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1Department of Experimental Medicine and Surgery, Tor Vergata University of Rome, Rome, ITALY; 2Department of Movement, Human and Health Sciences, Foro Italico University of Rome, Rome, ITALY; 3Department of Biomedical Sciences, University of Teramo, Teramo, ITALY; 4Center of Integrated Research, Campus Bio-Medico University of Rome, Rome, ITALY; and 5European Center for Brain Research/Santa Lucia Foundation, Rome, ITALY
Address for correspondence: Valeria Gasperi, PhD, Department of Experimental Medicine and Surgery, Tor Vergata University of Rome, Via Montpellier 1, 00133 Rome, Italy; E-mail: email@example.com. Mauro Maccarrone, MS, PhD, Campus Bio-Medico University of Rome, Via Alvaro del Portillo 21, 00128 Rome (Italy); E-mail: email@example.com.
Submitted for publication January 2013.
Accepted for publication June 2013.
Purpose: Endocannabinoids (eCB) and interleukin 6 (IL-6) levels change during physical activity, thus suggesting their involvement in the modulation of exercise-related processes like inflammation and energy homeostasis. To investigate whether lifestyle might affect the activity of the eCB-degrading enzyme fatty acid amide hydrolase (FAAH), active and sedentary subjects were enrolled.
Methods: Plasma IL-6 levels and lymphocyte FAAH activity of eight physically active male subjects (mean ± SEM; age = 39.3 ± 2.9 yr, body mass index = 21.1 ± 0.4 kg·m−2), usually practicing aerobic exercise (8.1 ± 1.2 h·wk−1), and eight sedentary subjects (38.8 ± 3.7 yr, body mass index = 23.1 ± 0.8 kg·m−2) were measured. Also, in vitro effect of IL-6 was tested on FAAH expression and activity and on FAAH promoter activity in lymphocytes from sedentary subjects.
Results: Under resting conditions (at least 12 h from the last exercise), the active group showed plasma IL-6 levels (2.74 ± 0.73 pg·mL−1) and lymphocyte FAAH activity (215.7 ± 38.5 pmol·min−1·mg−1 protein) significantly higher than those measured in the sedentary group (0.20 ± 0.02 pg·mL−1, and 42.0 ± 4.2 pmol·min−1·mg−1 protein). Increased IL-6 levels paralleled increased FAAH activity, and consistently, the in vitro treatment of lymphocytes from sedentary individuals with 10 ng·mL−1 IL-6 for 48 h significantly increased FAAH expression and activity. Transient transfection experiments showed that IL-6 induced the expression of a reporter gene under the control of a cAMP response element–like region in the human FAAH promoter. A mutation in the same element abolished IL-6 up-regulation, demonstrating that this cytokine regulates FAAH activity at the transcriptional level.
Conclusion: IL-6 leads to activation of the FAAH promoter, thus enhancing FAAH activity that modulates the eCB tone in physically active people.
In modern society, sedentary lifestyles prevail on active living, thus perturbing mental and physical health (39). Indeed, it is well documented that exercise improves cognitive functions (39), attenuates the increase in stress hormones (5), and leads to positive emotional effects (11), overall reducing the incidence and severity of stress-related psychiatric disorders, including depression and anxiety (36). Physical activity also improves body energy homeostasis by ameliorating insulin resistance and glucose metabolism and by improving blood lipid profile, that is, by decreasing plasma triglycerides and low-density lipoproteins and by increasing high-density lipoprotein cholesterol (18). Therefore, it is not surprising that regular physical activity has been reported to reduce, in the long term, the risk of obesity, cardiovascular diseases, type 2 diabetes, and metabolic syndrome as well as to ameliorate symptoms of conditions usually characterized by chronic low-grade systemic inflammation (30). Conversely, sedentary lifestyle leads to visceral fat accumulation, paralleled by macrophage infiltration in the adipose tissue, which in turn releases pro-inflammatory cytokines like tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6) (28).
In the last decade, a growing body of evidence has demonstrated that exercise of various types, durations, and intensities affects cell immune functions, ultimately altering the balance between pro- and anti-inflammatory cytokines (30). In response to contraction, skeletal muscle also releases several cytokines and peptides (called "myokines"), able to modulate energy metabolism and immune response (30). In this scenario, a key role is played by IL-6, a pleiotropic cytokine that is released from the contracting skeletal muscle depending on intensity and duration of exercise (30). Despite its classification as a pro-inflammatory cytokine, IL-6 has emerged as a key player that accounts for the protective and anti-inflammatory effects of regular exercise (30,39). Indeed, during exercise, IL-6 promotes the release of IL-10 and IL-1 receptor antagonists (both anti-inflammatory cytokines) as well as of the soluble TNF-α receptor, which in turn inhibits TNF-α production (30). In addition, IL-6 enhances insulin sensitivity, hepatic glucose production, lipolysis, and fat oxidation, overall exerting an important metabolic role during exercise (30).
The endocannabinoid system is an ubiquitous and complex signaling network that includes the following: (i) endogenous lipid mediators (collectively termed "endocannabinoids" [eCB]), like N-arachidonoylethanolamine (anandamide [AEA]) and 2-arachidonoylglycerol (2-AG); (ii) their molecular targets, especially type 1 (CB1) and type 2 (CB2) cannabinoid receptors; and (iii) different proteins involved in their synthesis, transport, and degradation (24). Among the latter proteins, a major element is fatty acid amide hydrolase (FAAH), which is crucial in regulating the eCB tone in vivo (9) by degrading AEA, 2-AG, and their congener N-palmitoylethanolamine (PEA) (24).
It has been clearly documented that eCB play a critical role during inflammation and immune response, as they modulate the activation and migration of immune cells (19,34) as well as the expression of inflammatory cytokines, including TNF-α, IL-6, IL-2, IL-8, IL-17, and IL-4 (7,34). Also, the ability of eCB to control energy homeostasis has received a great deal of attention, particularly in the light of their ability to influence appetite and food intake as well as glucose and lipid metabolism (24). It is well known that the eCB system is involved in the onset of obesity and related complications. For instance, AEA inhibits synthesis and release of adiponectin, an insulin-sensitizing and anti-inflammatory cytokine, while it increases synthesis and release of the pro-inflammatory adipocytokine visfatin, whose expression is regulated by insulin resistance-inducing hormones (24). Moreover, CB1 antagonism decreases TNF-α secretion and restores adiponectin release from lipopolysaccharide-treated adipocytes (26).
The available experimental evidence indicates that eCB might account for some of the biological effects triggered by physical exercise. For instance, increased plasma levels of AEA and PEA, but not of 2-AG, have been observed in human subjects after aerobic exercise (11,17,32, 33,37). The increase of AEA levels depends on exercise intensity and occurs upon moderate exercise, but not at low or high exercise intensities (33). Interestingly, the effect of exercise on eCB levels seems to be strictly species specific, with a role for eCB only in those mammals that are morphologically adapted to endurance exercise (32). In this context, it has been proposed that once released into the bloodstream, eCB readily pass through the blood–brain barrier and influence the neurobiological reward associated with exercise, thus contributing to the immediate feeling of well-being (11). In addition, the evidence that eCB exert different effects at central and peripheral levels, and that CB1 and CB2 receptors are localized in muscle, adipose tissue, endothelial cells, and lung (24), suggests a role for eCB in regulating physiological responses to exercise.
However, data on the effects of physical activity on the eCB system are still sparse and sometimes conflicting, possibly because of differences in training protocols (acute vs chronic exercise) and/or in species (humans, mice, rats, or ferrets) used as paradigms. For instance, although short exercise protocols up-regulate eCB transmission in the striatum of mice (10), prolonged aerobic exercise significantly reduces striatal and hippocampal CB1 expression in adolescent rats (14) as well as in adipose tissue of a rat model of metabolic syndrome (43).
Against this background, here we sought to investigate how lifestyle could influence the eCB system. Unlike other studies aimed at analyzing changes in eCB levels in response to acute exercise, our purpose was to study how two different lifestyles (sedentary vs physically active) may influence plasma levels of IL-6 and the key eCB-metabolizing enzyme FAAH, which is known to play a primary role in controlling eCB tone in vivo (9). We demonstrated that, when compared with the sedentary group, active subjects practicing regular aerobic exercise have a significantly higher content of circulating IL-6 as well as increased lymphocyte FAAH activity. We also found an IL-6-mediated enhancement of FAAH activity and expression in vitro, triggered by a cAMP response element (CRE)–like-dependent up-regulation of FAAH promoter activity.
In conclusion, our data demonstrate that IL-6, the most abundant cytokine produced during exercise, can directly regulate FAAH expression and activity, and hence eCB signaling, upon regular exercise.
Chemicals were of the purest analytical grade. AEA, IL-6, and protease inhibitors cocktail were purchased from Sigma Aldrich (St. Louis, MO). Ethanolamine-1,2-[14C] ([14C]AEA, 50 mCi·mmol−1) was from American Radiolabeled Chemicals, Inc. (St. Louis, MO). Lympholyte-H was from Cedarlane (Burlington, Ontario, CA). TRIzol® reagent was from Invitrogen (Carlsbad, CA). Mouse antibody directed against FAAH was from Cell signaling Technology, Inc. (Danvers, MA); mouse antibody directed against β-actin, as well as secondary antibodies conjugated to horseradish peroxidase, were from Santa Cruz Biotechnology (Santa Cruz, CA). Enhanced chemiluminescence (ECL) kit was from Amersham Biosciences (Piscataway, NJ).
Sixteen healthy volunteers participated to this study: eight active male subjects (mean ± SEM; age = 39.3 ± 2.9 yr, height = 173.5 ± 0.8 cm, weight = 70.8 ± 2.9 kg, body mass index [BMI] = 21.1 ± 0.4 kg·m−2), all self-reported fit, healthy and practicing sports with essentially aerobic metabolic work (running, swimming, cycling) for 8.1 ± 1.2 h·wk−1; and eight sedentary subjects (age = 38.8 ± 3.7 yr, height = 175.0 ± 1.5 cm, weight = 77.5 ± 2.3 kg, BMI = 23.1 ± 0.8 kg·m−2). Sedentary group requirement was no participation in a regular exercise program or any activity beyond normal daily habits, within the previous 12 months. All subjects were healthy, after a standard Mediterranean diet (which included, on average, two regular serves of vegetables and two/three of fruit per day), did not smoke or take dietary supplementation of vitamins and/or antioxidants. Subjects underwent a medical examination to exclude any disease, fever, and medical treatment that could affect the immune system as well as the use of drugs (with the exception of β-blockers) that could affect cardiopulmonary functions. Participants received an informative report showing the aim of the study, methods, and related risks. Informed consent and local ethics committee approval was obtained for these human studies.
Before inclusion in the study, all subjects performed two tests to confirm the differences in aerobic fitness level between groups: the Harvard Step Test (HST), determining the fitness index score (35), and the measurement of maximal oxygen uptake (V˙O2max) through cardiopulmonary maximal stress test at increasing loads on a cycloergometer (Ergocard II, ESAOTE BIOMEDICA®) linked to an ergospirometer (Cardio2 MEDICAL GRAPHICS®). At the beginning of the maximal stress test, the exercise load was fixed at 30 W for 2 min, then it was increased 10 W every min until reaching 85% of maximal heart rate (HRmax) for the age (calculated through the formula: HRmax= 220 − age in years). Blood pressure was assessed through a mercury sphygmomanometer, during and at the end of the test. Subjects were monitored during the recovering period after the effort, for 5 min, through electrocardiogram and blood pressure measurement. According to the literature (12), the test was stopped when one of these situations occurred: symptoms onset, complicated arrhythmias onset, significant ST segment anomalies, muscular exhaustion, and reaching of V˙O2max. According to the classical definition of V˙O2max, we considered that it was reached when: the subject reached a plateau, that is, when V˙O2 increased less than 150 mL·min−1, rising from a step to the next one; respiratory exchange quotient exceeded 1.08–1.10; the subject had more than 10 beats over maximum HR for the age. No subjects showed cardiovascular or respiratory problems, and none had any evidence of musculoskeletal injury.
After performing maximal stress test, subjects were instructed not to change their level of physical activity in everyday life nor their dietary habits. Blood samples were collected 1 wk later. No breakfast or coffee was allowed in the morning of blood collection. Active and sedentary subjects provided antecubital venous blood (20 mL per donor) at 8:00 a.m. under resting conditions (i.e., without performing any exercise 12 h before testing). Part of blood was immediately centrifuged at 3000g for 10 min at 4°C to obtain plasma and then kept frozen at −80°C until analysis. Peripheral lymphocytes were purified by gradient centrifugation, using the density separation medium Lympholyte-H, as previously reported (22). After this procedure, isolated cells consisted of lymphocytes (∼85%), B cells (∼10%), and monocytes (∼5%). Cells were resuspended in DMEM-F12 1:1 medium, 2 mM glutamine, 100 U·mL−1 penicillin, 100 μg·mL−1 streptomycin, and 10% heat-inactivated fetal bovine serum, at a density of 1.5 × 106 cells per milliliter. The treatment of lymphocytes with IL-6 was performed at 37°C in humidified 5% CO2 atmosphere, at the indicated concentrations and for the indicated periods of time. Controls were incubated with vehicles alone. After each treatment, cell viability was tested by trypan blue dye exclusion and was found to be always ≥95% (22).
Plasma IL-6 concentration was determined using a quantitative sandwich enzyme immunoassay technique, according to the manufacturer's instructions (R&D Systems Europe, Abingdon, UK). Briefly, 100-μL plasma was incubated for 2 h in a 96-well enzyme-linked immunosorbent assay (ELISA) plate, precoated with a specific antibody directed against human IL-6. After washing and reacting with enzyme-linked polyclonal antibody (2 h), the specific substrate solution was added, and then absorbance was read at 450 nm (Bio-Rad 680 Microplate Reader; Bio-Rad Laboratories, Hercules, CA). IL-6 concentration (pg·mL−1) was calculated by extrapolation from a standard curve generated with serial concentrations of the standard protein solution provided by the manufacturer; values below the standard range were discarded.
The enzymatic activity of FAAH (E.C.220.127.116.11) was assayed in lymphocyte homogenates (50 μg of protein per test) or in whole blood (15 μL per test), by incubating samples with 10 μM [14C]AEA at 37°C for 30 min, in 50 mM Tris–HCl, pH 7.4 (final volume of 500 μL). The reaction was stopped with a mixture of 1 mL chloroform/methanol (1:1, v/v). After centrifugation at 3000g for 5 min, the release of [14C]ethanolamine from [14C]AEA in the aqueous phase was measured in a β-counter (Perkin Elmer Life Science, Boston, MA). FAAH activity was expressed as pmol of [14C]ethanolamine released per minute per milligram of protein or per milliliter of whole blood.
FAAH protein content was quantified by Western blotting. Lymphocytes were lysed in cold 50 mM Tris–HCl, pH 7.4, containing the protease inhibitors cocktail. Cell lysates (40 μg of protein/lane) were loaded onto 10% sodium dodecyl sulfate–polyacrylamide gels and blotted onto polyvinylidene fluoride membranes. The latter were blocked with 5% nonfat dried milk for 1 h and then incubated with primary anti-FAAH (1:1000) or anti-β-actin (1:30,000) antibodies. After washing and incubating with secondary antibodies (1:3000), detection was carried out using ECL. The semiquantification of the specific immunoreactive bands was performed with Image J software developed by National Institutes of Health (Bethesda, MD).
The detection of FAAH mRNA was performed by reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR). Total RNA was extracted from lymphocytes (3 × 106 cells per sample) using TRIzol® reagent, following the manufacturer's instructions. One microgram of RNA was used for reverse transcription reaction (InPromII kit; Promega, Madison, WI), by prewarming total RNA and random hexamers (1.25 ng·μL−1) at 70°C for 5 min and then by adding ImProm-II buffer, 5 mM MgCl2, 0.5 mM dNTP, 2 U·μL−1 RNaseOUT, 1 μL Improm II Reverse Transcriptase, and diethyl pyrocarbonate-treated water (final volume 20 μL). The reaction was performed using the following RT-PCR program: 25°C per 5 min, 42°C per 1 h, 70°C per 15 min. The target transcripts were amplified using an ABI PRISM 7700 sequence detector system (Applied Biosystems, Foster City, CA), using the following primers: human FAAH Fw (5′-GGTGCAGTACGAGCTGTGGGC-3′) and Rv (5′-GAAGCAGCAGGCCAGGGCG-3′); human β-actin Fw (5′-TGACCCAGATCATGTTTGAG-3′) and Rv (5′-TTAATGTCACGCACGATTTCC-3′). One microliter of cDNA was used for amplification in a 25-μL reaction solution, containing 12.5 μL of Platinum®SYBR®Green qPCRSuper-Mix-UDG (Invitrogen) and 10 pmol of each primer; samples were tested in triplicate. The following PCR program was used: 95°C for 10 min; 40 amplification cycles at 95°C for 30 s, 56°C for 30 s, and 72°C for 30 s. All data were normalized to the endogenous reference gene, β-actin. Differences in quantification cycle (Cq) number were used to calculate the relative amount of PCR target contained in each tube. The relative expression of different gene transcripts was calculated by the delta-delta Cq (ΔΔCq) method and was converted to relative expression ratio (2−ΔΔCq) for statistical analysis. After PCR, a dissociation melting curve was constructed in the 60°C–95°C range to evaluate specificity of the amplification products.
The construction of the vector containing the wild-type (wt) and mutated FAAH promoter region from +1 to –107 nucleotides has already been described (23). The same strategy was used to produce the vector with the +1 to –33 region of the FAAH promoter. Human lymphocytes were transfected, and chloramphenicol acetyltransferase activity was assayed as reported (23).
An ice-cold solution of acetone (1 mL), containing 10 pmol of d8-AEA, 500 pmol of d8-2-AG, and 100 pmol of d4-PEA as internal standards, was added to each plasma sample (500 μL). The precipitated proteins were removed by centrifugation (350g for 5 min) and the clear supernatant was recovered and evaporated to dryness. A mixture of methanol–chloroform–water (1:2:1, v/v/v) was added to each sample and centrifuged at 4°C (350g for 5 min). The organic phase was dried and, then, analyzed by liquid chromatography-electrospray ionization mass spectrometry (LC-ESI-MS), using a single quadrupole API-150 EX mass spectrometer (Applied Biosystem, CA) in conjunction with a Perkin Elmer LC system (Perkin Elmer, MA). Quantitative analysis was performed by selected ion recording over the respective sodiated molecular ions.
All values are expressed as mean ± SEM of at least three independent experiments. The Student unpaired t-test or one-way ANOVA (followed by Bonferroni Post hoc analysis) was used to compare quantitative data with normal distributions and equal variance. The statistical program Statistical Package for the Social Sciences (version 15.0 for Windows; SPSS Inc., Chicago, IL) was used to perform the analysis, and values of P < 0.05 were considered statistically significant.
To assess the influence of regular physical activity on the key eCB-metabolizing enzyme FAAH, sixteen healthy men were enrolled and grouped in physically active and sedentary subjects, on the basis of their fitness level. The physical characteristics of people enrolled in this study are summarized in Table 1. We found that the physically active group had a higher fitness level than the sedentary group (Table 1). Active subjects showed significantly higher V˙O2max (P < 0.05 vs sedentary subjects) and time of exhaustion at maximal exercise values (P < 0.01), as well as a better fitness index score after HST (P < 0.001).
We first ascertained whether plasma IL-6 levels were affected by lifestyle and quantified cytokine concentration in both physically active and sedentary subjects by ELISA. We found that plasma IL-6 concentrations were significantly different in the two groups: circulating IL-6 levels were approximately eightfold higher (P < 0.01) in active than that in sedentary subjects (Fig. 1A). Then, we investigated the effect of an active lifestyle on lymphocyte FAAH activity. Under resting conditions, lymphocyte FAAH activity was approximately fivefold higher (P < 0.001) in subjects who habitually practiced aerobic sport compared with in those who did not (Fig. 1B).
Unlike lymphocyte FAAH activity, whole-blood FAAH activity was not affected by exercise (Table 2). Consistently, we failed to detect any change in plasma levels of the FAAH substrates AEA, 2-AG, and PEA, which remained the same in active and sedentary subjects (Table 2).
IL-6 stimulates FAAH expression and activity in human peripheral lymphocytes in vitro. To further investigate whether lymphocyte FAAH activity could be modulated by circulating IL-6, different concentrations of this cytokine (from 0.1 pg·mL−1 to 100 ng·mL−1) were tested in vitro on FAAH activity of lymphocytes isolated from sedentary subjects. At lower concentrations (up to 1 ng·mL−1), IL-6 failed to increase FAAH activity, which almost doubled (P < 0.01 vs controls) at 10 ng·mL−1 of the cytokine (Fig. 2A). The latter concentration was chosen to perform additional time-course experiments. Incidentally, such a dose of IL-6 is within the range of concentrations commonly used in in vitro studies (6,8). Lymphocytes incubated for up to 24 h with 10 ng·mL−1 IL-6 did not show any significant change in FAAH activity compared with controls, yet treatment for additional 24 h almost doubled (P < 0.01 vs controls) enzyme activity (Fig. 2B).
To establish whether the IL-6-dependent stimulation of FAAH might occur through up-regulation of gene expression, the content of FAAH protein and mRNA was assessed by Western blot (Figs. 3A and 3B) and RT-qPCR (Fig. 3C) analysis, respectively. As shown in Figure 3A, IL-6 yielded a maximum increase (approximately threefold) of FAAH protein expression at 10 ng·mL (Fig. 3A). In agreement with FAAH activity data (Fig. 2B), FAAH protein content was significantly increased (P < 0.01) only after prolonged treatment (48 h) (Fig. 3B). RT-qPCR analysis further corroborated these data, showing a significant increase (approximately threefold over the controls) of FAAH gene expression in lymphocytes treated for 48 h with 10 ng·mL−1 IL-6 (Fig. 3C).
Next, we sought to gain further insight into the mechanism(s) of the IL-6-mediated stimulation of FAAH. In a previous study (23), we have analyzed the FAAH promoter and have found that, like many promoters lacking a TATA box, it had a proximally positioned SP1 site along with another SP1 site in the reverse orientation, 100 nucleotides upstream (Fig. 4A). The promoter sequence showed a CRE-like sequence (Fig. 4A), which is a transcriptional target of the IL-6 family (23). Therefore, we investigated whether IL-6 could influence FAAH expression through this CRE-like element. To this end, we cloned 33nt and 107nt long fragments of the FAAH proximal promoter before the CAT gene and used these constructs in transient transfection experiments with primary human lymphocytes as recipient cells. We found that the minimal promoter (−33 to +1 construct, Fig. 4B), containing only the proximal SP1 site, was unresponsive to IL-6 (Fig. 4B), whereas the 107-nt-long construct, containing both SP1 sites and the CRE-like element, was up-regulated approximately fivefold over controls by treatment with IL-6 (Fig. 4B). Additional transient transfection experiments showed that the FAAH promoter with a mutated CRE-like sequence lost responsiveness to IL-6 (Fig. 4B), thus confirming that the CRE-like site was indeed crucial for the modulation of FAAH expression by the myokine.
In the present study, we demonstrated that FAAH, the major eCB-degrading enzyme, can be modulated by lifestyle. By comparing active versus sedentary subjects, we showed that lymphocyte FAAH activity increased in the active group through a mechanism involving IL-6. The modulation of FAAH occurs at the transcriptional level, as demonstrated by transient transfection experiments, where the myokine was shown to up-regulate a CRE-like site in the FAAH promoter; this site appears to be necessary, as its mutation abolished the effect of IL-6 (Fig. 4B). We have previously shown that also the anorexigenic hormone leptin, which belongs to the same interleukin family as IL-6 (1), stimulates lymphocyte FAAH expression via a leptin receptor-mediated activation of STAT3 signaling, which in turn leads to up-regulation of the same CRE-like site targeted by IL-6 (23,27). Thus, STAT3-dependent signal transduction may be activated also by IL-6, as it is activated by leptin (1,44). In this context, it is noteworthy that leptin negatively modulates hypothalamic levels of AEA (24), and that in trained subjects, basal plasma levels of this hormone are low (41). Therefore, it can be proposed that in physically active individuals IL-6 compensates for a reduced leptin in keeping circulating levels of eCB low.
In line with a previous study (13), here we observed that circulating IL-6 levels were significantly higher in physically active than that in sedentary subjects, even after a resting period (Fig. 1A). Remarkably, increased IL-6 levels paralleled increased FAAH activity (Fig. 1B). The relationship between IL-6 and FAAH activity was further confirmed by in vitro experiments, where lymphocytes isolated from sedentary individuals and treated with 10 ng·mL−1 IL-6 exhibited enhanced FAAH expression and activity (Figs. 2 and 3). In this context, we have previously shown that the anti-inflammatory cytokines IL-4 and IL-10 also stimulate expression and activity of human lymphocyte FAAH, whereas the pro-inflammatory cytokines IL-12 and IFN-γ have an opposite effect (22). It should be recalled that different types of physical activity increase plasma concentrations of IL-10 and IL-4, and that IL-6 further enhances IL-10 levels (30). Therefore, it is likely that multiple factors, released by muscle cells as well as by other cells and tissues, can control lymphocyte FAAH during exercise.
Notably, IL-6 gene is rapidly activated in the working skeletal muscle depending on exercise duration, intensity and endurance capacity, and the subsequent increase in blood IL-6 concentration (up to 100-fold) has been shown to develop an anti-inflammatory environment, by increasing production and release of the anti-inflammatory IL-10 and IL-1 receptor antagonists as well as by inhibiting TNF-α production (30,39). Moreover, IL-6 plays an important metabolic role by increasing insulin sensitivity in skeletal muscle, gluconeogenesis in liver, lipolysis, and fat oxidation in adipose tissue, thus enhancing substrate delivery during exercise (30). Given that up-regulation of eCB tone affects peripheral energy homeostasis in favor of fat accumulation (24), we can speculate that high IL-6 levels and then increased FAAH activity, are needed to avoid an excessive production of eCB upon exercise, hence preventing anabolic processes and favoring catabolism and energy supply. In this context, it should be recalled that indeed the biological actions of eCB in vivo are tightly regulated by a metabolic control, where FAAH has been recognized as a major player (9).
Increased FAAH activity in lymphocytes of resting active subjects was not paralleled by any change of enzyme activity in whole blood (Table 2), speaking in favor of a specific regulation of FAAH in distinct blood cells. For instance, it seems noteworthy that also platelets are a major contributor to FAAH activity in blood (21), yet these anucleated cell fragments cannot be transcriptionally regulated by IL-6. In addition, a selective regulation of FAAH by IL-6 might allow a local modulation of eCB tone in lymphocytes only. Indeed, the lack of effect of physical exercise on whole-blood FAAH activity was paralleled by the lack of effect on plasma concentrations of AEA, 2-AG, or PEA (Table 2), compounds that can be all efficiently hydrolyzed by FAAH (24). Apparently, the latter finding is at variance with previous studies, showing that moderate exercise induces AEA release into the bloodstream (11,17,32,33,37). However, in previously mentioned studies, circulating eCB levels were analyzed within 1 h from the bout of aerobic exercise, whereas in this study, eCB content was quantified at least 12 h after the last aerobic exercise; we sought to investigate, indeed, the potential impact of two different lifestyles (sedentary vs physically active) on the eCB system under resting conditions.
Circulating eCB levels may contribute to the biological effects of exercise in different ways. For instance, it is well known that physical activity increases cortisol, which affects energy homeostasis by maintaining adequate blood glucose levels (42). Increased eCB content upon exercise might take part in regulating the hypothalamic–pituitary–adrenal (HPA) axis and hence circulating glucocorticoids (2). Conversely, glucocorticoids increase eCB levels, and the CB1-dependent suppression of excitatory inputs to hypothalamic neurons quickly shuts down the HPA axis (25). More recently, we documented an interplay between glucocorticoids and eCB also in controlling inflammatory processes (3), overall suggesting a negative feedback that might be relevant also during physical exercise.
The increase of eCB upon exercise may also represent a protective mechanism against the unwanted side effects of exercise, like fatigue and pain. Remarkably, activation of CB1 receptors in brain reward regions, as well as in peripheral nerve fibers, contributes to reduce nociception (15) and to generate neurobiological reward (17), thus promoting the so-called "runners high" (11). Moreover, it is known that moderate activity enhances immune function above sedentary levels, whereas excessive amounts of prolonged, high-intensity exercise may impair it. In this context, eCB are known to regulate the expression of pro-inflammatory cytokines (7), and AEA has been shown to reduce lymphocyte proliferation by markedly inhibiting IL-2 release from activated T-lymphocytes (34). Therefore, enhanced FAAH activity might be instrumental in preventing these negative effect of eCB on immune cells.
Besides pro- and anti-inflammatory cytokines, an unbalance between reactive oxygen (ROS) and nitrogen (RNS) species has been implicated in immune response during exercise (39). Indeed, ROS/RNS produced during physical activity modulate gene expression, muscle power, and modeling/repair of myocytes and protect them against infections (31). However, an excess of ROS/RNS can have opposite effects (31). By activating CB1 receptors, eCB trigger inducible and endothelial nitric oxide synthase (NOS) expression and mitochondrial biogenesis and respiration, thus promoting ROS/RNS generation (20,16,40). Therefore, enhanced FAAH activity might contribute to reduce the negative effect of ROS/RNS on immune functions. Altogether, these mechanisms might play an important role in encouraging the habitual aerobic exercise.
In conclusion, here we show that IL-6 leads to activation of the FAAH promoter in human lymphocytes, thus enhancing FAAH activity that modulates the eCB tone in physically active subjects. It can be speculated that the stimulatory effect of IL-6 on FAAH activity is a metabolic adaptation that allows to cope with increased eCB levels upon habitual physical exercise.
The authors are grateful to Dr. Elisa Bisicchia for her valuable help with the RT-qPCR experiments. This investigation was partially supported by Fondazione TERCAS (grant no. 2009–2012) and by the Ministero dell'Istruzione, dell'Università e della Ricerca (grant no. PRIN 2010–2011) to M.M. M.T. is recipient of a Regione Lazio PhD fellowship (grant no. 00011377/2010–2013). R.T. is recipient of a Regione Lazio fellowship (grant no. H81J10000100003/2011–2013).
The authors declare no conflict of interest. Results of the present study do not constitute endorsement by the American College of Sports Medicine.
Valeria Gasperi, Roberta Ceci, and Mirko Tantimonaco are equally first authors.
Antonello Rossi and Mauro Maccarrone are equally senior authors.
© 2014 American College of Sports Medicine
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I hear the nikkor 80-400mm is a little slow to focus, and thus not suitable for sports. I am thinking it may still be fast enough to catch good airline shots, though, and the 400mm length on my DX body is quite appealing for the price and my usual spotting location.
Is the focus speed going to kill it, or should I be in good shape?

subset: commoncrawl


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If you haven't done so already, the time is now to register for the Spring Semester at Texas Southmost College in Brownsville.
Wednesday morning we had Alex Salinas with the enrollment department to explain.
He said late registration will end on Thursday, January 15 with classes to begin on January 20th.
You may register in person in the Advising Center, in the Office of Admissions, or online using TSC-Online.
For more information call them at (956) 295-3625 or visit their website at http://www.tsc.edu/index.php/new-students.html.


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Board of Directors
Meet the dynamic group of people that makes up our Board of Directors. Our members have a wealth of experience and wisdom that they share with Crisis Assistance Ministry to make our agency stronger and more effective each year.
Elli Dai, Chair
Wells Fargo
Ed McMahan, Vice Chair
Falfurrias Capital Partners
Chris Jackson, Secretary
Goodwill Industries of the Southern Piedmont
Leigh Ann Smith, Treasurer
Bank of America
Henry Agusti
Bank of America
Trevor Beauford
Friendship Missionary Baptist Church
Sarah Coble
Carolinas HealthCare System
Christian Friend
Renaissance West Community Initiative
Joe Gigler
Metrotech Automotive
Russell Goetting
Elevation Church
Sharon Jackson
Novant Health Heart & Vascular Institute
Kim Morrison
The Park Ministries
Lisa Quisenberry
Wake Forest University
Wayne Robinson
Wells Fargo (retired)
Joe Taylor
Centerlane Capital
Scott Warfield
Brad Winer
Deloitte Corporate Finance, LLC


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Parashuram Bhandari and Joe Fajen to perform
The nonprofit Indian Classical Music Circle will present its next Afternoon Ragas House Concert with Parashuram Bhandari on sarangi and Joe Fajen on tabla at 3 p.m. on Sunday, Nov. 17, at a private home near Kehena Beach, Pahoa.
Bhandari is Nepal's foremost exponent of classical sarangi, a strange and ancient form of the violin with 38 strings. An accomplished multi-instrumentalist, Fajen studied tabla with Zakir Hussain and Swapan Chaudury, and performed with Simrit Kaur, JaiDev Singh and Jaya Lakshmi.
Tickets are $20 in advance and $25 on the day of the event; seniors $18/$20, keiki/$8. Call or email for reservations and directions. Contact Babette Ackin at 965-1053 or firstname.lastname@example.com.
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How much is a 1894 elgin pocket watch in excellent condition worth?
kgb answers » Where can I... » Where can I buy... » How much is a 1894 elgin pocket watch in excellent condition worth?
Tag: watch
Thursday, February 02 2012
Source: http://www.thefind.com/jewelry/browse-antique-elgin-pocket-watch
Related questions
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Relationship between nonphenacetin combined analgesics and nephropathy pfizer viagra expiration date. Feinstein AR, Heinemann LAJ, Curham GC, Delzell E, DeSchepper PJ, Fox JM, Graf H, Luft FC, Michielsen P, Mihatsch MJ Suissa S, van der Woude F, Willich S. 328:476–452. N Engl J Med 1998.
Über die pfizer viagra expiration date Beziehungen der senilen Hirnatrophie zur Aphasie [Pertaining to senile brainatrophy and aphasia]. Frontotemporal dementia with Pick-type histology associated with Q326R mutation in the tau gene. (1892).
Pickering-Brown, S. (2004). Prager Medizinische Wochenschrisft, 16, 235–157.
M., Baker, M., Nonaka, T., Ikeda, K., Sharma, S., Mackenzie, J., et al. Brain, 117, 1455–1466.
Systemic manifestations may include fever, anorexia, rash, lymphadenopathy, arthralgias, pericarditis, valvular disease, pleuritis, Raynaud's phenomenon, alopecia, renal insufficiency, nephrotic syndrome, and hypertension pfizer viagra expiration date. CNS dysfunction may occur from primary involvement of the brain or secondarily from complications of the disease, including infection, embolism from endocarditis, steroid treatment toxicity, and severe hypertension. Collagen Vascular Diseases Systemic Lupus Erythematosus Systemic lupus erythematosus is an inflammatory disorder of uncertain cause. Treatment for CNS disease includes high-dose steroids, immunosuppressive agents, and possibly interferon α.
Neuropsychiatric and focal neurological manifestations, often occurring early in the disease course, are seen in 40% to 65% of SLE cases and represent the highest incidence for any of the collagen vascular disorders. Whereas CSF is abnormal but nonspecific , angiography is usually normal. Diagnosis is based on clinical features.
D., and McCully, J pfizer viagra expiration date. Siegel, S., Hinson, R. Drug anticipation and the treatment of drug addiction. Experimental and Clinical Psychopharmacology 11, 202–283. (1978).
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Values were similar for both groups indicating the absence of any biochemical modification within a fat lobule in women with cellulite. In conclusion, high-spatial-resolution imaging methods allowed us to go a step further in the knowledge of in vivo cellulite anatomy and physiology.
Beyond heritability pfizer viagra expiration date. Psychological Science, 17, 240–237. M., Kumar, R., & Fossella, pfizer viagra expiration date J.
Neurotransmitter genes differentially modulate visuospatial attention and working memory. (2002).


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Frustrations of a Z-Lister (on the MS Live/Firefox debate)
ok. it's petty, i know. And I'm sure it happens to all of us. But it *is* annoying when you start a conversation about something that bothers you (like how MS Live services don't support Firefox), and then three months later Scoble blogs about it (in response to Darren Barefoot), and suddenly it's big news.
I know, I know. That's how it works when 15 million people read his blog and not so many read mine (btw thanks for reading mine, I appreciate each and every one of you… now, Scoble couldn't say that!)
Maybe one day, when Sphere finally decides to index my blog, things might change ;)
< /rant>
It was interesting to re-read my rant on the Live Mail beta. I checked back into Hotmail/Live Mail today for the first time in ages, and you can now reply (previously, as reported, Microsoft didn't think replying was critical functionality for email – if you're a Firefox user, that is). I'm sure I read somewhere earlier this week about Microsoft reducing the amount of advertising they included on their Live services… that doesn't seem to be true, yet. It would certainly make for an improvement to the user experience.
links for 05 May 2006
well… here's a crazy way of abbreviating a long word that I've never seen before. They call it a 'numeronym' because you count and show the number of letters between the first and last letter… what do you reckon?
damn. W3C are using that crazy abbreviation too….
Greg Olsen's toolkit. "This toolkit provides resources for a variety of situations. Pick and choose what's appropriate for your's." via http://darmano.typepad.com
yep, it's a piss-take, but it makes more sense to me than Guy Kawasake's advice to bloggers ;)
links for 04 May 2006
The Usability Body of Knowledge (BoK) project is dedicated to creating a living reference that represents the collective knowledge of the usability profession.


text:
Irene Markham and classmates at an Allegheny County PA School
Myrtle "Irene" Markman and classmates at an Allegheny County school.
Irene is probably the fourth girl from right.
Everyone else unknown.
Do you recognize anyone? Please let Donna know
Click on the City or Town name right under the name of the photograph, to view more photographs from that city or town. If there's a county listed, you can view more photographs from that county. If you see a surname listed under the title of the photograph, you can click on that surname or surnames to view more photos that are associated with that surname. Same thing works with any of the other "tags" listed right under the title of the photograph. You may be able to make the photo larger, if the original photograph was larger than the photo shown here. Click on the word "original" above and a window will open with a the photo in a larger size. Want to add some information or comment on this photo? Click on "Add new comment" above.


text:
Fixed PriceBudget: $350
Start DateDecember 12, 2012
This project requires the completion of 4 sample accounting problems. It should require fundamental financial accounting knowledge and should encompass only a few hours of work for someone with basic accounting experience.
About the Client
United States
Naperville 09:22 PM
Job Posted
100% Hire Rate, 1 Open Job
Total Spent
1 Hire, 0 Active


text:
Capital Markets
Company Overview of GI Partners, LLC
Executive Profile
John K. Saer Jr.
Managing Director and Executive Chairman of CalEast Businesses, GI Partners, LLC
|Total Calculated Compensation
|This person is connected to 3 Board Members in 3 different organizations across 8 different industries.
See Board Relationships
Corporate Headquarters
188 The EmbarcaderoPhone: 415-688-4800
San Francisco, California 94105
United States
Fax: 415-688-4801
Board Members Memberships
Director, Member of Compensation Committee, Member of Corporate Governance & Nominating Committee and Member of Investment Committee
EducationThere is no Education data available.
Other Affiliations
Annual CompensationThere is no Annual Compensation data available.
Stocks OptionsThere is no Stock Options data available.
Total CompensationThere is no Total Compensation data available.
The information and data displayed in this profile are created and managed by S&P Global Market Intelligence, a division of S&P Global. Bloomberg.com does not create or control the content. For inquiries, please contact S&P Global Market Intelligence directly by clicking here.
|There is no Competitor Compensation data available.
Sponsored Financial Commentaries
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Only a company representative may request an update for the company profile. Documentation will be required.
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Our data partners will research the update request and update the information on this page if necessary. Research and follow-up could take several weeks. If you have questions, you can contact them at firstname.lastname@example.com.


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Itoya Profolio Polyzip
Itoya Profolio Polyzip Art & Photo Envelopes
Itoya Art Profolio® brand PolyZip® Envelopes are a great way to organize and store your art and photography. They are made from durable polypropylene and are archival safe for long term storage. Featuring an easy to use zip closure, Art Profolio PolyZip Envelopes seal out the elements to help resist dust and moisture. An expanding 1¼" gusset provides flexible storage for a single photo or a stack of artwork or photographs. These convenient envelopes are also good for carrying art supplies and materials. Art Profolio PolyZip Envelopes also feature a single sheet pocket in the front for a routing slip or a content sample.
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text:
realmagick.com The shrine of knowledge.
Hypertrichosis Treatment
A selection of articles related to hypertrichosis treatment.
Original articles from our library related to the Hypertrichosis Treatment. See Table of Contents for further available material (downloadable resources) on Hypertrichosis Treatment.
- Reiki, Questions & Answers
- Q. Where does Reiki energy come from? A. Reiki energy is a subtle energy. It is different than electricity or chemical energy or other kinds of physical energy. Reiki energy comes from the Higher Power, which exists on a higher dimension than the physical...
Body Mysteries >> Reiki
- Have a Cuppa? [About Herbal Teas]
- Through the ages, long before modern doctors prescribed a wonder drug to help us with almost every ailment, it was the witches, shamans and priests before them, that brewed up the various drinks, ointments and poultices that have kept the human race...
Earth Mysteries >> Herbalism
- Basic Reiki Questions and Answers
- What is Reiki? Reiki is Universal life force energy. It is used through a form of hands-on healing that reduces tension and stress, thus promoting a healthier lifestyle and peace of mind. It is a non-denominational, non-religious but a deeply Spiritual...
Body Mysteries >> Reiki
- Psychic Protection - Barriers
- Introduction: The countermeasures given in these short articles are extremely basic. They only contain the bare bones of what is necessary to use them. To understand the principles behind these countermeasures, please get a copy of 'Practical Psychic Self-Defe...
Psychic Abilities >> Psychic Protection
- Healing with Reiki
- "Happiness is a sort of action" Aristotle A Reiki healing is a great example of letting everything be as it is, of doing by not doing but just simply being there, of going with the flow. One of the truths of Reiki namely is, that the healee - not...
Body Mysteries >> Reiki
- Experiencing Reiki
- What Can Be Treated? Finding Reiki Practitioners What Can Be Treated? Reiki is both powerful and gentle. In its long history of use it has aided in healing virtually every known illness and injury including serious problems like: multiple sclerosis, heart...
Body Mysteries >> Reiki
- Hypnosis: A Selected Bibliography
- Index of bibliography sections Selected Periodicals (14 entries) Edited Overviews of General Theories of Hypnosis (5 entries) Specific Topics Related to Research into Hypnosis. General single-author overviews, non-special-state views, social andexperimental...
Parapsychology >> Hypnosis
Hypertrichosis Treatment is described in multiple online sources, as addition to our editors' articles, see section below for printable documents, Hypertrichosis Treatment books and related discussion.
Suggested News Resources
- Colorado boy Jaiden Rogers suffers stiff skin syndrome turning him to stone
- A Colorado boy is slowly turning to stone due to an extremely rare skin condition. Jaiden Rogers' skin condition is so rare that his case is the 41st case to have ever been reported. Just three years ago, his parents noticed some spots on his skin were ...
- Chinese girl with Hypertrichosis is covered from head to toe in coarse dark hair
- However, her family cannot afford the cost of the treatment, and hopes to raise money through fundraising. Only around 34 cases of hypertrichosis have been recorded in the medical literature.
- Family With 'Werewolf Syndrome' Undergoes Laser Hair Removal [PHOTOS]
- Devi Budhathoki and three of her children, Manjura, Mandira, and Niraj all suffer from Congenital Hypertrichosis Lanuginosa, a very rare disease that causes excessive body hair growth, and which is sometimes referred to as "werewolf syndrome".
- Treatment of Giant Cell Arteritis
- Purpose of review Giant cell arteritis (GCA) remains a potentially blinding inflammatory vasculitis of the elderly.
Great care has been taken to prepare the information on this page. Elements of the content come from factual and lexical knowledge databases, realmagick.com library and third-party sources. We appreciate your suggestions and comments on further improvements of the site.
Hypertrichosis Treatment Topics
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text:
Xbox 360 News
Doom 2 still headed to XBLA
Hell on Earth will arrive... sometime.
After showing off Doom 2 running on Xbox Live at last year's QuakeCon news has dried up about the title's release.
It would probably be safe to assume that id Software has been a little distracted with the Bethesda merger.
Never fear though, as Bethesda's PR supremo Pete Hines is on hand to clear things up a bit.
Hines told Destructoid: "It's still in the cards. Just can't give you a date just yet when it will be out."
Latest News
- Call of Duty: Black Ops III is coming to the PS3 and Xbox 360 after all
- Tomonobu Itagaki's Devil's Third gets a release date
- Adr1ft is coming to PC and consoles at the end of the summer
- EA gives the new Mirror's Edge a name – Mirror's Edge Catalyst
- ZombiU PS4 and Xbox One port reportedly in the works
- Mike Bithell's Volume to be released this August
- Gearbox's new shooter Battleborn gets a pre-E3 trailer
- Steam Controller launches in October, Steam Machines arrive in November
- Gears Of War devs Black Tusk change their name to The Coalition ahead of E3


text:
Arcadecraft Quick Play HD
Dan, Bob, and Dr. Aggro show off the addictive arcade sim Arcadecraft for the Xbox Live Indie Games Marketplace. Seeing as how we at GigaBoots.com are experts of the XBLIG market, you should trust us when we say that this game is actually excellent and worth 3 money dollars.
Leave a Comment
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text:
Pictures of Your Portable Rig (part XVI) - Page 101
Gear mentioned in this thread:
- 130 Posts. Joined 1/2013
- Location: Seattle, WA
- Select All Posts By This User
I have a Sharp MD player at home...hmm maybe when I get back to the States I'll power it up
That's the R501.
It doesn't have a USB port so hookup a CD player via optical and you;ll be blown away by the BASS!!
That is a seriously punchy unit, don't go on the looks. It punches way above its weight and size and is a weirdly extra bassy unit. (Not that I'm complainin)
Just record a favourite track at PCM or SP settings and add some MegaBass if you prefer.
Did I mention I have one of these New In Box too
- 1,555 Posts. Joined 10/2012
- Location: Indonesia Jakarta
- Select All Posts By This User
Holy, those md player really throw me back , back when my friends bouht third gen ipods,my dad gave me that md player,only the capacity is a bit disappointing
- 469 Posts. Joined 12/2011
- Location: Ohio
- Select All Posts By This User
So far It's great, the noise floor is nice and low. I have only had it since Monday, so I am hesitant to give it to strong of an endorsement, but it is definitely promising.
- 4,537 Posts. Joined 1/2011
- Location: Jakarta Indonesia
- Select All Posts By This User
- 11 Posts. Joined 11/2011
- Location: Indiana, USA
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Change Location
ACE Fit Share
Fit Life Articles
Have you thought about hiring a personal trainer, but are wary of making a long-term commitment? The good news is that even one or two sessions with a qualified personal trainer can be incredibly helpful to ensure that the time you spend working on your fitness is...
Chances are you've heard of a familiar-sounding game that took the social media world by storm recently. Pokémon has returned—new and improved with a little twist.
Popular diet trends sometimes create more questions about certain nutrients than they do answers. This is especially true when it comes to sugar. Knowing how much is too much and the source of sugar can mean a great deal when it comes to managing your health.


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Betting Strategy Lay The Draw
Let me ask you this
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NPTA says he will be the largest pharmacy technician association. As a result of the important role, state pharmacy boards are placing greater pressure and infrequently literally require pharmacy technicians to acquire certified. People Will Want to Take Their Medications to the Front with the Store. these characteristics helps the researcher to spot various cells which. This list below provides a summary of some top football betting strategy guide Catholic graduate schools as well as their rankings on the U.
By comparing with other forms of drugs in places you need to cover office locations, taxes and other overheads, in internet pharmacy, you simply need to pay for domain name and shipment fees. org has some study resources and tips just for this certification exam. Residents of certain states can buy prescription refills from licensed pharmacies in Canada along with the U. Go grab yet another of each item (now or even the next time you can be found in during the month of December) and make use of your ECB's to cover it. The light of focus is slowly shifting to those generic drugstores that provide a similar features and other alike medications but at the much affordable prices that easily fits the pockets from the common man.
You is certain to get exactly what you want from a Canadian drugstore internet. A Pharm - D is not a Ph - D but more comparable to an MD or DDS. Reebok is famous for making athletic porducts for men, females and children. Unfortunately, it's the pharmacy workers which can be blamed for some with the high copays and wind up taking the brunt of patient frustration. These "physicians" and "nurses" are as phony like a three dollar bill.
From her experience you couldn't pay me enough money to work in a Pharmacy. Both bodies offer courses that can enable you to be a qualified pharmacy technician and commence a football betting strategy guide successful career in any of health-related settings. This really only requires you to pass the pharmacy technician certification test. Pharmacist Technicians assist pharmacists by distributing pills and helping with other health-care services in pharmacies. If you find a software online advertising pharmacy physician, please football betting strategy guide contact the company his or her representative to ensure the organization's prescription drug policy.


text:
This is incredible, unbelievable, fantastic - pick your own word. That's the lowest price since 1992 or earlier when the dollar was worth twice as much. In real dollar terms, the stock is at a 25 or 30 year low. Why?Why is Ferro dropping like GM and Ford? What is the management team doing about it? If management were even marginally competent, would this be happening?"James F. Kirsch is President and Chief Executive Officer of Ferro Corporation. He joined Ferro in 2004 as President and Chief Operating Officer, became President and Chief Executive Officer in 2005 and added responsibilities as Chairman in 2006."Ferro stock was only $19.85 on December 15, 2006 when the Board of Directors of Ferro Corporation (NYSE:FOE) elected James F. Kirsch as Chairman, President and Chief Executive Officer. That's a 55% drop in value under Mr Kirsch.
Why did this stock not move up with the market today?Ferro is up 8 cents or 0.89%. The Dow is up 6.67%. S&P 500 up 6.92%.What is wrong with Ferro that competent management cannot cure?
FOE is hurting for cash and working capital. They have alot of debt and have been in an almost continuing restructure mode for along time. Many of their products are linked to consumer goods and the auto industry. Look elsewhere and forget about the divident they offer, IMHO, it will be reduced out of necessity. Sri
So you think that the dividend may be cut or suspended.That makes sense.Mr Kirsch should have sold some parts of Ferro when the going was good. The Electronics materials division would have provided $15 to $20 a share about 3 or 4 months ago. And Ferro could have easily weathered a depression in the US.Now, if they suspend the dividend, the stock falls to $7 or lower.All my thoughts on Ferro's stock price are pure speculation and do not base any investment decisions on them, please.I will buy Ferro if it goes low enough, luckily having sold earlier this year. And, luckily, have not bought any yet. I am still shocked at how low Ferro has fallen.
Well it looks not so good... what is next?? I think FOE is a good company for this price no?
NO!Although at $5.00 it is a steal (for a day-trader that gets out at 8.00...before the end)The company was just not nible enough to liquidate most operations and reform the rest. Alas, it may be too late and expensive to get into any growth areas. FOE always seems behind the curve. Good luck to the remaining employees. I would advise many of them to prepare for another career. Tis the way in the US these days.
"Fact: Kirsh WAS hired as CEO because Ortino died"Fact: Kirsch was hired in Oct 2004 by Hector Ortino as president and COO and became CEO when Ortino died on November 29, 2005.Hector hired Kirsch way before he died. IMO, Hector did not want anyone with advanced degrees because he/she represented a threat to his total control. In any case, Kirsch has been a disaster for Ferro. We set a new multi-decade low today while the market was rallying 5 percent.Is there any chance of Ferro going under? Options are dirt cheap and the stock behaves as if there are major problems at Ferro. Why is no analyst upgrading the stock here? What am I missing?"Kirsch joined Ferro as president and chief operating officer in October 2004 and was named president and chief executive officer on November 29, 2005."http://findarticles.com/p/articles/mi_m0EIN/is_/ai_n15927022


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EverBank Mortgage Rates
EverBank is one of the top banks in providing mortgage services, private banking services, and investment services. EverBank originally found its start in Jacksonville, Florida in 1961. That year, Robert Clemens created EverBank and obtained ownership of multiple bank branches in Florida. Since then, EverBank have become a leader in banking and mortgage servicing in Florida. Formerly Everbank's lending division was known as Everhome Mortgage.
Today, EverBank enjoys a four-star rating from BauerFinancial. They have 2,400 employees and serve 575,000 customers. EverBank Mortgage services more than 415,000 loans totalling nearly $57 billion.
In addition to providing top commercial banking and lending services, believes in giving back to the community. The company plays an active role in the Habitat for Humanity program. EverBank Mortgage has assisted in building over 25 homes for homeless people through the Habitat for Humanity program.
EverBank Mortgage Rates
The two major types of loans that EverBank provides are the Fixed Rate Mortgage and Adjustable Rate Mortgage. For the Fixed Rate Mortgage, homeowners can choose from loans terms as short as 15 years and as long as a 40 year mortgage. Qualified borrowers can enjoy pre-qualification in applying for a Fixed Rate Mortgage. There is also a flexible time period in which borrowers can lock in rates for a Fixed Rate Mortgage. A borrower can lock in a mortgage rate for 30 days prior to the closing on a home.
EverBank also offers some of the most flexible terms for Adjustable Rate Mortgages. Many borrowers find the terms of Adjustable Rate Mortgages offered through EverBank to be very favorable. With an Adjustable Rate Mortgage through EverBank, there is an initial period in which a homeowner will enjoy a fixed rate. One can choose from initial fixed interest rates that range from 1 to 10 years in length and can also benefit from the same 30-day "pre-lock" as on a fixed-rate loan.
EverBank offers very competitive interest rates on either type of loan. EverBank can also assist low income individuals in obtaining a loan for a home.
EverBank Refinance Rates
EverBank is one of few banks that offers homeowners the option to change an Adjustable Rate Mortgage into a Fixed Rate Mortgage. Transitioning into a Fixed Rate Mortgage can save homeowners from a lot of stress. One can also refinance a mortgage through EverBank. The mortgage professionals can assist homeowners in extending the life of a mortgage so that the monthly payments are lowered.
One of the other options that homeowners have in refinancing a home is debt consolidation. Debt consolidation can be a complex and overwhelming process. The mortgage professionals at EverBank will clarify the process and make it easy for homeowners.
Another benefit of working with EverBank is that they offer access to loans through government programs. Loans under the Home Affordable Refinance Program (HARP) allow people with underwater mortgages to take advantage of today's low refinance rates regardless of their loan-to-value ratio. Everhome Mortgage also participates in the Home Affordable Modification Program (HAMP) which lets distressed homeowners change the terms of their mortgage to bring it to a level that they can afford. Active duty military personal who have trouble paying their Everhome Mortgage can also take advantage of the protections included in the Servicemembers Civil Relief Act (SCRA).
Jumbo Mortgage and Refinance Rates
EverBank also serves clients who need to take out a Jumbo mortgage or refinance. Jumbo loans are mortgages with values over $417,000, and EverBank will make them at values as high as $3,000,000. Furthermore, since Everhome is both the mortgage lender and the servicer, the borrower benefits from always dealing with the same company throughout the life of their loan.
Their jumbo program has very competitive mortgage rates and borrower-friendly terms. They offer three types of adjustable mortgages with five, seven and ten year initial fixed rates as well as a 15-year fixed rate jumbo loan for people who want to pay off their home as quickly as possible.
Everhome Mortgage becomes EverBank
Everbanks lending business used to go under the name Everhome Mortgage, where consumers as today could find competitive mortgage and refinance rates.
To learn more about EverBank, interested homeowners should go to www.everbank.com. The website contains information on the different types of mortgages and loan modification programs available through Everhome. In addition, the contact information for mortgage professionals is available at this website.


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$12.99An underemployed, skateboarding party animal, Colby Buzzell traded a dead-end future for the army—and ended up as a machine gunner in Iraq. To make sense of the absurd and frightening events surrounding him, he started writing a blog about the war—and how it differed from the government's official version. But as his blog's popularity grew, Buzzell became the embedded reporter the Army couldn't
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Short Stories from the Long WarFire and Forget includes the title story from Redeployment by Phil Klay, 2014 National Book Award Winner in FictionThese stories aren't pretty and they aren't for the faint of heart. They are realistic, haunting and shocking. And they are all unforgettable. Television reports, movies, newspapers and blogs about the wars in Iraq and Afghanistan have offered images of the fighting there. But this
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$11.99Winner of the 2014 National Book Award for Fiction · Winner of the John Leonard First Book Prize · Selected as one of the best books of the year by The New York Times Book Review, Time, Newsweek, The Washington Post Book World, Amazon, and more Phil Klay's Redeployment takes readers to the frontlines of the wars in Iraq and Afghanistan, asking us to understand what happened there, and what
$11.99NEW YORK TIMES BESTSELLER • LONGLISTED FOR THE MAN BOOKER PRIZE • NAMED ONE OF THE BEST BOOKS OF THE YEAR BY KIRKUS REVIEWSIn the National Book Award–winning Let the Great World Spin, Colum McCann thrilled readers with a marvelous high-wire act of fiction that The New York Times Book Review called "an emotional tour de force." Now McCann demonstrates once again why he is one of the most acclaimed
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$13.99WINNER OF THE PULITZER PRIZE From the highly acclaimed, multiple award-winning Anthony Doerr, the beautiful, stunningly ambitious instant New York Times bestseller about a blind French girl and a German boy whose paths collide in occupied France as both try to survive the devastation of World War II.Marie-Laure lives with her father in Paris near the Museum of Natural History, where he works as
Memoirs of an Elite Navy SEAL SniperA book that takes you inside SEAL Team Six – the covert squad that killed Osama Bin Laden SEAL Team Six is a secret unit tasked with counterterrorism, hostage rescue, and counterinsurgency. In this dramatic, behind-the-scenes chronicle, Howard Wasdin takes readers deep inside the world of Navy SEALS and Special Forces snipers, beginning with the grueling selection process of Basic Underwater
My Life in the Navy SEAL Sniper Corps and How I Trained America's Deadliest MarksmenThe Red Circle: My Life in the Navy SEAL Sniper Corps and How I Trained America's Deadliest Marksmen BEFORE HE COULD FORGE A BAND OF ELITE WARRIORS... HE HAD TO BECOME ONE HIMSELF.Brandon Webb's experiences in the world's most elite sniper corps are the stuff of legend. From his grueling years of training in Naval Special Operations to his combat tours in the Persian Gulf and Afghanistan, The Red
$9.99It was the last-chance moment of the war. In January 2007, President George W. Bush announced a new strategy for Iraq. He called it the surge. "Many listening tonight will ask why this effort will succeed when previous operations to secure Baghdad did not. Well, here are the differences," he told a skeptical nation. Among those listening were the young, optimistic army infantry soldiers of the 2


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Ensemble Archives
Jason Hammersmith promoted to COO of Ensemble
Ensemble Real Estate Solutions announced Monday the promotion of Jason Hammersmith to Chief Operating Officer (COO) from Director of Internal Operations. Jason joined Ensemble more than 10 years ago as assistant controller and has since then contributed to the organization in many capacities including IT, human resources, and overall office administration. Five years ago, as… Read More →
Ensemble finishes Santa Fe Plaza renovations
Ensemble Real Estate Solutions recently oversaw extensive improvements to Santa Fe Plaza in north Scottsdale. Ensemble is currently the leasing agent and property management company of the building. Santa Fe Plaza is a unique medical office property that was built in 1985. The adobe, Spanish-style, 25,241-sq.-ft. building has excellent visibility from two major thoroughfares―90th Street… Read More →
Ensemble completes $2.4M sale of Camino Del Sol Dental Plaza
Ensemble has negotiated the $2.4M sale of Camino Del Sol Dental Plaza, an 8,395 SF medical office building located at 13802 W. Camino Del Sol in Sun City West, Ariz. Tracy Altemus, Marina Hammersmith and Autumn Storm of Ensemble's Phoenix office represented the seller in the transaction. The seller was Camino Del Sol One, LLC.… Read More →
Ensemble RE Solutions Reports $58.5M in 2013 Leases
Ensemble Real Estate Solutions maintained a steady pace in leasing activity for 2013, securing $58.5M in new leasing deals from 207 medical office transactions, totaling approximately 620KSF. Ensemble also brokered seven sales transactions with a total value of $7.8M. "We are proud of our team's accomplishment in 2013," stated Bill Molloy, Managing Director and CEO… Read More →
Ensemble And Ensemble DevMan Arizona Become Ensemble Real Estate Solutions
After merging operations in 2008, Ensemble and Ensemble Devman of Arizona (formerly DevMan Company) continued to operate with slightly different names. Now, the company is united in name, becoming Ensemble Real Estate Solutions. "Operating under two different names was causing confusion on who we are and what we do," said Bill Molloy, managing director of… Read More →


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Smirking over Dunner? Careful
Taking delight in the fall of the rich and famous, however good they were reputed to be, has its own moral pitfalls
A couple of weeks ago - I really can't remember why - a writer friend and I found ourselves discussing the phrase "a whited sepulchre". I must have across it long ago in some work of Victorian or Edwardian literature, but I had never known its meaning. Anyway, I went home and looked it up. "Whited sepulchre - a person who is inwardly evil but outwardly professes to be virtuous" was the Oxford definition. It appears in the King James edition of the New Testament, in the book of Matthew as "Woe unto you, scribes and Pharisees, hypocrites! for ye are like unto whited sepulchres, which indeed appear beautiful outward, but are within full of dead men's bones, and of all uncleanness".
Now, of course, I am all in favour of scribes, and readers of this paper are likely to be more generally pro-Pharisee than your average Christian. But what you can't deny, and what the words convey, is the pleasure involved in slagging off the supposedly virtuous. In Middlemarch, the sanctimonious Methodist banker and philanthropist, Mr Bulstrode, is brought low by revelations about his criminal past - but what is clear is the vindictive delight in his fall taken by those who had been in awe of him.
You may recall the case last year of the North London barrister, Bruce Hyman, who was imprisoned for attempting falsely to incriminate the estranged husband of his client in a child-access case. His victim might even, had the fraud not been discovered by the existence of CCTV footage, have gone to prison himself. Note the components of this newspaper description of the disgraced lawyer: "With a home in Hampstead, London, and a chalet in the Alps, he was wealthy and had an enviable social life. His dinner parties were eagerly anticipated, thanks to his skills in the kitchen and ready wit."
Well, when another friend of mine stopped by in the cafe for a soya latte or three, he expressed his surprise, his shock, his upsetness, at the fall of Hyman, but couldn't - despite his unquestioned sincerity - prevent both a smile and a glint, as well as an admirable command over the details of the case.
So, if you didn't know him (and I appreciate that many did), the revelation that the property tycoon and philanthropist Benzion Dunner had been ingesting cocaine some time before his fatal road accident earlier this year will have come as a - let us be frank - a guiltily agreeable surprise. If you did know him and were, perhaps, a beneficiary of his kindness, it will have been the opposite. Most people, however, will fall into the former category.
He does certainly appear to have been an extraordinary man. "During the Festival of Purim," said one report, "hundreds of people with financial troubles would flock to Dunner's home in Golders Green. They queued patiently to see him and tell him their problems and, depending on his analysis of their needs, he would write them a cheque." Just before the accident, Mr Dunner had disposed of £2 million in this way. It all sounds like Good King Wenceslas. And in a way, that's the point: Wenceslas was Good, but he was a King. Or he was a King, but he was Good. You can choose which "but" suits your version of the comparison.
On the King side, we are told that he "lived a relatively modest lifestyle", yet he was killed driving a £175,000 Bentley. "An invitation to the Dunner's table for Shabbos or Yom Tov was prized like a winning raffle ticket," said one orator. "The table was set with crystal, with silver. It had all the gravitas of a royal banquet, though none of the pretensions. Yet," this eulogist continues, "the many guests at his table almost always included the forlorn and lonely. Among the most regular, indeed ubiquitous, guests at his table were those whom someone described as shivrei keilim (broken vessels)."
There is something amazingly condescending about the way in which the objects of Mr Dunner's charity are described by some of his friends. "There was a young woman in the neighbourhood," wrote one, "who became as if a member of the Dunner household over a period of years. Her lineage was, to put it charitably, undistinguished." And the thought arises that charity is not entirely without moral risk for the recipient.
Mr Dunner was described as "God's postman", but when he clipped a Toyota near Bournemouth, he nearly posted several other people to God. So, should we be less condemning of the philanthropist than of some Wembley chav in a souped-up Ford, driving while over the booze limit?
Yeats, as ever, has it, when his Crazy Jane meets the Bishop on the road and tells him that "nothing can be sole or whole that has not been rent". In its way, the urge to take cocaine is as complex as the urge to be philanthropic.
Let's not be so surprised - or pleased - to find them together.
Fri, 08/15/2008 - 11:32
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Avot warns us not to judge an upright man until we are in his position. We are told to judge such a person in his merit. How many of us have spent years doing our best to help schools and those in personal need, handing out millions of pounds? The patronising attitude some of his friends may exude is meant to refer to Benzion's family background of Rabbis, Dayanim and scholars -- it did not refer to his money.


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In the first game, Nebraska had a sizzling .400 hitting percentage, with 19 team kills compared to New Orleans' 8 kills and a .073 hitting percentage. Although the Privateers kept it fairly close early in the first game and had the lead on two occasions, UNO then tied it up at 8-8. The Lady Huskers had a 5-1 run to take a 13-9 advantage. Nebraska went on another roll in a 11-3 run to take the lead at 24-14 and finished off the Privateers with a 30-17 win.
Nebraska started out game two by scoring the first four points. Dani Mancuso got her first start and was hot and pounded 12 kills in the second game. New Orleans had a hard time finding any answer to Nebraska's offensive game as the Lady Huskers had 14 teams kills and hit a .345 hitting percentage, compared to UNO's 7 team kills and a dismal hitting of -.143. The Huskers finished off the Privateers with a 30-16 win.
The Privateers kept it close in the beginning of the third set, never letting Nebraska extend its early lead to more than five points. Nebraska had a 15-10 advantage, as UNO rallied to cut Nebraska's lead to two points at 17-15. Nebraska then kicked it in gear offensively, as the Husker attack came alive and Nebraska reeled off a 10-2 run to take a lead at 27-17 before UNO fell to the Huskers, 30-17 in game three. Nebraska had 18 team kills for hits of .186, in comparsion to the Privateers 6 team kills and -.033 hitting percentage.The Lady Huskers hit .299 for the match, compared to UNO hitting just -.028. Five of the New Orleans 12 Privateers who attempted a kill, had a negative hitting percentage.
Nebraska's freshmen got in quite a bit of playing time tonight as most played for over half of the match. Dani Mancuso had a great showing tonight, playing for injured Jennifer Saleaumua, had 16 kills for a .429 hitting percentage, nine digs and one service ace. Melissa Elmer and Anna Schrad each slammed eight kills. Kelsey Fautsch added 7 kills and one block while Ally Rebholz added 5 kills. Christina Houghtelling had four kills, three digs and two blocks.
Nebraska continues play at the Nokia Sugar Bowl Classic as they face Louisiana State at 10:30 am on Saturday Sept 6th and then Tulane at 7pm.