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The mechanisms of ventilator-induced lung injury, an iatrogenic inflammatory condition induced by mechanical ventilation, are not completely understood. Toll-like receptor 4 (TLR4) signaling via the adaptor protein, myeloid differentiation factor 88 (MyD88) is proinflammatory and plays a critical role in host immune response to invading pathogen and noninfectious tissue injury. The role of TLR4-MyD88 signaling in ventilator-induced lung injury remains incompletely understood.
Mice were ventilated with low or high tidal volume (HTV), 7 or 20 ml/kg, after tracheotomy for 4 h. Control mice were tracheotomized without ventilation. Lung injury was assessed by: alveolar capillary permeability to Evans blue albumin, wet/dry ratio, bronchoalveolar lavage analysis for cell counts, total proteins and cytokines, lung histopathology, and plasma cytokine levels.
Wildtype mice subjected to HTV had increased: pulmonary permeability; inflammatory cell infiltration/lung edema; and interleukin-6/macrophage-inflammatory protein-2 in the lavage compared to control. In HTV, inhibitor of κB alpha decreased whereas phosphorylated extracellular signal-regulated kinases increased. TLR4 mutant and MyD88−/− mice showed markedly attenuated response to HTV, including less lung inflammation; pulmonary edema; and cell number, protein content, and the cytokines in the lavage. Furthermore, compared to wildtype, both TLR4 mutant and MyD88−/− mice had significantly higher inhibitor of κB alpha and reduced extracellular signal-regulated kinases phosphorylation following HTV.
TLR4-MyD88 signaling plays an important role in the development of ventilator-induced lung injury in mice, possibly through mechanisms involving nuclear factor-κB and mitogen-activated protein kinase pathways.
Mechanical ventilation is a widely used life-saving supportive measure in the management of a variety of critically ill patients. However, it is well known that such therapy may produce an iatrogenic condition referred to as ventilator-induced lung injury (VILI).1–3 Although the exact underlying mechanisms of VILI remain unclear, recent emerging evidence suggests that mechanical ventilation may activate an inflammatory response in the lung that may contribute to VILI.4–7 Recently, a critical role for Toll-like receptor in mediating the effects of mechanical ventilation on lung inflammation and injury has been reported.8,9
Toll-like receptors (TLRs) are pattern recognition receptors and are considered key mediators in inflammation and play an essential role in innate and adaptive immune responses.10 TLR4 is the first identified and one of the most studied TLR family members. TLR4 recognizes both pathogen-associated molecular pattern (e.g., lipopolysaccharide) and damage-associated molecular pattern (e.g., high-mobility group box 1 and heat shock proteins). Upon stimulation, TLR4 signals through two downstream pathways: myeloid differentiation factor 88 (MyD88-) and Toll/Interleukin-1 receptor-domain containing adaptor-inducing interferon-β (TRIF-) dependent pathways, ultimately leading to the activation of nuclear factor-κB (NF-κB) and the production of proinflammatory cytokines.11–14 It has been suggested that activation of NF-κB and activator protein 1 controls inflammatory responses through the induction of proinflammatory cytokines, while NF-κB activation is associated with phosphorylation of inhibitor of κB alpha (IκBα) and activator protein 1 activation depends upon activation of mitogen-activated protein kinases (MAPKs).10 The TLR4-TRIF pathway has been identified as a key genetic pathway in acid aspiration-induced lung injury.15 More recently, the role of the TLR4-TRIF signaling pathway has been suggested in a mouse model of VILI.16 Given that MyD88-dependent signaling mediates early phase activation of NF-κB and is a major proinflammatory pathway, we sought to test the hypothesis that in addition to TLR4-TRIF pathway that TLR4-MyD88-dependent pathway plays a key role in a mouse model of VILI and further explore the role of NF-κB and MAPKs in TLR4-MyD88 signaling pathway.
TLR4-functional C3H/HeOuJ (TLR4-wildtype (WT)), TLR4-inactive mutated C3H/HeJ (TLR4-mutant), and MyD88-sufficient (C57BL/6J, the background strain, MyD88-WT) mice were purchased from the Jackson Laboratory (Bar Harbor, ME). MyD88-knockout or null (MyD88-KO, MyD88−/−) mice were generated by Kawai et al.17 and were backcrossed > 10 generations into the C57BL/6J strain. All mice were female, 8–12 weeks of age, and weighed 20–30 g. Mice were fed with normal diet and water ad libitum and were housed in accordance with guidelines from the American Association for Laboratory Animal Care. All experimental animal protocols were performed in accordance with guidelines approved by the Animal Care and Use Committee at the University of Pittsburgh, Pittsburgh, Pennsylvania
Mice were anesthetized with ketamine (100 mg/kg body weight) and xylazine (10 mg/kg) intraperitoneally. Anesthesia was maintained by supplementing with one-third of the initial dose of anesthetic agents regularly at approximately every 45 min during the experimental period. The mice were placed in the supine position on an adjustable warming pad (FHC Inc., Bowdoinham, ME) to maintain at 37 ± 1°C by continuously monitoring with a rectal temperature probe. The trachea was exposed with a neck midline incision under sterile conditions and a 20-gauge, 1-inch-long sterilized metal catheter with smooth beveled tip was inserted and sutured, then connected to a small animal ventilator (Inspira ASV, Harvard Apparatus, Holliston, MA). Mice with mechanical ventilation were ventilated either at 7 ml/kg (low tidal volume, LTV) with 140 breaths/min or 20 ml/kg (high tidal volume, HTV) with 100 breaths/min, 0 positive end-expiratory pressure for 4 h after tracheotomy, while control mice underwent tracheotomy but breathed spontaneously. Both spontaneous and ventilated mice were supplemented with oxygen (approximately 35–45% the fraction of inspired oxygen as determined by an oxygen monitor and always maintained less than 50%). During ventilation, intraperitoneal administration of saline (0.01 ml/g body weight) at 45-min intervals was supplied to maintain intravascular volume status. The oxygen saturation and heart rate in the anesthetized mice were continuously monitored with MouseOx (Starr Life Science Corp., Oakmont, PA) and maintained within physiological range with supplement of oxygen and intraperitoneal administration of glycoppyrolate (0.01 μg/g body weight). Animals were given a lethal dose of the anesthetic agent at the end of 4 h mechanical ventilation prior to harvesting samples.
Lung injury was assessed by the alveolar capillary permeability to Evans blue albumin (EBA) as previous described.18 Briefly, Evans blue (EB, Sigma-Aldrich, St. Louis, MO) was dissolved in Ca2+-Mg2+ free phosphate-buffered saline (Invitrogen, Carlsbad, CA) in a concentration of 0.5% (5.2 mM). Evans blue dye conjugated to albumin (EBA) was prepared by adding bovine serum albumin (Fraction V, Sigma) to 0.5% Evans blue to a final concentration of 4% (0.6 mM). After dissolving thoroughly by gently stirring with a magnet bar, this EBA solution was then filtered sterilely through a 0.22-μm syringe filter and stored in aliquots at −80°C until use. Each aliquot was used only once for each animal to prevent cross contamination. To evaluate the alveolar capillary barrier function, EBA (20 mg/kg) was administered via the internal jugular vein one hour before euthanasia and tissue harvesting. At the termination of each experiment, all animals were euthanized and blood samples were obtained via the right heart for plasma EBA measurement. The pulmonary vasculature was then flushed with phosphate buffered saline to remove blood-borne elements. The right lung was ligated at the level of the right mainstem bronchus, excised, and weighed and stored in liquid nitrogen for subsequent Evans blue assay. After freeze/thaw, the lung tissue was homogenized in 2 ml phosphate buffered saline and incubated with additional 2 ml formamide (Sigma) at 60°C for 18 h. Formamide extracts were centrifuged (Beckman TLX, Fullerton, CA) at 15,000 × g for 30 min at 4°C and the centrifuged supernatants were collected to quantify lung EBA content by a dual wavelength spectrophotometric method (Model Du-640, Beckman) at 620 nm and 740 nm. EBA permeability index was calculated by dividing the corrected pulmonary tissue EBA absorbance at 620 nm per gram of lung tissue by the corrected plasma EBA absorbance at 620 nm.
Lung wet-to-dry weight ratio was used as an index of pulmonary edema formation. At the end of experimental period, mice were sacrificed and the right heart was flushed with phosphate buffered saline. Left lungs were weighed immediately after removal (wet weight) and again after drying in an oven at 65°C for 48 h (dry weight).
Lungs were fixed by inflation with 10% formalin through intra-tracheal instillation. After fixation, the lungs were embedded in paraffin, 4 μm sections were stained with hematoxylin and eosin, and sections were examined at light microscopic level.
Lung inflammation was evaluated by cell counts and protein content in bronchoalveolar lavage (BAL) fluid. The BAL procedure was performed with instillation of sterile phosphate buffered saline in 1.0 ml volume with four replicates. Approximately 80% of the instilled volume was retrieved. All samples were kept on ice until processed. Recovered BAL fluids were centrifuged (5 min, 2,000 rpm, 4°C). The pellet was resuspended in phosphate buffered saline and total cell numbers in BAL fluid were counted using a hemocytometer. The supernatants were frozen immediately on dry ice and stored at −80°C for total protein concentration measurement with BCA Protein Assay kit (Pierce Chemical Co., Rockford, IL) and analysis for cytokines.
Tumor necrosis factor-alpha, interleukin-6 (IL-6), interleukin-1 beta (IL-1β), interleukin-10 (IL-10), macrophage-inflammatory protein-2 (MIP-2) in BAL fluid and in plasma were analyzed by enzyme-linked immunosorbent assay (ELISA) according to the instructions of commercial ELISA kits (R&D systems, Minneapolis, MN). The detection threshold of the assay was: a) Tumor necrosis factor-α: 5.1 pg/ml; b) IL-6: 1.6 pg/ml; c) IL-1β: 3.0 pg/ml; d) IL-10: 4.0 pg/ml; and e) MIP-2: 1.5 pg/ml.
Frozen lung tissues were thawed and suspended in 10 μl/mg ice-cold RIPA lysis buffer with protease inhibitors (Santa Cruz Biotechnology, Santa Cruz, CA), homogenized, and centrifuged at 13,000 rpm for 10 min at 4°C to remove insoluble materials. Supernatant protein concentrations were determined with BCA Protein Assay kit (Pierce Chemical Co.). After addition of 2× sodium dodecyl sulfate loading buffer (Invitrogen), equivalent amounts of protein were separated by electrophoresis using 10% sodium dodecyl sulfate-polyacrylamide gel electrophoresis gels (Invitrogen). The proteins were then transferred onto polyvinylidene difluoride membrane (Invitrogen). Blots were blocked overnight at 4°C with Tris buffered saline containing 0.1% Tween-20 and 5% nonfat milk, then incubated with primary antibody for 1 h followed by horseradish peroxidase-conjugated secondary antibody for chemiluminescent visualization using enhanced chemiluminescence reagent (Perkin-Elmer Life Science, Boston, MA). Blots were stripped with stripping buffer (Pierce Chemical Co.) and reprobed with β-actin (Sigma). Films were scanned at 600 dpi in 16-bit gray-scale on an Epson Precision 4180 flatbed scanner (Epson America, Long Beach, CA). Densitometric analysis was performed using Image J software from the National Institutes of Health (Bethesda, MD). Antibodies against extracellular signal-regulated kinase (ERK), phosphorylated-ERK, IκBα were purchased from Cell Signaling Technology (Beverly, MA). Horseradish peroxidase-conjugated anti-rabbit, and anti-mouse antibodies were purchased from Santa Cruz Biotechnology.
Data were presented as mean ± SD from 4–6 animals for each experimental condition as indicated in the legends. Two-way or one-way analysis of variance was used to compare differences within groups followed by pairwise multiple comparison procedure (Holm-Sidak method). SigmaPlot statistical software ver. 10.0 (Systat Software Inc., Chicago, IL) was used for statistical analysis. Statistical significance was defined as P < 0.05. All P values were two-tailed.
As illustrated in figure 1A, in TLR4-WT mice subjected to HTV (20 ml/kg), but not LTV (7 ml/kg), there was marked increase in permeability compared to tracheotomized and spontaneously breathing mice. In contrast, in TLR4-mutant mice, there were no differences in EBA permeability among the three groups. Similarly, there was less pulmonary edema, as assessed by excess lung water measured by wet/dry weight ratio in TLR4-mutant mice compared to TLR4-WT mice following HTV (fig. 1B).
Figure 2 shows representative lung tissue histology following VILI that illustrates a marked increase in inflammatory cell infiltration, alveolar septal thickening, and pulmonary edema in the lung subjected to HTV in TLR4-WT mice compared to TLR4-mutant mice. Although both BAL total protein concentration and total cell counts were significantly higher in both TLR4-WT and TLR4-mutant mice in response to HTV mechanical ventilation compared to LTV and CON, TLR4-mutant mice showed significantly attenuated elevation of protein content and cell counts in BAL compared to TLR4-WT mice during HTV (table 1). As shown in table 1, in TLR4-WT mice, BAL fluid levels of IL-6 and MIP-2 increased significantly after 4 h of HTV compared with unventilated controls. In contrast to TLR4-WT mice, TLR4-mutant mice elicited significant but much less pronounced increase in IL-6 and MIP-2 after 4 h of HTV. LTV did not affect the BAL levels of IL-6 and MIP-2. Interestingly, 4 hours of LTV and HTV also induced a significant increase in the plasma IL-6 but not MIP-2 in both TLR4-WT and TLR4-mutant mice. Plasma MIP-2 levels were below the level of detection (the detection threshold for MIP-2 was 1.5 pg/ml) in both TLR4-WT and TLR4-mutant control mice although there were somewhat increase in plasma MIP-2 levels following HTV. Other cytokines (e.g., Tumor necrosis factor-α, IL-1β, IL-10) were undetectable in both BAL fluid and plasma in both TLR4-WT and TLR4-mutant mice following 4 h of HTV.
Since most TLR signaling pathways culminate in activation of the transcription factor NF-κB, we examined if HTV would lead to NF-κB activation and if TLR4 status affected such a change. Under normal conditions, NF-κB and IκBα form NF-κB/IκBα complexes in the cytoplasm that prevent NF-κB from translocating to the nucleus, thereby rendering it inactive. Phosphorylation and degradation of IκBα result in release of NF-κB from the complexes, enabling NF-κB to move into the nucleus where it activates the induction of proinflammatory cytokines. Thus, IκBα functions as an inhibitor of NF-κB, and NF-κB activation is associated with IκBα degradation.19–21 We therefore used IκBα degradation as an index of NF-κB activation. As shown in figure 3A, the lung IκBα protein level was decreased in response to HTV in TLR4-WT mice but maintained at the same level in TLR-mutant mice. Moreover, the mitogen-activated protein kinase (MAPK-ERK) in lung tissue became significantly more phosphorylated in TLR4-WT mice in response to HTV. Importantly, phosphorylated ERK (P-ERK) was significantly lower in TLR4-mutant mice compared to TLR4-WT mice following 4 h of HTV (fig. 3B).
As shown in table 2, WT mice showed a modest but significant increase in pulmonary permeability compared with the unventilated control mice and there was no significant change in alveolar permeability in MyD88−/− mice. Similarly, lung histology (fig. 4) showed that HTV elicited marked pulmonary edema, alveolar septal thickening, and increased inflammatory cell infiltration in MyD88-WT mice compared to MyD88−/− and control mice. Furthermore, HTV increased BAL protein content and cell number significantly in MyD88-WT mice compared to control. In contrast, MyD88−/− mice did not increase either protein content or total cell number in BAL following 4 hours of HTV compared to control spontaneously unventilated mice. Finally, MyD88−/− mice had much lower levels of cytokines in BAL compared to WT mice subjected to HTV (table 2).
Figure 5A shows that there was minimal degradation of IκBα and figure 5B shows MAPK-ERK phosphorylation, P-ERK in MyD88 −/− mice whereas there was significant degradation of IκBα and P-ERK in MyD88-WT mice following 4 h of HTV compared to control mice, suggesting both NF-κB and MAPK are involved in MyD88 signaling pathway in VILI.
In the present study, we tested the role of TLR4-MyD88 signaling in the development of VILI. In a mouse VILI model, HTV at 20 ml/kg led to a series of pathological changes consistent with VILI. These included increased alveolar permeability (fig. 1) with elevated cells and protein content in alveolar space (table 1), significant inflammatory cell infiltration and cytokine production in lung tissues (table 1), and activation of the proinflammatory NF-κB and MAPK-ERK pathways (fig. 3). We demonstrate that TLR4 is essential in the development of VILI and that the critical role of TLR4 is most likely mediated via MyD88 signaling since MyD88−/− mice have attenuated pulmonary inflammation and were protected from increased pulmonary vascular permeability (table 2). These results suggest that TLR4-MyD88 signaling pathway may be critical for the development of VILI.
A hallmark of acute lung injury (ALI) is structural impairment in the alveolar-capillary membrane barrier with subsequent increased pulmonary vascular permeability and inflammation. Although extensive research with numerous animal models has attempted to identify effective therapeutic strategies for ALI for almost 35 yr, at present, research on the effects of HTV mechanical ventilation has had perhaps the most significant impact on clinical practice, and mechanical ventilation with reduced tidal volume ventilation strategies is the only definitive treatment modality to improve survival in patients with ALI.3,22,23 However, emerging evidence suggests that mechanical ventilation, even at protective low tidal volume, may activate an inflammatory response in the lung and may cause or predispose to VILI.6–8,16 For example, data from computed tomography demonstrate that even current protective LTV may produce tidal hyperinflation in patients with acute respiratory distress syndrome due to its anatomical heterogeneity of damaged lung,24,25 from which VILI may be considered a regional phenomenon, and thus additional information on the effect of high (and low) tidal volume mechanical ventilation in experimental animals remains an important translational effort. Further improvements of this model may involve additional injurious stimuli to mechanical ventilation, as suggested by the importance of "two-hit" animal model of ALI that has been emphasized by the National Institutes of Health,26 to simulate comorbidities and complexities of ALI. Nonetheless, the standard VILI model that we adapted has been an important contributor to insights into VILI. It is noteworthy that we took great care to continuously monitor oxygen saturation and heart rate in the anesthetized mice. In addition, mice were supplemented with oxygen under anesthesia with the fraction of inspired oxygen less than 50% to prevent possible hypoxia while purposefully minimizing chances of hyperoxia.
Lung inflammation, induced by alveolar over-distention during injurious mechanical ventilation, is considered to contribute to VILI.27,28 Toll-like receptors have long been recognized to play a crucial role in innate immune response and adaptive immune response to pathogens and to non-infectious tissue injury.10–14 TLR4 is unique among the TLRs because it is the only known TLR able to activate both MyD88-dependent and TRIF-dependent signaling pathways.11,29 More importantly, it has been demonstrated that TLR4 is activated after mechanical ventilation with low tidal volume ventilation7 and plays a critical role in ALI induced by high tidal volume ventilation,9 lipopolysaccharide,30 acid aspiration,15 hemorrhage,31 and ischemia and reperfusion injury.32 It is generally considered that TLR4 induces two downstream signaling pathways: MyD88-dependent and TRIF-dependent pathways, simultaneously from the plasma membrane.13,14 Upon binding to endogenous activators, TLR4 forms a dimmer and recruits the downstream adaptor molecule MyD88, ultimately leading to the activation of NF-κB and activator protein 1, inducing transcription of proinflammatory genes, and resulting in cytokine production (fig. 6). However, a recent study also showed that TLR4 may activate these two signaling pathways in a sequential manner; the MyD88 pathway is induced from the plasma membrane, whereas the TRIF pathway is induced from endosomes.33 Lately, Vaneker and colleagues16 demonstrated that lung inflammation was induced by mechanical ventilation with a low tidal volume (8 ml/kg) and that the effect is TRIF-dependent. In general, we did not detect significant pulmonary inflammation with our LTV protocol (7 ml/kg) but it is noteworthy that we instrumented (e.g., tracheostomy) our spontaneously breathing controls whereas Veneker et al16 used uncatheterized spontaneous breathing mice as control. As such, it is possible that the tracheostomy itself produced a sufficient inflammatory response to obscure the effect of LTV and/or to predispose the mice to injury from additional insult such as HTV mechanical ventilation. Nevertheless, LTV mechanical ventilation did not change pulmonary function such as EBA permeability, BAL cell counts and protein content as well as TLR4 downstream signaling pathways such as degradation of IκBα and MAPK/ERK phosphorylation. However, there was two-fold increase in plasma level of IL-6 with LTV compared to spontaneously tracheotomized control mice, a similar finding with recent study7 using mechanical ventilation at a tidal volume of 10 ml/kg for 6 h, indicating a relative small extent increase of systemic levels of IL-6 may not correlate to pulmonary function. In the current study, we also demonstrated that MyD88−/− mice elicited marked attenuation in the lung injury, including pulmonary capillary leak, pulmonary protein and cell emigration, and IL-6 production following HTV mechanical ventilation. Moreover, we found that both TLR4-mutant and MyD88−/− mice had attenuated NF-κB and MAPK/ERK activation in the lung, suggesting that the TLR4-MyD88 signaling contributes to the pro-inflammatory response during VILI. Taken together, these data suggest that pulmonary TLR4-MyD88 signaling may play a pivotal role in the pathogenesis of VILI and is responsible for the inflammatory changes observed in the injured lung.
It is unclear how TLR4-MyD88 (and TLR4-TRIF) signaling is activated in response to VILI. Lipopolysaccharide, itself, the pathogenic ligand of TLR4 is responsible for TLR4 activation in Gram-negative bacterial infection, and might have been a contributing factor. Although its potential role was minimized in a recent study16 in which Vaneker et al carefully monitored the presence of lipopolysaccharide, we are uncertain of any contaminating levels during our protocols. Nonetheless, all our surgical procedures were done in a sterile environment. In addition, the sham control mice underwent the same surgical intervention and were used to offset the possible effect of lipopolysaccharide in the animal group that underwent mechanical ventilation. In addition to lipopolysaccharide, recent evidence suggests an important role of endogenous ligands released in the setting of noninfectious tissue in activating TLR4. Examples of these potential endogenous ligands include high-mobility group box 1 protein released from necrotic cells, oxidized phospholipids from local generation of reactive oxygen species, low molecular weight hyaluran and fibrinogen from degraded extracellular matrix, heat shock proteins from necrotic cells, and surfactant protein-A.34–42 In light of some controversy between the detrimental effects of oxidized phospholipids via intratracheal administration15 and the protective effects of oxidized phospholipids via intravenous route 43,44 in VILI, it may be particularly fruitful to clarify the role of oxidized phospholipids as an endogenous ligand and a potential future therapeutic agent, especially through intratracheal administration. It is possible that the extent and duration of cyclic stretch by mechanical ventilation may trigger different quantitative and qualitative oxidized phospholipids that may produce either antiinflammatory or proinflammatory effects to regulate pulmonary permeability.
In the Acute Respiratory Distress Syndrome Network study,3 plasma IL-6 levels had a positive correlation to patients' mortality when comparing patients with ALI supported by mechanical ventilation with LTV to that with HTV. In addition, lower tidal volume ventilation was associated with a decrease in plasma IL-6 levels.45 In our study, we confirmed the clinical studies as HTV elicited significant increase in IL-6 levels in both BAL and plasma following 4 h of HTV (table 1). The extent of IL-6 elevation correlates to increased BAL cell counts, indicating greater neutrophil migration and accumulation in the airspace. In the current study, we also found that HTV increased MIP-2 production in the bronchoalveolar lavage fluid (table 1 and and2).2). MIP-2 has been reported to be elevated in VILI and shown to augment migration of neutrophils into the alveoli.46 Although our data showed that LTV did not increase pulmonary permeability and pulmonary edema, LTV did not prevent increase of IL-6 in BAL and plasma, indicating that IL-6 may not be a causative factor for VILI, and increased level of IL-6 may be an adaptive host defense to potential injurious MV. Indeed in a recent study,47 IL-6 actually played a protective role in VILI and VILI is considered as a neutrophil-dependent process. The data from our group48 supports such a notion, which showed that the absence of neutrophil elastase potentially resulted in greater instances of VILI.
In the current study, we did not try to distinguish between the magnitude of contributions of downstream pathways of TLR4 (e.g., MyD88- or TRIF-dependent) signaling in VILI, as previous studies16 have also shown the role of TLR4-TRIF pathway in the development of inflammatory response in VILI. The strain of mouse used is a major confounding variable to contrast studies performed in different laboratories and we have systematically described this with respect to VILI.* In this regard, C57BL/6J are relatively resistant to HTV-induced lung injury (table 2). Nonetheless, within this strain (with MyD88 null mice being backbred on C57BL/6J background), it was apparent that MyD88−/− mice were resistant to VILI-induced increases in permeability, histopathologic damage, and cytokine production, consistent with an important role for this limb of TLR4 signaling.
The role of gender to VILI remains unclear and may have contributed to any differences from other existing reports. We chose female mice because they have been reported to have increased sensitivity to hyperoxia49, bleomycin50 and ozone51 induced acute lung injury.
No single animal model reproduces all of the characteristics of acute lung injury, and discrepancies exist between effective therapeutic approaches in animal studies and unsuccessful therapies in human clinical trials. Small animals, such as mice, are a very powerful research tool because they can be genetically modified to facilitate the detailed mechanistic study of complex pathways. It is technically challenging, however, to reproduce long-term mechanical ventilation in mice52 (compared to human patients) and thus in this regard, results from most animal studies need to be interpreted with caution. Nonetheless, short-term mechanical ventilation in rodents remains the most common model used and information derived from these studies has been useful in influencing clinical practice in humans.53,54 The mechanical ventilation model we used here combined high tidal volume ventilation and tracheotomy to reproduce clinical characteristics of acute lung injury in humans, namely increased pulmonary permeability and inflammation, although other factors may influence the magnitude of lung injury such as anesthetic use (e.g., sevoflurane, ketamine),55,56 variability of pressure support57 and positive end-expiratory pressure.58 The insights gained from the study may still have some important clinical implications. Although lung-protective ventilation strategies using low tidal volume with limited airway pressure and appropriate positive end-expiratory pressure has been proposed as a current recommendation for the management of critically ill patients, however, a world-wide survey has been found that it is not uncommon for critically ill patients to still be ventilated with high tidal volume.59 In addition, recent computed tomography images for patients with lung injury have demonstrated nonhomogeneous distribution of pulmonary aeration and thus normally relatively small aerated lung regions may receive the largest part of tidal volume and thereby be exposed to excessive alveolar wall tension and stress due to overdistention.25,60 From a clinical point of view, the high tidal volume mechanical ventilation mouse model is still of value in clinical relevance. The emerging evidence of clinical trials and animal models of VILI, including our current study, has shown that routine use of low tidal volume seems beneficial in all patients requiring mechanical ventilation especially for those patients with preexisting lung injury and inflammation.
In summary, our results demonstrate a critical role of TLR4 and its adaptor MyD88 in the development of VILI. The TLR4-MyD88 signaling pathway may possibly act via the mechanisms involving activation of NF-κB and MAPK. Strategies to modulate NF-κB and MAPK activation and routine use of low tidal volume mechanical ventilation may have potential therapeutic benefits in patients suffering from VILI.
The current study shows Toll-like receptor 4 via myeloid differentiation factor 88 signaling plays an important role in the development of ventilator-induced lung injury possibly through mechanisms involving nuclear factor-κB and mitogen-activated protein kinase pathways.
Supported in part by funding from the National Institutes of Health and National Heart, Lung, and Blood Institute (Bethesda, Maryland), Grants HL79456 (to L.M.Z) and HL 65697 (to B.R.P) and the Seed grant from the Department of Anesthesiology, University of Pittsburgh Medical Center.
The authors would like to thank Yulin Liu, M.D, Ph.D., Associate Professor and Director of Cytology in the Department of Pathology, Allegheny General Hospital, Pittsburgh, Pennsylvania for his technical assistance in pathohistology.
*Presented at the Annual Meeting of the American Society of Anesthesiologists, New Orleans, Louisiana, October 20, 2009, A1278.
Presented in part at the Annual Meeting of the American Society of Anesthesiologists, New Orleans, Louisiana, October 20, 2009.
Received from the Department of Anesthesiology, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center.
PubMed Central Canada is a service of the Canadian Institutes of Health Research (CIHR) working in partnership with the National Research Council's national science library in cooperation with the National Center for Biotechnology Information at the U.S. National Library of Medicine(NCBI/NLM). It includes content provided to the PubMed Central International archive by participating publishers.


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The news of Art of Anarchy's existence was announced in January 2015. On paper it looks like 'just another super group' that wouldn't get much traction that will disappear into the musical abyss.
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Olive Boutique HotelAguadilla St. #55 Condado San Juan 00907
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- Conference center
- 24-hour front desk
- Total number of rooms - 15
- Number of floors - 3
- ATM/banking
- Bar/lounge
- Breakfast available (surcharge)
- Free newspapers in lobby
- Concierge services
- Dry cleaning/laundry service
- Elevator/lift
- Express check-in
- Express check-out
- Designated smoking areas (fines apply)
- Designated smoking areas
- Tours/ticket assistance
- Free WiFi
- Computer station
- Laundry facilities
- Library
- Multilingual staff
- Valet parking (surcharge)
- Garden
- Terrace
- Picnic area
- Luggage storage
- Restaurant
- Safe-deposit box at front desk
- Year Built 2012
- 24-hour business center
- Self parking (surcharge)
- Number of buildings/towers - 1
- Outdoor pool
- Wedding services
Family Friendly Amenities
- Outdoor pool
- Free Wi-Fi
- Laundry facilities
- DVD player
Available in all rooms: Free WiFi
Available in some public areas: Free WiFi
Self parking (surcharge), Valet parking (surcharge)
Room Amenities
- Premium TV channels
- DVD player
- Hypo-allergenic bedding available
- Premium bedding
- Air conditioning
- In-room climate control (air conditioning)
- Phone
- Free local calls
- Minibar
- Free bottled water
- Daily housekeeping
- Turndown service
- Designer toiletries
- Private bathroom
- Bathrobes
- Free toiletries
- Hair dryer
- Shower only
- Rainfall showerhead
- Iron/ironing board
- In-room safe
- Desk
- Blackout drapes/curtains
- Satellite TV service
- Free WiFi
- Room service
- Down comforter
- Egyptian-cotton sheets
- Individually furnished
- Individually decorated
- Pillowtop mattress
Where to Eat
Continental breakfasts are available for a surcharge and are served each morning between 7 AM and 10 AM.
Sage Steak Loft - This fine-dining restaurant specializes in international cuisine. Guests can enjoy drinks at the bar. Open select days.
Room service is available.
Nearby Things to Do
The recreational activities listed below are available either on site or nearby; fees may apply.
- Golfing nearby
- Snorkeling nearby
- Surfing/boogie boarding nearby
- Kayaking nearby
- Scuba diving nearby
- Windsurfing nearby
- Bicycle rentals nearby
- Hiking/biking trails nearby
- Ecotours nearby
- Golf lessons available nearby
- Boat tours nearby
To make special requests for accessibility needs, please note them at check-out when you book your room.
- Accessible bathroom
- In-room accessibility
Hotel Policies
Check-in time starts at 3 PM
Minimum check-in age is 18
Check-in time ends at midnight
Check-out time is noon
Payment types
- Pets not allowed (service dogs only)
You need to know
Extra-person charges may apply and vary depending on hotel policy.
Government-issued photo identification and a credit card are required at check-in for incidental charges.
Special requests are subject to availability upon check-in and may incur additional charges. Special requests cannot be guaranteed.
Only service animals are allowed
No rollaway/extra beds available
No cribs (infant beds) available
- Resort fee
Optional extras
- Fee for continental breakfast: USD 12.99 per person (approximately)
- Self parking fee: USD 22.3 per night (in/out privileges)
- Valet parking fee: USD 20 per day (in/out privileges)
Hotel Name
- Olive Boutique Hotel
- Olive Boutique Hotel San Juan
- Olive Boutique San Juan
- Olive Hotel
- Olive Hotel Boutique
We should mention
Reservations are required for massage services and spa treatments. Reservations can be made by contacting the hotel prior to arrival, using the contact information on the booking confirmation. A resort fee is included in the total price displayed. Children 15 years old and younger are not permitted at this property. Only registered guests are allowed in the guestrooms.
Awards & Affiliations
- The property is a member of the Small Luxury Hotels of the World.
Enjoy monthly brunch at O:liva
Stay at the Olive Boutique Hotel during the last Sunday of every month and enjoy a delectable rooftop brunch at O:liva at the reduced price of USD$65.
Valid for all room and rate categories. Complete details available upon check-in. Offer may not include taxes or gratuities. Other restrictions may apply.


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The Gentle Giant Blood Line, Champion TT Temperament Tested
Have one Red and Rust Baby Girl that deposit was returned Home Owners ass would not let him have A doberman
First 2 pictures are Mother Heidi and Father Guardian pictures with AKC Papers
His ...
Aug 31 -
Clarksville :
Camden - Dogs & puppies
8 wk old AKC Reg. Bull mastiff Puppies!! Vet checked, dewormed, vaccinated according to age, current on flea and heartworm prevention. Parents on site. Litter of 9. Dam 90lbs Sire 135. Lots of champion bloodlines in dams side. Very well socialized puppy. Call or text for more pics/info Cash,Check, or Credit Cards accepted
(706) 315-8970 Located outside of Auburn, AL. Willing to ...
Aug 26 -
Columbus (GA) :
Opelika - Dogs & puppies
These 5 beautiful pups are ready to go to their forever homes. Raised with livestock, they come from a line of excellent guardians. Their mother, father and two siblings live on the farm as well and we have virtually no losses from coyotes, hawks, black vultures or other dogs, yet these gentle giants are great with other pets, chickens and children. They've had their first round of puppy ...
Aug 20 -
Lexington :
Sandgap - Dogs & puppies
Unleashed kennels ga has 1st pick male available off Baylor off Duke City Pit bulls Ch IVY and Leprechaun Kennels OMALLEY the 140lbs giant x Lexi from Royal Crest Kennels born 2/20/16. picture of parents and grandparents listed.
Baylor is 120lbs 25" head and 22" tall
Lexi is 80lbs 21" head and 20" tall
Aug 14 -
Atlanta :
Auburn - Dogs & puppies
AKC registered St. Bernard puppies available first week of September. Mom and Dad on site, all paperwork available at time of pick up. Dewormed and all shots will be completed prior to pick up. Both mom and dad are inside pets and are gentle giants. Please add us on Facebook SophienMax Nienaber for uploded photos and videos of the parents and puppies. For further information or questions ...
Aug 4 -
Cincinnati :
Cincinnati - Dogs & puppies
We'll be sending text message alerts for your subscription to


text:
Crimp Connector Kit, Terminal Type: Connector, Number of Pieces: 120, Number of Sizes: 4
- Item# 1YML2
- Mfr. Model# 10067
- Catalog Page# N/A
Using 360° Viewing:
- Rotate: Use top-to-bottom, side-to-side by use of mouse arrow.
- Zoom In: Double click on image.
- Zoom Out/Reset: Put photo at full zoom & then double click.
- Shipping Weight 1.08 lbs.
Product Details
Technical Specs
- Item Crimp Connector Kit
- Connector Assortment Type Crimp Terminals
- Kit Type Connector
- Terminal Type Connector
- Number of Pieces 120
- Includes (5) Red #6 Stud, (5) Red #10 Stud, (5) Blue #10 Stud, (5) Blue 1/4" Stud, (5) Blue 3/8" Stud, (5) Yellow #10" Stud, (5) Yellow 1/4" Stud, (5) Yellow 3/8" Stud, (5) Yellow 1/2" Stud Ring Terminals, (5) Red #10, (5) Blue #10, and (5) Yellow #10 spade Terminals, (5) Clear, (10) Red, (15) Blue, and (10) Yellow Butt Connectors, (5) Red 1/4 Tab and (5) Blue 1/4 Tab Female Couplers, (5) Red 1/4 Tab and (5) Blue 1/4 Tab Male Couplers, and Plastic Case
- Number of Sizes 4
- Sizes Included 22-24 AWG ,18-20 AWG, 14-16 AWG, 10-12 AWG
Compliance and Restrictions
This product contains a chemical that is regulated under California Proposition 65.
Warning: This product contains a chemical known to the State of California to cause cancer.
Warning: This product contains a chemical known to the State of California to cause birth defects or other reproductive harm.
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Hotels in Northampton
Search Northampton Hotels
Trending now in Northampton
- Most bookedPark Inn by Radisson Northampton
322 people looked at this hotel in the last hour
Most recent review
"Meeting friends for a meal in the City Centre. The Hotel is well placed and has on site parking whiech is free for residents. Staff were great - very friendly, came across as genuine and warm. Reception, lifts and Superior Rooms all fine. Didn't see standard rooms, and didn't use dining/breakfast..."
A Traveller, Sep 2016, GB
320 people looked at this hotel in the last hour
Most recent review
"Our room was very clean but there was no remote control for the tv so we were unable to use this. Not a problem for us as we arrived late in the evening and checked out straight after breakfast but still disappointing. Also there were only tea/coffee making facilities for 2 people despite there..."
R, Sep 2016, GB
308 people looked at this hotel in the last hour
Most recent review
"Originally booked a family room for 4 adults (parents and 2 teens). Barely made it through night one in tight quarters of family room. Teens shared sofa bed which was miserable as expected. Bathroom modern but very small as was entire room. Added a second room for our remaining two nights and tha..."
A Traveller, Jul 2016, GB
272 people looked at this hotel in the last hour
Most recent review
"Lovel staff, great room, really clean, selection at breakfast was great and really good value for money"
A Traveller, Sep 2016, GB
261 people looked at this hotel in the last hour
Most recent review
"The title says it all. Some decent restaurants across the street. Clean and comfy."
P, Sep 2016, GB
238 people looked at this hotel in the last hour
Most recent review
"Meeting with a relative in this hotel, convienient for his short stay, we had less opportunity to experience all it has to offer and thus we did not experience its resturant. The room, staff and swimming pool however were all excellent. Thus our stay could not have been more pleasant."
A Traveller, Sep 2016, GB
205 people looked at this hotel in the last hour
Most recent review
"Excellent service, decent room and really good price. The only problem was the half open bath which I don't think it is a good idea because the toilet area gets wet when you shower. Apart from that, everything was excellent including the breakfast and dinner. Will definitely stay there again."
A Traveller, Sep 2016, GB
18 people looked at this hotel in the last hour
Most recent review
"3 Nights while we attended the Cropredy Festival. This is our hotel of choice when we come up every year.It ticked all the boxes in terms of our requirements.Staff are friendly and gave good service."
A Traveller, Aug 2016, GB
13 people looked at this hotel in the last hour
Most recent review
"Only real complaint is the road at the back, if you room is on this side, there's only a hedge between it and your window. There wasn't much traffic, but every car was heard. The room was nice, the bed was great. It was too warm even with the heating off though, and with not being able to have th..."
A Traveller, Aug 2016, GB
9 people looked at this hotel in the last hour
Most recent review
"Very friendly staff. Have stayed there before. The hotel is a little tired in places, but value for money. Think the food in the restaurant could be better & better menu. In all enjoyed my stay and the staff made me feel very welcome especially Martin & Amy. The hotel is an old building with cha..."
A Traveller, Aug 2016, GB
View Northampton Hotels on a map
Best Northampton Hotels
Things to see
You simply can't visit Northampton and not make time to see the Market Square. Few others in Britain can compare to it in terms of spectacle and heritage: there has been trading going on here since as far back as 1235. Linked to the main shopping area of Abington Street, the Market Square teems with colorful stalls selling everything from homemade jams to traditional pies to bags and shoes. Spend an afternoon having a leisurely wander, and admire the picturesque terraced buildings that surround on all sides. Another great landmark is the Northampton Guildhall, which stands on St Giles' Square. With its intricately carved arches, and its many statues and friezes of saints, it's a striking monument to the Victorians' taste for all things Gothic, and just one example of Northampton's rich history. If you fancy getting out of the town while you're in the area, you can also visit Flore – an idyllic village 7 miles from Northampton, on a hillside facing the River Nene. Just 5 miles from Northampton lies Althorp, the 17th Century home of the Spencer family, and the final resting place of Diana, Princess of Wales.
Hotels in Northampton
While it may not be a cosmopolitan metropolis to rival London or Manchester, there's still a very wide range of Northampton hotels to suit all travelers. On a romantic break? You might want to try one of the larger manor houses on the outskirts of the town – you can expect, stylish, contemporary décor in the guestrooms, and some have saunas, tennis courts, and health clubs to make your stay all the more memorable. There's also a good selection of chain hotels in Northampton offering tried and trusted comforts as well as facilities like free WiFi and on-site bars and brasseries – perfect for business travelers.
Where to stay
Unless you've chosen to book one of the aforementioned, grand Northampton hotels a bit further out, the center of the town is really the place to be during your stay here. It means you'll have the bustle of Abington Street on your doorstep (no cars go there, so you can stroll and window shop to your heart's content), as well as the Market Square and the many old Victorian buildings that give the center its identity.
How to get to
Northampton is well connected with the rest of the UK, with direct train services to major cities including London, Coventry, and Birmingham available from Northampton Station. If you're flying in from abroad, you might choose to land at Birmingham Airport. From here you simply hop onto the Rail-Link monorail which will whisk you to Birmingham International Station, where you can get the train to Northampton with a journey time of under an hour. If you're flying into Luton, you'll be able to make use of one of the frequent coach services to Northampton.


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E-Mail email@example.com
Building PT, Zi. 4.1.20
Phone +49 (0)941 943-3783
Fax +49 (0)941 943-4989
Research and teaching in the Gruber Research Group is focused on the analysis of outstanding professional performers and educational means to foster their acquisition of expertise. Studies are conducted in a variety of domains (for example medicine, business management, science, music, and arts), using a large variety of empirical research methods (from eye-tracking analyses to biographical records of practice activities). The GRG trusts that the key to understanding reproducible superior performance is the notion that expertise can be acquired through deliberate practice. Effortful training activities lead to domain-specific cognitive, physiological, motor and perceptual adaptations. In addition to such individual adaptations, social adaptations are investigated as well in order to understand the social embedding of expertise, for example the changing participation in professional networks during the growth of individual excellence.
Summer term 2016
During the summer term 2016, Professor Gruber spends a research sabbatical at the University of Turku, Finland. His deputy during this period is Helen Jossberger, Ph.D..
At the 8th EARLI SIG 14 conference 'SIGnature: Bridging Professional Development Research' – held in Regensburg from 24-26 August – Linda Puppe was awarded with the Best Poster Award. Springer sponsored this award with a voucher of € 250,-. Congratulations! Here is the link to the poster.
From June 16th until 18th 2016, the annual doctoral candidate meeting took place at Haus Johannisthal in Windischeschenbach.
PhD students and Post-Docs of the Chairs for Educational Science I, II & III, as well as the Chair for School Research, School
Today we welcome our new secretary, Katrin Lessel-Schuler. Experienced in managing courses at an adult education centre and being a foreign language correspondent, she will support the team at our department as well as students.
We wish her a good start and look forward


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Popular Diets
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new to your site love all i have seen/read always have been heath nut started out with weigths years ago and have let myself go some need to get back to it thanks wonderful recipesposted Feb 20th, 2010 3:36 pm
This recipe works great by substituting crushed almonds for the parmesan cheese...delicious
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The information provided within this site is strictly for the purposes of information only and is not a replacement or substitute for professional advice, doctors visit or treatment. The provided content on this site should serve, at most, as a companion to a professional consult. It should under no circumstance replace the advice of your primary care provider. You should always consult your primary care physician prior to starting any new fitness, nutrition or weight loss regime.


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"Excellent Lecture"
I have to admit, I bought this lecture on an Audible sale and was only mildly interested in the topic. But Prof. Drout is so obviously fascinated by this subject that he made me fascinated as well. He talks in "normal" language, and has just the right amount of humorous rambling every once in a while that it felt like he was just chatting with me in my living room. I thoroughly enjoyed this lecture and highly recommend it whether you are interested in this subject or not!
"Enjoyed every bit of the lecture"
Prof. Drout livelily explains Anglo-Saxon history, culture, literature, and its people in his work "The Modern Scholar: The Anglo-Saxon World". I felt as if I was learning about someone so close to me, instead of some distant culture happened a long time ago in the history. Despite of the length (7+ hours), I truly enjoyed every bit of the lesson. Now I am listening for the second time!
"Family History"
I had always thought I was probably German until I started my geneology and found most of my family lines that had german sounding names fed into o from Great Britian. This book directly tells my family history in that section and time in the world.
I truly enjoyed this. I listened to it really just because this is one of my favorite topics. I was also teaching it at the same time and found some info that I could share with my students. Drout is a good lecturer. I can tell he really enjoys this topic, and I imagine that his class would be very worthwhile.
"Great Primer"
I've been a part time lover of Anglo Saxon studies for close to 25 years. While most of this was review for me, Professor Drout's passion made it fun to listen to as a good refresher. As a lover of colonial America and Virginia in particular, I also found his work challenging some of my assumptions. Recommend.
"Superb overview"
Such a great overview of interesting history and literature. Up to Professor Drout's excellent standards.
"Another great lecture"
Michael Drout, as always, knows his subject and is able to communicate his enthusiasm.
The little bit you think know you know about Anglo-Saxons is probably mostly mistaken, as I found out. This is one of my favourite lecturers.
"Totally juvenile and disorganized"
Stop constantly announcing what you have or are going to talk about. I don't want to hear about Hitler's and the Victorians' thoughts about the Anglo Saxons. I wanted to hear about the Anglo Saxons.
Anger. The thought that if one of my 7th grade students presented this as a report I would probably have given him a fairly good report, but I would also have expected it to be about 7/8 shorter.
This is the first time I have been upset enough to write a review, and I have bought hundreds of books from Audible.
"Interesting and upbeat"
He does a a great job of making a subject others would render dull, quick paced and interesting. This history is very relevant and seldom studied.
"Absolutely excellent!!!!!!"
This lecture series is really really wonderful. Informative, interesting and hilarious. I'm eagerly looking forward to listening to more lectures by Drout!!!!!


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Rent Teaching and Learning History in Elementary School 1st edition today, or search our site for other textbooks by Jere E. Brophy. Every textbook comes with a 21-day "Any Reason" guarantee. Published by Teachers College Press, Teachers College, Columbia University.
Need help ASAP? We have you covered with 24/7 instant online tutoring. Connect with one of our tutors now.


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Standardized testing is a hot-button issue. Here's what it looks like locally for the 2016-17 school year.
Standardized testing is a hot-button issue. Here's what it looks like locally for the 2016-17 school year.
Why put limits on kids' creative impulses when artistic activities clearly benefit real-world performance?
Whether it's visual art, music, dance or drama, the arts do much to nurture creativity and imagination in children. The following local institutions offer arts education for kids: Belmont Academy 1900 Belmont Blvd., Nashville 460-6346 • belmontacademy.net Operated under the Belmont University College of Visual and Performing Arts, the Academy offers private instruction for all… Read more »
You've heard about brain training for the elderly – but what about for your rambunctious child? A growing body of evidence shows there's something to cognitive training for the younger set.
Your high school student will need to take one or both of the college entrance exams during his junior year of high school. Here are an expert's tips for helping him prepare for the test.
Coding is quickly becoming less of an extracurricular and more like a life skill — one that may someday lead to a good job.
Ready or not, the new school year has begun. Get crackin' with our back-to-school tips.
Want your child to produce outstanding grades? A few brainiac strategies are in order!
Texting and hanging out on various social media sites — parents not welcome — makes it seemingly impossible to be your child's cyber shield. Here's how to help keep her safe.
"A labyrinth of disconnected and poorly conceived reforms" is how Williamson County School Superintendent Mike Looney describes the current situation being played out in education right now in Tennessee.


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A Decade Of Out-Performance: Inside WisdomTree's Dividend-Weighted Strategies
A decade ago, WisdomTree changed passive investing with the introduction of a sweeping series of dividend-weighted indexes.
WisdomTree Chief Investment Strategist Luciano Siracusano discusses our approach to dividends and how several WisdomTree
strategies outperformed traditional beta benchmarks over the past 10 years.
Below you will find links to our latest whitepapers, investment cases and current research.
You can also read economic and market commentary from our thought leaders and connect with us on social media.
WisdomTree Fundamental U.S. Short-Term High Yield Corporate Bond Fund seeks to track the performance of select issuers in the short-term U.S. non-investment-grade corporate bond ("junk bond") market that are deemed to exhibit favorable fundamentals and opportunities for income. Learn more about the Index SFHY is designed to track.
Why SFHY?
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Fundamental Fixed Income Blog Posts
This information must be preceded or accompanied by a prospectus, click here to view or download prospectus. We advise you to consider the fund's objectives, risks, charges and expenses carefully before investing. The prospectus contains this and other important information about the fund. Please read the prospectus carefully before you invest.
There are risks associated with investing, including possible loss of principal. Fixed income investments are subject to interest rate risk; their value will normally decline as interest rates rise. High-yield or "junk" bonds have lower credit ratings and involve a greater risk to principal. Fixed income investments are also subject to credit risk, the risk that the issuer of a bond will fail to pay interest and principal in a timely manner or that negative perceptions of the issuer's ability to make such payments will cause the price of that bond to decline. While the Fund attempts to limit credit and counterparty exposure, the value of an investment in the Fund may change quickly and without warning in response to issuer or counterparty defaults and changes in the credit ratings of the Fund's portfolio investments. Please read the Fund's prospectus for specific details regarding the Fund's risk profile.
WisdomTree Funds are distributed by Foreside Fund Services, LLC in the U.S. only.


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CNET: Canadian MP3 player tax challenged
"MP3 player manufacturers, including Apple Computer, Dell and Hewlett-Packard, are challenging a recent regulatory ruling in Canada that would impose an extra fee of as much as $25 on iPod-like digital music players.
The Copyright Board of Canada ruled in December that hard drive-based digital music players should be subject to fees aimed at compensating musicians, songwriters and record labels for copyright infringement. Similar fees are placed on blank audio tapes and CDs, and manufacturers typically pass on the costs to the consumer.
A group of retailers, including Wal-Mart Stores and Best Buy, also is appealing the decision, which will be heard by a federal court."
Related Stories
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You can't have legal downloads AND cheap players for the downloads…
I doubt much of the tax will end up in the hands of the artists….
Posted by dethbrakr in Irvine, CA on January 13, 2004 at 7:42 PM (CST)
Newsflash from next month:
Black market emerges in Canada as American iPods cross the border.
Posted by Atomic Bomb in Irvine, CA on January 13, 2004 at 7:48 PM (CST)
we will send you our marijuana and you can send us ipods. i got mine on usa apple.com. 100 bucks cheaper than canada apple, although they just dropped the price on canada site.
Posted by bkush in Irvine, CA on January 13, 2004 at 8:02 PM (CST)
soon thousands will flock for the cheap weed and free music downloads!
Posted by wfbberzerker in Irvine, CA on January 13, 2004 at 8:59 PM (CST)
The tax is total BS. It assumes you are stealing music and should pay more.
Not everyone does.
Posted by Eriamjh in Irvine, CA on January 14, 2004 at 5:03 AM (CST)
Hah! Canadia!
So if they charge on Hard Drive based mp3 players, when will it be that they will charge tax on hard drives themselves because they can play music?
What about IC chip recorders? Laptops, desktops. Hey, PalmOS and WinCE plays mp3's! I guess they should tax that too?
Canada makes me laugh.
Canadia. LOL.
Posted by cabbit in Irvine, CA on January 14, 2004 at 5:04 AM (CST)
Oh well. No big deal for me. Small price to pay for living in a safe, sane country.
Posted by MeshAir in Irvine, CA on January 14, 2004 at 10:17 AM (CST)
There's nothing sane about silly taxes. There is no rational basis for the Canadians taxing MP3 players. Next thing you know, the Canadian iPods will have to have at least 1/3 Canadian music like their radio stations do!
Posted by coonass in Irvine, CA on January 24, 2004 at 10:06 PM (CST)
As a Canadian living in the U.S., I would point remind everyone that Canadians are really quite dastardly. We have shipped our two most evil inventions to the U.S. and no one has even noted the beginning of the end for the U.S.
The first are Canadian Geese. Evil things.
And then… the kicker… Celine Dion!
Now that's evil.
Posted by ParkJammer in Irvine, CA on September 28, 2004 at 8:38 PM (CDT)
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Home > Eyeglasses > Vienna Design > UN537 (01)
New Releases
Size and availability
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Free outbound and return shipping
30-day money-back guarantee
Low prices
UN537/01 Eyewear
With these designer eyeglasses, you are always perfectly dressed. The new Vienna Design underlines that you are a trendsetter. For the current season the renowned label sets the standards with its collection for 2016. The UN537 is available in the Edel-Optics online shop in other styles from Vienna Design collections 2015 and 2016.
The unisex Vienna Design model makes no distinction between men and women. Eyewear is in. Full rim is extremely popular, because you feel that you get more eyeglass for your money. It is not just about their resilience, but also about the visibility of material and design, which are of the highest quality. The square frame is a classical shape, highlighting the straightforwardness of the personality. The metal frame is very light and comfortable to wear. It is both robust and classy. The colour gold is absolutely hip in 2016. This Vienna Design lends any outfit a certain something. With gold, darker skin types can never go wrong.
With the help of our digital dispensing optician, your prescription lenses can be configured according to your own requirements. Anti-reflective and cleaning coatings, antistatic and lotus effect are included as standard for plastic lenses.
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- Graduate Studies
- Admissions Course Information CSEM/CAM Alumni CS/CSEM Joint Degree CSEM Faculty Funding / Fellowships Student Resources Student Success
- Programs
- CSEM Graduate Studies JTO Fellows Postdoctoral Fellows Moncrief Endowed Positions Moncrief Grand Challenge Faculty Awards Moncrief Undergraduate Summer Internship CSE Certificate Program Carey Scholarship
ICES Reports
ICES Reports are authored by ICES Faculty, in collaboration with other Researchers, Visiting Scholars, Post-Doctoral Fellows, and CSEM Students under their supervision. Although they may represent the work of a single ICES Faculty member, the reports are more often a collaboration, and are meant to be a temporary outlet for the work prior to publication in refereed journals and conference proceedings. ICES Report are not meant to be an outlet for the work of non-ICES researchers, scholars, or students that was completed elsewhere, without ICES Faculty collaboration and/or without direct support from ICES/ICES contracts (where such collaboration/support has been noted in an "Acknowledgements" section).
16-21 — "Coupled variational formulations of linear elasticity and the DPG methodology"
Federico Fuentes, Brendan Keith, Leszek Demkowicz, and Patrick Le Tallec
September 16, 2016
16-20 — "An Adaptive DPG Method for High Frequency Time-harmonic Wave Propagation Problems"
Socratis Petrides and Leszek F. Demkowicz
September 6, 2016
16-19 — "A Spacetime DPG Method for the Schrödinger Equation"
L. Demkowicz, J. Gopalakrishnan, S. Nagaraj, and P. Sepúlveda
September 6, 2016
16-18 — "Mixed methods for two-phase Darcy-Stokes mixtures of partially melted materials with regions of zero porosity"
Todd Arbogast, Marc A. Hesse, and Abraham L. Taicher
August 12, 2016
16-17 — "Multi-degree C^k smooth polar splines: a framework for design and analysis"
Deepesh Toshniwal, Hendrik Speleers, René R. Hiemstra, and Thomas J. R. Hughes
June 20, 2016
16-16 — "Implicit boundary integral methods for the Helmholtz equation in exterior domains"
C. Chen and R. Tsai
June 16, 2016
16-15 — "A phase-field formulation for fracture in ductile materials: Finite deformation balance law derivation, plastic degradation, and stress triaxiality effects"
Michael J. Borden, Thomas J. R. Hughes, Chad M. Landis, Amin Anvari, and Isaac J. Lee
June 13, 2016
16-14 — "Immersogeometric cardiovascular fluid–structure interaction analysis with divergence-conforming B-splines"
David Kamensky, Ming-Chen Hsu, Yue Yu, John A. Evans, Michael S. Sacks, and Thomas J. R. Hughes
May 16, 2016
16-13 — "Multirate Undrained Splitting for Coupled Flow and Geomechanics in Porous Media"
Tameem Almani, Kundan Kumar, and Mary F. Wheeler
May 12, 2016
16-12 — "Stability of Multirate Explicit Coupling of Geomechanics with Flow in a Poroelastic Medium"
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text:
Citigroup creates 440 IT jobs in Northern Ireland
Citigroup is creating 440 IT jobs at in a technology and operations centre in Belfast over the next five years.
The IT jobs are part of the banking...
Citigroup is creating 440 IT jobs at in a technology and operations centre in Belfast over the next five years.
The IT jobs are part of the banking group's plan to create more than 500 new roles.
According to the Belfast Telegraph, deputy first minister Martin McGuinness said, "Over the next five years, Citi plans to create 440 new high-quality roles in its technology and operations divisions and a further 61 new specialist posts in its legal and compliance division."
Your exclusive guide to CIO trends
A collection of our most popular articles for IT leaders from the first few months of 2016, including: - Corporate giants recruit digitally-minded outsiders to drive transformation - Analytics platforms to drive strategy in 2016 - Next generation: The changing role of IT leaders.
By submitting your email address, you agree to receive emails regarding relevant topic offers from TechTarget and its partners. You can withdraw your consent at any time. Contact TechTarget at 275 Grove Street, Newton, MA.
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Government business support group Invest Northern Ireland contributed £8.4m to the project.
The investment signals that business volumes are on the up for banks. This contrasts with two years ago when the worst effects of the credit crunch were being felt. In November 2008, US bank Citigroup announced plans to cut its workforce by 52,000 jobs across all businesses and geographies.
Citigroup CEO Vikram Pandit said the bank would cut 20% of its employees at the group.
The latest figures from CWJobs.co.uk show that the financial services sector is advertising the most IT contractor and permanent roles.
Enjoy the benefits of CW+ membership, learn more and join.


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Longchamp Le Pliage Néo Large Bag
£120.00 Product Code 5269508
- Overview
Longchamp reinvents its iconic Le Pliage collection in a more urban, modern style. The Le Pliage Néo Large Handbag is crafted in lightweight, tactile nylon with a luxe leather trim. Complete with two types of straps, for various styling possibilities, this effortlessly practical bag is perfect for every lifestyle.
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Monday, September 26, 2016
About the Book
About the Authors
Buy Our Book
Resources for Instructors
Book Store
Press Room
Professional Speaking
HRMS Discussions
Contact Us
It is time for SMBs to get ready. Workforce Ready
Thursday, May 16, 2013
Announcing... Bring your Colleague for FREE... The Journey - Aligning your HRMS Strategy with your Business Strategy
Thursday, April 25, 2013
Toronto, ON - Wednesday, May 22, 2013
Selecting and Implementing HR/Payroll Software Art or Science?
Monday, March 11, 2013
Mississauga, ON
2013 Talent Management Systems Market: Explosion of Growth and Change - by Josh Bersin
Thursday, December 6, 2012
Josh Bersin,
CEO, President, Bersin & Associates
BigData in HR: Why it's Here and What it Means - Josh Bersin
Tuesday, November 20, 2012
Bersin & Associates
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on line
Human Resources Management Systems
A Practical Approach (3rd Edition) Now Available!
HR Manager's Guide to Human Resources Management Systems: A Practical Approach, 3rd Edition
A human resources management system (HRMS) is more than a human resources information system (HRIS). It is what the name implies; an information management system accessible to staff at all levels, designed to ensure that the organization's most important resources — its people — are recruited, selected, developed, employed, deployed, and supported most effectively.
Texts on human resources information systems commonly focus on developing and implementing systems that gather, store, and report human resources data in a timely fashion, in forms that are useful to human resources personnel, line management, and other users. In writing this book, we have attempted to go further than this, by focusing as well on the uses of an HRMS as a critical management tool.
This book is designed to reach a diverse audience, including:
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• Information systems professionals who will be working on an HRMS project and want to learn more about the business and user perspective on such systems; and,
• Post-secondary school students taking a general HRMS course.
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Highlands Of Preston
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text:
Newegg.com - A great place to buy computers, computer parts, electronics, software, accessories, and DVDs online. With great prices, fast shipping, and top-rated customer service - once you know, you Newegg.
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Showing Results: Most Recent
This review is from: MSI MSI Gaming A88XM GAMING FM2+ / FM2 AMD A88X SATA 6Gb/s USB 3.0 HDMI Micro ATX AMD Motherboard
Pros: Full Feature Motherboard
Cons: I am on my 2nd Motherboard. I encountered the same issue with the bios. After configuring the bios, save and exit. On reboot, nothing. Reset bios with jumpers, freezes on "entering setup" screen. I am CompTia certified and went through all the troubleshooting step which include removing all peripherals.
Other Thoughts: Setup:
MSI A88XM Gamming Motherboard
GSkill 2133 Aries
I very seldom write reviews. It seems as performance increases, so do issues with components. I have been a MSI fan for a long time. This may change that view. If you search the internet, there are a few people who have had the same issue. I guess if you do a lot of configuration in the bios, this issue may eventually occur.
This review is from: ASRock 970 Extreme3 R2.0 AM3+ AMD 970 SATA 6Gb/s USB 3.0 ATX AMD Motherboard
Pros: 1. One of the few 775 motherboards available.
2. Use of DDR 3 Memory
3. Onboard video
Cons: 1. Motherboard Failure to properly identify CPU.
2. ASRock memory compatibility list for compatible 2x4 memory modules.
3. Motherboard is difficult to set up if you do not have some technical background.
Other Thoughts: 1. I have an old intel E4300 duo core cpu. The motherboard improperly detects it as a E6320. Being detected as such limits OCing. I had this cpu OC'd to 3.01 on my previous board.
2. Initially the MB did not boot with DDR3 modules I had purchased for this motherboard. As you may have read in some of the previous reviews, some purchasers said the MB was DOA, did not boot, etc. This MB is very particular as to the DDR 3 modules being used. If you plan to go this route, plan to purchase DDR 3 modules that use 1.5 volts. I had purchased 1.65 V modules initially when the board failed to boot. The ASRock site have little to no DDR3 2x4 modules listed as compatible.
3. BIOS settings are very limited.
a. Voltage settings are nil to none
b. CPU FSB is linked to memory
c. BIOS must be reset when changing from DDR2 to DDR3 (don't forget the manual pin setting).
Hope this is helpful for those looking for a replacement 775 MB.


text:
Explore your surroundings to find an escape from the bathroom! As Afro Ninja, you have no idea why you've been confined to the lavatory. Your only mission is to get out of there by any means necessary. Click around to gather items for your escape!
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Free personalized radio that
plays the music you love
Cheese Smoothie
Features of This Trackelectronica roots
an instrumental rap style
basic rap roots
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dominant use of riffs
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Thursday, 29 September 2016
Last updated 11 hours ago
Jun 4 2014 | 8:35am ET
A possible nominee to lead the troubled U.S. Department of Veterans Affairs could face tough questions about his ties to a hedge fund.
President Barack Obama is considering Delos Cosgrove, CEO of the Cleveland Clinic, for the job, which opened last week with the resignation of Secretary Eric Shinseki following an internal review that found an agency rife with mismanagement, treatment delays and falsified records. But Cosgrove, an Air Force veteran and heart surgeon, comes with a bit of controversy of his own.
Cosgrove's links to hedge fund Foundation Medical Partners were criticized in 2005. The fund invested in companies that conducted studies at the clinic.
The controversy, which included another doctor involved with a different hedge fund, led the Cleveland Clinic to tighten its conflict-of-interest policy. An internal review criticized Cosgrove's disclosure practices, but did not accuse him of any ethical violations.
Sep 26 2016 | 10:20am ET
Tonight's U.S. Presidential debate, infamously coined the "Humbling in Hofstra...
Sep 27 2016 | 7:24pm ET
American watch manufacturer Vortic, which started out restoring antique pocket watch...
Sep 2 2016 | 5:01pm ET
Deal sourcing and origination is only going to get more competitive given current...


text:
Former Pahokee standout Raheam 'Trouble' Buxton dismissed from Western Michigan's football team
Pahokee graduate Raheam Buxton has been dismissed from Western Michigan's football team, the Kalamazoo Gazette reported. …
7:59 pm Sep. 27, 2011
Pahokee graduate Raheam Buxton has been dismissed from Western Michigan's football team, the Kalamazoo Gazette reported. …
8:21 pm Feb. 3, 2010
With every signing ceremony, there must come at least a little theatrics…
At Pahokee, De'Joshua Johnson dug something Tennessee orange out of a box and tossed it over his shoulder before pulling out a Florida State hat and putting it on, Raheam Buxton threw a Miami hat into the crowd at the auditorium before donning a Western Michigan hat (Miami pulled its offer to him), and Chris Dunkley announced he …
11:51 pm Feb. 2, 2010
Everybody thinks they know, but nobody knows for sure — including me.
10:02 pm Jan. 22, 2010
Pahokee coach Blaze Thompson said safety Raheam Buxton no longer has a scholarship offer from the University of Miami.
7:23 am Jan. 17, 2010
The University of Miami was the first school to identify Pahokee safety Raheam Buxton as a BCS prospect, doing so before Buxton had ever established any kind of reputation on the field, but Buxton has …
6:06 pm Nov. 1, 2009
Glades Central senior Greg Dent, a standout at wide receiver and in the secondary, has committed to play for the Miami Hurricanes.
6:12 am Sep. 24, 2009
Prior to Friday night's game against Cardinal Newman, Pahokee will hold a pre-game ceremony in remembrance of Norman "Pooh" Griffith. Sunday will mark the one-year anniversary of Griffith's death.
3:47 pm Sep. 2, 2009
Neither Atlantic nor Pahokee was able to schedule a spring game, so it has been months since their players hit anyone else on another team. Couple that with the fact that Pahokee is opening a …
1:07 pm Jul. 31, 2009
Some rival fans laughed at Miami when the Hurricanes gambled by offering Pahokee safety Raheam Buxton, who saw little playing time last season, a scholarship in May. Apparently, Purdue and Tennessee did not think it …
1:14 pm Jul. 20, 2009
Pahokee senior Raheam Buxton's career with the Blue Devils has been marked by injury, ineligibility, immaturity, a major position change and a lot of time on the bench.
And now, before he has put together even …
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Macaroni & Cheese
Total Time
Prep 35 mins
Cook 25 mins
Mmmm...rich, cheesy, and comforting! I have successfully cut this recipe in half for my family of four and we still have leftovers, so the servings are quite generous.
Ingredients Nutrition
- 340.19 g elbow macaroni, uncooked
- 103.53 ml butter
- 88.74 ml flour
- 709.77 ml skim milk
- 7.39 ml salt
- 4.92 ml dry mustard
- 1.23 ml pepper
- 2.46 ml garlic powder
- 354.88 ml sharp cheddar cheese, shredded
- 354.88 ml swiss cheese, shredded
- Cook macaroni about 5 minutes and drain.
- Meanwhile, melt butter over medium heat in large saucepan.
- Whisk in flour and cook 1 minute.
- Gradually whisk in milk and add salt, mustard, garlic powder, and pepper.
- Cook, stirring constantly, until thicked and just beginning to boil.
- Reduce heat and simmer 5 minutes.
- Remove from heat.
- Add cheeses and stir until melted.
- Stir in macaroni and transfer to greased 2 1/2 quart casserole dish.
- Bake at 350 degrees for 25 minutes.
- Let stand 5 minutes before serving.
Most Helpful
I'm not a fan of the blue box stuff and have never made mac and cheese before so I decided to try this recipe(because of the picture!). I used gruyere cheese in place of the swiss(used what I had on hand) and that was the only change to the recipe. It was easy to make, rich, cheesy and delish! Thank you.
This was so good. Creamy and cheesy. I halved the recipe but put in a little extra dry mustard and a dash of tabasco just to spice it up a little. We loved it and will have it again. Gloria
This was excellent. At first I thought it was going to be too dry, but it turned out perfect. I love the flavor that the garlic powder and dry mustard gave it. Will be making this again. Thanks.


text:
Intelligun – Fingerprint Safety
Continuing with our opinions on choices to secure a firearm in a car, right this moment we regarded at the Safecase Biometric Safe Like the choices earlier than, the Lock State Gun Vault provides concealment, accessibility and security to your firearm in a car. It has a small finger pad on the entrance and a button to activate the finger pad.
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Biometric gun safes are identical to another secure on the market besides that they are opened by fingerprint recognition. Manufacturers understand that a gun proprietor may want their gun to be accessible to extra than just them in case of an emergency, so professional manufacturers program the safe to recognize a couple of set of fingerprints. These safes ensure that youngsters, intruders, and anybody else whose fingerprint is not in the protected cannot gain access to the gun even accidentally. Common Biometric Gun Protected Fashions
While most gun vaults up to now have been secured with keys or a move code, immediately you can purchase a biometrics gun protected. These subsequent generation biometric type safes give you the newest in expertise on the subject of gun safes. A few of the biometric gun secure choices available actually use each biometric locking measures in addition to a key or pass code. Varied traits or traits can be used to unlock these units, together with a retinal scan, facial recognition, signatures, fingerprints, and extra. Fingerprint Gun Protected


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Proven programming skills, including Perl or Python, R, and at least one compiled language. The Bioinformatics Data Scientist Developer will design, develop,...
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