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Acute kidney injury (AKI) frequently leads to systemic inflammation and extrarenal organ dysfunction. Volatile anesthetics are potent anti-inflammatory agents and protect against renal ischemia-reperfusion injury. Here, we sought to determine whether isoflurane, a commonly used volatile anesthetic, protects against AKI-induced liver and intestinal injury, the mechanisms involved in this protection, and whether this protection was independent of the degree of renal injury. Bilateral nephrectomy-induced AKI under pentobarbital sodium anesthesia led to severe hepatic and intestinal injury with periportal hepatocyte vacuolization, small intestinal necrosis, apoptosis, and proinflammatory mRNA upregulation. In contrast, isoflurane anesthesia reduced hepatic and intestinal injury after bilateral nephrectomy. Mechanistically, isoflurane anesthesia upregulated and induced small intestinal crypt sphingosine kinase-1 (SK1) as SK1 mRNA, protein, and enzyme activity increased with isoflurane treatment. Furthermore, isoflurane failed to protect mice treated with a selective SK inhibitor (SKI-II) or mice deficient in the SK1 enzyme against hepatic and intestinal dysfunction after bilateral nephrectomy, demonstrating the key role of SK1. Therefore, in addition to its potent anesthetic properties, isoflurane protects against AKI-induced liver and intestine injury via activation of small intestinal SK1 independently of the effects on the kidney. These findings may help to elucidate the cellular signaling pathways underlying volatile anesthetic-mediated hepatic and intestinal protection and result in novel clinical applications of volatile anesthetics to attenuate perioperative complications arising from AKI.
- acute kidney injury
- acute renal failure
- apoptosis
- inflammation
- necrosis
- sphingosine-1-phosphate
acute kidney injury (AKI) is a major clinical problem during the perioperative period (24) and often leads to multiorgan dysfunction and systemic inflammation, contributing to significant morbidity and mortality in hospitalized patients. Hepatic dysfunction occurs frequently in patients with AKI and leads to other complications such as intestinal barrier dysfunction, respiratory failure, and multiorgan failure frequently complicated by sepsis (10). Recently, we showed that AKI leads to rapid hepatic and intestinal injury in mice with increased inflammation, apoptosis, and necrosis mediated by upregulation of the proinflammatory cytokines TNF-α, IL-17A, and IL-6 (46).
Virtually all patients undergoing general anesthesia in the United States are exposed to volatile anesthetics, and therefore volatile anesthetics are one of the most widely used drugs during the perioperative period. Fortuitously, in addition to their analgesic and anesthetic properties, volatile anesthetics produce tissue protection in several organs including the heart (21), kidney (33), liver (50), and brain (59). We previously demonstrated that volatile anesthetics protected against renal ischemia-reperfusion (IR) injury in vivo by reducing renal cell necrosis and attenuating inflammatory leukocyte and cytokine attack (32). However, the detailed mechanisms and exact cellular targets of volatile anesthetics to mediate this multiorgan protection remain to be fully elucidated. Most volatile anesthetics are lipophilic molecules (3) and are known to modulate the plasma membrane and sphingomyelin metabolism in the renal cortex (37). One of the major components of sphingomyelin metabolism involves sphingosine kinase (SK)-mediated production of sphingosine-1-phosphate (S1P). Modulation of SK and S1P signaling is particularly attractive as this pathway has been shown to be an important regulator in promoting cell growth and survival and the inhibition of apoptosis (17, 53).
In this study, we aimed to 1) determine whether volatile anesthetics protect against liver and intestine injury after AKI; 2) demonstrate whether this protection was independent of the effects of volatile anesthetics on the kidney; and if so 3) identify the cell type targeted by volatile anesthetics to mediate multiorgan protection; and 4) test whether volatile anesthetics activate SK/S1P signaling. Therefore, we used a murine model of bilateral nephrectomy to test the hypothesis that volatile anesthetics activate the SK1/S1P pathway in the small intestine to protect against AKI-induced hepatic and intestinal injury. We demonstrate here that isoflurane reduced hepatic and intestinal proinflammatory cytokine upregulation and intestinal apoptosis and necrosis via induction of SK1 in small intestinal crypts.
Isoflurane [2-chloro-2-(difluoromethoxy)-1,1,1-trifluoro-ethane] was purchased from Abbott Laboratories (North Chicago, IL). SKI-II [4-[[4-(4-chlorophenyl)-2-thiazolyl]amino]phenol] was purchased from Tocris Bioscience (Ellisville, MO). Unless otherwise specified, all other reagents were purchased from Sigma (St. Louis, MO).
Murine model of bilateral nephrectomy.
All animal protocols were approved by the Institutional Animal Care and Use Committee of Columbia University (New York, NY). We used male C57BL/6 (20–25 g, Harlan, Indianapolis, IN) or SK1KO (20 to 25 g, kindly provided by R. L. Proia, NIH, Bethesda, MD) mice. The generation and initial characterization of SK1 knockout (SK1KO) mice have been described previously (2). These mice are congenically derived on a C57BL/6 background.
In our model of bilateral nephrectomy, mice were initially anesthetized with intraperitoneal pentobarbital sodium (50 mg/kg body wt, or to effect, Henry Schein Veterinary, Indianapolis, IN), and after midline laparotomy, both kidneys were removed. After closure of the abdomen in two layers, the mice were then exposed to an additional 4 h of equipotent doses of either pentobarbital sodium or isoflurane [1.2% or 1 minimum alveolar concentration (MAC; defined as the concentration of volatile anesthetic in the lungs that is needed to prevent movement in 50% of subjects in response to a painful stimulus)] as described previously (33). The mice were placed on a heating pad under a warming light to maintain body temperature ∼37°C.
To test the effects of SK inhibition, SKI-II (50 mg/kg) was administered to mice subcutaneously 15 min pre- and 4 h postnephrectomy. SKI-II is an SK-selective inhibitor with minimal effects on other kinases (11), and this dose was shown to have effective inhibition of activity without significant toxicity (12).
For experiments involving sham operation or bilateral nephrectomy, all samples (including plasma and tissue) were collected from mice 5 h after sham operation or bilateral nephrectomy, as previous studies demonstrated that liver and intestinal injury peaked at this time point after bilateral nephrectomy (46). For experiments involving sham exposure to pentobarbital sodium or isoflurane (SK mRNA and protein expression, SK1 immunohistochemistry, SK activity, and S1P measurement), mice were exposed to 4 h of pentobarbital sodium or isoflurane (without sham operation or bilateral nephrectomy) and allowed to recover for 1 h. Samples were collected 5 h after initial anesthetic exposure.
Plasma alanine aminotransferase activity and creatinine level.
Plasma alanine aminotransferase (ALT) activity was measured using an Infinity ALT assay kit according to the manufacturer's instructions (Thermo Fisher Scientific, Waltham, MA). Plasma creatinine was measured by an enzymatic creatinine reagent kit according to the manufacturer's instructions (Thermo Fisher Scientific).
Histological analysis of liver and small intestine injury.
For histological preparations, liver or small intestine (jejunum and ileum) tissues collected from mice were washed in ice-cold PBS and fixed overnight in 10% formalin. After automated dehydration through a graded alcohol series, tissues were embedded in paraffin, sectioned at 5 μm, and stained with hematoxylin-eosin (H&E).
Detection of small intestinal apoptosis after bilateral nephrectomy.
We detected small intestinal apoptosis with terminal deoxynucleotidyl transferase biotin-dUTP nick end-labeling (TUNEL) staining. In situ labeling of fragmented DNA was performed with TUNEL stain (green fluorescence) using a commercially available in situ cell death detection kit (Roche, Indianapolis, IN) according to the instructions provided by the manufacturer.
Assessment of liver and small intestine inflammation and SK expression.
Liver and intestine inflammation was determined by measuring mRNA encoding markers of inflammation, including IL-6, IL-17A, ICAM-1, monocyte chemoattractive protein 1 (MCP-1), macrophage inflammatory protein 2 (MIP-2), and TNF-α (Table 1). In addition, SK1 and SK2 mRNA levels were measured. Semiquantitative real-time RT-PCR was performed as described (34).
Vascular permeability of liver and small intestine after bilateral nephrectomy.
Changes in liver and small intestine vascular permeability were assessed by quantitating extravasation of Evans blue dye (EBD) into the tissue as described previously (48).
Immunoblotting analyses of small intestine.
Small intestinal tissues in mice were collected and homogenized in lysis buffer [20 mM HEPES (pH 7.4), 2 mM EGTA, 1 mM DTT, 1% Triton X-100, 10% glycerol, and protease inhibitor cocktail (Calbiochem, La Jolla, CA)] on ice with a glass homogenizer. The homogenates were centrifuged for 20 min at 16,000 g. The supernatant was collected and used for immunoblotting as described earlier (25). The samples (50–100 μg protein/lane) were separated on 9 or 12% SDS-PAGE and then transferred to Immobilon membranes (Millipore, Bedford, MA). The membranes were blocked with blocking buffer (5% nonfat dry milk in TBS containing 0.1% Tween 20) and incubated overnight with polyclonal anti-SK1 (3297; 1:1,000 dilution; Cell Signaling, Beverly, MA), anti-SK2 (ab37977; 1:2,000 dilution; Abcam, Cambridge, MA), or monoclonal anti-β-actin (A5316; 1:5,000 dilution) antibodies diluted in blocking buffer at 4°C. After being washed, the membranes were incubated with horseradish peroxidase-conjugated donkey anti-rabbit or sheep anti-mouse (1:5,000 dilution; ECM Bioscience, Versailles, KY) antibodies for 1 h at room temperature. Finally, the membranes were detected with enhanced chemiluminescence immunoblotting detection reagents (Amersham, Piscataway, NJ) with subsequent exposure to a CCD camera coupled to a UVP Bio-imaging System (Upland, CA). The band intensities of the immunoblots were within the linear range of exposure for all experiments.
Immunohistochemical detection of SK1.
We used immunohistochemistry to detect small intestinal SK1. Paraffin-embedded intestine sections from mice were deparaffinized in xylene and rehydrated through a graded ethanol series to water. Antigen retrieval was performed in 95°C 10 mM sodium citrate (pH 6.0) for 10 min. Endogenous peroxidase activity for all sections was quenched with 0.3% H2O2 while nonspecific binding was reduced by blocking with buffer containing 1% bovine serum albumin. The slides were stained for SK1 in sequential incubations with rabbit anti-mouse SK1 primary antibody (AP7237, 1:50 dilution; Abgent, San Diego, CA) overnight at 4°C, horseradish peroxidase-conjugated goat anti-rabbit IgG (PI-1000, 1:200 dilution, Vector Laboratories, Burlingame, CA) for 1 h at room temperature, and diaminobenzidine reagent (Vector Laboratories) for 2 min. A rabbit IgG (I-1000, Vector Laboratories) was used at the same concentration as the primary antibody as a negative isotype control for all experiments.
In vivo intestine enzyme preparation from mice and SK activity assay.
Small intestine tissues from mice were collected and homogenized mechanically in cell lysate buffer [100 mM sucrose, 1 mM EGTA, 20 mM MOPS, pH 7.4, 5% Percoll, 0.01% digitonin, protease (Calbiochem) and phosphatase inhibitors] on ice. After a 1,000-g spin for 15 min to pellet cellular debris, protein concentrations were determined. SK activity was measured as described by Vessey et al. (57) using 20 μg of protein, with some modifications as described (30).
HPLC detection of S1P.
S1P levels were measured in the small intestines of mice using HPLC as described (29).
Protein determination.
Protein content was determined with the Thermo Scientific bicinchoninic acid protein assay reagent with bovine serum albumin as a standard.
Statistical analysis.
The data were analyzed with Student's t-test when means between two groups were compared. One-way ANOVA plus Tukey's post hoc multiple comparison test was used when multiple groups were compared. In all cases, a probability statistic <0.05 was taken to indicate significance. All data are expressed throughout the text as means ± SE.
Isoflurane protects against acute hepatic injury after bilateral nephrectomy in mice.
All animals awakened from anesthesia following bilateral nephrectomy with pentobarbital sodium or isoflurane exposure. There were no observable differences in the condition and health of the mice between the two groups. As demonstrated previously (30), there were no changes in systemic arterial blood pressure, renal blood flow, or core body temperature between pentobarbital sodium- and isoflurane-anesthetized mice. Five hours after bilateral nephrectomy, there was a rise in plasma creatinine (mg/dl) with pentobarbital sodium exposure (Cr =1.23 ± 0.08, n = 10, P < 0.001) compared with sham-operated mice (Cr = 0.45 ± 0.03, n = 6). With a complete lack of renal function, however, there was no significant reduction in plasma creatinine with isoflurane exposure (Cr =1.12 ± 0.04, n = 8, not significant).
Mice developed acute hepatic injury after bilateral nephrectomy with pentobarbital sodium exposure as indicated by a rise in plasma ALT above sham levels (Fig. 1A). In contrast, isoflurane exposure after bilateral nephrectomy protected against liver injury with a significant reduction in plasma ALT levels (Fig. 1A).
To evaluate the role of SK in mediating the protective effects of isoflurane, we treated some animals with a selective SK inhibitor SKI-II before bilateral nephrectomy. SKI-II administration had no detrimental effects on renal function (Cr = 0.43 ± 0.04, n = 3) in sham-operated mice. Plasma ALT levels increased in SKI-II-treated mice exposed to pentobarbital sodium after bilateral nephrectomy compared with sham-operated mice (Fig. 1B). There was no reduction in plasma ALT levels with isoflurane exposure. In addition, we utilized a strain of mice deficient in SK1 enzyme. SK1KO mice exposed to pentobarbital sodium after bilateral nephrectomy had elevated plasma ALT levels compared with sham-operated mice with no reduction in plasma ALT levels with isoflurane exposure (Fig. 1B). Taken together, these data indicate that the protective effects of isoflurane on hepatic function after bilateral nephrectomy are abolished with inhibition of SK1 enzyme in mice.
Isoflurane exposure reduces hepatic vacuolization and small intestinal necrosis and apoptosis.
In Figs. 2 and 3, the protective effects of isoflurane anesthesia are further supported by representative histological slides collected from mice after sham operation or bilateral nephrectomy. Pentobarbital sodium exposure after bilateral nephrectomy led to nuclear and cytoplasmic degenerative changes, cellular vacuolization, leukocyte infiltration, and congestion in the liver (Fig. 2, B and D) and profound epithelial necrosis, villous swelling, and apoptosis in the small intestine (Fig. 3, A and B). Isoflurane exposure after bilateral nephrectomy significantly attenuated these injuries in the liver (Fig. 2C) and small intestine (Fig. 3, C and D).
We failed to detect significant TUNEL-positive cells in small intestinal sections from sham-operated mice exposed to pentobarbital sodium (Fig. 4A) or isoflurane (Fig. 4B). Mice exposed to pentobarbital sodium after bilateral nephrectomy (Fig. 4C) showed many TUNEL-positive cells in the small intestine (representative of 4 experiments) whereas mice exposed to isoflurane after bilateral nephrectomy (Fig. 4D) had a reduction in TUNEL-positive cells in the small intestine.
C57BL/6, but not SK1KO, mice exposed to isoflurane after bilateral nephrectomy show reduced proinflammatory gene expression in the liver and small intestine.
We measured proinflammatory mRNA expression in the livers and intestines of C57BL/6 mice after sham operation or bilateral nephrectomy. We found increased mRNA expression of TNF-α, ICAM-1, IL-17A, MCP-1, MIP-2, and IL-6 in the livers and small intestines of mice exposed to pentobarbital sodium after bilateral nephrectomy compared with sham-operated mice (46). When mice were exposed to isoflurane after bilateral nephrectomy, there was significantly reduced expression of some proinflammatory mRNAs (TNF-α, IL-17A, and MIP-2) in both the liver and intestine compared with pentobarbital sodium exposure (Fig. 5A). In contrast, MCP-1 and ICAM-1 expression were not reduced with isoflurane exposure after bilateral nephrectomy in both the liver and intestine. Interestingly, isoflurane exposure decreased IL-6 expression in the liver, but not intestine, after bilateral nephrectomy. We also measured proinflammatory mRNA expression in the livers and intestines of SK1KO mice after sham operation or bilateral nephrectomy. In contrast to C57BL/6 mice, there were no reductions in proinflammatory mRNAs in the livers or intestines of SK1KO mice exposed to isoflurane after bilateral nephrectomy compared with pentobarbital sodium-exposed mice.
Isoflurane exposure decreases hepatic and small intestinal vascular permeability after bilateral nephrectomy.
We measured liver and small intestinal vascular permeability after sham operation or bilateral nephrectomy using EBD. EBD binds to plasma proteins, and its appearance in extravascular tissues reflects an increase in vascular permeability (5). Bilateral nephrectomy caused significant increases in vascular permeability as measured by increased EBD content compared with sham-operated mice in the liver, jejunum, and ileum (Fig. 6). Vascular permeability was significantly decreased with isoflurane exposure after bilateral nephrectomy in the liver, jejunum, and ileum.
Isoflurane increases small intestinal SK1 mRNA and protein expression.
We measured SK mRNA and protein expression in the small intestines of sham mice (without operation) after exposure to either pentobarbital sodium or isoflurane. Isoflurane exposure increased small intestinal SK1 mRNA expression (Fig. 7) and protein expression (Fig. 8) in mice compared with pentobarbital sodium exposure. However, there were no changes in SK2 mRNA or protein expression in the small intestine after isoflurane exposure (Figs. 7 and 8). In addition, the livers of sham mice exposed to pentobarbital sodium or isoflurane demonstrated a similar increase in SK1 mRNA and protein expression with no change in SK2 mRNA or protein (data not shown).
Isoflurane increases small intestinal crypt SK1 expression.
We used immunohistochemistry to detect SK1 expression in sham mice. Isoflurane exposure increased staining for SK1 in the small intestine. Specifically, we saw increased expression of SK1 protein in the small intestinal crypts with enhanced staining in the nuclei and cytoplasm. (Fig. 9, C and D, representative of 4 experiments), compared with pentobarbital sodium exposure (Fig. 9, A and B). Staining specificity was confirmed with negative, isotype-specific control antibodies (data not shown).
Isoflurane increases small intestinal SK activity and S1P levels.
We measured SK enzymatic activity and S1P levels in the small intestines of sham mice (without operation) after exposure to either pentobarbital sodium or isoflurane. The small intestines of mice exposed to isoflurane demonstrated higher SK activity compared with the small intestines of mice exposed to pentobarbital sodium (Fig. 10A). Correspondingly, small intestinal S1P levels were higher in mice after isoflurane exposure than after pentobarbital sodium exposure (Fig. 10B). However, we were unable to detect an increase in SK activity in the livers of sham mice exposed to pentobarbital sodium (relative SK activity = 1.00 ± 0.03, n = 4) compared with isoflurane (relative SK activity = 1.01 ± 0.08, n = 4).
In this study, we have demonstrated that a clinically relevant concentration of isoflurane (1.2% or 1 MAC) administered to mice after bilateral nephrectomy reduced hepatic and small intestinal injury by reducing inflammation and apoptosis and improving vascular permeability. We show that isoflurane-mediated liver and intestine protection did not require intact renal function and was independent of the effects of volatile anesthetics on the kidney. In addition, isoflurane induced small intestinal SK1 mRNA, protein expression, and enzymatic activity with higher small intestinal S1P levels. We also confirmed the critical role of SK1 as isoflurane failed to protect mice treated with an SK inhibitor (SKI-II) or mice lacking the SK1 enzyme.
Perioperative AKI remains a clinically significant problem, and the development of postoperative AKI (1) and extrarenal dysfunction following AKI, including hepatic and respiratory failure, were independent predictors of in-hospital mortality (40). The inflammatory response following AKI has both local and systemic effects including endothelial and proximal tubule injury with release of proinflammatory cytokines and chemokines and the recruitment of leukocytes such as macrophages, neutrophils, and T lymphocytes (6). It is clear that the effects of AKI are not limited to the kidney but frequently spread to distant organs including the lung (31), heart (27), brain (36), and liver (15).
We have previously demonstrated the protective role of volatile anesthetics in renal IR injury (33). Here, we aimed to determine whether volatile anesthetics mediated protection in the liver and small intestine after AKI and whether this protection was independent of the protective effects of volatile anesthetics in the kidney. Therefore, we used a model of nonischemic AKI with bilateral nephrectomy in mice. Bilateral nephrectomy can be used to distinguish the effects of impaired renal function from those of renal IR injury (31). Both renal IR and bilateral nephrectomy lead to extrarenal dysfunction such as lung injury (28, 31) and hepatic injury (15). However, differences in the genomic response (18) and cytokine response (19) between renal IR and bilateral nephrectomy have been described. Serum levels of keratinocyte-derived chemokine and granulocyte-macrophage colony-stimulating factor increased significantly after renal IR but not bilateral nephrectomy (19).
Previous studies showed rapid hepatic injury and inflammation after ischemic or nonischemic AKI (15, 46). In addition, we demonstrated massive small intestinal injury (apoptosis, inflammation, and necrosis) after ischemic or nonischemic AKI (46). The gut has long been suspected to play a key role in initiating the early hyperdynamic response to sepsis (58), and recently we demonstrated that the inflammatory mediator IL-17A was released by small intestinal crypt Paneth cells after AKI in mice (47). IL-17A released from Paneth cells caused hepatic injury and a proinflammatory cascade, including upregulation of TNF-α and IL-6. In addition, hepatic and small intestinal inflammation was attenuated when mice were treated with antibodies to TNF-α, IL-17A, or IL-6 or in mice lacking TNF-α, IL-17A, or IL-6 (46). In this study, isoflurane decreased the mRNA expressions of proinflammatory cytokines MIP-2, IL-17A, and TNF-α in the liver and small intestine after bilateral nephrectomy.
Indeed, the anti-inflammatory effects of volatile anesthetics have been demonstrated as they decreased the inflammatory response of alveolar macrophages to endotoxin (54) and protected mice against zymosan-induced inflammation and acute lung injury (41). IL-17A, in particular, produced primarily by a subset of T cells known as Th17 cells, is involved in innate immune defense and inflammation (45). IL-17A-producing Th17 cells can be found in the intestinal lamina propria of healthy mice (20) but rarely in the spleen, mesenteric lymph nodes, or Peyer's patches (4). In addition, Paneth cell-derived IL-17A mediated TNF-α-induced shock (56), and we showed that Paneth cell IL-17A production increases after AKI, leading to higher levels of additional cytokines, including TNF-α (47), which is a mediator of the inflammatory cascade seen after AKI (9). In this study, we demonstrate upregulation of intestinal crypt SK1 and increased S1P synthesis by isoflurane. Taken together, we propose that intestinal S1P generation with subsequent reductions in IL-17A and TNF-α, both produced in intestinal crypts, mediate the anti-inflammatory effects of volatile anesthetics, potentially leading to multiorgan protection.
The expression of IL-6 after bilateral nephrectomy was reduced with isoflurane exposure in the liver, but not in the small intestine, demonstrating a divergent effect of isoflurane on the liver and small intestine. IL-6 was involved in the progression of liver inflammation to hepatocellular carcinoma (42) but was shown to protect enterocytes against cell death and apoptosis and mice against intestinal IR injury (22). Therefore, selective reduction of hepatic IL-6 generation without concomitant reduction of intestinal IL-6 would explain potent hepatic and intestinal protection with isoflurane treatment. The expressions of MCP-1 and ICAM-1 did not change with isoflurane exposure after bilateral nephrectomy, perhaps reflecting the importance of intact renal function to better metabolize and excrete inflammatory mediators affecting the expression of these two cytokines, as studies in chronic renal failure patients suggest the importance of renal clearance of proinflammatory mediators (49). Moreover, we further demonstrate the importance of SK1 in mediating the anti-inflammatory effects of isoflurane as isoflurane exposure failed to reduce expression of proinflammatory mediators in both the liver and intestine in mice lacking SK1.
Volatile anesthetic-mediated protection has been demonstrated in organ systems such as the brain (59), heart (21), and lung (41), and the protective effects of volatile anesthetics in the kidney (30), HK-2 cells (29), and brain (59) may involve activation of the SK/S1P pathway. With this knowledge, we hypothesized that volatile anesthetic-mediated activation of SK1/S1P signaling in the small intestine would protect against extrarenal organ dysfunction following bilateral nephrectomy. Using both a pharmacological inhibitor (SKI-II) and a genetic knockout mouse model (SK1KO), we demonstrated the key role of the SK1/S1P pathway in mediating the protective effects of volatile anesthetics in the liver and small intestine after bilateral nephrectomy. Using immunohistochemistry, we determined that isoflurane exposure upregulated SK1 in small intestinal crypts. Taken together, these data show that isoflurane activates SK1/S1P signaling in small intestinal crypts to protect the liver and intestine after bilateral nephrectomy.
S1P has multiple roles in cellular signaling and in particular, the "sphingolipid rheostat" balances the prosurvival effects of S1P against the apoptotic effects of sphingosine and ceramide (38). S1P protected intestinal cells from apoptosis via Akt activation (16) and reduced IR injury in the lung (43) and kidney (35). S1P binds to five known G protein-coupled receptors (GPCRs; S1P1-5) (53) and FTY720, a sphingosine analog that is phosphorylated in vivo, activates the S1P1-receptor to produce lymphopenia by reducing lymphocyte egress from lymph nodes. FTY720 is protective in models of liver ischemia (26), bowel ischemia (55), and renal ischemia (13).
SK catalyzes the conversion of sphingosine to S1P, regulating the sphingolipid rheostat, and is stimulated by agents such as agonists of growth factor receptors (e.g., PDGF, VEGF, NGF, and EGF), TGF-β, and TNF-α (17). There are two known isoforms, SK1, which promotes cell growth, and SK2, which inhibits cell growth and promotes apoptosis (14). SK1 mediates ischemic postconditioning in mouse hearts (23) and protects against lipopolysaccharide-induced lung injury via downregulation of JNK (8). Mice deficient in the SK1 enzyme had poor recovery from anaphylaxis and delayed histamine clearance, while mice deficient in the SK2 enzyme had rapid recovery from anaphylaxis (44). In contrast, certain models of inflammation such as Crohn's disease show a deleterious effect of SK as mice treated with an SK inhibitor (39) or mice deficient in the SK1 enzyme (51) had reduced inflammation and colon damage.
In our model, mice were protected from AKI-induced liver and intestinal injury with exposure to isoflurane after bilateral nephrectomy (i.e., postconditioning). Clinically, volatile anesthetics can be administered outside of the operating room (in the intensive care unit) (52), and this may prove to have therapeutic benefits in patients identified as having suffered from AKI. Anesthetics have multiple physiological effects, including alterations in hemodynamics and regional disturbances in blood flow. We have previously shown that volatile anesthetics did not significantly alter systemic blood pressure, renal blood flow, or core body temperature compared with pentobarbital sodium (30). Metabolites of volatile anesthetics, such as inorganic fluoride from methoxyflurane, have direct nephrotoxic effects, but isoflurane has minimal metabolism and has not been shown to have nephrotoxic effects (7). Volatile anesthetics may have both local and systemic effects in reducing the severity of hepatic and intestinal injury following bilateral nephrectomy, so in an in vivo study it is difficult to distinguish between direct cytoprotective effects on hepatocytes and small intestinal crypts and systemic effects such as leukocyte modulation, preservation of endothelial barrier integrity, and reduction of proinflammatory cytokines.
In conclusion, we have shown that isoflurane activates small intestinal crypt SK1/S1P signaling to reduce hepatic injury and small intestinal apoptosis, necrosis, and inflammation after bilateral nephrectomy. Advancements in treating AKI-mediated extrarenal organ dysfunction may be made as the mechanisms of protection are further elucidated.
This work was supported by National Institutes of Health Grants R01 DK-058547 and R01 GM-067081.
No conflicts of interest, financial or otherwise, are declared by the authors.
- Copyright © 2011 the American Physiological Society


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Assédio Moral no Ambiente de Trabalho
Aspectos jurídico-legais do AMAT
Miralux Woodon 26 June 2012
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What is JotForm?
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ACE-01 Tumbler
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1966 Dodge Coronet 500 15672 Miles Sunburst Orange 470 Automatic
- Location: Bismarck, North Dakota, United States
- Condition: Used
- Make: Dodge
- Model: Coronet
- Type: sedan
- Year: 1966
- Color: Sunburst Orange
- Number of cylinders: 8
- Transmission: Automatic
- Interior color: Black
- Vehicle Title: Clear
- Options: Leather Seats
1966 Dodge Coronet overview
1966 Dodge Coronet 500 YEAR END BLOWOUT PRICE!-á WAS 39,900.00 NOW-á36,900.00 -á This is a beautiful, rare, one of a kind Coronet that has been completely restored and is also a Midwest Mopar winner in 2010. As pictures will show this car is incredible! Bumpers have been color matched and the car is SUPER clean! This car shows SO incredibly well! The panels are nice and smooth with nice contours and the lines are CRISP! You can walk this car and look down panels with confidence at any angle! The nice long lines really complement the stance of this car well. The black accented grill and rear trim both do an excellent job of creating contrast in color. The glass on this car is also really clear and looks great! Headlights and tails look great with ZERO weather or road damage. The doors open and close as they should with no issue and the jams are painted just as well as the exterior! The interior is incredible as well and you will notice color matched door panels, center console and dash! This paint on the interior looks beautiful and complements the black interior well! The door panels are CLEAN and have been rewrapped. All hardware works as it should also! The dash is beautiful with CLEAR gauges that work! The dash mat looks NEW and is free of sun damage. There has been an addition to the car with some modern gauges to monitor fuel and temp. The seats look to have never been sat on before and are free of stress cracks. The same can be said for the rear. The headliner is tight and CLEAN! Carpets are clean and free of rips. This is a super clean car inside and out! SHOW or STREET ready, your choice! Under the hood rest a 400 stroked to a 470 that has been built by Indy. It puts 560hp to the crank and is backed by a 727 auto trans that works with a 8 -+ 3.55 geared rear end that also has a Detroit locker! The engine bay as you will see is SUPER clean and has been detail painted showing just as good as the exterior! The engine has been dressed with all kinds of aluminum and it looks very at home in between the fenders! The staggered wheels give it a mean stance and look really good as well with a nice deep dish to them! This car starts, drives and runs STRONG! One of the fastest Mopar cars I have sat it!! Make sure to have a look at the HD video below and hear this car! It is a BLAST to drive and pulls through every gear well! This car will NOT disappoint you in any way! HD Video -áhttps://youtu.be/xDZiVvSi7hk -á -á -á If you have any questions please call-áBob-áat-á701-751-4427 Or email-árides@rides-autosales.com GOT A TRADE WEGÇÖRE INTERESTED!! THANKS FOR LOOKING!!
Contact the seller


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Perkins Restaurant & Bakery Map
6920 Wayzata Blvd.
763-546-5404 | Make Restaurant Reservations | Menu
Use this map to Perkins Restaurant & Bakery to get there and back safely. If the "Get directions" pop-up does not appear, click the green arrow to get driving directions to and from this restaurant.
Find out which restaurants and chefs top the list of GAYOT's 2016 Annual Restaurant Awards.


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MSI Z77A-G45 Intel 7 Series Z77 Motherboard and Intel Core i5-3470 Processor and Patriot Viper Xtreme 4GB Desktop Module BundleItem#: M69-7203 | Model#: Z77A-G45 Bundle
Currently Out Of Stock!
Additional Resources
MSI Z77A-G45 Intel 7 Series Z77 Motherboard Bundle Product Details
Additional Resources: Product Manuals
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Manufactured by: MSI
Warranty provided by: MSI
UPC No: 890552754809
Mfg Part No: Z77A-G45 Bundle
Box Size:
( Length:0, Width:0, Depth:0)
Shipping Weight: 7.3500 pound(s)
Click here for full warranty and support information
- MSI logos are registered trademarks of MSI. All others trademarks and copyrights mentioned herein are the property of their respective owners.


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Mead, Jim, Manganaro, Carol, Repenning, Charles A. and Agenbroad, Larry D. Palaeoecology and Palaeoenvironments of Late Cenozoic Mammals/Early Rancholabrean Mammals From Salamander Cave, Black Hills, South Dakota. 17+ p.
Salamander Cave is a small cavern with a natural trap entrance. The Horse Room contains a small fauna produced by the infilling from a now sealed entrance. Uranium-seris analysis of speleothems and horse bone indicate that the Horse Room is recording a local faunal community approximately 252,000 years old. Sixteen taxa are recognized. Extinct taxa include the rodents Mictomys cf. M. meltoni, Microtus paroperarius, & Terricola meadensis along with Canis cf. C. dirus, Equus sp. and Camelops sp. Extra-limital species include Cynomys (Leucocrossuromys) sp. and Lepus cf. L. americanus. The fauna may mark the youngest co-occurrence of the extinct rodent species. The Black Hills offer a desirable location to examine evolutionary changes and speciation following immigration because of their unique 'middle ground' location in North America.


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cost geneva, troche sans-serif;">cialis 34, 34); background-image: initial; background-attachment: initial; background-origin: initial; background-clip: initial; background-color: white; background-position: initial initial; background-repeat: initial initial; ">His Holiness Pope Benedict XVI made his debut this week on Twitter. Not only that, but the Vatican also have a Facebook page,Youtube, and Flckr feed. I think this falls right in line with my earlier post. "What is Your Online Identity" the Catholic church has been dominated by scandal the past few years and I believe they finally see the importance of having a direct line of communication with the people they serve. Having a direct line allows you to be the first to admit your short-comings, but also be the first to report on the good.
All religious organization should be embracing technology. So many today use e-readers like the Kindle (pictured above) and bibles apps and I believe its imperative your able to speak the language of the people to get your message heard. It doesn't mean the message changes, but it allows you to communicate more effectively and use technology to your advantage.


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The Stephen King mini-series Storm of the Century (1999) caused a shower in our shorts, since it provided our first look at Julianne Nicholson. This former model had managed a few screen roles, but Storm was a breakout role that, well, didn't break out much besides our zippers. Julianne's had a slow climb to stardom. She's been talented and ravishing in failed TV series such as The Others and Presidio Med, but Julianne wouldn't really become a rising star until 2004. She got top billing in ...Join Mr. Skin for the full bio >>
Sophie and the Rising Sun (2016) - as Sophie Willis
Shadows & Lies (2010) - as Ann
Puccini for Beginners (2006) - as Samantha
Flannel Pajamas (2005) - as Nicole
Her Name Is Carla (2005) - as Carla
Kinsey (2004) - as Alice Martin
Eyewitness (2016) - as Helen Torrance
The Red Road (2014-2015) - as Jean Jensen
The Good Wife (2012-2015) - as Callie Simko
Boardwalk Empire (2010-2014) - as Esther Randolph
Conviction (2006) - as Sara Finn
Law & Order: Criminal Intent - as Detective Megan Wheeler
Presidio Med - as Dr. Jules Keating
Ally McBeal (1998) - as Jenny Shaw
The Others - as Marian Kitt


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RESPONDING to the impact of the Tour de France's passage through the district cost Airedale Hospital about £40,000.
Addressing fellow board members at an Airedale NHS Foundation Trust board meeting, director of operations Stacey Hunter said this sum had been required to pay for the hospital's contingency measures.
She explained Airedale had needed to ensure it had enough staff in place to deal with any major surge in demand.
She added that while the weekend of July 5 and 6 had been busy, she noted that this one-off event had been extremely well handled.
Non-executive director Anne Gregory said: "It was a good story of disparate organisations coming together to make something work."
She also asked whether Airedale had received any external contingency funding for the Tour. Ms Hunter replied: "Not as yet, we're involved in ongoing dialogue with NHS England about that."


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As we had reported earlier, Colors has announced to scrap three shows, out of which two of them are - Chakravartin Ashoka Samrat and Krishnadasi. The other show is yet to be announced. Krishnadasi team have already shot a climax scene. While the third show in question was Swaragini!
Initially, Colors' show Swaragini was topping the TRP charts. But, recently, the TRPs have dropped, and hence the rumours of the show going off air started doing the rounds. The fans were disappointed about the same. Read on to know more...
In Pic: Swara Trying To Shoot Herself To Prove Her Innocence
Fans feared that their favourite show Swaragini might end, as it was not promoted as well as there were no promos on it. But, the producer has finally listened to the fans' queries, and has released a major promo, indicating that the show is not ending!
In Pic: Lakshya & Sanskar Fight
A close source from the show was quoted by an entertainment portal as saying, "Swaragini fans were very upset for an absence of promotional activity of the show in the sense that the promos were missing on the channel or elsewhere."
Swaragini & Sasural Simar Ka Maha Sangam!
The source added, "However, Rashmi Sharma has listened to their queries and released a major promo of Swaragini on the channel along with Sasural Simar Ka; which is going to be a Maha Sangam episode on this Sunday."
Swaragini Not Going Off Air
The source further added, "The viewers were impatient and wanted to know whether Swaragini too would be going off-air along with Krishnadasi and Chakravartin Ashoka Samrat. But with this action, the producer has cleared the rumors and viewers can rejoice again and watch their favorite show for a longer period."
Swara & Ragini Reunite
According to the reports, the Mahasangam will have Sasural Simar Ka's Simar helping Swara in finding the property papers that Adarsh has hidden. This will also re-unite the two sisters Swara and Ragini.
Dadi, Adarsh & Parineeta
Ragini overhears Dadi, Adarsh and Parineeta's conversation. She will get to know that Dadi was behind the separation of both sisters as well as Maheshwari-Gadodia families.
Story So Far...
Currently, on the show, Lakshya and Ragini (Tejaswi Prakash Wayangankar) are convinced by Adarsh and Parineeta that Swara and Sanskar are cheaters.
As we all know, Sanskar's mother Sujatha had accepted money from Adarsh, and the blame comes on Sanskar. They had framed Sanskar because of which the two brothers and sisters got separated! Unfortunately, the money was fake, and Sujatha was feeling guilty for her deeds.
Annapoorna and Durga Prasad believe what Adarsh showed them, and they take Lakshya and Ragini to the Maheshwari house. Adarsh and Parineeta act innocent in front of them and reveal that they did all the drama to expose Swara and Ragini!
Also, Dadi, who wanted Sharmista and Shekar to get separated, remain successful.
Swara and Sanskar are shattered to see their family separated and they try to resolve the matter. Swara meets Ragini, while Sanskar meets Lakshya. But, the meeting would be a disaster as Sanskar and Lakshya start fighting, while Swara decides to shoot herself to prove her innocence!
Stay locked to this space for the latest updates of the show...


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Product code: 13048
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The Oral-B Pulsonic Brush Heads have precision bristles that remove surface stains for naturally whiter teeth.It follows the contours of your teeth for an effective overall clean, and remove significantly more plaque than a manual toothbrush.To keep your teeth looking their best, it s recommended that you change the head on your electric toothbrush about every three months.
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text: This is an automated email from the git hooks/post-receive script. It was generated because a ref change was pushed to the repository containing the project "Cluster Project". http://sources.redhat.com/git/gitweb.cgi?p=cluster.git;a=commitdiff;h=a006cbd31804652e23ab5dde423b2b2e7fa03f76 The branch, master has been updated via a006cbd31804652e23ab5dde423b2b2e7fa03f76 (commit) via fe771387a087c01f2867005cef4c445050b93472 (commit) from beeb2070953548ecf38751294e5371a668f73ee2 (commit) Those revisions listed above that are new to this repository have not appeared on any other notification email; so we list those revisions in full, below. - Log ----------------------------------------------------------------- commit a006cbd31804652e23ab5dde423b2b2e7fa03f76 Author: Lon Hohberger <lhh redhat com> Date: Thu Jun 26 11:56:35 2008 -0400 [fence] fence_xvmd: Add KVM support; misc cleanups. * WARNING WARNING WARNING: Changes the default URI to KVM. You must specify uri="xen:///" in cluster.conf to use Xen now (or -U xen:/// on the command line) * fence_xvmd -h now displays appropriate cluster.conf related help information. * This commit simply fixes authorship of the previous patch; apparently git lets you commit as root even if a different user checked it out... commit fe771387a087c01f2867005cef4c445050b93472 Author: Lon Hohberger <lhh redhat com> Date: Thu Jun 26 11:53:44 2008 -0400 Revert "[fence] fence_xvmd: Add KVM support; misc cleanups." This reverts commit beeb2070953548ecf38751294e5371a668f73ee2. ----------------------------------------------------------------------- Summary of changes: hooks/post-receive -- Cluster Project


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Who would prefer a bike ride over a limo? Who would prefer stepping in an outrageous balloon printed jumpsuit than over a pretty little dress? Well we all know the answer! Her name is printed in the page three of the newspapers and magazines almost every day. She is none other than Lady Gaga herself.
She has always blown herself over the top. She has repeatedly managed to surprise us by her completely out of the box fashion styles. She had a weird aura around her. She has always showed the paparazzi a side of hers which no celebrity has ever dared to show. But she still manages to top the music charts. She still managed to get the most love out of us. She still managed to be our favourite.
Lady Gaga always takes us by utter surprise. And she was at it yet again. Lady Gaga was in Danish Capital, Cophengham for one of her gigs. And there she decided to go on a shopping spree. What not many of us are aware about is the fact that when Lady Gaga goes shopping she splashes her big bucks like water. It was exactly the same the case at this little shopping spree that she took.
Lady Gaga decided to pick up another 21 bags of the eccentric clothes that she adorns herself in. And if precisely described the 21 bags contained only vintage gear that the Lady had shopped for. Who said that shopping was an easy task? It certainly wasn't for Miss Lady Gaga! Who decided to step out for a beer pint to quench her thirst?
Did I forget to mention her obnoxious attire? I absolutely did. Not the kinds to ever disappoint her fans, Lady Gaga stepped out in outrageous attire for her retail therapy. She dressed herself in a parachute shaped dress with a black horn designed hat to go perfectly with it. However before stepping out for her refreshing pint of beer, Miss Lady Gaga chose to change in yet another pretty dress. Well was it pretty or umm… Actually isn't it true that pictures speak for themselves. Check out Lady Gaga stepping out for her beer with her poochie darling in tow.
She ditched her limo ride for a bike. Her fans were surprised to see her paddle around the streets rather than a hop, skip and jump drive in her limo.
Lady Gaga at 26 is an American music singer and a trend setter. She is a world famous name and is popularly known for her extravagant make up and fashion styles. Lady Gaga has become a household name with her popular numbers 'Born This Way', 'Poker Face' and 'The Fame Monster'. Lady Gaga derives an inspiration from one of the greatest singers of the world, Michael Jackson.


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Each month, Rated People connects over 50,000 homeowners with quality tradesmen - simply enter your job details in the form above to get started.
We'll match your job to the relevant tradesmen in your area - those interested will pay to see your contact details and call you to quote.
As each tradesman expresses interest in quoting on your job, we'll send you their profile and ratings to help you choose the right one for you.
After the work is complete, return to the site and rate your tradesman based on their quality of work, reliability and value for money.
Added 02/09/2014
Door handle broken on Upvc door. Need new handle replaced and fitted only - lock works fin...
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Added 14/05/2014
Upvc back door will not open, possible shoot bolts jammed. Need door opening and locking mechanism...
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Added 26/03/2014
Unsold lead, updated details: Just moved into the house - discovered French doors (upvc double...
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Went the extra mile to make good my old gate and made sure I was able to unlock without any difficulty. He will be boarding my loft in a week's time as well.
Managing your job is easier with the Rated People Homes App, download it today.


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Ironhide wrote:SotE's first level was superb but the rest is mostly rubbish apart from a couple of the other flying bits, the on foot sections were a massive mistake imo and really put me off the game.
Wow thanks I'm really looking forward to it now
Green Gecko wrote:Please remove the protective film from that BT box.
Drumstick wrote:I've made mention before in here of my friends and I'd Mario Party 2 sessions...
jawafour wrote:As usual, my eyes are drawn to analysing other things in the picture and, beyond the BT box, some of the items I can spot are a stack of Nintendo games, a collection of key rings, a PS3 Slim... and a Liverpool FC mug with (I think) a "something-Fox" ornament behind it.
Green Gecko wrote:That picture looks surprisingly unstretched.
Please redove the protective film from that BT box.
mysteriousdave wrote:Just bought a new non-colour N64 and my main telly doesn't have S-Video. Such fail.
What's the next best option? New TV I guess? I'm guessing RGB mods etc are still pricey.
Drumstick wrote:Is RGB Scart not a thing anymore?
Green Gecko wrote:Drumstick wrote:Is RGB Scart not a thing anymore?
I think I might have been wrong about that entire thing.. It isn't included in pal machines. Unless Andy XL thinks s video is better?
It definitely is included in SNES and MD (model 1).
Drumstick wrote:What is wrong with the basic scart connection that all N64s were shipped with? The one that will also plug into a Gamecube.
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text: Yobe State University 2016/2017 UTME 2nd Batch Admission List Out The Management Of Yobe State University has released the 2016/2017 UTME 2nd batch admission list. The list has been compiled in PDF File and uploaded online.Applicants are advised to Click Here and download the1st batch admission list here. Click Here To Download The 2nd Batch Admission List. NOTE: Please be informed that collection of admission letters would be communicated to you in due course. AHMED RILWANU BAKARI ADMISSIONS OFFICER FOR: REGISTRAR POSTED ON November 25, 2016 Category: Admission, Post-UTME, YSU


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Typically most business leaders and entrepreneurs face the same challenge everyone faces during the holidays—too much to do and too little time! You need to keep your business going, at least for the majority of December, yet you have added responsibilities taking up your time: professionally, you have to deal with year-end financial concerns, employees requesting time off, and office decorations and parties; personally, you have home decorations, presents to buy, and maybe travel plans. So how do you keep your sanity and actually pull it all off—and manage to have a happy holiday?
One way may be to re-focus on the reason for the season. What are the winter holidays all about? How do you get off the treadmill of activity and commercialism and back into the heart of these times of sacredness and celebration? What is the reason for the season for you personally? This is something that may be different for everyone, so take a few minutes before the hustle begins to look inside yourself and remember what the holidays mean to you. Here are some ideas that may help you reconnect with the spirit of the season:
1. Giving & Receiving: When you focus on how you can give, you wind up receiving so much in return. Giving, however, doesn't need to be about how much you spend on presents. Consider giving as an expression of caring and a way of saying thank you. The bonus you give to staff or contractors says you appreciate their loyalty and exceptional service. The gift you give family members and friends says thank you for being in my life. Additionally, you need to be a good receiver, since those who appreciate you need to show it too. So accept that purple striped tie that you find obnoxious or the box of chocolates you can't eat, with grace and a smile.
2. Gratitude: Of course, Thanksgiving is the perfect time for expressing your thanks or gratitude. It's unfortunate that we need the holidays to remember to be grateful for what we have and to express gratitude to those we appreciate. When sending holiday greetings to business associates, employees, family, or friends, take the time to add a personal note and tell each one what you value about them. It works wonders for both of you.
3. Connection: What a great excuse to spend time with those you usually don't have time for. At work, you'll enjoy being with your co-workers and staff in a social context and getting to know them in a deeper way. This in turn can only enhance your working relationship. At home, you may connect with family members and loved ones you only see at holidays. This keeps that contact alive and replenishes your heart.
4. Celebration: It's time to party. New Year's Eve is especially a great time to kick up your heels, drink champagne, and dance the night away. You work hard all year, so you deserve some playtime. Get into the spirit of the New Year and celebrate in the way that works for you. Some enjoy partying while others prefer a quiet celebration: a hike in the woods, a walk on the beach—time to reflect on the year past and the year ahead. Create the observance of these occasions with meaningful activities.
5. Renewal: Holidays are everyone's excuse to take a break, and that means you too! Your body and your brain need some time off when you don't think at all about your work. Allow yourself at least a few days at Thanksgiving, Christmas/Chanukah, and the New Year to wind down. With a rested body and mind, you'll be full of energy and creativity for a terrific year ahead.
Want more success in your life and business? Contact Cheryl Vallejos, Author, Motivational Speaker, Certified Business Coach and Consultant at email@example.com and sign up for the free "Monthly Leadership Tips" e-zine and the bonus FREE 37-page leadership guide eBook at Monthly Leadership Tips .


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Stylish Retail or Offices
20, Seaview Road, Paraparaumu Beach, Kapiti Coast
By Negotiation
- Proposed Usage
- Retail
- Floor Area
- 68.00 m²
- Property ID
- 1bs48n1
In the heat of Paraparaumu Beach, this property is only coming to market because the current tenant needs larger premises.
This space, on two levels of approximately 68sqm, is a little gem. The entry would make for a reception or showroom, whilst stepping down into the main area, further retail or office space is provided.
The facilities are excellent, particularly the well fitted out kitchen.
Currently divided into three spaces, don't let this be a restriction - the landlord will work with you.
The surprise package is the outdoor area comprising of a secure walled garden and deck with sunshade and a steel shed of approximately 5sqm.


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Andy Edwards is an inspiring and motivating professional speaker who delivers memorable presentations and training interventions on business relationships, business growth, understanding others, leadership, influence, attitude, motivation and team-building.
As a business growth consultant, he helps business owner/managers to profitably increase turnover by at least 46% - and often much more!
As the founder of Re£ationomic$ (creating tangible value from business relationships), Andy runs events in the UK, Europe, USA, the Middle East and beyond.
A sought-after keynote speaker, masterclass presenter, trainer and coach, Andy is regularly booked for national conferences, staff conventions, away-days and AGMs for talks which are motivational, engaging, thought-provoking and fun.


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Elijah Wood on Harvey
"I always come back to Harvey with Jimmy Stewart. It's a really profound movie, and I gain something new every single time I see it. I love a film about a man who lets go of reality because he's disappointed when he looks at the world around him. His disappointment manifests itself into a giant white rabbit. I see his rabbit character as more of a choice, and it's beautiful." Elijah Wood, Actor
What is your memory of Harvey?
remembers Harvey...


text: ELP-362D Emergency Locator Beacon 3 Internal Construction The major internal components of the beacon include a printed circuit board assembly, a urethane-encapsulated transducer assembly, and a battery. The battery is contained in its own, separate, user accessible compartment. Theory of Operation The printed circuit board assembly generates all the necessary logic functions to produce a pulse with the desired characteristics. The pulse is then transformed from a CMOS level square wave to a much larger 37.5 kHz sinusoidal pulse by a transformer. The output of the transformer drives the urethane-encapsulated transducer, which propagates through the housing in the form of a tuned 37.5 kHz acoustic signal. Locating the Beacon When the beacon is immersed in water, it will begin to radiate an acoustic signal which can be received and transformed into an audible signal by either the Teledyne Benthos, Inc. APR-272 or DPL-275A Acoustic Pinger Receivers. When used in conjunction with the Teledyne Benthos, Inc. Model DHA-151 Directional Hydrophone, either pinger receiver can be used as a shipboard portable receiver to determine the general vicinity of the aircraft. After the area is known, a diver can be deployed with the DPL-275A, which will give the exact location of the aircraft. Other equivalent pinger receivers may also be used. Figure 1-4 Locating the Aircraft After Water Activation User's Manual June 2011


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Daily except SundayDuration
3 hoursStart time
Start time: Between 1600h (4:00pm) - 1630h (4:30pm)
Duration: 3 hours
Your hotel in Langkawi.
(Please mention your hotel name and address at the time of booking. If you do not have this information now, please contact the local activity operator 24 hours prior to the start of the tour with these details)
Your hotel in Langkawi
Brimming with an abundance of natural scenery, the islands around Langkawi are the perfect getaway and are some of the most beautiful in Southeast Asia.
You will be picked-up from youir hotel in a coach for your Langkawi Archipelago Sunset Cruise. The Langkawi archipelago offers a spectacular variety of water activities. The sunset dinner cruise is a great way to spend an evening.
After a day exploring quirky attractions on the island, you may want to look forward to a relaxing evening gazing out across the blue waters. Whether you want to unwind on the fantastic sun deck or simply lay back on the cushions reading a book, then the sunset cruise is for you.
Taking approximately 3-hours, this leisurely cruise will take you through the picturesque panorama of Langkawi's southern islands which remain refreshingly untouched.
Be mesmerised by a stunning view of the sun as it reaches the horizon and casts dramatic sunset colours across the sky. The golden light of the sunset gives the scenery a mystical atmosphere. The cruise includes an open bar of beer, wine, cocktails and soft drinks as well as a barbeque dinner. And if you would like to cool off in the clear blue ocean waters, try out 'salt water jacuzzi'. You will return to the marina at dusk.
On arrival back to shore – at the end of a fabulous evening cruise – you will be taken back to your hotel.
Please call the activity operator at least 24 hours prior to start of the tour to reconfirm departure details.
Surcharge of MYR 30 per passenger for pick-up from the Datai, Andaman, Four Seasons and Tanjung Rhu
The confirmation voucher includes the local activity operator's contact details and local telephone numbers at the destination. They will happily answer any logistical questions you may have
Your Guide to Living on the Road
The post The Ten Commandments of Campervanning appeared first on The Guidebook - isango!.
Finding the flakiest pastry, coolest clothing and hidden bars
The post A Day In Paris appeared first on The Guidebook - isango!.
Joy-riding through overlooked outback, winding wine routes and country lanes.
The post 6 Lesser-Known Road Trips You Should Add To Your Bucket List appeared first on The Guidebook - isango!.


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How many days in advance can you crumb coat a cake? Can it stay out on the counter during this time or does it need to be refrigerated? Thanks!
I usually bake my cakes on Thursday morning, then after they're cooled I will fill and crumb coat. I allow the cakes to settle for the day and then cover in fondant late Thursday night, decorate on Thursday or Friday depending on the complexity of the cake, deliver on Saturday.
I bake my cakes on Monday, wrap well and freeze. I take out on Thurs., defrost then crumbcoat. I then chill and put my buttercream on, then back in frig. Friday I decorate. Hope this helps.
If I have a cake due Saturday, I would bake Thursday and make all my frostings. Then Crumb coat early Friday morning and finish decorating throughout the day.
I have major problems baking and frosting same day. Major air pockets!
At the earliest, I would bake Wednesday crumb coat Thursday and decorate Friday.


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About the Book
Midlakes High Schools production of My One and Only in book form! Can this be true. I know we have the movie but this book includes full color pictures, lyrics and parts of the script! The book goes in order by acts and songs and backstage pictures of tech. you can look at the first 15 pages of the book with the book preview! So this is just like the companion book to your movie!
Features & Details
- Category Entertainment
Small Square, 7×7 in, 18×18 cm
34 Pages
- Publish Date May 13, 2009
- Tags Midlakes Theater 2009 production of My One and Only
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Kobe Bryant admitted to watching a few games during the first week of the NBA season. But playing again? Not a chance. He doesn't miss it. "Not even a little bit," Bryant said Tuesday morning at the launch of his latest signature Nike shoe, the "Kobe A.D."
"It's strange to think a couple years ago, to be in this emotional space would be unfathomable. But I mean not even a smidge, which I'm very thankful for, because it's made my transition seamless and I can really just watch and just enjoy the games."
Source: Ramona Shelburne of ESPN
Make sure to follow Basketball Insiders on Twitter at @BBallInsiders.


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Serve, Share, and Support are the guiding principals of North American Training Solutions. We follow these principals by providing superior safety, skills training and education for Commercial, Utility, Municipal, Governmental and other Green Industry related industries. Innovation, quality, flexibility and customer satisfaction are the cornerstones of our business.
Our mission is to deliver innovative and professional arboriculture training and education that exceeds customers expectations and business needs.
Customized Training Programs:
Any of our arborists training programs can be specially customized to meet the training and budget needs of your organization. Please review our course listing and contact our office to discuss a private, customized training course and the costs associated.
Features and Benefits of NATS Training:
– North American Training Solutions provides specialized, simple solutions to training needs across the United States.
North American training Solutions specializes in practical training, educational seminars and certification for arborists and other high angle industries.
We Provide:
– Highly trained and experienced instructors
– Custom made programs and seminars
– Focus on safety and technique
– Training / Seminars at your facility or offsite
– Competency testing
– Exposure to the latest techniques and equipment
– 1 – 3 day hands-on programs
We offer First Aid and CPR Training through the National Safety Council in English and Spanish.
All of our training courses are offered in English and Spanish / Todos nuestros cursos se ofrecen en inglés y español.


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Big data analytics typically prompt a 26 per cent improvement in enterprise performance ��� but too many organisations remain hobbled in their ability to exploit big data because much of it is locked away in departmental silos and because skills to analyse the data remain scarce.
{loadposition bev}A report released today from the Economist Intelligence Unit, commissioned by Capgemini, has found that that data, along with access to land, capital and labour is a key ingredient of enterprise productivity. However organisations surveyed report a series of challenges in terms of their ability to exploit big data.
The deciding factor: big data and decision making is the result of a survey of more than 600 executives ��� almost half of them c-level or board members. It found that where big data analytics was deployed, on average a 26 per cent improvement in business performance was achieved ��� with expectations that could rise to 41 per cent over the next three years.
However 56 per cent of organisations recognised data silos as a major problem in terms of getting to information that could otherwise support better decision making.
This was not surprisingly a particular challenge for large enterprises according to the report. However it suggested that the emergence of ���trusted data aggregators���, a term coined by Gartner analyst Kurt Schlegel, might help big business overcome the problem.
These aggregators could operate internally or externally according to the report, and provide a safe repository for an enterprise���s data drawn from multiple silos. Deepak Nangia, managing director for business development and marketing for Capgemini in Australia, acknowledged though that data silos remained a particular barrier to big data analysis in companies which were regularly restructured, and where multiple silos built up over time.
However he said that ���There are some technological advances that will help overcome organisational silos ��� putting data in the cloud,��� for example. ���When you do that at an organisational level the silos break down and there is potentially the opportunity to do analysis at an organisational level.
���This is a technical solution rather than an organisational redesign,��� he added.
{loadposition bev}Internationally the sectors which reported most use of hard analytics using big data were the financial sector, energy and resources and healthcare. Mr Nangia said that the survey showed that the Australian financial sector was a particular fan of big data analysis.
He said that internationally 65 per cent of financial services organisations reported making decisions based on hard, data-based analytics. Regionally that figure was slightly higher, at 68 per cent.
However in Australia it was a much higher with 74-75 per cent of local financial institutions reporting basing their decision making on big data. All four big banks have recently been at pains to espouse the long term value that they see in big data analysis in terms of being able to develop better products and services, and also market products to customers more accurately.
Mr Nangia said that he believed Australia���s current prowess in terms of data analytics was founded on the local banks��� focus on risk and compliance.
While different sectors seem to be moving at different paces in terms of data analysis, Mr Nangia said that a common problem was access to skills.
Large enterprises weren���t in general worried about the volume of data they might have to analyse, or access to the technology to support that analysis, instead ���what is missing are the data analysts.��� Mr Nangia said that it was important universities worked with industry in order to ensure graduates were equipped with the skills needed to interpret and apply big data.
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Entry requirements
If enrolling for the +3 route, a taught master's degree in related disciplines with a minimum of 65% average mark and 70% or higher in the dissertation component. If enrolling for the 1+3 route, a minimum of an upper-second class honours (or equivalent) undergraduate degree
Months of entry
January, October, April
Course content
The MPhil/PhD in Economic Geography aims to provide students with a rigorous and quantitative approach to the study of socio-economic phenomena that have a spatial and geographical nature, as well as their implications. This focus follows a general trend in the discipline and the growing need of policy advice to be solidly grounded in well-documented empirical regularities and properly established causal links. In order to satisfy these demands, the doctoral programme will provide students with advanced and up-to-date training in both traditional areas of economics - such as economic geography and spatial, urban and real estate economics - as well as more institutional approaches to these issues - such as those encompassed by regional science and local economic development. Moreover, the doctoral experience at the LSE will expose students to an international, vibrant and multi-disciplinary research environment.
Students can expect to leave the programme with a solid command of the following skills: (i) a critical understanding of the extent, nature and consequences of spatial disparities in economic performance, and the ability to identify appropriate policy responses; (ii) a rigorous analytical, methodological and quantitative approach to the subject; (iii) a solid understanding of the recent developments in the fields of economic geography and spatial economics; (iv) the ability to apply knowledge to new problems and contexts; and (v) the background required for a successful career in research and academia, as well as in consultancy or government policy.
Given the high profile of our programme, previous doctoral students in the 'Economic Geography' cluster have found employment in academic and public research institutions, as well as work in international organisations (e.g. OECD, UNCTAD/WTO, European Commission, World Bank), the private/consultancy sector (e.g. McKinsey, Ernst & Young), or in high profile positions in governmental institutions (e.g. regional development bodies, ministries of business, innovation and foreign affairs).
Department specialisms
Economic Geography and Regional Science; Environmental Economics and Policy; Cities and Development
Information for international students
Fees and funding
Qualification and course duration
Course contact details
- Name
- Student Recruitment Office
- firstname.lastname@example.com
- Phone
- +44 (0)20 7955 6613


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Richard Lord: Williams women's golf hires coach
Williams College's nationwide search for a women's golf coach turned out to have an international flavor to it as well.
The school has hired Tomas Adalsteinsson, a native of Iceland, who has served as the men's and women's golf coach at Macalester College in St. Paul, Minn., since 2012.
Given its chilly name and geographical position — 67.08 north latitude (Pittsfield is at 42.4501) — Iceland might seem to be an unusual environment for a golf coach to grow up in. But, apparently, while the golf season is short (May to September), Iceland is a golf-crazed country.
According to Golf Digest, there are more golf courses per captia there than in any country in the world — 65 courses for an island nation with 321,000 inhabitants. The courses are even open 24 hours a day in June and July given that the sun never sets.
Adalsteinsson, who graduated from the University of Iceland in 2007 and earned a master's degree in Sports Psychology from John F. Kennedy University in Pleasant Hill, Calif., in 2011, has a strong background as a player and coach in golf and soccer.
He competed internationally as a member of the Icelandic national golf team and also has a UEFA B soccer coaching license. Before going to coach at Macalester, he coached women's soccer at Carleton College. He has also worked with professional golfers on their mental game, serving as a sport psychology consultant.
"The search committee was impressed by coach Adalsteinsson's broad range of athletic experience and his strong golf background," Williams College Athletic Director Lisa Melendy said in a statement. "His background in sport psychology will bring another dimension to our faculty."
Adalsteinsson replaces Bill Kangas who did a tremendous job the past two seasons as the interim coach after replacing Erika DeSanty, who left following the 2014 season to become the head women's golf coach at Princeton University.
Kangas, who is also the Ephs' men's ice hockey coach, led the Williams women to the NCAA Division III national championship in 2015 and to a fifth-place NCAA finish in the just-completed 2016 national tournament.
"I want to also extend my gratitude to Bill Kangas who took on the role of interim head coach with enthusiasm and deep caring for the team and the program," Melendy said. "He has guided the team well through this time of transition, and I know the players hold him in great respect and affection."
Adalsteinsson will inherit a team that should once again be one of the nation's top Division III squads. None of the five golfers who competed in the national tournament in Texas were seniors.
"First of all, I want to thank Lisa Melendy and the members of the search committee for this incredible opportunity," Adalsteinsson said in a statement. "Through this process, I have been greatly impressed by the people in the Williams community, and I am excited to be joining a college with such rich history of academic and athletic excellence. ... I look forward to starting to work with the exceptional student-athletes of Williams women's golf to build on the tradition of success they have created."
Wyckoff Country Club member Michael Mertes shot an even-par 71 to win the Championship Division in Friday's Stockbridge Classic at Stockbridge Golf Club by one shot over Longmeadow Country Club's Jack Dombek.
Matt Scarafoni (Country Club of Pittsfield) and Matt Kennan (Greenock Country Club) were the top finishers among the Berkshire County players with rounds of 5-over 76. They tied for sixth place.
Former Massachusetts Senior Player of the Year Bob Linn (Berkshire Hills Country Club) shot a 2-over 73 to tie for Senior Division honors with Connecticut golfer Ray Underwood (Torrington Country Club). Torrington CC golfers finished 1-2 in the Legends Division with Bud Pepin firing a 75 and Dick Weigold a 76.
The tournament action at the historic club will continue on Saturday and Sunday with the Stockbridge Trophy, a 36-hole best-balll event.
Club members Chris Shields and Randy Driscoll are the defending champions but they will be challenged by a field that features a number of strong teams.
The Northeast New York PGA's Stroke Play Championship will be played on Tuesday and Wednesday at Taconic Golf Club in Williamstown.
There is little doubt that Scott Berliner will be the golfer to beat will be when the section's top professionals tee it up at the Williamstown layout in the 36-hole event. The Hiland Park (N.Y.) Golf Club professional is the five-time defending champion.
Berliner is off to another strong start this season, capturing the first section tournament with an even-par 70 at Wyantenuck Country Club. He then lost in a playoff to Ian Breen, of Colonie (N.Y.) Golf and Country Club, in the second event at the Saratoga Polo and Golf Club. Berliner and Breen both shot 3-under 67.
Host head professional Josh Hillman, Eric Mabee (CC of Pittsfield), David Strawn (Egremont Country Club), Steve Mazzariello (Stockbridge GC), Tom Sullivan (Wyantenuck CC), Chris Polidoro (Cranwell Spa and Golf Resort) and Peter Egarzian (Taconic GC), will represent Berkshire County in one of the section's two biggest events.
Hillman is a past champion, winning in 2008, and is capable of being in the title chase, especially on his home course.
Mabee, in his second year as the head professional at the CC of Pittsfield, has an impressive tournament resume that suggests he could be a threat to Berliner's domination. He qualified for the PGA National Club Pro Championship in 2014 and narrowly missed repeating the feat last summer, finishing in a tie for second behind Berliner in the NENY PGA Section Championship. He lost in a playoff to Breen for the second of two qualifying spots for the national tournament.
Taconic GC member Dylan Dethier missed qualifying for the Massachusetts Open by three shots in a qualifier at The Ranch Golf Club in Southwick on Thursday.
The former Mount Greylock High School and Williams College golfer shot a 2-over 74 to tie for 20th place.
Former Worthington Golf Club member James Patterson, now a member of Tekoa Country Club, posted a 76. Wyantenuck Country Club head professional Tom Sullivan withdrew from the tournament.
The Mass. Open will be played at Worcester Country Club in June.
To contact Richard Lord: firstname.lastname@example.com or 413 281-2226.
If you'd like to leave a comment (or a tip or a question) about this story with the editors, please email us. We also welcome letters to the editor for publication; you can do that by filling out our letters form and submitting it to the newsroom.


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Pressure outlet condition is ignored
I just found, that for my rotating case (moving reference frame) the intended gauge pressure (-1000Pa) is ignored.
So, when I check the static pressure I get values from -1400Pa up to +1100Pa (for three outlets, where each have a gauge pressure of -1000Pa). But the heat transfer results seem to be reasonable. Also, the mass flow rate at the outlets is almost the same as in the non-rotating case (gauge pressure of -1000Pa is achieved at all outlets)....
Anyone recognized the same?
I guess it's because of "Radial Equilibrium Pressure Distribution" ....
.... but still the first outlet of the different outlets-rows have more or less with the same distance to axis of rotation ....
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Designed with practicality in mind, this air compressor is extremely robust and has an adjustable height towbar and road lights. Powered by a super reliable 49 HP Kubota engine which is EPA Tier 4 final compliant, it has to be one of the most efficient air compressors on the market.
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Auburn's 2014 slate includes visit to Kansas State
AUBURN, Ala. (AP) — Auburn will open the 2014 season against Arkansas and visit Kansas State.
Tigers face the Razorbacks on Aug. 30 in their first opening game
against a Southeastern Conference team since a 46-13 win over
Mississippi in 1995. Auburn released the schedule on Wednesday.
The season includes a Sept. 20 visit to Kansas State, the first since 1978.
rotating SEC East opponent is South Carolina on Oct. 25 at Jordan-Hare
Stadium. The Tigers swept the regular season and SEC championship game
meetings during the 2010 national title season.
The Tigers' other
nonconference opponents include San Jose State (Sept. 6), Louisiana Tech
(Sept. 27) and Samford (Nov. 22) before closing against Alabama.