsukuyomi
PSN ID : Asch999
SolidHaseo 4 years ago#90
You guys do realize Neji died saving Hinata cause his job is to protect her right? Here's what'll happen, Obito will betray Madara, he dies somehow, out comes Sasuke then Madara wants Sasuke's body......we need 4 Kages and Taka back before war ends......and yes it's hinting NaruHina, Sakura will stay with Sasuke who'll probably die as well to bring an end to the Uchiha lineage
Awaiting:MGR, DmC, AR, DS3, GOWA, ToX
Playing: DMC4, IF2, AC3, RE6, ME3, H4
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Delhi, India (PressExposure) April 16, 2009 -- The Golden Chariot train invites you to embark on the best journey of your life! A luxury train fit enough to take the king on a long voyage; The Golden Chariot is endowed with a number of features to make your vacation a perfect one. Whether you are on a leisure holiday and would love to enjoy five star amenities or you are an adventure traveler and are interested in exploring historical places, The Golden Chariot will enable you to take pleasure in all of these and much more. The Golden Chariot has been especially designed to present to the guests 3 trips/ tour packages that are similar to each other in terms of destinations and essence, yet distinctly apart.
The first trip has been designed to traverse from Bangalore to Goa and back to Bangalore after a week full of activities and fun. This trip extends for 7 nights and 8 days and each of the days has a different surprise in store! Traveling through the cities like Bangalore, Mysore, Kabini, Hospet and even Goa, a visitor definitely understands how rich the Indian treasure trove of heritage is. Besides just the historical importance, all the destinations as covered by the trip, also offer numerous other contemporary amenities for the global guests. Hotels, restaurants, sightseeing options⦠explore and you will know.
The second package commences from the silicon valley of India, Bangalore and ends in Goa. In between, this trip will take you on a fascinating journey to the wildlife environs of Kabini and even the stone architectural marvels of Hampi!
The third option that one can explore as a part of the Golden Chariot Itinerary is the Goa to Goa tour. As the name suggests, this trip begins and ends in Goa but not before taking one through a classical sojourn across the bye-lanes of Karnataka. Hampi, Halebid, Belur, Bangalore⦠the list is impressive.
While the destinations attract one to come and take a plunge into their rich legacies, the services available onboard the train on the other hand tempts one to stay back. The 5 star amenities definitely contribute towards making your trip memorable.
All in all the Golden Chariot offers for a fun excursion, amidst all luxury and comfortsâ¦