text:
We investigated the effect of cardiac-targeting erythropoietin (EPO)-encapsulated liposomes with sialyl LewisX (SLX) on myocardial infarct (MI) size, left ventricular (LV) remodeling and function, and its molecular mechanism for repairing infarcted myocardium. In rabbits, MI was induced by 30 min of coronary occlusion followed by reperfusion. EPO-encapsulated liposomes with SLX (L-EPO group), EPO-encapsulated liposomes without SLX (L-EPO without SLX group), liposomes with SLX without EPO (L group), or saline (saline group) were intravenously administered immediately after MI. MI sizes and numbers of microvessels were assessed 14 days after MI. Prosurvival proteins and signals were assessed by Western blot analysis 2 and 14 days after MI. Confocal microscopy and electron microscopy showed the specific accumulation of liposomes with SLX in the infarcted myocardium. MI and cardiac fibrosis areas were significantly smaller in the L-EPO group than in the other groups. LV function and remodeling were improved in the L-EPO group. The number of CD31-positive microvessels was significantly greater in the L-EPO group than in the other groups. Higher expressions of EPO receptors, phosphorylated (p)Akt, pERK, pStat3, VEGF, Bcl-2, and promatrix metalloproteinase-1 were observed in the infarct area in the L-EPO group than in the other groups. EPO-encapsulated liposomes with SLX selectively accumulated in the infarct area, reduced MI size, and improved LV remodeling and function through activation of prosurvival signals and by exerting antifibrotic and angiogenic effects. EPO-encapsulated liposomes with SLX may be a promising strategy for active targeting treatment of acute MI.
- erythropoietin
- liposome
- Akt
- angiogenesis
- infarct size
recent studies (4, 28) have suggested that erythropoietin (EPO) exerts a cardioprotective effect in cases of acute myocardial infarction (MI). With systemic administration, however, the beneficial effects in the context of MI are observed when large doses of EPO are administered, which are frequently accompanied by polycythemia and, therefore, the potential for thromboembolic complications (2, 14). We (15) previously reported that a EPO-gelatin hydrogel patch applied to the heart, but not systemically administered EPO, reduced MI size and improved left ventricular (LV) remodeling and function. However, since this method needs a surgical approach, we developed a noninvasive cardiac-targeting drug delivery system to deliver EPO to the infarct zone. Thus, we aimed to determine whether post-MI treatment with EPO-encapsulated liposomes with siaryl-LewisX (SLX) reduces infarct size and improves LV remodeling and function and investigated the local molecular mechanisms underlying the beneficial effects of liposomal EPO.
All rabbits used in this study received humane care in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals (NIH Pub. No. 85-23, Revised 1996). The study protocol was approved by the Ethical Committee of Gifu University School of Medicine (Gifu, Japan).
Male Japanese White rabbits weighing ∼2.5 kg were anesthetized with an intravenous injection of ketamine (10 mg/kg) and zylazine (3 mg/kg), and additional doses were given when required throughout the experiment. Once anesthetized, animals were then intubated and ventilated with room air supplemented with a low flow of oxygen using a mechanical ventilator (tidal volume: 25–35 ml, respiratory rate: 20–30 breaths/min, model SN-480-5, Shimano, Tokyo, Japan). Serial blood gas analysis was performed, and ventilatory conditions were adjusted to maintain arterial blood gas within the physiological range. Surgery was performed under sterile conditions. The carotid artery and jugular veins were cannulated to monitor peripheral arterial pressure and administer drugs, respectively. Thereafter, rabbits were systemically heparinized (500 U/kg), a thoracotomy was performed in the left fourth intercostal space, and the heart was exposed after excision of the pericardium. A 4-0 silk suture on a small curved needle was passed through the myocardium beneath the middle segment of the large arterial branch coursing down the middle segment of the anterolateral surface of the LV. Both ends of the silk suture were then passed through a small vinyl tube, and the coronary branch was occluded by pulling the snare, which was fixed by clamping the tube with a mosquito hemostat. Myocardial ischemia was induced for 30 min. Myocardial ischemia was confirmed by S-T segment elevation on the ECG and regional cyanosis of the myocardial surface. Reperfusion was confirmed by myocardial blush over the risk area after release of the snare.
Preparation of liposomes with SLX, Cy5.5-encapsulated liposomes with SLX, and EPO-encapsulated liposomes with SLX.
Liposomes were made from a mixture of dipalmitoylphosphatidylcholine, cholesterol, dihexadecylphosphate, ganglioside, dipalmitoylphosphatidylethanolamine, and sodium cholate using the improved cholate dialysis method (41, 42). Cy5.5-encapsulated liposomes, in which Cy5.5 was bound to human serum albumin, were prepared as previously described by Hirai et al. (12). To prepare EPO-encapsulated liposomes, the lipid film was resuspended with 10 ml EPO (180,000 IU) solution, and the transparent micelle was generated by sonication. EPO-encapsulated liposomes were obtained after ultrafiltration of the micelle solution using a PM10 membrane (Millipore). Hydrophilization with Tris and SLX conjugation on the surface of liposomes were carried out as previously described (12). Finally, 5 ml of EPO-encapsulated liposomes with SLX solution contained 25,000 IU EPO (5,000 IU/ml). The final concentration of lipid in the liposomes encapsulating Cy5.5 or EPO was in the range of 2.5–3.1 mg/ml. Liposome particle size was measured using Zetasizer Nano-S90 (Malvern) at 25°C, and the mean particle size was ∼100 nm in diameter.
Accumulation of liposomes in infarcted cardiac tissues.
Rabbits underwent 30 min of coronary occlusion and reperfusion. Liposomes in which the fluorescent substance Cy5.5 were encapsulated (0.5 ml) were intravenously administered immediately after reperfusion. At 24 and 48 h and on 7 and 14 days after reperfusion, rabbits were euthanized under deep anesthesia, and their hearts were excised. Liposomes without SLX in which Cy5.5 was encapsulated were also intravenously administered immediately after reperfusion, and the heart was excised at 48 h of reperfusion. Hearts were immersed in iced PBS at <4°C immediately after death. Tissues (∼3 × 3 × 2 mm each) obtained from the risk area, including from the MI and from the nonrisk area of each heart, were embedded in OCT compound (Miles Scientific) and snap frozen in liquid nitrogen. OCT compound-embedded tissues were sectioned with 4 μm thickness using a cryostat for immunohistochemical analysis. Immunohistochemical staining was performed using Hoechst 33342 for nuclear staining with an indirect immunoperoxidase method; immunohistochemical stainings were performed using monoclonal anti-actin (α-sarcomeric) antibody (Sigma-Aldrich) at 1:500, which cross reacts with rabbit tissues. These were observed using confocal microscopy (LSM510 NLO, Zeiss, Tokyo, Japan).
Electron microscopy.
To trace the liposomes at the subcellular level in vivo, we used recently developed SLX-containing liposomes encapsulated with colloidal gold (SLX-Lipo-Gold) (21). The mean particle size of SLX-Lipo-Gold was estimated to be 135 nm, and it contained colloidal gold particles with a diameter of 8 nm (21).
Rabbits underwent 30 min of coronary occlusion and reperfusion. SLX-Lipo-Gold (500 μl) was intravenously administered immediately after reperfusion. At 48 h post-MI, rabbits were euthanized under deep anesthesia, and their hearts were excised. Cardiac tissue was quickly cut into 1-mm cubes, immersion fixed with 2.5% glutaraldehyde in 0.1 mol/l phosphate buffer (pH 7.4) overnight at 4°C, and postfixed in 1% buffered osmium tetroxide. Specimens were then dehydrated through a graded ethanol series and embedded in epoxy resin. Ultrathin sections (90 nm) double stained with uranyl acetate and lead citrate were examined under an electron microscope (H-800, Hitachi, Tokyo, Japan).
Measurement of cardiac tissue EPO content.
The amount of EPO in the cardiac tissue in the risk (infarct area and border area) and nonrisk areas at 48 h and 14 days after reperfusion was measured by ELISA (Mitsubishi Kagaku Bio-Chemical Laboratories, Tokyo, Japan).
In total, 105 rabbits were initially enrolled in this study: 45 rabbits for infarct size measurements at 14 days after infarction, 40 rabbits for Western blot analysis or immunohistochemical analysis at various periods of time, and 20 rabbits for the detection of accumulation of liposomes in the infarcted cardiac tissues using the fluorescent substance Cy5.5 and colloidal gold and for measurements of cardiac tissue EPO contents. In the 4 study groups used to measure infarct size at 14 days after infarction, 45 rabbits were initially enrolled and were subjected to 30 min of coronary occlusion followed by reperfusion, as shown in Fig. 1. Of these animals, five rabbits were excluded because of death during the experiments due to ventricular fibrillation during 30-min ischemia: two rabbits in the group that received saline treatment (saline group), one rabbit in the group that received liposomes with SLX without EPO (L group), one rabbit in the group that received EPO-encapsulated liposomes without SLX (L-EPO without SLX group), and one rabbit in the group that received EPO-encapsulated liposomes with SLX (L-EPO group). The remaining 40 rabbits survived for 14 days for the measurement of infarct size. In the saline group, saline (0.5 ml) was intravenously injected immediately after reperfusion. In the L group, liposomes with SLX encapsulating no EPO were intravenously injected immediately after reperfusion. In the L-EPO group, liposomes with SLX encapsulating 2,500 IU/kg EPO were intravenously injected immediately after reperfusion. In the L-EPO without SLX group, liposomes without SLX encapsulating 2,500 IU/kg EPO were intravenously injected immediately after reperfusion. Rabbits were killed at 5 h and 2 and 14 days after MI (n = 10 rabbits/group).
Blood sampling.
Blood samples (0.3 ml each) were collected from an ear vein before and 14 days after MI for peripheral blood cell counts using an automatic cell count analyzer (Sysmex XE-2100, Sysmex, Nagoya, Japan).
Physiological experiments.
Echocardiography (SSD2000, Aloka) was performed on 14 days post-MI, and ejection fraction, fractional shortening, and LV end-diastolic and end-systolic dimensions were obtained. Arterial blood pressure and heart rate were also measured via a catheter introduced into the carotid artery. A micromanometer-tipped catheter (SPR 407, Millar Instruments) was inserted into the LV to record ±dP/dt.
MI size and histological analysis.
To measure the risk area, excised hearts were mounted on a Langendorff apparatus, and Evans blue dye (4°C) was injected via the aorta for 1 min after reocclusion of the coronary branch. The LV was then weighed and sectioned into seven transverse slices parallel to the atrioventricular ring. Each slice was weighed, incubated in a 1% solution of 2,3,5-triphenyltetrazolium chloride (TTC) for 10 min at 37°C to visualize the infarct area, and photographed. The areas of the ischemic regions and the infarcted myocardium were traced on each LV slice, multiplied by the weight of the slice, and expressed as a percentage of the risk region or the LV. Each slice was then fixed in 10% buffered formalin for 4 h, embedded in paraffin, and cut into 4-μm-thick sections with a microtome. These sections were stained with hematoxylin-eosin and Masson trichrome. Since it is generally accepted that the Evans blue dye-TTC method is not reliable to evaluate infarct size at time points after 72 h of reperfusion because of remodeling due to scar shrinkage within the infarct, we further assessed the infarct size histologically. For transeversely sliced preparations with infarction at the level of papillary muscle, LV wall areas and Masson trichrome-positive areas were calculated using an image analyzer connected to a light microscope (LUZEX-F, NIRECO, Tokyo, Japan) and, the histological infarct size was then obtained by expressing the Masson trichrome-positive area as a percentage of LV wall area.
We used an indirect immunoperoxidase method for immunohistochemical staining of cardiac sections on day 14 post-MI. The primary antibody used was monoclonal mouse anti-human CD31, an endothelial cell marker (1:100 dilution, Dako), which cross reacts with rabbit tissues.
Western blot analysis.
Cardiac tissue samples for Western blot analysis were taken from the viable area close to the infarcted area in the ischemic area. The "border area" in this study was defined as the viable area close to the infarcted area in the ischemic area. Western blot analysis was carried out using lysates from heart tissues at 5 h and 2 and 14 days post-MI. Proteins were separated, transferred to membranes using standard protocols, and then probed with antibodies against the EPO receptor (EPOR) (E4644, Sigma), P-selectin (sc-6941, Santa Cruz Biotechnology), E-selectin (sc-6939, Santa Cruz Biotechnology), VEGF (RDI-VEGFabm-12, Fitzgerald), promatrix metalloproteinase-1 (pro-MMP-1; F-67, Daiichi Fine Chemical), tissue inhibitor of metalloproteinase-1 (TIMP-1; sc-6832, Santa Cruz Biotechnology), transforming growth factor-β (TGF-β; sc-65378, Santa Cruz Biotechnology), and Bcl-2 (sc-7382, Santa Cruz Biotechnology). Phosphorylation of Akt, ERK, and Stat3 was assessed using antibodies against Akt, phosphorylated (p)Akt, ERK, pERK, Stat3, and pStat3 (all from Cell Signaling). Blots were visualized by means of enhanced chemiluminescence (Amersham), and signals were quantified by densitometry. α-Tubulin (analyzed with an antibody from Santa Cruz Biotechnology) served as the loading control.
Statistical analysis.
All values are presented as means ± SE. Differences among the saline, L, L-EPO without SLX, and L-EPO groups were assessed by ANOVA combined with a Scheffé's method (Stat View, J5.0 software). P values of <0.05 were considered significant.
Cardiac accumulation of liposomes.
We observed that the fluorescent substance Cy5.5 accumulated not in the noninfarct area but in the border area of the myocardium at 24 and 48 h and 7 and 14 days after MI (Fig. 2A). There was no accumulation of Cy5.5 in the control myocardium. Cy5.5 was not observed in the myocardium in which liposomes without SLX were administered (Fig. 2B).
Electron microscopy.
We obtained detailed localization data of SLX-Lipo-Gold particles in the rabbit myocardium by examining colloidal gold signals in liposomes under an electron microscope. Colloidal gold particles were abundantly distributed in the cytoplasm of capillary endothelial cells and cardiomyocytes and in the extracellular space (Fig. 2C). In contrast, we could not find sufficient evidence of colloidal gold-containing liposomes without SLX (data not shown).
EPO levels in the heart.
The level of EPO in the infarct border area was significantly higher in the L-EPO group than in the saline group at 48 h after infarction but not at 14 days after MI (Fig. 3).
Peripheral blood cell count.
There were no differences among the groups in white blood cell, red blood cell, and thrombocyte counts or hematocrit before and 14 days after MI (Table 1).
Physiological experiments.
There were no significant differences in heart rate or systolic and diastolic blood pressures among the three groups at 14 days post-MI (Fig. 4A). LV end-systolic dimension (saline group: 16.6 ± 3.1 mm, L group: 15.8 ± 1.4 mm, and L-EPO group: 13.9 ± 1.7 mm) and LV end-diastolic dimension (saline group: 11.0 ± 2.2 mm, L group: 11.8 ± 0.5 mm, and L-EPO group: 9.3 ± 1.3 mm) were significantly smaller, whereas LV ejection fraction (saline group: 52.8 ± 4.9%, L group: 53.6 ± 3.7%, and L-EPO group: 61.2 ± 4.7%), fractional shortening (saline group: 23.7 ± 1.9%, L group: 26.1 ± 3.3%, and L-EPO group: 33.4 ± 4.9%), +dP/dt (saline group: 4,909.5 ± 530 mmHg/s, L group: 5,152.8 ± 259 mmHg/s, and L-EPO group: 5,763.9 ± 521 mmHg/s), and −dP/dt (saline group: −3,839.1 ± 651 mmHg/s, L group: −4,103.4 ± 366 mmHg/s, and L-EPO group: −4,539.3 ± 613 mmHg/s) were significantly larger in the L-EPO group than in the saline or L group (Fig. 4B).
MI size and histological analysis.
On day 14 post-MI, there were no significant differences in the area at risk as a percentage of LV among the saline (29.2 ± 4.3%), L (29.9 ± 6.0%), L-EPO without SLX (31.6 ± 6.2%), and L-EPO with SLX (31.8 ± 6.8%) groups (Fig. 5A,a). LV weights and volumes of nonrisk areas as a percentage of the LV were 4.7 ± 0.2, 4.4 ± 0.6, 4.3 ± 0.4, and 4.6 ± 0.7 g and 71.2 ± 4.6%, 70.1 ± 6.0%, 68.4 ± 2.4%, and 70.9 ± 4.7% in the saline, L, L-EPO without SLX, and L-EPO with SLX groups, respectively, and there were no significant differences among the groups. MI size as a percentage of the LV was significantly smaller in the L-EPO group (18.7 ± 3.7%) than in the saline (29.0 ± 5.4%), L (26.2 ± 3.3%), or L-EPO without SLX (24.6 ± 4.3%) groups (Fig. 5A,b). Histological assessment of MI size as a percentage of the LV as assessed by Masson trichrome staining was also significantly smaller in the L-EPO group (13.0 ± 6.4%) than in the saline (27.3 ± 8.4%), L (26.5 ± 4.8%), or L-EPO without SLX (19.3 ± 3.3%) groups (Fig. 5B).
Western blot analysis.
Western blot analysis revealed that myocardial expressions of E-selectin and P-selectin were both markedly upregulated in the ischemic area of myocardium in the L and L-EPO groups compared with those in the saline group at 5 h after MI (Fig. 6A). Myocardial expression of EPORs was markedly stronger in the L-EPO group than in the saline or L groups on day 2 post-MI (Fig. 6B). In the ischemic area, pAkt, pERK, and pStat3 were significantly higher in hearts from the L-EPO group than in those from the saline or L groups on day 2 post-MI (Fig. 6B). Expression of pro-MMP-1, VEGF, and Bcl-2 was upregulated in hearts from the L-EPO group but not in the saline or L groups on day 2 post-MI (Fig. 6B). On day 14 post-MI, expression of EPOR, pAkt, pERK, pro-MMP-1, and VEGF, but not pStat 3 or Bcl-2 (data are not shown), was significantly upregulated in the L-EPO group compared with the saline or L groups (Fig. 6C). There were no differences in the expression of TIMP-1 or TGF-β among the three groups.
On day 14 post-MI, the density of CD31-positive microvessels (capillary density) was clearly greater in the infarct border area in the L-EPO group than in the saline or L groups (Fig. 7). However, there were no differences in the densities of CD31-positive microvessels in the remote noninfarct area or in the infarct area among the three groups.
Active targeting of EPO-encapsulated liposomes with SLX.
Liposomes are usually used in cancer treatment for drug delivery to target specific organs to prevent the degradation of chemotherapy agents (6, 26, 35). These delivery systems deliver the drugs by controlling the distribution of liposomes by adjustment of particle size and the electric charge of the surface, i.e., a passive delivery system (7, 19, 37). In contrast, it has been reported that the specific recognition and binding between selectin and the sugar chain convey an active targeting ability to liposomes (40, 43). In the inflamed region, E-selectin and P-selectin are expressed on the cell surface of vascular endothelial cells. On the surface of leucocytes, the sugar chain called SLX is present and can bind with E-selectin and P-selectin, and leucocytes roll on the vascular endothelial cell and thus accumulate specifically in the inflamed region (3, 36). Since inflammation occurs in the MI region, the application of liposomes with SLX for MI will specifically and efficiently deliver substances to inflamed regions. As a matter of fact, in the present study, as shown in Fig. 6A, the expression of E-selectin and P-selectin was upregulated in the infarct area of the myocardium at 5 h after MI. Furthermore, as shown in Fig. 2, A and B, although Cy5.5-encapsulated liposomes without SLX did not accumulated in the infarct border area, Cy5.5-encapsulated liposomes with SLX accumulated in the infarct border areas of the myocardium as long as 14 days after MI. However, the accumulation of Cy5.5 in the infarcted myocardium only shows that EPO-encapsulated liposomes with SLX reached the infarcted myocardium and does not necessarily mean that EPO was released from the liposome as long as 14 days after MI. As a matter of fact, the cardiac tissue level of EPO in the border area was significantly higher in the L-EPO group than in the saline group at 48 h after MI, but there were no differences in cardiac tissue levels of EPO between the groups 14 days after MI. This suggests that EPO will be gradually released from the liposome as long as 48 h but not as long as 14 days after MI.
The diameter of the liposomes was ∼100 nm, and this size of liposomes can pass through microvessels. SLX on the surface of liposomes combines with E-selectin and P-selectin expressed on vascular endothelial cells in the infarct areas of myocardium; liposomes then accumulate into infarct areas of the myocardium. In the present study, electron microscopy revealed that colloidal gold particles were abundantly distributed in the cytoplasm of capillary endothelial cells and cardiomyocytes and in the extracellular space, as shown in Fig. 2C. These findings indicate that some liposomes may be incorporated by endothelial cells and are then extravasated and reach the myocardium. Furthermore, since the level of EPO in the MI border area was significantly higher in the L-EPO group than in the saline group, as shown in Fig. 3, our results suggest that liposomes with SLX can deliver EPO selectively to the local infarct areas of the myocardium. Furthermore, since the liposome with SLX is made of phospholipids, after incorporation into tissues, it is considered to eliminate through the metabolism system of lipids.
Effect on MI size and LV remodeling and function.
There have been some reports (4, 8, 22, 27) showing that systemic pre- and postischemic treatment with EPO has a cardioprotective effect, such as a MI size-reducing effect in rats, and others (16, 24) have reported that EPO administered at reperfusion did not show any MI size-reducing effect in sheep and pigs. In rabbits, Parsa et al. (28) reported that EPO administered even at the time of reperfusion at doses of 1,000 and 5,000 IU/kg significantly reduced MI size, although cardiac function was not improved. However, we (15) have previously reported that EPO intravenously administered immediately after reperfusion at a dose of 1,500 IU/kg for 5 days (7,500 IU/kg in total) did not reduce MI size but that an EPO-gelatin hydrogel patch containing only 1,500 IU/kg EPO applied to the surface of the ischemic area of the heart (1/5 of the dose administered for systemic EPO treatment) significantly reduced MI size 14 days after MI. LV end-systolic and end-diastolic dimensions were significantly smaller, whereas LV ejection fraction, fractional shortening, and ±dP/dt were significantly larger in the EPO-gelatin hydrogel patch group than in the saline group (15). These data suggest that the application of a locally high concentration of EPO in the heart is needed to achieve a sufficient cardioprotective effect of EPO.
In the present study, 1 ml of liposome with SLX, which contains 5,000 IU EPO (∼2,000 IU/kg EPO), administered intravenously immediately after reperfusion significantly reduced MI size compared with that in the saline, L, or L-EPO without SLX groups (Fig. 5). Since it has been reported that SLX itself has cardioprotective effects against ischemia and reperfusion injury and reduces myocardial infarct size (5, 33), we examined the effect of liposome with SLX (L group) on MI size. As a result, in the present study, liposomes with SLX without EPO did not significantly reduce MI size. LV ejection fraction, fractional shortening, and ±dP/dt were significantly larger in the L-EPO group than in the saline or L groups. LV end-diastolic and LV end-systolic dimensions were significantly smaller in the L-EPO group than in the saline or L groups. These data suggest that post-MI treatment with EPO-encapsulated liposomes with SLX reduces MI size and improves LV remodeling and function. As a matter of fact, the infarct size-reducing effect of EPO-encapsulated liposomes with SLX was significantly greater than that of EPO-encapsulated liposomes without SLX. This may be explained by the results of a previous report (5) showing that the accumulation of Cy5.5-containing liposomes with sugar chain SLX to inflammation or tumor regions was significantly higher than control Cy5.5-containing liposomes without SLX at 24 and 48 h after administration. Therefore, EPO-encapsulated liposomes with SLX constitute an active cardiac-targeting noninvasive drug delivery system.
Expression of EPORs and their downstream signal transduction.
It has been previously reported that EPORs are expressed in the heart (33). Our Western blot analysis confirmed those earlier findings and further showed that application of an EPO-encapsulated liposome with SLX significantly upregulated cardiac expression of EPORs (Fig. 6, A and B). We (12, 25, 38) have previously reported an upregulation of EPORs in the heart by treatment with EPO, which we again confirmed in the present study. Although the mechanism for the upregulation of EPORs is unknown, a recent study (17) has revealed a positive feedback loop between EPO and EPORs through GATA-1 activation.
Phosphatidylinositol 3-kinase/Akt, MAPK/ERK, and JAK-STAT are all known to be downstream mediators of EPOR signaling in cardiac cells, both in vitro and in vivo (28). Moreover, activation of Akt, ERK, and Stat3, which mediate prosurvival signaling, was upregulated in ischemic areas of hearts in the L-EPO group but not in the saline or L groups. This suggests that EPO delivered by liposomes stimulated EPORs and their downstream signal transduction.
We observed significant phosphorylation of Stat3, Akt, and ERK in the ischemic myocardium on day 2 post-MI in the L-EPO group. The JAK-STAT pathway has been reported to play an important role in ischemic preconditioning, thereby reducing ischemic damage to the heart (18). Activation of Akt has also been reported to play an important role in ischemic preconditioning, thereby reducing MI size (25). Ischemic postconditioning is also a cardioprotective mechanism (39), which is mediated by Akt and ERK signaling (10). As mentioned above, Stat3, Akt, and ERK are all prosurvival signals. In the present study, on day 2 post-MI, Stat3, Akt and ERK were all activated in the ischemic area of the myocardium, and these prosurvival signals may have contributed to the cardioprotective effects. On day 14 post-MI, Akt and ERK were still activated, but Stat3 was not. These findings suggest that activation of Stat3 may play a role only in the early phase post-MI but that activation of Akt and ERK lasts as long as 14 days post-MI, as previously reported (15).
EPO has been reported to stimulate neovascularization (44). In the present study, myocardial expression of VEGF was upregulated and the density of CD31-positive microvessels was increased in the L-EPO group. VEGF is known to increase capillary density (11, 34), and the EPOR system reportedly plays an important role in angiogenesis in response to hindlimb ischemia through upregulation of the VEGF/VEGF receptor system in mice (31). In the present study, expression of Bcl-2 was upregulated in the ischemic area of the myocardium in the L-EPO group on day 2 post-MI. This suggests that the expression of Bcl-2 may play a role in the early phase after MI. However, since there were no differences in the number of TUNEL-positive myocytes among the groups (data are not shown), Bcl-2 may have acted as an antioxidant and protected against necrosis (1).
On day 14 post-MI, MI size and LV systolic and diastolic dimensions were all smaller in the L-EPO group than in the saline or L groups. The fibrotic areas, as assessed by Masson trichrome staining within the infarct area, were smaller in the L-EPO group than in the saline or L groups. The progression of tissue remodeling after MI depends on the balance between antifibrotic and fibrotic factors. There were no differences in the expression of TIMP-1 or TGF-β fibrotic factors among three groups. However, expression of the collagenase MMP-1, an antifibrotic factor, was upregulated in the infarct border zone in the L-EPO group at 2 and 14 days post-MI. In post-MI heart failure models in which MMPs are typically upregulated, MMP inhibitors have been reported to exert beneficial effects on both cardiac structure and function (9, 23, 29). On the other hand, the volume of reactive granulation and/or scar tissue after skin injury, burn, or surgery frequently becomes excessive, resulting in hypertrophic scarring. In the heart, excessive fibrosis accelerates cardiac remodeling and deteriorates cardiac function, as seen in ischemic and dilated cardiomyopathies. In such cases, an increase in MMP expression may exert a protective effect via proteolysis of excessive collagen. Consistent with this idea, a post-MI increase in MMP-1 induced by hepatocyte growth factor exerted a beneficial effect on the heart via its antifibrotic action (32), and an increase in MMP-1 induced by granulocyte colony-stimulating factor reduced the size of fibrotic areas in MI hearts (20, 30). Furthermore, mice with cardiomyocyte-restricted deletion of Stat3 are reportedly susceptible to inflammation-induced heart damage and show a dramatic increase in cardiac fibrosis (13). Thus, activation of MMP-1 and Stat3 in the L-EPO group may be involved in the reduction in myocardial fibrosis, resulting in improved LV function.
EPO-encapsulated liposomes with SLX reduced MI size and improved LV remodeling and function through the activation of Akt, ERK, and Stat3, by exerting antifibrotic effects through the activation of MMP-1 and Stat3, and by angiogenic effects through the activation of VEGF. EPO-encapsulated liposomes with SLX may be a promising strategy for active cardiac-targeting treatment of acute MI.
This work was supported by a grant from the Gifu University Graduate School of Medicine (to S. Minatoguchi) and by a grant from Fukuda Foundation for Medical Technology (to S. Minatoguchi).
No conflicts of interest, financial or otherwise, are declared by the author(s).
Author contributions: Y.Y., T.F., M.K., and S.M. conception and design of research; Y.Y., H.K., M.I., S.S., T.F., and M.K. performed experiments; Y.Y., H.K., M.I., S.S., H.U., T.A., K.N., T.F., and M.K. analyzed data; Y.Y., H.K., M.I., S.S., H.U., T.A., K.N., and T.F. interpreted results of experiments; Y.Y., H.K., S.S., H.U., T.A., K.N., G.T., and H.F. prepared figures; Y.Y., G.T., and H.F. drafted manuscript; Y.Y., G.T., H.F., and S.M. edited and revised manuscript; S.M. approved final version of manuscript.
The authors thank Akiko Tsujimoto and Tosie Otsubo for technical assistance.
- Copyright © 2013 the American Physiological Society


text:
Fathiya Isamii
Last quote by Fathiya Isamii
Dec 05 2016 Refugees
This page is completely dedicated to what Fathiya Isamii has to say. All of Fathiya Isamii's quotes are organized here by date and topic. The most recent quote attributed to Fathiya Isamii came from an article called UN refugee agency hands out aid to those uprooted from Mosul: "We just want you to push them out.".
Take our quote verification challenge and find out !
Quotes by Fathiya Isamii
Dec 05 2016
We just want you to push them out.feedback
Previous : Fathi Sheikh Khalil
Next : Fathy Mhareb>
Quote Verifier
Check if the quote you read on social networks is authentic
This webpage has been created by a robot: errors and absent quotes cannot be totally avoided

subset: commoncrawl


text:
Capstone / Coughlan Pub - First Aid Basics
Have you ever scraped a knee or been stung by a bee? Maybe mom or dad gave you first aid to help. Learn how First Aid Basics help people before they can see a doctor.
Old Browser Detected
We have detected you are using a browser that is not supported by this site. You may continue to browse, however, you may notice some performance issues with the site.
For a complete experience, please upgrade to one of the following browsers:
Troubleshooting Dialog
Unless asked specificly to view this box, you can disregard everything in here.


text:
talent marketing
Mindcor's long-term strategy is to engage with senior candidates outside of specific briefs. This provides us access to a large pool of candidates who have indicated that they are willing to explore new employment opportunities.
Our focus in building strategic, long-term relationships means we also understand the strategies and associated talent requirements of our clients. Through this understanding, we can easily identify those talented senior and executive individuals who would be attractive to our clients looking to hire the best talent in order to build great businesses.
We at Mindcor know that our clients are willing to meet with top calibre candidates outside of any immediate vacancy, a reflection of the reality that many leading organisations are on the constant lookout for exceptional talent. We meet many experienced and talented candidates every day in the course of our work. This combined with our in-depth understanding of the kind of people that could add value to our clients results in us offering an introduction of the candidate to the client should a potential match arise.
We acknowledge that time is of equal value to our clients and candidates alike. This means that we will only seek to initiate an introduction once we have a clear understanding of both the client and the candidate, including their needs and desires, in order to ensure that it will be a mutually beneficial match.
To guarantee that only the best talent gets marketed, candidates are only identified as high potential once they have been thoroughly interviewed against a generic set of executive competencies. In the event that a client expresses interest in a particular candidate, we can further explore their match by assessing them against the specific competencies for the role or organisation.
We facilitate the process in order to ensure that all the expected verifications, including competency-based references, credit rating, criminal record, and qualifications, has been conducted. It is only in the event that a client's recruitment needs have been successfully met that a placement fee would become payable.


text:
15 € voucher15€ Off orders exceeding at least 300€
Would you like to search for an alternative product?
Search for "Bieco Pull-along duck".
You will see an automatic translation
of the product description.
A great gift for little beginners or toddlers!
The sweet duck accompanied and everywhere your little treasure. Merry she watched your world discoverer, because thanks to the cord the cheerful duck can be drawn.
Make your offspring a delight!
Product details:
This product has been unfortunately not yet rated in your language.
Be the first to rate this product
© 2017 by kidsroom.de GmbH & Co. KG | Baby and children products - worldwide shipping
Only sold for private use.* excl. VAT and shipping


text:
Darcy is an adorable teddy bear of a 3 year old Great Pyrenees. Weighing in at 63 lbs., this fluffy girl appears larger than she actually is.
A New Chance Animal Rescue, Inc. P.O. Box 215 Bedford Hills, NY 10507 (914) 205-7066 firstname.lastname@example.com
Copyright © 2017 Site by Graphics For Good


text: I tried to manually update to 2.1. It didn't work, even though when I look at settings, about phone, it says 2.1 update. But it's not 2.1. It has the same interface as 2.0. Ok, when I go into recovery mode there is an error at the bottom of the screen. It reads E:can't open /cache/recovery/command.I only have 4 options at the top of the screen, reboot system now, apply sdcard update.zip, wipe data/ factory reset, and wipe cache partition. Now I have reset the phone to the factory cond. twice, it still says 2.1 update. I did root it 2-3 weeks ago, but I put it back to default due to the ota update. It went back to 2.01 no problem. I can't do that now. I do know that when I rooted it I had more options in the recover mode. I don't have them now. Can anyone help me with this? Thanks


text:
Status: Closed
Know more about this business than we do? Cool! Please submit any corrections or missing details you may have.Help us make it right
Be the first YellowBot user to add photos or videos of Bumble Beads
When I see a piece of jewelry that I like, my first insinct is to ask myself "can I make that?" I recently got inspired when watching an episode of Pretty Little Liars. The earrings I noticed on the…
Bumble Beads has a great selection of beads, chain and other items for jewelry design. They also offer great classes with patient and informative instructors. Location wise, they are right on…
Bumble Beads opened in 2004. This store offers beading and stringing supplies as well as beading classes. You can stop in and make your own piece of jewelry with a huge variety of beads. If you are shy or unsure, the friendly staff here offers free in-store demos. Bumble Beads also hosts beading parties for children or adults.
If you don't see your business listed on YellowBot, please add your business listing.
YellowBot wants to get your input! If you have a comment, find a bug or think of something neat we should do, let us know by emailing us.
© 2007-2017 Solfo, Inc. – All rights reserved


text:
A Wartrukk is an Ork vehicle primarily used for transporting Orks across the battlefield at breakneck speeds. Because Orks don't really have much of a concept of personal space, Wartrukks are often piled with as many Orks as won't fall off, if even that. Sometimes they have runners mounted on the sides of the Trukk so more greenskins can cling on to the sides and get stuck in faster. Some of the more intelligent Orks wait for the Trukk to slow down some before jumping off said runners. Wartrukks are usually armed with Big Shootas on the front, as well as some rather spikey bullbars so the drivers don't miss the thrill of close combat. The Wartrukk serves well to be launched into battle guns blazing, to unload a heap of greenskins into the fray. Because of Ork inventiveness and little in the way of standardization, no two Wartrukks ever look quite the same.[1][2a]
Wartrukks are built for speed and speed alone, and usually have little in the way of armor plating.[2c]
- 1: Codex: Orks (3rd Edition), pg. 13
- 2: Codex: Orks (4th Edition)
- 2a: pg. 41
- 2b: pg. 93
- 2c: [Needs Citation]
- 3: GW Website Wartrukk
- 4: Warhammer 40,000: Dawn of War II - Retribution
- 5: Freebooterz: Space Ork Army Lists, pg. 42
- 6: Warhammer 40,000: Dawn of War
|Light Vehicles
|Warbike • Warbuggy • Wartrakk • Wartrakk Skorcha • Grot Bomb Launcha • Trukk • Big Trakk
|Grot Tank • Grot Mega Tank • Looted Wagon • Mekboy Junka • Battlewagon • Gunwagon • Bonebreaka • Braincrusha • Bonecruncha • Gutrippa • Spleenrippa
|Killa Kan • Deff Dread • Mega Dread • Meka Dread • Gorkanaut • Morkanaut
|Super-Heavy Vehicles
|Kill Blasta • Kill Bursta • Kill Krusha • Battlefortress • Gunfortress
|Super-Heavy Walkers
|Stompa • Supa-Stompa • Gargant • Steam Gargant • Mekboy Gargant • Great Gargant • Mega Gargant
|Big Guns • Soopa Guns • Squig Katapult • Pulsa Rokkit
|Deffkopta • Warkopta • Fighta • Dakkajet • Burna-Bommer • Blitza-Bommer
Fighta-Bommer • Wazbom Blastajet • Heavy Bommer • Minelayer • Landa • Other
|Beasts of War
|Squig • Squiggoth • Gargantuan Squiggoth • Orkeosaurus


text:
French far-right leader won't repay $321k in misused funds to European Parliament
France's leading ultra-right politician and presidential hopeful Marine Le Pen has refused to return some 298,000 euros (321,300 dollars) in misused funds to the European Parliament, ignoring her repayment deadline.
The European Parliament has been trying to recover a total of 340,000 euros (366,600 dollars) from Le Pen — who is a member of the legislative body — charging that two of her parliamentary aides worked for her National Front Party back in France while they were supposed to be at the Parliament's headquarters in Brussels.
In an initial letter to Le Pen, the Parliament demanded the repayment by January 31 of 298,497 euros for wages paid to her legislative assistant Catherine Griset from December 2010 to February 2016.
In a second letter to Le Pen, the parliament sought to recover by February 28 an additional 41,554 euros (44,200 dollars) for salary paid to her bodyguard.
The initial letter came after European Anti-Fraud Office (OLAF) revealed in a report last year that while Griset's contract stipulated that her workplace be the Parliament's headquarters in Brussels, she had been "unable to prove that she continually resided in Belgium" or that she was "regularly present at her place of work."
OLAF also took note of the fact that Griset held a "recognized position" at Le Pen's party headquarters in the suburbs of Paris during the time she was supposed to work as a legislative aide at the Parliament's head office in Brussels.
Read more:
Meanwhile, Le Pen could see her salary cut in half by the Parliament if she failed to comply with its demand to pay back the misappropriated funds, according to sources cited by French media.
Le Pen has challenged the Parliament's reimbursement demand as a "unilateral and illegal decision," denying any wrongdoing.
Her attorney censured the repayment order last October as a "political maneuver" to "undercut Marine Le Pen's work at the European Parliament."
The far-right leader hopes to win France's presidential race this spring on a platform of opposing France's membership in the European Union.


text:
I'd say Dems work for their money and Republicans wait for welfare. Corprate welfare. Games up. No more free money. Get a job.
You allmost got it Civet. it goes like this. The dems work very hard to get their hands on the money of others so they can give it away on welfare. The only free money appeares to be ours and I have a job thanks. Get a life or better yet an education in life. It's easy, pull your head of out your Marx and look around.


text:
Dinehart-Holt House Rental Rates
Dinehart-Holt House Rental
The Dinehart-Holt House is available for special occasions such as weddings, anniversaries, bridal and baby showers, groom's dinners, birthdays, graduations, reunions, luncheons, tea parties, club meetings, recitals, etc… The house is listed on the National Register of Historic places, so some restrictions will apply.
Kitchen facilities are available for use if needed; you must furnish your own dishes and utensils. Chairs are available for up to fifty guests.
A damage deposit of $150 is required at the time of reservation to be refunded after the event. No alcohol is allowed unless provided through a licensed caterer.
Call 836-6533 for details.
Rental Rates for the Dinehart-Holt House:
Up to 25 guests $50.00
25 to 50 guests $75.00
50 to 100 guests $100.00


text:
It's weird to praise a hitter who is still hitting below .200, but Alex Avila deserves it.
Hitting .250 in July and .310 since the All-Star Break, the Detroit Tigers catcher is also hitting .500 with men in scoring position and is now tied with Miguel Cabrera with 17 RBIs for the month. That's not even bringing up the two home runs he has hit in the last two days, one of which was a majestic grand slam off Stephen Strasburg that may still be circling around Detroit.
You know you are always going to get solid defense and smart game-calling from Avila. Pitchers love having him behind the plate and they easily can find a rhythm with the 26-year-old, making him the preferred catcher of every pitcher on the roster.
However the bat had been so bad that it overshadowed the defense. Fans were beginning to wonder if a randomly-selected ticket-holder would be better off having a go in Avila's spot in the batting order rather than see him swing and miss at three pitches in the dirt. That's all changed now.
Avila is clearly confident at the plate now; he is taking balls and swinging at strikes. While that seems simple, it's easy for a batter to take themselves out of balance and out of at-bats mentally when they're in a slump. Avila is guessing correctly now and getting himself in counts where he can sit back and wait for fastballs, which he has always had a great ability at getting in front of and crushing.
With his hitting of late, it's no wonder why the Tigers have been one of the hottest teams in baseball since the All-Star break. If he continues to keep hitting like he is, the Tigers have to like their chances of playing deep into October again this season.


text:
Receive a direct teaching from the Holy Spirit, uniquely personal for you. An everlasting grace and individual blessing flows directly into your soul!
Restore your vitality, clear energetic imbalances and relieve your stressors!
More >
Spirituality 4 Kids:
Discover the Real You! eBook
Sign up for our newsletter and receive our FREE ebook, Pray, Sing, Dance and Play with Us.
Welcome! I'm Rev. Donna Korth, and I'd like to give you a warm Hearts Center welcome to our Heartfriend Wisdom Blog!
If you would like to give a presentation or submit an original article on spiritual, health, "green" or gardening topics please email email@example.com or call Donna Korth at 903.885.2495.
We look forward to hearing from you!
David Christopher Lewis
Soft cover, 258 pages; includes 16 beautiful color plates from French-Canadian visionary artist Mario Duguay and practical meditation exercises.
Buy now!
This important new book offers a unique understanding of the power of a radiant aura. It shows us that to create an effulgent, rainbow-colored energy field—supercharged with light and spiritual purpose—we must first enter into the space of being where all life is felt and embraced as sacred. We must focus on body, mind and spirit—and on the truth that, at our essence, we are dynamic spiritual beings.
Buy now!
Archive of Database of Heartfriend Presentations
Prayers and Songs
Media Center
Broadcast Replays
Broadcast Calendar
Ascended Master Wisdom
Heartfriend Wisdom
Landmark and Featured HeartStreams
HeartShare Teleclasses
Foundational Teachings
Violet Laser Light
Understanding the Human Aura
Ascended Master El Morya
Sun Yoga, Sun Gazing
The Seven Chakras
Meru Univerity
About Our Courses
Current Course
Hearts Center Store
Featured Store Products
The Benefits of Meditation
Meditation 101
Ways to DonateCall our help desk: 630-894-4410Contact The Hearts CenterPrayer RequestHearts Centers Worldwide
Follow us on Social Media!


text:
|21 Mar 2010
Lenovo Z60m issue no sound (already tried work-around)
Hi there
I downloaded the SoundMax driver version 6.xxx which was recommended HERE but I have a slight problem.
I am running Home Premium OEM for the Japanese market. Now while I can read Japanese fine the issue I've encountered is that the Device Manager set up is actually different from the US version. I eventually found screen shots of the US walk through for using Device Manager and confirmed that things are actually located in different spots on the menus and whatnot.
So I am not confident that what I'm trying to do exactly mirrors the process outlined in the above-quoted post, although it should be the same...
That being said, I managed to find a way to 'update driver', however, in the recommended file I downloaded HERE I could not find the file named ADIHdAud.inf so I was not able to specify it when updating the driver. All in all I just couldn't get the work around noted above to work for me.
Simply using setup.exe also failed, as it did not find my speakers or SoundMax equipment.
Can anyone here possible supply me with the necessary driver ADIHdAud.inf and/or point out where it is in the zip file I downloaded, and could someone possibly give me an alternative or slightly more detailed walk through for installing it?
Thanks very much
Edit: Here's a photo of what I'm talking about
If its too small to see here's the link:
|My System Specs
|Thread Tools
|Similar help and support threads
Lenovo, windows 7 64, no sound
Hello, I see many similar threads here but no one helps me to solve an issue with sound on my desktop computer Lenovo with 64 bit windows 7 OS. In Device Manager under Sound, video and game controllers I have listed Realtek High Definition Audio and under properties of that message "This device...
|Sound & Audio
Lenovo g500 Windows 7 sound does not work.
Aslam O Alaikum, Friends, I am facing very strange problem with my laptop. I have lenovo g500 with Windows 7 installed in it. I am facing trouble with sound of this system. When I starts my Machine some times sound stops working. To get sound back I used to uninstall sound drivers and...
|Hardware & Devices
lenovo y460p touchpad sound and sound does not work
hello i wanted to report a problem i have on my PC regarding the sound..there is no sound without the headphones and my touchpad sound buttons do not work it has been a month already i tried downloading realtek drivers from this site it does not work again..i can only hear sound with my...
|Sound & Audio
IBM z60m No sound?
Hello! After searching the forums, I can see other's with the same issue, however no fix posted? Does anyone know why my IBM z60m has no sound after a clean install of Windows 7? I had sound before? Now I have nothing, not even with external speakers or headphones. When I go to the device...
|Sound & Audio
Lenovo Z60m
Okie, while I go off and search for answers, I'll pose this one,.. I installed build 7100 on my Lenovo Thinkpad Z60m last night, ran windows update, all the hardware seems to be found okay, but for some reason the audio side of things is seeing the laptop as having S/Pdif audio, which it...
|Hardware & Devices
Sound problems with Lenovo
i recently upgraded to Windows 7 and it says that there is no audio playback devices installed i tried installing drivers already, troubleshooting, and uninstalling then reinstalling the driver to no avail someone please help it would be highly appreciated
|Sound & Audio
|Our Sites
|Site Links
|About Us
|Find Us
Windows 7 Forums is an independent web site and has not been authorized, sponsored, or otherwise approved by Microsoft Corporation. "Windows 7" and related materials are trademarks of Microsoft Corp.
© Designer Media Ltd
All times are GMT -5. The time now is 07:49.


text:
Vinayak Kumar
Associate Editor
Born in New Delhi, India, but raised in Brooklyn and New Jersey, Vinayak is a freshman in Wharton majoring in Finance and Physics in the college. His interest in law grew from learning about law and policy as a Lincoln Douglas and Policy debater in high school. In addition to being involved with PULJ, he is a Teller for SFCU, an ITA, and in the Global Macro division of WITG. In his free time, he enjoys reading philosophy books and playing blues guitar.


text:
Auto companies are flocking to the Iran Auto Industry International Conference that will be held on November 30, 2013, according to the head of the Iranian auto-parts manufacturers association, Sasan Ghorbani. He said that visas will be made available to participants to meet a spike in demand following a recent Geneva agreement that eased trade restrictions on Iran.
With the lifting of the sanctions, companies eyeing the Iranian auto industry have started signing up for the Saturday conference, including Frenc carmaker Renault SA and Italian group Pininfarina SpA, as listed in the event's Web site.
The participation of these companies brings the promise of investment into the Iranian economy that has been experiencing recession due to sanctions. Their arrival could also add to the post-Geneva optimism evident by the recent rise in the value of the Iranian rial since the accord was signed.
The agreement, which could be replaced with a final deal in six months, will lift some trade sanctions on Iran while restricting the country's nuclear program. This paves way for global companies to penetrate Iran, which has around 77 million people.
According to the United States, the agreement will result to $7 billion in benefits over six months for Iran, which is equal to around 2.7 percent of the Middle East country's output in the period based on World Bank data.
The amount includes $1.5 billion in revenue from the suspension of sanctions on industries like autos and petrochemicals. Since the agreement was signed Nov. 24, the Iranian rial has appreciated almost 4 percent against the US dollar in the unregulated market, according to five money changers interviewed by Bloomberg in Tehran.


text:
There are no items in your cart at this time.
Select your desired product options and we will notify you when it is back in stock.
Finn Comfort shoes are one of the leading comfort footwear manufacturers. With their extraordinary orthopedic support and luxurious comfort they are the perfect balance for any occasion. Finn Comfort shoes are hand-made and promote good health and well being.
Features include:
Sign up to receive new arrival, sale & special event info from us.
Note: we do not share your personal information with anyone. Period.
"So happy with your customer service and the help they have provided me in helping me both order and return items."
©2017 Footwear etc.. All Rights Reserved. For any questions or assistance call 1-800-720-0572.


text:
A modern business intelligence approach can propel your company forward with unparalleled speed and accuracy. Your Start-to-Finish Guide to Implementing Vital Business Intelligence Strategies is a blueprint for successful BI planning and execution.
Smart clients
Smart's personal approach will help you find IT talent.
Smart candidates
Work with Richmond's Best.
Our Story
We opened Smart Resources for one reason…to propel what's possible for business when great people meet technology.
learn more
"I've been working with some of the same consultants for more than eight years now. They really enable me to focus on and deliver more dedicated strategy for our business."
Group Vice President
"Working with Smart has been a really positive experience. They don't act like a contracting firm; they are like an employer. They have great benefits and are very engaged with their employees. They do an excellent job keeping in touch and reaching out, not to mention their awesome collaborative events like monthly lunches, painting nights and more! "
SMART Resources Employee
"Smart is a partner, not a vendor. I've continued to work with them as I've moved in my career because the quality of their resources and the depth to which they go to look for them is incomparable."
Regional Data Warehouse Manager
We're as passionate about technology as you are. And we're also all about people. We work diligently to match you with the perfect opportunity.


text:
You have Adblock enabled. Adblock has been known to cause issues with site functionality. If you experience any difficulties, please try disabling Adblock. Close
Add to Favorite List:
Create a new folder:
Awesome busty babe shows off sexy body
Recognize a pornstar in this video?
Help make pornstars easier to find on Tube8 by telling us who is in this video.
Thanks! The pornstar names will be added to this video when enough users submit the same names.
You must enter a pornstar name that already exists in our database.
- Category: Amateur
- Views: 9,473
- Added: 5 years ago
- Description: Super sexy amateur teen babe with awesome natural big tits flashes her awesome boobs and ass in a public place.
- Tags: public flashing pov european hardcore shaved teen
- Pornstars: Add Pornstar
- Favorite by: 2
- Report This Video
Video Comments
All Video Comments (0)
Video Results For:
Sort by:
Sorry, we couldn't find any pages containing
Watch some of our most popular Tube8.com porn videos: Homepage or Category page


text: Sparc & Experiment1 - The New Tingz [OUT NOW ON DANK N' DIRTY DUBZ] by SPARC published on 2011-09-28T15:15:51Z After a year of quality releases, Dank 'N' Dirty Dubz is celebrating its 1 year anniversary with a massive 18 track compilation focusing on the deeper, darker, and melodic side of bass music. This release showcases a wide variety of bass-heavy sounds by some brand new up and comers as well as some long-time veterans. Prepare yourselves for for an amazing journey. Previews from the compilation will be uploaded periodically, so keep an eye on this set for the latest updates! To help promote this release, we will be giving out 7 Free Downloads between now and the day of the release! Please be sure to spread the word about this massive project and support the release when it hits all online stores on December 30th, 2011. BIG UP TO ALL THE SUPPORTERS!!! Artwork by Ashleigh's Abstractions. http://www.facebook.com/AshleighsAbstractions Mastered by DUBTHUGZ www.dubthugz.com Genre Dubstep Comment by Vital Subsistence pretty. :) 2015/03/20 16:31:29 +0000 Comment by Antoine Olivier Dion Really awesome, i'm out of words... 2013/08/25 22:52:21 +0000 Comment by therealmonky proper nice flowing track!!! 2012/05/19 13:45:56 +0000 Comment by CHOPBOX yeah this is noice 2012/03/20 08:00:20 +0000 Comment by Terris So beautiful. big ups man 2012/02/21 05:21:56 +0000 Comment by onetwo4 fatter than a gravy chuggin lumpkin 2011/12/05 22:50:30 +0000 Comment by Ted-E such an amazing tune!! can't stop listening to this one 2011/12/05 22:18:10 +0000 Comment by Neurotic Noise Official Good work Bristol, greetings. 2011/11/30 21:39:42 +0000 Comment by Neurotic Noise Official Good synyh, is very nice!! :D 2011/11/30 21:39:23 +0000 Comment by SPARC @pilot-48: haha 2011/11/13 10:22:13 +0000 Comment by SPARC SUBSTEP find more deep tunes like this from myself @ http://www.soundcloud.com/sparcsubstep 2011/11/10 18:02:37 +0000 Comment by astrochimp1 very dreamy dubz m8s, drifty, like the melody of the synth 2011/10/29 17:20:25 +0000 Comment by Alexander Cabrera BOOM! 2011/10/22 12:15:23 +0000 Comment by Newpool Music Very soulful part... Well done... 2011/10/22 12:13:31 +0000 Comment by LORDZ FOLLOW NEW SC awesome ! big up dank n dirty dubz ! 2011/10/22 11:29:02 +0000 Comment by Alego ●`● This is wat its all about! nice production :) 2011/10/22 11:18:17 +0000 Comment by VELI x Ansari chilled track might want to add more layers though keep up the gd work 2011/10/22 10:51:05 +0000 Comment by Karl Who nice chilled track bro. the bass could be a little louder. 2011/10/22 10:46:27 +0000 Comment by Dub-All Or Nothing nice chilled track. 2011/10/22 10:38:20 +0000 Comment by SkunkDubstep lovin the vibes on thiss 2011/10/22 10:21:36 +0000 Comment by FloE like the intro 2011/10/22 10:16:09 +0000 Comment by Primal Dubstep I like very much! keep up good work! 2011/10/22 10:11:25 +0000 Comment by Monkey Puzzla sweet track, nice to hear a bit of uplifting dubstep 2011/10/22 09:38:26 +0000 Comment by Monkey Puzzla nice vibes 2011/10/22 09:37:51 +0000 Comment by DannyPalm really love this beuatiful intro. Can dream my self away 2011/10/22 09:20:51 +0000 Comment by AaronDrako nice intro 2011/10/22 09:06:50 +0000 Comment by T Brudvik spaaarc <3 my man! 2011/10/22 08:59:26 +0000 Comment by Dulcet Tonez uk lovely work 2011/10/22 08:50:50 +0000 Comment by Patchyberlin O.o pretty smooth nice work with the background & the atmosphere ! good job ! :) 2011/10/22 08:42:28 +0000 Comment by pharmeceutikle Very chill! 2011/10/22 08:19:50 +0000


text:
Talon Build Guide by
Not Updated For Current Season
This guide has not yet been updated for the current season. Please keep this in mind while reading. You can see the most recently updated guides on the browse guides page.
Thank You!
Your votes and comments encourage our guide authors to continue
creating helpful guides for the League of Legends community.
Mid Talon
Talon Build
Ability Sequence
Not Updated For Current Season
The masteries shown here are not yet updated for the current season, the guide author needs to set up the new masteries. As such, they will be different than the masteries you see in-game.
This is a pretty average long guide to Talon, I hope you enjoy and that you learn something.
Masteries are pretty standard Physical Damage. I would take the instead of mostly because Talon is a Physical Damage burster who deals tons of damage with his spells, you are a great threat to their Ad Carry and Ap casters. If you play Talon right, you will notice that you will kill their carries like Vayne and Ashe within a second. Ezreal can be pretty annoying because of his but as you silence him you would do be able to do some great damage before he flees.
Well, there are a lot of different factors to point in here. Armor penetration is a really good choice on Talon
Why not flat AD? Well, as you know, Talon is mostly a threat with his spells. And those physical abilities like Rake will do great damage with Armor Pen. This is why you build a Brutalizer as fast a possible, it will give you such a a boost early game.
His spells doesn't really have any big AD ratioes, do whatever you want but Armor Penetration is a better choice.
Starting items
Boots of Speed and 3x Health Potionshttp://edge1.mobafire.com/images/btn-view.png
After first recall, you can pick up 2 Dorans blades


text:
A fun-filled day from 9:00 AM to 3:00 PM
The annual Round Lake Area ChamberFest/Expo is a large community event sponsored by the Round Lake Area Chamber of Commerce. It is always a fun-filled day and this year it will include photos with the Easter Bunny, kids crafts, bouncies, plenty of local retail booths and much more! Below is the flier from the Round Lake Area Chamber of Commerce detailing more about this event that you won't want to miss!


text:
All results
1 - 1 of 1 listing
Newly listed Sort
Select sortingNewly listed Lower price first Higher price first
Book stacks
A. Book Stack-Main Unit (Double Sided): Size 92"x36"x22" Made of MS Iron with Powder Coated, Seven shelves on each side. Pillar Made of 18G, Shelves of 20G, Foot of 16G, Bracing of 18G, Brackets of 20G, Side Panels Made of Prelaminated Board of 18mm. With add on facility. Colour Ivory, Price Rs.1350...
Hisar in Haryana (India)
27000.00 Rsview Event Services published 1 year ago viewed 23x
- 1


text:
The ``Not So Ordinary`` Texas Wineries!
Sample and purchase wine from the best ``not so ordinary`` Texas Wineries October 7-8, 2017
Thanks to the following wineries for joining us last year in 2016!
Bernhardt Winery | 936.894.9829
9043 County Road 204, Plantersville, TX 77363
At Bernhardt Winery our mission is to produce quality wines and to provide a fun tasting experience in a warm environment. We are a small mom and pop boutique winery producing classic varietals and unique blends. We carry traditional wine merchandise, along with fine jellies, jams and sauces.
Dionisio Winery | 713-906-2499
2635 Miller Ranch Rd.#103, Pearland, TX 77584
We specialize in wine tasting for the curious type wanting to know a bit of viticulture and the wine-making process or the novice wanting to learn how to taste and appreciate quality wines.
Griffin Meadery | 281.610.2135
The legendary Griffin is known as the guardian of treasures. At Griffin Meadery we take great care and pride in the creation of small batch, premium quality wine and we treasure our liquid gold.
Haak Vineyards & Winery | 409-925-1401
6310 Avenue T, Santa Fe, TX 77510
With deep passion, Haak Winery is dedicated to creating wines of distinction that accompany the memories of all who taste our wines and visit our estate. As the first winery and only commercial vineyard in Galveston County, we are excited to offer you premium wines made in the great state of Texas.
Los Pinos Ranch Vineyards | 903.855.1768
658 County Road 1334, Pittsburg, TX 75686
Los Pinos Ranch Vineyards is a destination winery located just two hours east of Dallas and four miles south of Pittsburg, Texas. Started in the year 2000, the 40 acre estate nestled in the piney woods of East Texas offers tastings, tours, tapas, chef specials, live jazz and Tuscan cottages for overnight rental. A delightful selection of dry wines produced from our Texas High Plains vineyards and sweet wines from our estate vineyards compliment the cuisine for those seeking a bit of escapism, wine and romance.
Maydelle Country Wines | 903.795.3915
County Road 2108 | Rusk, Texas 75785
The spirits of our rebellious forefathers, ambitious pioneers, and audacious grandparents reside at Maydelle Country Wines. Taking what they had and using it to grow this country is the spirit in every bottle of our Maydelle Country Wines.
Messina Hof Winery & Resort | 800.736.9463
4545 Old Reliance Road | Bryan, Texas 77808
The Tasting Room at Messina Hof showcases its immense wine selection suitable for any palate. Among these award-winning wines, there is a reserve selection of ultra-premium and library wines you cannot get anywhere else. Visitors can also shop for all their wine accessories, personalized labels, gifts and apparel.
Perrine Winery | 979.703.1843
900 Harvey Road, Suite 6, College Station, Texas 77840
All of the grape juice and crushed grapes we use to make our wine are grown and packaged by someone else. While this may seem a bit odd at first, it allows us to choose grape varietals from some of most renowned grape growing regions in the world.
Pleasant Hill Winery | 979.830.8463
1441 Salem Road, Brenham, Texas 77833
Pleasant Hill Winery celebrated its 13th year in April. More than a dozen award-winning wines are produced. There is a wine to please every palate from dry reds and whites to sweet wines and ports. Grapes come from the Brenham vineyard, the Texas Davis Mountains vineyard – featuring Cabernet Sauvignon and Sauvignon Blanc – and from vineyards all over the great state of Texas.
Red Road Vineyard | 903.897.9353
105 W Front St. 405, Naples, Texas 75568
Come join us at the Red Road Vineyard and Winery, where your wine experience will be like that of an
Irish country lane, pleasurable with every taste, right down to the last sip.
Established in 2001, Red Road Vineyard and Winery (RRVW) is family owned and operated,
in the business of making new friends, new memories, and good wine.
South Texas Wind Vineyard & Winery | 361.526.4662
16375 Hwy 183 South, Refugio, TX 78377
The winery and vineyard is family owned and operated, and it is the goal of the family to produce exquisite white, red, fruit and dessert wines. All of our wines are aged in stainless or glass and some of our red wines are aged with French Oak.
Water To Wine – Houston Winery | 713-662-9463
3331 Westpark, Houston, TX 77005
Water 2 Wine is an actual operating winery where all of our wines are fermented on site. We buy grapes from only the finest vineyards. With access to more than 100 wines from 13 countries, we satisfy your cravings for world class wines.


text:
COM 275 Entire Course
For more course tutorials visit
COM 275 Week 1 DQs
COM 275 Week 3 DQs
COM 275 Week 5 DQs
COM 275 Week 7 DQs
COM 275 Article Rebuttal Paper
COM 275 Audience Analysis and Reception
COM 275 Capstone Discussion Question
COM 275 Article Rebuttal Paper
For more course tutorials visit
Write a 350- to 700-word rebuttal to the article using valid arguments and supporting data. In your rebuttal, offer an analysis in which you do the following:
Analyze the reliability, credibility, and validity of the data used by the author.
Identify any logical fallacies in the argument.
Format your rebuttal consistent with APA guidelines.
COM 275 Checkpoint Persuasion
For more course tutorials visit
What different persuasive approaches would you use on the following audiences: a boss, a peer, a challenging person, and an open-minded person? Why would your approach differ with each?
COM 275 Knowing Your Audience Paper
For more course tutorials visit
Resource: "Over 30 Workers Trapped After Chilean Copper Mine Collapse" article located on the student website
Research additional articles and information about the Chilean mine collapse.
Write a 700- to 1,050-word paper using this and other articles as a resource. Because communications must be designed with the audience in mind, answer the following questions:
What are some considerations to remember given the...


text:
"I just wanted to let you know that our table plan has arrived and is absolutely gorgeous! I can't thank you enough for the wonderful service and for managing to get everything to me so promptly"
Claire, London
"We are very pleased with our wedding stationery. The quality is superb, and the customer service was outstanding. I can't wait to post my invites out to our family and friends." - Mary-Anne, Bournemouth
|Shop Stationery
|About Ivy Ellen
|My Ivy Ellen


text:
|Shipping Weight
|350.00 g
Good ergonomic design is another classic hallmark of knives from Mora of Sweden. They are solid, substantial, and feel good in the hand when you use them. Mora knives are also designed so that you can work with high precision, regardless of whether it is a Classic Mora knife, an Ergonomic Mora knife or an Erik Frost craftman's knife.
The Erik Frost 120 is a excellent (dare we say indispensable) woodcarving knife with a thin, tapered blade of laminated steel, and an oiled birchwood handle.Blade Thickness: 2.7mm
Blade Length: 60mm
Total Length: 165mm
Net Weight: 69g
Comes with a plastic sheath.


text:
so what did google get that was worth $9bn?
Google on Wednesday confirmed that it has signed an agreement to sell its Motorola handset business to Lenovo for $2.91 billion in a mixture of cash and stock. Google will retain the majority of Motorola's patents, but Lenovo will gain access to 2,000 patents as well as the Motorola brand and trademark portfolio.
Lenovo has agreed to pay Google $660 million in cash and $750 million in stock, with the remaining $1.5 billion to be paid out over the next three years.
"Lenovo has the expertise and track record to scale Motorola Mobility into a major player within the Android ecosystem. This move will enable Google to devote our energy to driving innovation across the Android ecosystem, for the benefit of smartphone users everywhere," Google CEO Larry Page said in a statement.
Dennis Woodside, Motorola's CEO and former Google executive, echoed this sentiment: "As part of Lenovo, Motorola Mobility will have…
View original post 168 more words


text:
In today's world, there are a lot of people that don't prefer the usual medical treatments and manipulations for the treatment of their recent or long term musculoskeletal injuries .
The term 'chiropractic' is derived from Greek and it means 'To perform with hands'. Today, chiropractors are specially educated in treating the joints and muscles of the body with their hands.
Chiropractics are regarded as the health care professionals that deal with the diagnosis, treatment and prevention of the diseases and disorders which are linked with the musculoskeletal system of our body. Chiropractic treatments are categorized into the alternative medicine.
The basis of the chiropractic treatment is mainly laid upon the spinal adjustments. Chiropractics believe that all the disorder and discomfort caused because of a blockage in the pathway of the nerves because of some compression or any other factor.
Chiropractic adjustment or spinal adjustments are the terminologies used by the chiropractics to describe their method of spinal manipulation.
Chiropractic treatment can be used not only for spinal adjustments but also for other joints and tissues.
Before the chiropractic treatment, the patient is always examined thoroughly. The main purpose of the treatment is to establish a correct diagnosis and then to decide the proper form of treatment. Diagnosis can be formed on the basis of general physical examination, history of the patient and x-ray examination.
Chiropractic treatment is usually painless. The chiropractor chooses the most appropriate treatment according to the condition of the patient. Treatment options include :
- Manipulation treatment
- Soft tissue treatment.
Chiropractic treatment is becoming increasingly popular between people seeking for the remedy of their pain.


text:
The European Court of Justice has ruled that part of Lovells' conduct in a major competition case amounts to abuse and, as a result, has ordered parties to pay their own legal fees.
The court ruled last Wednesday in the 13-year TACA case relating to rate-fixing by 17 shipping lines, that Lovells made unusually long applications, which were "for the most part unfounded", and this amounted to an "abuse".
As a result the court declared that the conduct of the applicants, all of which were represented by Lovells, had, "substantially added to the burden of dealing with this case, thus needlessly adding in particular to the costs of the Commission".
Nonetheless, the firm did successfully overturn what had been a record fine of E273m (£163.5m), against the shipping companies, which is the largest annulment of any EC competition law fine to date.
Lovells' litigation partner Matthew Levitt said the legal team – led by fellow partner John Pheasant who also conducted the advocacy – was pleased with the result, which has been widely perceived as a setback for the Commission.
However, he described the court's ruling on costs as "unfair". "On costs I would not agree with the way the court expressed this point," he said.
The court said that each application was 500 pages long and contained annexes of approximately 100 files. Levitt said this was misleading as each application said the same thing, with an additional 100 pages relating to three of the four applications made by non-European shipping lines.
"Ninety-eight per cent of them were identical," Levitt added.


text:
This Is My Home
This is Bill Tall Bull's digital story titled "This is my Home" from the Colorado History Museum's Imagine a Great City: Denver at 150 exhibit. This story was made in a workshop facilitated by The Center for Digital Storytelling's Denver office. Posted in conjunction with Mile High Stories.
Tags: 1860s, 2000s, arapaho, bill tall bull, cheyenne, sand creek


text: An introduction to the process of graphic arts production with emphasis on the various methods and techniques translating ideas and information to print material. The primary focus will be on production, layout and typography as they apply to print media, advertising and public relations. Newspaper, magazine and newsletter formats are discussed.


text:
- Please select a date to see the proper prices!
Description of the accommodation:
Rooms, services Courtyard Salina would be glad to host you for a memorable journey in Salina. The hotel is offering 80 nicely furnished rooms to stay in to those seeking accommodation in Salina. Since the hotel has an own restaurant, you may also try fine local meals on the spot. Available wellness services will provide you the opportunity to refresh yourself, an indoor pool will also be waiting for you. The café and the bar are an ideal place to host a personal meeting or a pleasant evening talk. If you wish to learn more about the exact scope of services provided by Courtyard Salina (including those available for an extra fee) or about the equipment of the rooms, you can find the complete list on the information sheet below.
Payment Depending on the selected date, room and price, you may need to provide credit card guarantee or advance bank card payment to finalize your reservation.
Arrival, opening hours The earliest time to check in to your room is 15:00, the latest time to check out of your room is 12:00. The personnel of the hotel can speak in English with you.
Courtyard Salina rooms Rooms
- Please select a date to see the proper prices!
Accommodation services
- Indoor pool
- Jacuzzi
Bar, Cafe, Elevator
Own restaurant
Hairdryer, Fridge, Desk in the room, Microwave oven, Washing machine, Tea/coffee-maker


text:
Credit Advice
Have a question? Have advice to share? The combined knowledge and experience of everyone in the Credit Karma community can help you. Enter your question or help others below to get started!
QuestionPosted in Mortgage
Question By
0 People Helped
He works, I stay home. Is there any chance of us getting financed for a mortgage loan? I know most places require a 620 or higher.... will my score combined with his be enough? Should we even bother?
We are selling our current home, looking like we will get about $14,000 for a down payment, annual income is 50k. Thoughts?
Thanks in advance.
Reply to this Question
Write your response:
The Credit Advice pages of the Site may contain messages submitted by users over whom Credit Karma has no control. Credit Karma cannot guarantee the accuracy, integrity or quality of any such messages. Some users may post messages that are misleading, untrue or offensive. You must bear all risk associated with your use of the Credit Advice pages and should not rely on messages in making (or refraining from making) any specific financial or other decisions.


text:
Heroes and Villains
Buck Dharma
Lady Jaye Breyer P-Orridge
Lady Jaye Breyer P-Orridge, Genesis P-Orridge's literal other half, has passed away. I found out from a post at Mysterious Glow / Texas Tarot. Here's the notice that was posted on the P-Orridge site:
Lady Jaye died suddenly on Tuesday 9th October 2007 at home in Brooklyn, New York from a previously undiagnosed heart condition which is thought to have been connected with her long-term battle with stomach cancer. Lady Jaye collapsed and died in the arms of her heartbroken "other half" Genesis Breyer P-Orridge.
Being overwhelmed by the enormity of their loss, Genesis and the other surviving band members of Psychic TV / PTV3 are not able to properly meet the demands of touring and performance. Obviously, her absence onstage, the conspicuous loss of her unique charisma, music and humour would be an unbearable emotional reality to confront night after night.
A sad day for Psychic TV fans. Our condolences to Genesis.
I was really sad when I saw that.
You have to hand it to the P-Orridges, they really 'walked it like they talked it." Genesis believes that in the future, people will no longer be binary (male-female). It seems like they were trying to speed that process up.


text:
Dancing in Denver + Add to My Sports
Dancing in Denver
Sportsvite makes playing Dancing in Denver hassle free.
- Find recreational Dancing games and events in Denver
- Connect with other recreational Dancing players and Dancing teams in Denver
- Organize your own Dancing games and events in Denver
Ready for the big time?
It's free, it's easy, and it rocks!Sign Up Now Log In
Denver Dancing Cities & Neighborhoods
Manage Dancing Teams
Create and organize your own Dancing team! Sportsvite has the web's best team management tools, and they just got even better, with overhauled rosters, schedules and more!


text:
Search for a name or phrase
Search for a name or phrase
using quick search
Find the right name for your baby using our advanced search tool
's Stuff
My Name Ratings
Review and change the name ratings you've made throughout the site
My Lists
Create a private list of your favorite names or share it with the Nameberry community to flex your naming muscles
Names I Follow
Manage all the name subscription emails you've set up
Account Settings
Change your email address and your password
Or Register
- this week
Share Julienne on Facebook Share on Facebook
Share Julienne on Twitter Share on Twitter
Share Julienne on Google Plus Share on Google+
Love the name Julienne
Dislike the name Julienne
Follow Julienne
Please Register or Login
We're excited that you have an opinion about the name Julienne. To rate names on Nameberry, please register for an account or log in to an existing account.
Would you like to follow Julienne?
You will receive an email (no more than once per day) summarizing any new mentions of Julienne on Nameberry. Would you like to follow Julienne?
People who liked Julienne also liked:
Aaron Ace Alexa Alix Allegra Alyssa Ariadne Aristotle Artemisia Ashton Auden Augusta Austin Brady Brielle Britta Caius Callaghan Casper Cassius Christian Clark Collin Dominick Duke Dylan Echo Elena Eliana Elianna Emmanuelle Eric Gavin George Gianna Griffith Hero Heron Honoria Jill Jolie Julianna Julianne Juliet Julietta Kane Karl Keane Kirsten Kristen Lawrence Levi Lilliana Lincoln Liv Livia Macauley Mackenzie Madison Malachi Mariana Marianna Marius Mathis Mercer Mercer Mireille Monet Olympia Philip Phoenix Prue Rebekah Reese Stephen Tarquin Tate Thayer Tristan Tycho Tyler Victoire Von Xander Xavier


text:
Posted September 17th, 2006, 09:43 PM
My DH and I will be on Royal Caribbean's Brillance of the Sea Panamal Canal Cruise this February. We are very excited about the Caribbean Train, Boat and Bus Adventure but.......the first sentence of the boat description states "your will be given life jackets TO WEAR during the cruise on the Tortugero Canals". None of the other tours of the canals talk about wearing life jackets, but they also don't seem to offer the opportunity to see as much as this tour offers. Here's my question....has anyone done this tour? Can you describe the type of boat is used or better yet, does anyone have pictures? I just want to make sure there is no chance of us tipping over and landing in the water with the crocodiles.


text:
Hover to zoom. Click to expand
Price $16.95
Irwin® has once again set the standard for quality snips. Their new Offset Snips feature cold-formed blades that are stronger and sharper than any other brand. The serrated offset jaws are designed to make straight or tight circular cuts with equal ease while keeping your hand safely away from the work. And Irwin's exclusive new ProTouch® ergonomic grips maximize comfort while increasing leverage, creating a snip you can trust every time.
Copyright 2015 - Aircraft Tool Supply Company


text:
Wessex FM News
Wessex Water Splash Out
8:27am 28th June 2013
National watchdog, The Consumer Council for Water (CCWater), has praised the decision of Wessex Water to invest an additional £50M at the company's own expense, into improving services for customers.
Wessex Water has become the latest utility firm to respond positively to CCWater's call for water companies to share their financial gains and successes with its customers.
Charles Howeson, Western regional chair for the Consumer Council for Water, told Wessex FM that:
This is good news for Wessex Water's customers. We are very pleased to see Wessex commit to this additional investment, which is something we have been pressing for across the country. This extra money should make a significant difference to the services provided to its customers."
This additional funding will be invested in a range of services across the company, including £30 million to help improve drains and sewers, £6.5 million to boost online services and nearly £2 million on support for customers struggling with debt and other financial issues.
Wessex Water will be contributing to the around £290 million that CCWater has gained in extra investments over the past few years and will be adding to the already 300,000 customers that have been helped with their complaints and enquiries about their local and national sewerage services.
Sign up for the latest local news direct to your inbox


text:
A TEN-screen cinema and six restaurants could be created alongside new shops as part of a further redevelopment scheme for The Moor in Sheffield.
Plans have been submitted to Sheffield Council by Scottish Widows Investment Property Partnership Trust, landlord of the shopping street, for the site below Debenhams.
The scheme would see creation of 18,000 square metres of mixed retail and leisure which will potentially include the cinema and eateries - along with a pedestrian route into Charter Square.
Ranald Phillips, director of Ashcroft, agents for Scottish Widows, said: "This is another phase of Scottish Widows' rolling programme of regeneration and investment in The Moor which demonstrates its commitment to developing Sheffield's city centre.
"Retailers and leisure outlets want to come to Sheffield and we are aiming to provide them with the right environment and facility to do this. If planning consent is granted then we hope to start on site in 2013."
Next year will also see the completion of improvements to paving on the upper Moor, the new £16.5 million markets and a neighbouring building which is set to be the permanent home of TJ Hughes department store. Another block is also due to be redeveloped next year, the former McDonalds building opposite Debenhams.
The improvements are part of what Mr Phillips has described as a project to turn The Moor into 'The Oxford Street of Sheffield'.
Sheffield Council chief executive John Mothersole said: "I think we can conclude that what we are seeing is the comprehensive rebirth of The Moor for shopping and leisure.
"I have only been in Sheffield 14 years but people keep telling me how great The Moor was for shopping. Hopefully we will be able to bring those memories back to life."


text:
Javonta Boyd, a 6-foot-3, 290-pound defensive tackle from Northeast H.S. in St. Petersburg, Fla., has several scholarship offers at this point, including one from Louisville.
Premium Content
Subscribe today to read the full article and get everything Rivals has to offer.
- Member-only message boards
- Exclusive highlights and recruiting interviews
- Exclusive coverage of Rivals Camp Series
- Breaking recruiting news


text:
For patients having cataract surgery or Clear Lens Exchange, an exciting new option is a multifocal lens implant which is designed to provide both distance and near vision. These include the Alcon ReSTOR Intra-Ocular Lens and the Tecnis Multifocal Intra-Ocular Lens.
Over the age of 40, the natural lens in the eye loses its ability to focus up close, and patients must wear reading glasses or bifocals for near vision tasks such as reading.
The multifocal lens is implanted in your eye at the time of cataract surgery or Clear Lens Exchange, and is designed to provide a full range of vision, from near through distance vision, and greatly reduce your dependence on glasses.
In clinical studies, 80% of patients receiving these implants reported that they never needed glasses for any activities, including driving, playing sports, watching television, working on the computer or reading fine print.
A multifocal implant is not an option for every patient, and your surgeon at New Vision Laser Center will discuss whether it is right for you. Contact us to find out if a multifocal implant might be an option for you.
View next page: LASIK Testimonials


text:
There are days when I have to remind myself that I'm an adult and can make adult decisions on a daily basis. I often forget that I'm no longer a struggling 20 year old and I don't have to eat ramen for dinner or ask my mom for advice on everything (I still do this. The advice, not the ramen). So for the first time ever I'm going to make some goals for myself and make every effort to stick to them. I figure if I write them down, it'll help me be more conscious.
- Pray more! I pray all the time. In the car, at work, while I'm sitting at home, but it's almost as an afterthought. I have a great relationship with God, but I have trouble letting go and letting him lead. This goal should really be to worry less, but in doing that I need to put my trust and faith in God, so I think praying more is appropriate.
- Lose 70lbs. Even though my surgery will help greatly with this, it's just a tool and I still have to be extremely aware of what I'm putting in my body and what I'm asking it to do. I want 2017 to be my healthiest year yet.
- Blog consistently. I know this will be one of the hardest goals for me, but I'm determined to make it happen. Sometimes I get too caught up in other things or in self doubt. Thinking that I don't have anything to say or whatever I write will be uninteresting. And it may be complete garbage, but the only way to get better is to keep writing and keep putting out content.
- Get back into the dating world. Ugh! Can I be honest and say that I'm not looking forward to this? Having to sit through bad dates where I don't like the guy or he doesn't like me. Having to get through polite conversation only to discover that you'll never talk to the person again. On the other hand though, I want the newness of discovering someone that could really change your world. I've been single for a long time now and this is the scariest goal for me because I will seriously have to get out of my comfort zone, but that's the point, right??
I was going to try for a few more goals, but I think I'll stick with four for now and revisit and revise if/when I need to. And March is right around the corner, so I better get started!!
(header photo credit: Brigitte Tohm)


text:
"... elegant and provocative... Exhibit[s] a subtle mastery of Heidegger's works." Review of Metaphysics
"... splendidly precise study of Heidegger... to be recommended not only to Heidegger scholars but also to those interested in the question of what philosophical thinking has as its task in the modern technological world." Religious Studies Review
"... indispensable to understanding the later Heidegger." Choice


text:
Mischa Barton Goes on First Date With 'DWTS' Partner Artem Chigvintsev. Hello guys, now this blog want to share with you most recent update of Mischa Barton Goes on First Date With 'DWTS' Partner Artem Chigvintsev, Please read below
Mischa Barton might not have gotten very far on this season of Dancing With the Stars, but The O.C. alum got more out of the show than expected.
A source confirms to ET that Barton and her DWTS partner, Artem Chigvintsev, have started dating. The pair were spotted out at The Little Door, a quaint French restaurant in Los Angeles, on Wednesday night.
WATCH: Mischa Barton Eliminated From 'DWTS' After Earning Her Highest Score Yet
"They've been in touch after the show and care about each other but this is the first proper date," a source told ET, adding that the pair are "transitioning into more than friends."
"He is the reason she's looking happier recently. She has become giddy when talking about him and quite smitten with him." The source added, "He's pursued her for a while, and she's coming around," calling their outing "an official date."
After the two shared a meal, they went to Chateau Marmont where the actress introduced the dancer to some of her pals.
(Photo: Instagram)
MORE: Olivia Wilde Calls Mischa Barton Her Best On-Screen Kiss
Barton, 30, hasn't referenced the romance on her social media accounts yet, but on Wednesday she posted several solo shots of herself to Instagram, writing, "Sending you all love, light and laughter on this Wednesday night" and "Good Night," with a heart emoji.
Barton was the second contestant to be eliminated from DWTS in early April. "It was definitely, maybe more than I had bargained for in a lot of ways," Barton told ET at the time. "But I'm so happy I tried something that's that foreign to me, and you know, had this experience with these guys."
Chigvintsev added, "I think that's why it's tough to go home because I feel like we've been through so much in these past five weeks, [more] than people get in years."
The week after her DWTS exit, Barton also admitted to ET that she and Chigvintsev keep in touch, saying, "Yeah, we talk."
I want that the update on Mischa Barton Goes on First Date With 'DWTS' Partner Artem Chigvintsev shared here at www on4top com can energize your day.