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Propofol (2,6-diisopropylphenol) is an anesthetic drug with antioxidant and antiinflammatory properties, documented both in vitro and in experimental models of ischemia-reperfusion injury and septic shock. These properties have been related to the similarity of its chemical structure to that of endogenous tocopherols, which are phenol-containing radical scavengers. This study evaluated the effects of propofol on alpha- and gamma-tocopherol (alpha- and gamma-T) levels and on selected markers of oxidant-antioxidant and inflammatory status in patients undergoing cardiac surgery.
Patients were randomly assigned for anesthesia with either propofol (propofol group, n = 22) or sevoflurane (control group, n = 21). Plasma levels of alpha- and gamma-T, individual antioxidant capacity, malondialdehyde, and interleukin 10 were measured before, during, and after anesthesia. In addition, levels of the proinflammatory prostaglandin E2 as a marker of cyclooxygenase-2 activity and those of interleukin 10 were measured in whole blood cultured with bacterial lipopolysaccharide.
Gamma-T levels increased significantly during surgery in propofol group (P < 0.0001 vs. control group). By contrast, alpha-T similarly decreased in both groups. Malondialdehyde and interleukin 10 increased markedly and individual antioxidant capacity decreased, without differences between groups. Prostaglandin E2 levels measured 24 h after anesthesia induction were significantly lower in the propofol than in the control group. In vitro studies highlighted the different capacity of gamma- and alpha-T to impair prostaglandin E2 synthesis by human monocytes challenged with bacterial lipopolysaccharide.
The antiinflammatory properties of propofol that may be linked to its effect on gamma-T levels could be relevant in controlling the inflammatory response that accompanies tissue injury during reperfusion.
PROPOFOL (2,6-diisopropylphenol) is an anesthetic drug widely used intravenously in surgical procedures.1Several studies, both in vitro and in animal models, have reported for this drug a scavenging activity against a broad range of free radicals, including peroxynitrite.2–4Whether this effect applies in patients is still controversial.3The antioxidant profile of propofol has been related to its chemical structure, which is similar to that of phenol-based scavengers such as the endogenous tocopherols.5α-Tocopherol (α-T), the major isoform in the tocopherol pool in human plasma, is the main lipid-soluble chain-breaking antioxidant preventing lipid peroxidation in biologic membranes.6Conversely, γ-tocopherol (γ-T) is far more active than α-T in quenching peroxynitrite,7–9which plays a critical role in cell or tissue damage associated with inflammation, shock, and ischemia–reperfusion injury.10Moreover, γ-T, unlike α-T, reduces proinflammatory eicosanoids through inhibition of cyclooxygenase (COX)-2 activity, in vitro and in vivo , in animal models of inflammation.11,12
Besides its antioxidant properties, propofol has antiinflammatory effects.13At clinically relevant concentrations, it impairs neutrophil and macrophage functions14–16and reduces the levels of proinflammatory cytokines in vitro 17and in vivo , in experimental models of inflammation18,19and in patients undergoing coronary artery bypass grafting.20,21In addition, it increases the levels of the antiinflammatory and immune regulatory cytokine interleukin (IL)-10 when added in vitro in cultured human whole blood (WB).22
Ischemia–reperfusion oxidative injury occurs during cardiac surgery requiring an on-pump procedure. Increased production of reactive oxygen species can rapidly overcome endogenous antioxidant defenses and cause membrane injury and mitochondrial dysfunction.23–27Higher levels of proinflammatory cytokines, e.g ., IL-6 and IL-8, also contribute to organ dysfunction and morbidity,28whereas an increase of IL-10 is thought to counterbalance the effect of proinflammatory cytokines.29Moreover, in vivo data indicate that endogenous IL-10 is an important regulator of eicosanoid production in response to bacterial lipopolysaccharide.30
Propofol has been shown to reduce the levels of proinflammatory cytokines in patients undergoing coronary artery bypass grafting,20,21but whether this anesthetic drug influences the oxidant–antioxidant balance and other inflammatory components of myocardial reperfusion injury in patients undergoing cardiac surgery is unknown.
This study was designed to evaluate the effect of propofol, at doses used to induce and maintain anesthesia, on the plasma oxidant–antioxidant profile and on the inflammatory status in patients undergoing cardiac surgery. In addition, the mechanism by which propofol exerts its antiinflammatory effect has been explored by in vitro studies in human adherent monocytes.
Materials and Methods
All chemicals were obtained from Sigma Chemical Co. (Milan, Italy) if not otherwise specified. Propofol was administered using a commercially available target-controlled infusion system (Diprifusor; AstraZeneca S.p.A, Milan, Italy).
Patients and Study Design
Patients scheduled to undergo elective cardiac surgery with cardiopulmonary bypass (CPB) were enrolled in this prospective, randomized, controlled study after approval from the institutional review board (Centro Cardiologico Monzino, Milan, Italy) and written informed consent. Inclusion criteria were stable angina, left ventricular ejection fraction greater than 40%, and age 60–80 yr. Exclusion criteria were aortic valve stenosis, angina on arrival in the operating room, and acute myocardial infarction during the past 7 days. Preanesthetic medication included morphine (0.1 mg/kg) and atropine (0.07 mg/kg), administered intramuscularly 1 h before surgery. Intravenous cefazolin (30 mg/kg) was administered before instrumentation. Monitoring was performed by five-lead electrocardiography with continuous ST-segment analysis (leads II and V5), radial artery catheter, pulse oximetry, and triple-lumen catheter or pulmonary artery catheter (Swan-Ganz) inserted through the right internal jugular vein. Patients were assigned to one of two groups by means of a random computer-generated list. Anesthesiologists were unaware of the due treatment until the morning of surgery, after patient enrollment. In the propofol group, anesthesia was induced by propofol and remifentanil, simultaneously administered according to a target-controlled infusion protocol (2.5–4 μg/ml propofol, 10–12 ng/ml remifentanil). Anesthesia was maintained with propofol (1.5 μg/ml) and remifentanil (8–12 ng/ml), decreasing to 1.2 and 4 ng/ml, respectively, during CPB. In the control group, anesthesia was induced by thiopental (4–6 mg/kg) and maintained with inhalation of sevoflurane (1–2%) in an oxygen–air mixture and remifentanil (8–12 ng/ml, target-controlled infusion) for the entire procedure, with the exception of CPB, during which midazolam (50–100 μg · kg−1· h−1) was administered intravenously and remifentanil was reduced (4 ng/ml). During the procedure, the control group also received the propofol vehicle (100 ml Intralipid®; Fresenius Kabi Italia S.r.l., Verona, Italy), because it contains tocopherols. In both groups, tracheal intubation was facilitated by succinylcholine (0.1 mg/kg) and pancuronium (0.1 mg/kg). Lungs were ventilated at normocapnia in an air–oxygen mixture (fraction of inspired oxygen [Fio2]= 0.5). Patients received 300 U/kg heparin before cannulation, and activated clotting time was kept above 450 s during the extracorporeal procedure. CPB was performed with a roller or centrifugal pump and a hollow-fiber oxygenator in mild hypothermia (32°–34°C). The circuit was primed with 1.0 l Normosol® (Abbott Laboratories, North Chicago, IL), 5% glucose (500 ml), 18% sodium bicarbonate solution (100 ml), and 18% mannitol solution (100 ml), given just before the opening of the aortic cross clamp. Blood flow in the bypass was titrated to ensure a mean arterial blood pressure between 55 and 75 mmHg (at least at 2.4 l · min−1· m−2). Additional boluses of norepinephrine and nitroglycerin were used to maintain the pressure within the range. Hematocrit was kept between 18% and 25%. The myocardium was protected by administration of cold antegrade and retrograde multidose blood cardioplegia. At the end of the procedure, all patients received an intravenous bolus of morphine (0.1 mg/kg) and were transferred to the intensive care unit without reversal of muscle relaxation. Here, both groups were ventilated in mandatory minute ventilation (Dräger Evita 4; Drägerwerk AG & Co., Lübeck, Germany) and extubated when they fulfilled the following criteria: adequate response to verbal stimuli, body temperature greater than 36°C, blood loss less than 100 ml/h, hemodynamic stability, respiratory rate between 10 and 15 breaths/min, partial pressure of carbon dioxide less than 45 mmHg, and arterial oxygen saturation greater than 96% with an Fio2of 0.5. Postoperative analgesia was obtained by remifentanil perfusion (0.1–0.25 μg · kg−1· min−1) until extubation, and with tramadol if required (visual analog score >3).
Blood Sampling
Blood was collected from the radial artery into pyrogen-free EDTA before induction of anesthesia (T0, baseline), 30 min after the beginning of CPB (T1), after protamine administration and on-pump weaning (T2), at arrival in the intensive care unit (T3), and 24 h after anesthesia induction (T4). Plasma was obtained by centrifugation at 4°C and stored at −80°C until analysis. For studies with cultured WB, additional blood samples from a subgroup of patients (14 in propofol group and 15 in control group) were collected in heparin at T0and T4.
Whole Blood Experiments
Aliquots of WB were cultured for 24 h at 37°C with or without 10 μg/ml bacterial lipopolysaccharide (Escherichia coli 0111:B4). Acetylsalicylic acid (30 μm) was added to samples to prevent COX-1 activity. After centrifugation (700g for 15 min), prostaglandin E2(PGE2) and IL-10 levels were determined by commercially available enzyme immunoassays (Prostaglandin E2EIA Kit-Monoclonal; Cayman Chemical, Spi-bio, Montigny le Bretonneux, France, and Endogen Human IL-10 ELISA Kit; Pierce Biotechnology Inc., Rockford, IL, respectively). All samples were determined in duplicate.
Peripheral Blood Mononuclear Leukocyte Isolation and Monocyte Culture
Peripheral blood mononuclear leukocytes (PBMLs) were isolated by density gradient centrifugation over Ficoll-Paque (Amersham Biosciences Europe GmbH, Milan, Italy), as previously described,31from aliquots of blood collected in heparin at T0and T4from a randomly selected subgroup of 11 patients. After isolation, PBMLs were rinsed with phosphate-buffered saline supplemented with 0.5% bovine serum albumin and 2 mm EDTA and were counted. The pellet was stored at −20°C until analysis. For in vitro studies, PBMLs obtained from venous blood of healthy donors were suspended in medium-199 supplemented with 10% human AB serum (5 × 106/ml) and plated in tissue culture dishes for 90 min at 37°C.32Adherent cells were 85–90% monocytes, as determined by nonspecific esterase staining. Monocytes were incubated for 18 h with α- or γ-T, dissolved in ethanol. Lipopolysaccharide (100 ng/ml) was then added, and incubation was continued for further 24 h. For the evaluation of COX-2 activity in terms of PGE2synthesis, monocytes were washed and incubated for 30 min in Hank's buffer (pH 7.4) containing 1 mg/ml bovine serum albumin and 10 μm arachidonic acid. Adherent monocytes were then harvested in lysis buffer, pH 6.8, and Western blot analysis was performed as described.32
Determination of α- and γ-Tocopherol Levels
α-Tocopherol and γ-T concentrations were measured by high-performance liquid chromatography.33Plasma samples and PBMLs, resuspended in lysis buffer, were extracted with organic solvents, injected into a Discovery C18 reversed-phase column (250 × 4.6 mm, 5 μm; Supelco/Sigma-Aldrich, Bellefonte, PA), and eluted with methanol (100%), as mobile phase.
Determination of Malondialdehyde
Plasma total malondialdehyde was detected by high-performance liquid chromatography with a method modified from Carbonneau et al . 34Briefly, plasma (200 μl) was subjected to alkaline hydrolysis (1 m NaOH, pH 13) at 60°C for 1 h. After acidification (2 m HClO4, pH 1) and centrifugation (13,000g for 10 min), supernatants were treated with 2-thiobarbituric acid (0.2% wt/vol) for 1 h at 100°C. After cooling, the samples were centrifuged at 13,000g for 10 min. Supernatants were injected into XBridge C18 reversed-phase column (150 × 4.6 mm, 5 μm; Waters Co., Milan, Italy) and eluted with 10 mm phosphate buffer (30% MeOH, pH 7), as mobile phase, at a flow rate of 1 ml/min. Malondialdehyde levels were measured by a fluorometer (Jasko FP1520; Tokyo, Japan: λEx515 nm, λEm553 nm). The peak areas were integrated using commercial software (EZStart; ESA Biosciences, Chelmsford, MA). The sample concentrations were calculated from calibration curves using 1,1,3,3-tetraethoxypropane as standard. Calibration of the analytical procedure gave a linear signal over the malondialdehyde range of 0.25–4 μm (r = 0.9992), with a quantification and detection limits of 0.15 and 0.05 μm, respectively. The intraassay and interassay coefficient of variations were 2.4% and 9.2%.
Measurement of Individual Antioxidant Capacity
Plasma individual antioxidant capacity (IAC), a parameter that provides a measure of the overall protection against oxidative damage, was measured by a commercially available spectrophotometric assay (OXY-Adsorbent Test Diacron®; Diacron International, Grosseto, Italy). Samples were tested for their capacity to neutralize massive oxidation by hypochlorous acid, and IAC values were determined by reading the absorbance at 505 nm.
Measurement of Interleukin 10
Interleukin-10 levels were determined in plasma by a commercially available enzyme immunoassay, as described for WB experiments. All samples were determined in duplicate.
Statistical Analysis
Sample size was calculated from a pilot study on the primary outcome (effect of propofol on γ-T levels in patients who underwent cardiac surgery). Twenty-one subjects per group allowed a 90% statistical power to detect a between-group difference of 0.15 μg/ml in peak levels of γ-T, with an α error of 0.05. Results are expressed as mean ± SD, unless otherwise stated. Variables whose distribution was markedly skewed (IL-10 levels, both in plasma and in WB, PGE2levels in WB, European System for Cardiac Operative Risk Evaluation [EuroSCORE], duration of intubation, and blood loss) were log10transformed before analyses. All other variables were nearly normally distributed.
Baseline data were compared between the two groups by Student t test or Fisher exact test, when appropriate. To minimize the intersubject variability, individual variations of analytes in plasma, during and after surgery, were analyzed as delta versus baseline. However, absolute values were also analyzed to check the consistency of the results. The time course of the analytes was compared between groups by a repeated-measures analysis of covariance with a group × time factorial design. The group effect, the time effect, and the group × time interaction were assessed. As post hoc analyses, we tested the within-group difference of each time point versus baseline, controlling for multiple testing by the Bonferroni method. The association between PGE2production and γ-T was assessed by the Pearson correlation on log-transformed data. The in vitro effect of increasing doses of α- or γ-T on PGE2synthesis by monocytes was assessed by analysis of covariance with isoform (α- or γ-T) × concentration factorial design. The different effect of the two isoforms was assessed by testing the isoform × concentration interaction. Analyses were performed using SAS statistical package version 8.2 (SAS Institute, Cary, NC). All P values reported are two-sided and are considered statistically significant at less than 0.05.
Characteristics of the Patients
Sixty-five patients undergoing cardiac surgery were assessed for eligibility (fig. 1). Two patients refused to participate and 19 did not meet the inclusion criteria. After randomization, the baseline blood sample from one patient was unusable, and therefore, it was excluded from data analysis. Patients assigned to the propofol or control group were comparable for age, body mass index, risk factors, and type of surgical procedures (table 1). A nonsignificant imbalance was observed for sex distribution. The biochemical values in plasma did not significantly differ between the two groups (table 2). The two treated groups were also comparable for PGE2and IL-10 levels measured in WB cultured with or without lipopolysaccharide for 24 h (table 3). Changes in blood cellular profile assessed at baseline and 24 h after anesthesia induction were similar in the two groups (P = 0.22, 0.34, and 0.67 for leukocytes, erythrocytes, and platelets, respectively). No significant differences between the two groups were found in the perioperative course or in the outcomes, except for a borderline statistical difference in the time of intubation (table 4). No patients died or experienced major complications (myocardial infarction, acute respiratory distress syndrome, cerebral accidents, or cardiogenic or septic shock; table 4).
Time Course of α- and γ-Tocopherol Levels
The α- and γ-T levels in plasma measured before (T0), during (T1, T2), and after surgery (T3, T4) are shown in figures 2A and B. α-T levels decreased significantly in both groups 30 min after ischemia induction and on pump start (T1), and remained low during and after surgery (T2, T3) and the first postoperative day (T4). No significant difference between groups was observed (fig. 2A). In contrast, the two groups differed markedly in γ-T levels, which progressively and significantly increased in the propofol group, returning to basal values 24 h after surgery (fig. 2B). In the control group, γ-T levels remained roughly unchanged during and after surgery.
Because an association between sex and tocopherol levels have been reported,33the time course of tocopherols was reanalyzed, after adjusting for sex, to control for the excess of women in the propofol group. Similar results for the treatment effects were obtained (F = 0.72, P = 0.40 for α-T and F = 41.4, P ≤ 0.0001 for γ-T).
γ-Tocopherol levels measured at T4in PBMLs from a subgroup of patients were higher in the propofol group (1.42 ± 0.72 ng/103PBMLs [mean ± SD], n = 4 in propofol group and 0.67 ± 0.37, n = 7 in control group; P = 0.045). An analogous significant difference between groups was not observed in α-T levels (7.15 ± 6.52 ng/103PBMLs in propofol group and 5.00 ± 4.23 ng/103PBMLs in control group; P = 0.51). The small sample size, however, limits the statistical power of this comparison.
Time Course of Oxidant–Antioxidant Balance
The different effect of the two anesthesia regimens on γ-T levels in plasma was not mirrored by changes in the oxidative status (figs. 2C and D). Measurement of malondialdehyde, as an index of lipid peroxidation, showed no appreciable difference between the two groups of treatment. Malondialdehyde levels markedly increased during surgery with a progressive decline after ischemia induction and on-pump beginning (T1) in both groups (fig. 2C). As a reflection of the increase in malondialdehyde, IAC levels significantly declined during surgery, again with no difference between the two groups (fig. 2B). After surgery, IAC levels remained lower than at baseline, although a trend toward baseline values was detected (fig. 2D).
Time Course of Interleukin-10 Levels
Changes of plasma IL-10 levels in the propofol and control groups before, during, and after surgery are shown in figure 3. IL-10 increased during surgery, with no significant difference between groups. A complete return to baseline values was observed at T4.
The time courses of α- and γ-T, malondialdehyde, IAC, and IL-10 were also analyzed using actual instead of delta values, and superimposable results were obtained: Specifically, the effect of propofol on γ-T levels was associated with a P value of 0.005.
Prostaglandin E2and Interleukin-10 Production in Whole Blood Cultured Ex Vivo
Prostaglandin E2production, as an index of COX-2 activity, was measured in WB collected at T0and T4and then cultured for 24 h either in the absence or in the presence of 10 μg/ml lipopolysaccharide. The reduction of lipopolysaccharide-induced PGE2production, relative to preoperative levels, was significantly more marked in the propofol group than in the control group (fig. 4A). In contrast, no significant difference between groups was detected when IL-10 levels were measured in the same experimental system (fig. 4B).
Of interest, significant negative correlations between PGE2production induced by lipopolysaccharide in WB at T4and γ-T levels were found, both in plasma at the end of surgery (T3; r =−0.44, P = 0.04) and in PBMLs (r =−0.65, P = 0.04).
Different Effects of α- and γ-Tocopherol on Prostaglandin E2Synthesis in Human Adherent Monocytes
To assess the effect of α- and γ-T on COX-2 activity, we performed in vitro experiments (n = 10) on adherent monocytes exposed to lipopolysaccharide (100 ng/ml) in the presence or absence of α- or γ-T. Lipopolysaccharide markedly increased PGE2synthesis from 0.30 ± 0.34 to 4.8 ± 1.2 ng/ml. The increase was dependent on COX-2 induction (figs. 5A and B). γ-T, preincubated with monocytes for 18 h before lipopolysaccharide addition, concentration-dependently reduced PGE2levels (fig. 5A), without affecting COX-2 expression (fig. 5B). The effect of the same concentrations of α-T on COX-2 activity was less apparent (fig. 5A): The slopes of COX-2 activity inhibition versus tocopherol concentration were significantly different for the α- and γ-T isoforms (P = 0.016 for the interaction term).
This study shows, for the first time, that propofol selectively enhances the levels of γ-T in the plasma of patients undergoing cardiac surgery and that this effect may account for the reduction of PGE2synthesis observed in their WB cultured with lipopolysaccharide. This finding is reinforced by the in vitro observation that γ-T inhibits lipopolysaccharide-induced PGE2synthesis in human adherent monocytes.
The increase of γ-T after propofol infusion observed in this study is in accordance with data obtained in animal models of ischemia–reperfusion and septic shock.35,36The comparison with control patients, who received the vehicle only, ruled out the possibility that this increase was dependent on the tocopherol content of the propofol vehicle.37
γ-Tocopherol was still raised in mononuclear leukocytes 1 day after the induction of anesthesia, which suggests that these cells may represent a suitable compartment for γ-T accumulation, as already observed for other tissues.12,38This feature may account for the lower PGE2levels observed in cultured WB from propofol patients 1 day after the intervention. The antiinflammatory effect of γ-T observed ex vivo is supported by the results obtained in vitro , in adherent monocytes. In these cells, in agreement to what has been shown in murine macrophages and Caco2 cells,11,39γ-T counteracts the synthesis of PGE2mediated by COX-2 induction. γ-T acts posttranscriptionally on COX-2 activity, leaving COX-2 protein levels unaltered, as already reported for other cell types.39
Plasma levels of malondialdehyde, a marker of peroxidative stress, sharply increased 30 min after the beginning of bypass surgery, reflecting the switch of reactive oxygen species and isoprostane production during ischemia–reperfusion.24,26Along with the increased pro-oxidant status, antioxidant defenses declined, as shown by the time course levels of IAC, an index of the overall protection against oxidative damage. The elevation of systemic malondialdehyde and the decrease of IAC levels during bypass surgery were similar under the two anesthesia regimens, despite the selective and marked increase of γ-T occurring in the propofol group. Therefore, our findings do not support a greater antioxidant effect of propofol, at the doses used in this study, with respect to the control treatment. We cannot, however, exclude the possibility that propofol infused at higher doses for a longer time period would exert an antioxidant effect, as reported by others.21,40
Of interest, γ-T is characterized by selective antioxidant properties that are not shared by α-T and that may result in distinct biologic effects.7Although the biologic or clinical significance of our findings is far to be clear (indeed our study was not powered to assess differences in clinical outcomes), indications exist that a walnut diet, resulting in increased γ-T levels, improves endothelium-dependent vasodilation in hypercholesterolemic patients41and in healthy subjects.42In addition, a 6-week supplementation of γ-T (800 mg/day), resulting in doubled plasma levels of γ-T (similarly to what observed in propofol treated patients), reduced biomarkers of inflammation, i.e ., plasma C-reactive protein and urine nitrotyrosine, in subjects with metabolic syndrome.43
Our data show that IL-10 levels increase in plasma during surgery, as observed in patients undergoing elective major surgery and coronary artery bypass graft surgery.44,45The increase of IL-10 may be due to a counterregulatory response to the proinflammatory status induced during and after the surgical intervention. Increased levels of proinflammatory cytokines such as tumor necrosis factor α, IL-6, and IL-8 play a key role in the inflammatory cascade that follows cardiac surgery and that can lead to adverse perioperative events,46whereas antiinflammatory cytokines such as IL-10 significantly limit these complications.47It has been reported that propofol reduces the release of proinflammatory cytokines both in vitro 48and in patients undergoing abdominal and coronary artery bypass graft surgery.20,49With respect to control anesthesia, propofol did not significantly suppress the increase of plasma IL-10 during surgery or affect its production in lipopolysaccharide-cultured WB, an experimental condition in which the synthesis of PGE2is, conversely, markedly reduced. This finding suggests that propofol, by increasing γ-T levels in cells, selectively targets the proinflammatory PGE2, sparing the capacity of WB to synthesize IL-10. The positive effect of propofol on the balance between antiinflammatory and proinflammatory cytokines has been highlighted also in surgical settings that do not require CPB and that, therefore, are not associated with ischemia–reperfusion injury.50–52
The increased γ-T levels observed in the propofol group could be attributed to the interaction of propofol with CYP3A4, for propofol is mostly eliminated by CYP3A4-mediated catabolism,53and tocopherols are metabolized by side-chain ω-oxidation and consecutive β-oxidation through a CYP3A-dependent mechanism.54,55The selective effect of propofol on γ-T levels may be explained by the different turnover and metabolic rates of the two tocopherol isoforms, possibly related to their chemical structure.55,56
It should be mentioned that potential limitations may have affected the results of our study. Basic hemodynamic parameters could not be measured continuously in all patients because, according to the clinical practice of our institution, only selected patients had a Swan-Ganz catheter in place. Therefore, the influence of these parameters on γ-T or other analytes cannot be excluded. In addition, differences in anesthetic regimens other than propofol may have affected γ-T levels. To our knowledge, however, a specific effect of any of the drugs administered in the control treatment on γ-T has never been documented. Although a protective effect of sevoflurane against reperfusion injury has been reported,57this could be hardly put in relation with a decrease, or even with a lesser increase, of plasma γ-T.
Moreover, the sample size of the study did not allow enough statistical power to detect small differences in several of the comparisons reported. Specifically, the lack of significance in the comparison performed on α-T levels in PBMLs and on IL-10 production in WB should be considered with due caution.
The use of delta values in the statistical analysis also deserves some clarifications. Our approach was adopted a priori to control the intersubject variability. In addition, when the analysis was performed using actual values, similar results were obtained: As expected from the reduced statistical power, P values were generally higher (data not shown), but the significance of the main findings was unchanged.
In conclusion, our data show that γ-T levels are significantly increased in patients treated with propofol, compared with patients treated with the control anesthetic regimen. This effect was detected both in plasma and in mononuclear leukocytes and is associated with reduced COX-2 activity. These findings suggest for propofol a novel antiinflammatory effect, which may be relevant in controlling the inflammatory response related to tissue injury after reperfusion. Whether this antiinflammatory effect translates into a clinically significant outcome remains to be determined on the basis of properly powered clinical trials.
The authors thank Loredana Boccotti (Technician, Institute of Cardiology, University of Milan, Milan, Italy) for her expert technical assistance.


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How to Disable the Limit of Meeting Length for Room Calendars in Office 365?
Introduction: Efficiently managing meetings is crucial for any organization's productivity, and one common challenge is ensuring that meetings don't run longer than necessary. In a fast-paced workplace, time is a valuable resource, and lengthy meetings can hinder progress on other important tasks. Fortunately, with the power of Office 365, specifically
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Mental Health First Aid Milton Keynes
Milton Keynes MHFA courses
Taking a Mental Health First Aid (MHFA) England course gives you the countries leading certificate in Mental Health First Aid to become a MHFAider®. The MHFA course is part of an international programme with over 5 million people trained in MHFA skills worldwide and over 500,000 in England alone.
The course is grounded in research, and extensively evaluated. The training is in-depth but our experienced instructors keep this light and easily digestible whilst being incredibly thought provoking. See the full MHFAider® course outline
We run MHFA courses every month in Milton Keynes and individual places can be booked (see below) You can also organise private group training if you have a group of 6 or more people to train.
Milton Keynes MHFA
09:15 - 17:00 Each Day
February 2024
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June 2024
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Booking MHFA training for 6 or more people?
You have the option of private group training on your chosen dates. Please contact us for bespoke pricing firstname.lastname@example.com
All course materials provided: Detailed workbook to keep, Digital manual, MHFA England lanyard,
Certification. Now also includes three years access to the MHFAider® support app and benefits.
Pricing: We have some subsidised places available for £300pp (otherwise usually £325pp as valued by MHFA England) Multi booking discounts apply, please ask for details based on your numbers.
Many organisations are opting to train staff in MHFA ahead of anticipated legislative change, however if you are self funding your place please ask about our free instalment payment options.
Venue: Milton Keynes Business Centre, Foxhuter Drive, MK14 6GD.
Ample free parking on site.


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Snapshots by Gloria Freeland -- Jan. 15, 2004
A different sort of holiday
For an adult, the holidays are often a somewhat bittersweet experience. We look forward to Christmas with eager anticipation just as our children do, but often for very different reasons. Their heads are filled with thoughts of gifts, while we wonder how they will enjoy what Santa, their parents and others will give them. But those of us who have left our childhood far behind for most of the year find our thoughts drifting back to our own youth with fleeting feelings of wishing we could return to those times.
And New Year's Day can easily produce an even stronger sense of mixed feelings. We look ahead to the new year which lies before us while reflecting on the old one which has passed.
All of these feelings were amplified for my family this year. While Art went North to be with his relatives, Mariya, Katie, Mom and I went South to Bolivia to visit my sister and family. It was the first Christmas in our 16 years together that Art and I were apart. We didn't like being separated, but we knew we would both have a good time and could share what we were experiencing through daily e-mails.
The reasons for going this particular year also produced a blend of emotions. Mariya will be completing high school in May, which is a traditional turning point in most lives. And my niece Gabriela reached 15 in early January, the age in Bolivia where a girl crosses the imaginary line to become a woman.
On Dec. 21 we said goodbye to winter and the low relatively flat plains of Kansas. The next day we arrived in Bolivia's capital La Paz, which is surrounded by the peaks of the Andes mountains. No capital city in the world has a greater elevation. Its two million people live at an altitude about twice as high as Denver. The comparatively thin air takes a while to get used to and some visitors experience problems with headaches caused by a lack of oxygen.
My sister Gaila, her husband Humberto and their two girls were waiting for us at the airport. We jostled through the immigration and customs lines and then got into two taxis that took us to their home in the southern zone of the city. We spent most of the remaining part of that day resting.
But by the next day, we were ready for some Bolivian-style shopping. We went downtown to find street vendors, men and women in business suits, women in felt bowler hats and colorful embroidered shawls, men bent over by the heavy loads they were carrying on their backs, and mangy dogs competing for space on the sidewalk. The narrow cobblestone streets were filled by buses, trucks and compact cars.
Bolivian culture is a strange blend of Catholicism mixed with native beliefs, such as deep reverence for the Pacha Mama -- Mother Earth -- and the custom of carrying small figures of different animals to ensure luck in certain aspects of life -- a condor for safe travels, an owl for knowledge, a frog for fortune, a turtle for long life, a fish for good health, a snake for courage or a puma for power.
I again felt a strange mixture of emotions. Our senses were overloaded by the sights, sounds and smells. One moment I was enjoying the multi-colored aguayos -- textiles the women sling over their backs and tie around their necks to carry babies or produce -- the spectacular colonial architecture and the wonderful aroma of baking bread. The next I was repulsed by the odor of rotting vegetables or feeling sad for the beggars extending their hands for a few Bolivianos, worth about 13 cents each. Then I was startled by a vendor saying, "Señora, cómprame papas" -- Lady, buy some of my potatoes.
We didn't buy potatoes, be we did purchase some alpaca scarves and hats, tiny nativities constructed inside eggshells and painted clay vases.
It was still two days until Christmas would arrive, but our emotional Christmas stocking had already been stuffed to overflowing.
A woman sells llama fetuses and good-luck charms at
the witches� market in downtown La Paz, Bolivia.


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We're excited to announce that an NCAA meet is set to return to Elevate the Stage Toledo in 2024!
The 2021 National Champions, the Michigan Wolverines, will compete head to head on podium with the Rutgers Scarlet Knights in an exciting Big10 matchup on Friday, February 16, 2024 at 7:00 p.m. ET.
Purchase your tickets today!
The intuitive and user-friendly design of Elements_Efi has been specifically crafted to reduce the learning curve for users, making it accessible to people of all skill levels and backgrounds.


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Intraday Futures Quantitative Researcher
We are excited to announce a new opportunity for highly talented intraday futures quant researchers. Our client, a tier 1 hedge fund based in New York City, is looking for an experienced Intraday Futures Quantitative Researcher to join their dynamic quant research and trading team. The successful candidate will be responsible for conducting research and handling implementation for intraday trading signals across global futures/FX markets.
Key Responsibilities:
- Work collaboratively with the trading team to optimize the current trading strategy and identify/implement new trading signals
- Research and implement new trading tools to improve the trading efficiency
- Lead signal research for new alphas in global intraday futures/FX
- Collaborate with the broader quant research and trading team
- Advanced degree (MS/PhD) in a technical or quantitative discipline such as mathematics, statistics, physics, computer science, etc.
- Strong proficiency with Python/C++
- 1+ year of experience in hands on research for intraday futures/FX trading signals
- Ability to understand the optimization of trading systems and strategies in a low latency environment


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DUBROVICHI (Ryazan Region) (Sputnik) — Russia's upgraded Tu-160M2 supersonic bomber may make its maiden flight as early as in late 2018, the nation's Aerospace Forces commander said Thursday.
Last year, Russia announced the comeback of the Soviet-era Tupolev Tu-160 (NATO reporting name Blackjack) in its upgraded Tu-160M2 variant, pushing back the final phase of developing the next-generation PAK-DA bomber until later.
"The first Tu-160M2 is expected to take off by the end of 2018, followed by full-scale production in 2021," Col. Gen. Viktor Bondarev told journalists.
The Russian Defense Ministry estimates that serial production of the upgraded strategic supersonic bomber will begin in 2023. It plans to buy at least 50 aircraft.


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Shellac is more likely to play Reykjavik than Detroit, and more likely to release songs on flexi-discs in Dutch comic books than provide MP3s on their website, Shellac (or Shellac of North America) will always be known for doing it their way. That's what the guys write about themselves on their myspace-page. Producer and guitarist Steve Albini, drummer Todd Trainer and bassist Bob Weston have carved out a sizable niche in the sewage-infested gutters of underground rock & roll. As with Big Black, Shellac provides a forum for Albini to air his thoughts on the uglier side of humanity, though lowering the perversity and upping the humour a notch. An early claim was that all Shellac songs concerned either baseball or Canada, sometimes both in the same song… Always featuring a raw sound, the band's recordings rarely (if ever) employed overdubs. Economy and precision were always at the top of the priority list. Shellac tours at a sporadic pace, usually in geographic locations they want to visit, and frequently playing in unconventional confines such as riverboats… Well, the A is proud to host them in a proper venue in Luxembourg.
- Venue: den Atelier
- Where: 54 rue de Hollerich, 1740 Luxembourg
- Doors: 7:00 pm


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The disk does not have english audio and subtitles. Swiete ksiegi hinduizmu wedy najprawdopodobniej powstaly ok. Roni telewizja kablowa 3 generacji, internet swiatlowodowy. View a custom newsfeed of your favorite artists and models.
A executable file after downloading it onto their computer. Kasia kmiec assistant planner, community planning city. Hailing from gliwice, poland, kasia sokallas stunning voice has entertained audiences in the united states and across europe. Kasia sokalla vocalist, boston, southern nh, north of boston. Polish release, cover may contain polish textmarkings.
To get the latest information you can contact the property you have booked to check if they can accommodate you. A magna cum laude graduate of berklee college of music, kasia established herself as a worldclass artist including. As you might have heard, service has got into trouble and you cannot download your original files without paying extra to them. Jest absolwentka akademii muzycznej w katowicach, gdzie studiowala na wydziale jazzu i muzyki rozrywkowej kariera. Kasia wojtasik quilling artist use paper strips to create pretty things. Download kasia torrent or any other torrent from the other pictures. Discover more music, concerts, videos, and pictures with the largest catalogue online at. Kasia klich w tobie tone radio edit official audio. Shop for vinyl, cds and more from katarzyna klich at the discogs marketplace.
Kasia kolodziejs kkolodziej software portfolio devpost. This tiny ruby script will try to fetch all your original photos without accessing ftp, but. Listen free to kasia klich calvados calvados yaro remix, calvados wersja instrumentalna. Telewizja kablowa 3 generacji, internet swiatlowodowy. No art or text might be reproduced without prior written permission. Lubie wszystko co kobiece i z tym zwiazane, przebieranie sie, malowanie, szukam kogos z kim mozna by wspolnie realizowac te fantazje. Where can i send a letter of concern about a threat to a world heritage site, or a site on the list of world heritage in danger. Join facebook to connect with katarzyna klich and others you may know. Discover top playlists and videos from your favorite artists on shazam.
View kasia kmiecs profile on linkedin, the worlds largest professional community. Please be aware that due to the current circumstances, it may take us longer than. She studied jazz vocal, and went on to become a successful and recognizable polish artist. Criminals use social engineering tactics to trick inexperienced computer users into opening the win32trojandownloader. Rodo, informujemy, iz panstwa dane osobowe zawarte w plikach cookies sa przetwarzane w celu i zakresie niezbednym do udostepniania niektorych funkcjonalnosci serwisu. Where can i send a letter of concern about a threat to a. Program posiada wyszukiwarke, dzieki temu nie trzeba odwiedzac strony wrzuta. The world heritage committee relies on citizens to play an active role in protecting world heritage sites. Pojawiala sie goscinnie w nagraniach innych wykonawcow. By using our website and our services, you agree to our use of cookies as described in our cookie policy. The mysterious masked group blood cultures returns with a record of bubbling. This setting will switch the output refresh rate to the best refresh rate that is supported by the display and by the hardware kodi is running on as reported by edid when playing a video file. See the complete profile on linkedin and discover kasias connections and jobs at similar companies.
Pisala teksty piosenek dla zenskiej grupy taboo pod koniec lat 90. Cluster is hosted on comicgenesis, a free webhosting and site automation service for webcomics. Zapraszamy do zapoznania sie z jej funkcjonalnosciami, nasza oferta oraz informacjami o firmie. She earned her masters of arts majoring in piano solo performance from fryderyk chopin academy of music in warsaw. Facebook gives people the power to share and makes the world more open and connected. See the latest soccer live score information, fixtures and results for 8 january 2017, brought to you by livescore today. Due to the current situation related to the coronavirus, we understand you may need to change your travel plans. You can also visit our help centre for support with making changes to your booking. Her solo albums include lepszy model 2002, kobieta szpieg 2003, zaproszenie 2006 and porcelana 2008, all of which were produced by yaro. A is a trojan downloader that installs various types of threats on affected computers. Find art for sale at great prices from artists including paintings, photography, sculpture, and prints by top emerging artists like kasia derwinska.
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We independently selected these deals and products because we love them, and we think you might like them at these prices. E! has affiliate relationships, so we may get a commission if you purchase something through our links. Items are sold by the retailer, not E!. Prices are accurate as of publish time.
I know, I know. It seems way too early to even be reading the word "fall" right now when we're still in the middle of summer, but like it or not, the changing of the seasons is right around the corner. While all these huge summer sales are going on, it would be a waste to not take advantage of all the great deals on fall fashion finds.
When the temperature starts to cool down and the weather changes from nice and sunny to nice and cloudy, you're going to need a few essentials to keep you warm. Good thing big sales events that are happening right now don't exclusively have summer items—they have tons of deals on fall clothing too! For example, the Nordstrom Anniversary Sale has so many big deals on things like coats, sweaters, boots, and pants that you're definitely going to need when the fall comes around. Other brands like Madewell, Everlane, J.Crew, and Old Navy also have sales you should check out.
Use your time right now to score discounts on fall items that would otherwise be a pretty hefty investment if you buy it during the season. Trust me, you'll thank yourself later. Read on for our favorite fall fashion finds on sale right now.
Free People Homecoming Plaid Blanket Scarf
Don't forget, fall season is coming up, and this oversized Free People scarf is the perfect accessory to bundle up for the cold weather.
Thread & Supply Plaid Woven Shacket
Take the classic plaid flannel look up a notch with this woven "shacket" at the Nordstrom Anniversary Sale.
Madewell Cable Ashmont Cardigan Sweater
Of course, fall is cardigan season. Get this chunky knit fisherman cardigan that will definitely become a staple in your wardrobe this upcoming season.
Athleta Arrival Trench
When the fall season brings its seasonal showers, you need to be prepared. Get this lightweight trench coat from Athleta that also has a cinched drawstring waist so you don't lose your shape in the fabric.
Champion Campus French Terry Quarter Zip Sweatshirt
If you are looking for a chill, comfy look for the fall, you need to get this quarter zip sweatshirt from Champion. It's super cozy, but also moisture-wicking for added comfort.
Lauren Ralph Lauren Double Breasted Wool Blend Coat
Get this wool blend coat for the cool seasons coming soon from Lauren Ralph Lauren. This coat has a classic mens-wear inspired look that will become a versatile staple piece in your closet for layering. You don't want to miss this seal.
Levi's LEVIS Ex-Boyfriend Trucker Jacket
If you've been meaning to get a Levi's denim jacket, now's your chance. You can get this light wash, distressed trucker jacket for only $40 at Nordstrom Rack.
Abercrombie Vegan Leather Shearling Jacket
Get this super chic leather jacket on sale at Abercrombie for more than half off. It's the perfect outerwear to keep yourself warm while also having a flawless outfit.
Steve Madden Haylan Chelsea Boot
What better place to get a long-lasting, high quality pair of shoes than from Steve Madden? These suede booties are the perfect fall shoe.
AllSaints Maeve Knee High Chelsea Boot
There's no such thing as too many pairs of boots. These leather knee-high ones from AllSaints have elastic side panels for a more snug fit and are perfect to wear with a cute plaid skirt.
Levi's Ribcage Ripped High Waist Ankle Straight Leg Jeans
Who doesn't love a good pair of Levi's? You can get this pair of classic high waisted jeans for $32 off. It is made with a soft cotton blend, but still has limited stretch like other Levi's. You are getting a straight leg jean with a little distressing that will definitely become a staple in your wardrobe.
Everlane The Organic Wide-Leg Pant
If you want an alternative to denim, these wide leg pants fit perfectly into a classic fall aesthetic. These warm mustard yellow pants have a "waist-nipping, butt-boosting, leg-lengthening look" that will definitely make you stand out.
Good American Good Skate High Waist Wide Leg Jeans
Good American is known for their high quality and size inclusive denim, and everyone needs a go-to pair of jeans in the fall. These pants from Good American have a fashionable wide leg and looser fit.
UGG Discoquette Genuine Shearling Slide Slipper
UGG is a huge seller at the Nordstrom Anniversary Sale, so make sure to grab a pair for yourself to wear in the upcoming fall and winter seasons. This style of UGG slippers is super trendy right now. They come in six different colors.
Steve Madden Cassady Loafer Mule
Grab a pair of Steve Madden shoes for $30 off at the Nordstrom Anniversary Sale. This pair of loafers come in a mule style with a chain link detail that lets you dress with a classy, professional style while still feeling relaxed. This loafer comes in six colors or patterns.
AllSaints Cleo Balloon Sleeve Top
AllSaints is a great brand to shop luxury items at a lower price point, and you can get even more deals at the Nordstrom Anniversary Sale. This elegant wine red top is $80 off and it would make a perfect outfit for a holiday party with the silky balloon sleeves and mock turtle neck.
J.Crew Relaxed Cashmere T-shirt
You can get a lot of J.Crew clothing on sale right now, so you should take advantage of the discounts on their popular cashmere which is great to keep you nice and cozy for the fall. This best-selling cashmere shirt is on sale for $40 off.
Free People Isla Cable Stitch Tunic Sweater
Everyone needs a good cable knit sweater, especially with fall right around the corner. This sweater from Free People is in a tunic style which will have an oversized fit and end around the mid thigh. You can choose from five colors.
If you're looking for more sales to shop today, check our list of the best activewear deals you can score at the Nordstrom Anniversary Sale.


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Bali Villas
Advertising Bali, Advertising Bali Company, Advertising Bali Neon Box, Advertising Bali Signboard, Advertising Bali Papan Nama, Advertising Bali Reklame, Advertising Bali Baliho, Advertising Bali Billboard, Advertising Bali Spanduk, Advertising Bali Banner
Villa Damai
Step into an oasis set amongst a tropical garden and unwind with the tranquility of tropical breezes swaying through the trees. Let your senses free and discover the magic of Villa Damai…..your secret and exclusive Balinese Hideaway.
Location | : | Seminyak |
Price | : | US$ 225 – US$ 295 |
Setting | : | Complex of Villas |
Bedrooms | : |
Villa Damai Besar
4 bedrooms double storey villa on 900 m2 land area. 3 bedrooms on the 1st level and the master bedroom on the 2nd level. The bedrooms open on to the swimming pool, sunbathing area & tropical gardens. Each bedroom has air conditioning, en-suite bathroom, daybed and wardrobe. Fully equipped kitchens with separate dining & lounge areas, private entrances, satellite TV on 42″ Plasma TV, DVD and full housekeeping service.
Villa Damai Bali is managed by an experienced team who will ensure that your every holiday need is looked after. Villa Damai Bali provides the quality and service one would expect from the natural warmth and hospitality of the Balinese. Invite friends for cocktails, or a dinner party overlooking the garden & pool, all catered for by our skilled villa staff.
Each one of the 4 villas includes:
– Spacious bedrooms all with en-suite bathrooms with modern facilities
– Ultra large Master bedroom
– All bedrooms are air-conditioned with mosquito nets, safe deposit boxes and basic bathroom items
– A large swimming pool with deckchairs, towels and sun umbrellas
– A high ceiling and airy living room adjoining the charming dining room
– Trained staff at your service to provide personalized service to ensure your stay is memorable
– 24hr security
– Unlimited Wi-Fi connection
– Flat screen TV, DVD player and cable with 50 international channels
– Fully equipped kitchen
– Baby-sitting or child minding service can be arranged at extra cost
– Vehicle rentals, excursions with guides, massages, dinners etc. can be arranged upon request
– 24 hours hotline services in case of emergency problems
Present by:
Bali Advertising, Advertising Bali,Bali Advertising and Printing, Advertising and Printing Bali, Bali Printing, Printing Bali, Bali Acrylic Media, Acrylic Media Bali, Bali Baliho, Baliho Bali, Bali Banner, Banner Bali, Bali Billboard, Billboard Bali, Bali Car Branding, Car Branding Bali, Bali Cutting Stiker, Cutting Stiker Bali, Bali Digital Printing, Digital Printing Bali, Bali Graphic Design, Graphic Design Bali, Bali Web Design, Web Design Bali, Bali Interior, Interior Bali, Bali Letter Timbul, Letter Timbul Bali, Bali Neon Box, Neon Box Bali, Bali Neon Sign, Neon Sign Bali, Bali Produk Las, Produk Las Bali, Bali Shop Branding, Shop Branding Bali, Bali Spanduk, Spanduk Bali, Bali T Banner, T Banner Bali, Bali Umbul-Umbul, Umbul-Umbul Bali, Bali Photography, Photography Bali, Bali Brosur, Brosur Bali.


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Optimize everything!
E-commerce is nothing without the physical logistics that deliver it. It's the truck drivers, warehouse workers and distribution managers who are the true infrastructure of online commerce. They need digital tools to optmise and fine-tune every detail of their operation to keep meeting ever-growing consumer expectations. And they need networks that let them do it.
Digitalize your vehicles and optimize your fleet
Telia Connected Vehicle is an end-to-end solution that consolidates all of your vehicle's digtal systems and puts them an onboard screen for your drivers and a cloud-based dashboard for you.
For drivers it simplifies the increasingly digital nature of driving. It gives them real-time data from all of the digital systems in the vehicle on one screen.
For fleet managers – whether you operate 2 or 200 vehicles – it gives you the ability to manage and optimise your vehicles and fleet in real time. As well as your cloud-based portal, you can also feed data into your existing management systems via API.
Drive your fuel costs down
In anything measured in kilometres and hours; efficiency matters. Nowhere is this more true than in transport, and as the largest cost component of most supply chains, even small efficiency improvements compound into big differences.
Ecodrive is one of these apps. It gives drivers real-time feedback on how their driving performance affects fuel consumption. By understanding how braking, acceleration and gear changes affect the vehicles fuel consumption; you can save up to 12% on fuel costs and emissions. Read more
A flexible network that won't break
Connectivity is the oil that keeps the supply chain running smoothly. Your network needs to be able to evolve with your business. That's why we deliver modular and scalable connectivity solutions that give you maximum control. A Software-Defined Wide Area Network (SD-WAN) gives you control so you can maximise the performance for your core online functions, such as cloud applications. At the same time, you can reduce the connectivity costs of functions that are less business-critical, such as email and periodic reporting. Because SD-WAN is a cloud-based solution, you don't have the cost or risk of being stuck with obsolete technology. Read more about SD-WAN and Business Defined Networks.
Provide great customer service in all channels at once
Great customer experience means not only giving your customers visibility of where their cargo is, but also an easy and frustration-free way to communicate with you. Telia Ace is a customer service platform that lets your occupants communicate with you on their terms. Phone, chat, email, social media and text are all combined onto a single platform that makes it simple for your customer service team to respond quickly and solve problems in a timely manner. Learn more about Telia Ace Customer Service Platform.
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Top Tips to Get Your Little Ones Brushing
For many parents, teaching kids good dental hygiene is a twice-daily struggle, but it's a hassle worth having. Teaching your kids about the importance of brushing from a young age will help them form good habits into adulthood. But sometimes, however hard you try to get them to brush, they just don't seem to want to budge. If you're a parent, here are some tips on getting your child used to an oral hygiene routine.
Let them be your brushing partner
You've been brushing your child's teeth for them but now's the time for them to do it themselves. Children look up to their parents and love to copy what they do, so let this be something you and your child can do together. As they observe the way you brush your teeth, they will eventually copy and adhere to your style of brushing. Having a routine helps them to get used to brushing at a specific time and to learn how long to brush for. You will eventually become their brushing partner.
Make brushing an activity
If something isn't exciting it's hard to get your child to stick to it, so why not turn to brush into a game? Having things such as a mini sand timer can help them to keep an eye on how long they brush their teeth – they can stop when the sand timer is done. You can also purchase specific toothbrushes that light up for the recommended time of brushing – they will then know when to stop when the light goes off. Another alternative to this is to play a 2-minute song. Once the song is over, they can stop brushing. Making brushing into a fun little challenge will hopefully keep them wanting to win every single time.
Visit the dentist regularly
Getting your child used to the dental practice as soon as possible can instil good habits that will last a lifetime. Once they start to visit the dentist regularly, it allows your child and the dentist to form a positive relationship, making it much easier for them to return in the future.
At Harwood Dental, we think little teeth need just as much care as big teeth do. That's why when you visit with us, we can help you with teaching your children about how important it is to clean their teeth properly, as well as show them what they need to do. For more on our child dentistry, please do not hesitate to contact us. You can also visit our website for even more information.


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Software Essentials
These are all must-have software applications for your PC. The best part is that all are absolutely FREE!
CamStudio – Free Streaming Video Software
CamStudio is able to record all screen and audio activity on your computer and create industry-standard AVI video files and using its built-in SWF Producer can turn those AVIs into Streaming Flash videos (SWFs)
URL: http://www.camstudio.org/
Java Runtime Environment
Java allows you to play online games, chat with people around the world, calculate your mortgage interest, and view images in 3D, just to name a few.
URL: http://www.java.com/en/download/index.jsp
The way you listen, watch, manage and sync your media. Winamp is for people who like to customize, tinker and tweak: offering the widest range of extensions, skins, and services to add to your listening experience.
URL: http://www.winamp.com
Adobe Reader
Download free Adobe Reader X software to easily view, search, print, and comment on PDF files. Now more secure with Protected Mode.
URL: http://get.adobe.com/reader
Mozilla Firefox
Mozilla Firefox is a free and open source web browser descended from the Mozilla Application Suite and managed by Mozilla Corporation.
URL: http://www.mozilla.com
CDBurnerXP is a free application to burn CDs and DVDs, including Blu-Ray and HD-DVDs. It also includes the feature to burn and create ISOs, as well as a multilanguage interface.
URL: http://cdburnerxp.se
Please do not hesitate to let us know if you would like to see anything added to this list.
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text: Thank you for everything you did for me in helping me land this new role. I really had a feeling about them so thank you for sticking with me. Special thank you to Emma, for putting me forward and to Kristen, for the interview preparation! This job is an amazing opportunity for my career and will benefit my family as I seek to support them in the best way I can!


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Garmin inReach Mini
A "First Look" at the Garmin inReach Mini
This is original content from NewsBreak's Creator Program. Join today to publish and share your own content.
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Near Akron, Ohio, the Vineyard is named after Margaret's late daughter Sarah, killed in a tragic auto accident in 1998. The fields are now tended and cared for in her memory. The name is believed to be a good fit for the land, for as the seasons come and go, Sarah's Vineyard will reshape the abandoned fields into the image of a countryside once lost but not forgotten. After four years of hard work and dedicated service from the staff and volunteers, Mike and Margaret's vision came to life when the winery doors opened in May of 2007. The rustic, relaxed atmosphere sets the perfect backdrop for any occasion and is unique to Akron and surrounding areas.
Vineyard and Winery
The winery is constructed from a pre-civil war hand-hewn timber frame and finished with cherry, aspen, poplar, walnut, and maple. The barn's support beams were initially located near Cloverleaf High School off State Route 224 in Medina County, Ohio. The barn was disassembled and moved to the Cuyahoga Valley National Park.
The Tasting Room
The tasting room focuses on the winery's main principle that houses the kitchen, bar, and main seating area. The tasting room keeps the rustic theme set with handmade wooden tables and a bar. It also serves as the art gallery, where you can browse and purchase local and national artists ranging from paintings, pottery, glass suncatchers, and other hand-crafted goods.
The Loft
The Loft was the first addition to the winery and was completed in 2011. It is a beautiful two-level space that overlooks the main tasting room. The loft serves as the party rental space and frequently hosts customer events such as bridal showers, birthday parties, and rehearsal dinners. When it is not rented, it serves as extra seating for the guests.
The Garden
The stunning and educational butterfly garden lines your walk as you enter the winery. Exotic flowers, plants, a koi pond, and a small waterfall are some of the features of this area. They also have several picneic tables available for guests, which offer a peaceful setting for private or group seating. Bed Bug Exterinator Akron
The Deck
The deck provides breathtaking views of the grapevines just outside the main tasting room. Watch as the vines grow over the season and dance in the wind. The deck is the best way to enjoy the true essence of the vineyard and Cuyahoga Valley National Park through the seasons. Feel free to walk the rows of vines and check out their beautiful fruit for yourself.
Address: 1204 W Steels Corners Rd, Cuyahoga Falls, Akron, OH
Check out other attractions like Stan Hywet Hall and Gardens


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Firstly, the variety is mind-blowing. No matter what mood I'm in or what genre I want to explore, there's always a station that caters to my taste. I've stumbled upon some hidden gems I wouldn't have found otherwise. https://radiointernetowe.online/
Another thing I love is the accessibility. With online radio, I can tune in from anywhere, whether I'm at home, work, or on the go. It's like having a personal DJ at my fingertips 24/7.
But the best part? The community! Many online radio stations have chat rooms or forums where fellow music lovers gather to discuss and share their favorite tracks. It's a great way to connect with people who share your passion.
So, if you haven't given online radio a try, I highly recommend it. It's a game-changer for music enthusiasts like me. What are your favorite online radio stations or experiences? Let's swap recommendations!
I just wanted to share my recent experience with online radio
Moderators: b1o, jkerr82508
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Re: I just wanted to share my recent experience with online radio
grrch.. what a dirt blast adversiting.. damn, the AI+GPT becomes ever more human like.. hmmpf...


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How Liability Differs From Responsibility In Injury Law
Posted on: 12 March 2021
Liability is the central concept in the work of a personal injury attorney. If you're trying to figure out whether you can sue or file a claim against a defendant's insurance, the big question is whether you can make liability stick. For someone who doesn't provide personal injury attorney services, liability may sound an awful lot like responsibility. There are some big differences between the two so take a look at them. [Read More]