text:
Activation of pancreatic stellate cells involves an EMT-like process
- Authors:
Affiliations: Pancreas Institute of Nanjing Medical University, Nanjing 210029, P.R. China
- Published online on: December 8, 2015 https://doi.org/10.3892/ijo.2015.3282
- Pages: 783-792
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Pancreatic cancer is the fourth leading cause of cancer-related deaths in men and women in the US (1). The most common type of pancreatic cancer is pancreatic ductal adenocarcinoma (PDAC). PDAC is one of the most lethal cancers with a low 5-year survival rate and limited therapeutic options. Although the etiology of PDAC is still unclear, chronic pancreatitis (CP) has been identified as one of the potential precursors of PDAC (2,3). A relationship between CP and PDAC has been elucidated in rodent disease models (4). In both CP and PDAC, a desmoplastic reaction occurs in the pancreas stroma, characterized by a collagen-rich extracellular matrix (ECM) and activated associated inflammatory cells (5–8). One of the important reasons that chemotherapy does not work well in PDAC patients is because drugs are poorly delivered to the tumor due to this dense stroma abundant with collagens, glycoproteins and low-density vasculature (9,10).
It has been demonstrated that activated pancreatic stellate cells (PSCs) play a central role in the desmoplastic reaction in the pancreas (11–13). PSCs were first described by Watari et al in 1982 (14), and were successfully isolated by Apte et al (15) and Bachem et al in 1998 (16). Under normal physiological conditions, PSCs are mainly located in periacinar and interlobular areas of the pancreas and maintain a quiescent phenotype characterized by abundant vitamin A-containing lipid droplets in the cytoplasm (15). These quiescent PSCs keep the balance between ECM synthesis and degradation. However, in diseases such as CP and PDAC, PSCs transform or transdifferentiate into an activated phenotype, which are devoted to stroma remodeling (17). During this transdifferentiation process, PSCs change their morphology and function as follows: i) they change into a myofibroblastic shape and lose their vitamin-A containing lipid droplets; ii) they acquire migration and ECM modulation capacity; and iii) they upregulate expression of α-SMA, vimentin, desmin and GFAP. While scientists have previously tried to control or reverse this process of PSC activation, the mechanisms involved in the activation process are not fully clarified.
Activated PSCs not only act as positive regulators of cell proliferation and migration, but inhibit tumor cell apoptosis. In turn, cancer cells can facilitate the activation, proliferation, migration and ECM production of PSCs. Such features prompt local tumor progression as well as regional and distant metastasis (18,19). Therefore, a better understanding of the mechanisms of PSC transdifferentiation is crucial for research on the pathogenesis and clinical treatment of CP and PDAC.
PSC activation shares many common morphological and functional changes with the epithelial-mesenchymal transition (EMT) process. EMT is the basis for wound healing in response to chronic injury induced by toxic, viral, metabolic, or immunological factors (20,21). The EMT process turns an epithelial cell into a mesenchymal cell and has been widely studied in the field of embryogenesis, tissue fibrosis and cancer metastasis (22–24). Typically, EMT is characterized by the expression of specific cell-surface proteins and cytoskeletal proteins, as well as changes in ECM proteins production, followed by activation of transcription factors. For example, EMT is characterized by upregulated expression of vimentin and N-cadherin, and downregulated expression of E-cadherin, accompanied by enhanced expression of transcription factors, such as Snail, Slug, and Twist (25,26). The EMT process is divided into three different types (1–3). Type 2 EMT is characterized by conversion from endothelial or epithelial cells into fibroblasts, which are responsible for tissue inflammation and fibrosis, such as that seen in PDAC (27,28). Morphological changes, with redistribution of stress fibers and increased migratory capacity, are other main features of the EMT process.
Due to these similarities between EMT and PSC activation, we hypothesized that activation of PSCs may involve an EMT-like process. Indeed, it has previously been reported that an EMT-like process is involved in transdifferentiation of quiescent hepatic stellate cells (HSCs), a homology of PSCs in the liver (29). We tested our hypothesis by examining the functional alterations and expression of EMT-related genes during the activation process of PSCs in vitro. By studying this process of PSC activation, we aim to uncover novel therapeutic targets for treatment of CP and PDAC.
Materials and methods
Harvesting rat pancreas
All animal studies were reviewed and approved by the Ethics Committee of Nanjing Medical University in accordance with the established standards of the humane handling of research animals. Male Sprague-Dawley rats (150–300 g) were obtained from Vital River Laboratories (Beijing, China). Rats were kept in standard laboratory conditions with light-dark cycles of 12–12 h and free access to chow and water. Rats were sacrificed by decapitation, before undergoing laparotomy. Rat pancreas was dissected and placed into cold 0.9% NaCl solution.
Isolation of quiescent PSCs
Quiescent PSCs were isolated from rat pancreas with enzyme digestion and Nycodenz gradient centrifugation as described previously (15). Briefly, after connective tissue and blood vessels were removed, pancreatic tissue was slowly infused with 10 ml enzyme solution (mixture of collagenase P, protease and DNase) until all lobules were swollen and well infused. The pancreas tissue was pre-incubated, finely minced and incubated again, in order to obtain a cell suspension. After washing, PSCs were obtained by ladder centrifugation with Nycodenz solution. Cells were cultured in DMEM/F12 (Wisent, Canada) supplemented with 10% fetal bovine serum (FBS) (Wisent, Canada), 4 mM L-glutamine (Sigma-Aldrich, St. Louis, MO, USA) and 1% penicillin-streptomycin (Thermo Scientific Hyclone, Waltham, MA, USA) at 37°C with 5% CO2. Cells were subcultured at 90% confluence in the following passages.
Characterization and identification of isolated cells
Morphological appearances of isolated cells were assessed under a contrast-phase microscope with blue-green autofluorescence at 320 nm from lipid droplets within the cytoplasm. PSCs were evaluated by immunocytochemistry/immunofluorescence (ICC/IF) and immunocytochemistry (ICC) using antibodies specific for PSC markers, α-SMA, desmin, vimentin, and GFAP. Antibodies for epithelium and macrophage markers (pan-CK, CK19, CD68) were used as negative controls to rule out possible cell contamination. Cells were seeded and stained in a 24-well plate (Corning Inc., NY, USA). ICC/IF and ICC were performed with standard procedures. The primary antibodies and their working dilutions were as follows: rabbit anti-α-SMA 1:100 (Abcam, Cambridge, MA, USA); rabbit anti-desmin 1:200 (Abcam); rabbit anti-vimentin 1:100 (Cell Signaling Technology, Beverly, MA, USA); mouse anti-GFAP 1:500 (Sigma-Aldrich); rabbit anti-CK19 1:300 (Abcam); mouse anti-CD68 1:100 (Abcam); and mouse anti-pan-CK 1:100 (Thermo Fisher Scientific, USA). DAPI and hematoxylin were used for nuclear counterstaining in ICC/IF and ICC, respectively. Cells were observed under a fluorescence microscope (Nikon Ti, Japan).
Cell migration assay
Cell migration assays were carried out in 24-well transwell chambers with polycarbonate filters (pore size, 8 μm; Merck Millipore, Billerica, MA, USA). A total of 2×104 cultured cells, at 40 h and on day 10 after isolation, were plated in serum-free medium in the upper chamber, and media containing 10% FBS alone was added to the lower chamber. After 40 h of incubation, residual medium in the upper chamber was removed carefully with a pipette. Cells on the surface of the filter membrane were fixed and stained with crystal violet staining solution (Beyotime, Shanghai, China) according to the manufacturer's instructions. Penetrated cells on the lower surface of the membrane were examined and counted under the microscope, before being removed with a cotton swab. Non-penetrated cells were assessed via the same method. Migration rates were calculated with the following formula: number of penetrated cells divided by the total number of both penetrated and non-penetrated cells.
Live cell motility assay
For cell motility studies of PSC, a live cell imaging system was used. There are many essential elements for this system. Firstly, a camera was mounted on the pressurized chamber on the stage of a Nikon TE 2000-E inverted optical microscope. Secondly, the microscope employed a number of computer controlled motorized systems in order to rapidly reconfigure the microscope during automated image acquisition. Finally, a small cell incubator on the microscope was used to control the cell environment and maintain our samples in a humidified and CO2 enriched atmosphere. The system was kept in a darkened room with ambient temperature maintained close to 25°C. The entire process was controlled by NIH-Elements AR software, and the following image processing was performed using Image-Pro Plus 6.0. Cells were cultured in 6-well plate and single cell movements was tracked with automatic record of a series of continuous images at an interval of 2 min under 100 magnified vision over 72 h. Cell motility capacity was assessed with the length of cell movement track over a fixed time.
Total RNA isolation and quantitative RT-PCR
Total RNA was extracted from quiescent and activated PSCs cultured in 6-cm Petri dishes with Qiagen RNeasy Micro kit (Qiagen, Mannheim, Germany) according to the manufacturer's instructions. Agarose gel electrophoresis was used for quality control of the isolated RNA. Reverse transcription was conducted using PrimeScript RT Master Mix (Takara, Dalian, China), while quantitative reverse transcription polymerase chain reaction (qRT-PCR) was performed using FastStart Universal SYBR Green Master (ROX) (Roche, Germany) on a StepOne Plus Real-Time-PCR System (Applied Biosystems, Waltham, MA, USA) according to the manufacturer's instructions. The PCR program consisted of an initial enzyme activation step at 95°C for 10 min, followed by 45 cycles of amplification with 95°C for 15 sec, followed by incubation at an appropriate temperature for 1 min. Finally, a melting curve profile was set at 95°C (15 sec), 60°C (1 min), and 95°C (15 sec). β-actin was used as an endogenous control to which each gene of interest was normalized. Relative quantification was calculated by the ΔΔCT method and normalized based on the designated control. Primer sequences used in qRT-PCR are shown in Table I.
Western blotting
Total proteins were prepared with a protein extraction kit (Beyotime) and quantified by the bicinchoninic acid assay (BCA) method (Beyotime) according to the manufacturer's instructions. Polyvinylidene fluoride (PVDF) membranes (Millipore) were blocked in 5% non-fat dried milk in phosphate-buffered saline with Tween-20 (PBST) and incubated overnight at 4°C with appropriate primary antibodies [rabbit anti-α-SMA, dilution 1:200 (Abcam); rabbit anti-vimentin, dilution 1:1,000 (Cell Signaling Technology); rabbit anti-S100A4, dilution 1:250 (Abcam); rabbit anti-N-cadherin, dilution 1:200 (Santa Cruz Biotechnology, Dallas, TX, USA); mouse anti-E-cadherin, dilution 1:1,000 (Abcam); rabbit anti-BMP7, dilution 1:1,000 (Abcam); rabbit anti-Slug, dilution 1:700 (Abcam); and rabbit anti-Snail, dilution 1:1,000 (Cell Signaling Technology)]. Membranes were then washed and incubated for 2 h at room temperature with secondary horseradish peroxidase-conjugated anti-mouse IgG or anti-rabbit IgG (Cell Signaling Technology). All protein expression levels were normalized to β-actin (Abcam).
Statistical analysis
Statistical analysis was performed using SPSS, version 13.0 (SPSS, Inc., Chicago, IL, USA). All experiments were repeated in triplicate, and the most representative data are shown in this report. Numeric data were expressed as mean ± standard deviation (SD). Statistical significance between two groups was determined by the Student's t-test, with P-values <0.05 considered statistically significant.
Isolation and identification of rat quiescent and activated PSCs
The yield of rat quiescent PSCs was ~4 to 7 million cells per gram of pancreatic tissue. Freshly isolated PSCs remained quiescent within the first 48 h of primary culture as indicated by their typical round or polygon shape and autofluorescence from lipid droplets in their cytoplasm (15). After 48 h, they began to transform to an 'activated' form, acquiring fibroblastic characteristics and losing their lipid droplets. Apte et al previously demonstrated that freshly isolated PSCs cultured on plastic were gradually activated after 48 h and fully activated after 7 days in vitro (15). For this reason, we chose cells cultured for 40 h after isolation as representative of the quiescent state and cells cultured for 10 days as representing the fully activated state (Fig. 1). Primarily cultured cells were positive for PSC marker (α-SMA, vimentin, GFAP and desmin) staining in ICC and ICC/IF (Fig. 2). To exclude possible contamination with macrophages and epithelial cells, the purity of PSCs were confirmed with negative immunostaining with CK19, CD68, and pan-CK (Fig. 3).
Figure 1
Isolation of rat pancreatic stellate cells (PSCs) in vitro. (A) Light microscopy of quiescent PSCs after 40 h in culture, magnification, ×200. Cells were round or polygon in appearance and showed abundant lipid droplets in the cytoplasm. (B) Transient blue-green autofluorescence at 320 nm could be examined due to the presence of vitamin A in the cytoplasm after 24 h in culture, magnification, ×200. (C) Cell culture 10 days after isolation showing that PSCs developed a fibroblast-like morphology and lost most of their lipid droplets, magnification, ×100.
Figure 2
Expression of cellular markers in isolated pancreatic stellate cells (PSCs), magnification, ×100. (A, C, E and G) Immunofluorescence staining for isolated PSCs. DAPI (blue) was used to counterstain the nuclei. (B, D, F and G) Immunocytochemistry staining for isolated PSCs. Hematoxylin (purple) was used to counterstain the nuclei. (A and B) α-SMA [(A) red; (B) brown]. (C and D) Vimentin [(C) green; (D) brown]. (E and F) GFAP [(E) red; (F) brown]. (G and H) Desmin [(G) green; (H) brown].
Figure 3
Immunofluorescence staining of macrophage and epithelium markers in isolated pancreatic stellate cells (PSCs), magnification, ×100. DAPI (blue) was used to counterstain the nuclei. (A) CK19; (B) CD68; (C) pan-CK [if positively stained (A) was green, while (B) and (C) were red].
Cell migration ability is promoted after PSC activation
PSC migration ability was assessed using transwell chambers with 40-h incubation time. More cells migrated to the lower surface of the membrane 10 days after isolation compared with those isolated after only 40 h. In order to rule out possible differences in cell adherence and proliferation ability after activation, the cell migration rate was calculated. Increased cell migration rate was observed after PSC activation (Fig. 4).
Figure 4
Activation of pancreatic stellate cells (PSCs) promotes their migration ability (qPSCs, quiescent PSCs, and aPSCs, activated PSCs). (A) Cells were fixed, staining and counted after 40 h of a transwell migration assay. Cells on the upper surface and lower surface of polycarbonate membrane represent non-penetrated and penetrated cells, respectively. (B) Significantly more cells migrated after activation compared with their quiescent counterparts, as indicated by more cells in the lower surface after migration assay. Data are expressed as mean ± SD from three biological replica, *P<0.05. (C) An increased migration rate was observed in activated PSCs (10 days after isolation), compared with quiescent cells. Data are expressed as mean ± SD from three biological replica, *P<0.05.
Live cell motility rate is increased after PSC activation
Cell motility capacity was assessed by live cell imaging system. PSC motility capacity was increased after cell activation, as the activated PSCs moved a longer distance during a fixed culture time. The real-time images of randomly chosen monitored cells are showed in Fig. 5. At the same time, PSCs underwent characteristic morphological changes in vitro, including loss of lipid droplets, increased cell volume and transition to a myofibroblastic phenotype, which is in accordance with our previous findings (15,16).
Figure 5
Changes in pancreatic stellate cell (PSC) motility capacity after cell activation as assessed by live cell imaging system. Asterisks indicate the chosen single cell under the microscope, and the cross indicates the fixed reference in the continuous imaging. (A) Continuous imaging of quiescent PSC cultured in live cell imaging system for 72 h. The cell movement track is shown in the last image (merged). (B) Continuous imaging of activated PSC (10 days after isolation) cultured in live cell imaging system for 60 h. The cell movement track is shown in the last image (merged). (C) Cell motility capacity assessed by the average length of the movement track of five randomly selected single cells over the culture time. Motility capacity was improved in activated PSCs compared to quiescent cells, which is indicated by an increased length of their movement tracks. Data are expressed as mean ± SD from three biological replica, *P<0.05.
Changes in the expression of an EMT-related gene panel after PSCs activation
To determine whether PSC activation involve an EMT-like process, we analyzed expression of epithelial markers E-cadherin, bone morphogenetic protein 7 (BMP7), and desmoplakin, and the mesenchymal markers N-cadherin, fibroblast-specific protein 1 (S100A4), vimentin, fibronectin1, and collagen1α1, during the PSC activation process by qRT-PCR. E-cadherin, BMP7 and desmoplakin were significantly downregulated, while N-cadherin, S100A4, vimentin, fibronectin1 and collagen1α1 were upregulated in activated PSCs after 10 days of in vitro culture compared with quiescent PSCs (Fig. 6).
Figure 6
Quantitative real-time PCR indicating that pancreatic stellate cell (PSC) activation is accompanied by alterations in expression of a panel of EMT-related genes. Compared to quiescent PSCs (40 h after isolation), there were significantly decreased expression of epithelial markers (E-cadherin, BMP7 and desmoplakin), together with increased expression of mesenchymal markers (collagen1α1, fibronectin1, N-cadherin, vimentin and S100A4) and EMT-related transcription factors (Snail1 and Slug) in activated PSCs (10 days after isolation). Data are expressed as mean ± SD from three biological replica, *P<0.05.
Since the Snail transcription factor family, such as Snail and Slug (also known as Snail1 and Snail2), is reported to play a crucial role during the EMT process, we used qRT-PCR to examine the expression of Snail1 and Slug during PSC activation. Both Snail1 and Slug mRNA levels increased significantly in activated PSCs compared to quiescent PSCs. We also examined the expression of EMT-related genes at the protein level by immunoblotting. Western blot analysis confirmed that the decreased protein expression of epithelial markers, including E-cadherin and BMP-7, was accompanied by increased expression of mesenchymal markers (i.e., N-cadherin, vimentin, S100A4) after PSCs were activated (Fig. 7). Furthermore, the two EMT-related transcription factors, Snail and Slug, also showed increased expression at the protein level during PSC activation.
Figure 7
Western blotting indicating alterations in protein expression in activated pancreatic stellate cells (PSCs). In contrast to quiescent PSCs (40 h after isolation), the protein levels of the epithelial markers (E-cadherin and BMP7) were downregulated, while mesenchymal markers (collagen1α1, fibronectin1, N-cadherin, vimentin and S100A4) and transcription factors (Snail1 and Slug) were upregulated in activated PSCs (10 days after isolation).
Previous studies proved that PSCs stimulated the EMT process of cancer cells, and thereby elevated tumor migration and invasion (30). The present study provides novel evidence that PSC activation induced EMT-related gene expression in vitro. We also observed significant alterations in morphology and migration capacity when PSCs were fully activated. We found that PSC activation was accompanied by downregulation of E-cadherin and upregulation of N-cadherin, vimentin, collagen1α1 and fibronectin1 gene expression.
Besides the classical molecular regulators of EMT described above, we also examined expression of BMP7 and S100A4. Bone morphogenetic proteins such as BMP7 belong to a large family of cytokines, which regulate various biological processes including cell proliferation, apoptosis, differentiation and morphogenesis (31). A close relationship between BMP signaling and EMT during embryogenesis, fibrosis and cancer development has been elucidated by several studies (32–34). BMP7, in particular is recognized as an antagonist of EMT induced by TGF-β (35,36). In this study, BMP7 expression was significantly decreased in activated PSCs.
S100A4 is a member of the calcium-binding S100 protein family, and has been associated with cell proliferation, cellular adhesion, reconstruction of the ECM, angiogenesis and cellular motility (37–39). Cells that express both α-SMA and S100A4 are identified as fibroblasts (40) and S100A4 is expressed in fibroblasts during type 2 EMT (41). In our study, when PSCs maintained a fully activated state, S100A4 expression was notably increased.
Furthermore, the present study proves that the Snail and Slug transcription factors were related to the activation of PSCs. The vertebrate Snail genes mediating EMT are divided into two subtypes: Snail1 and Snail2 (also known as Slug) (42,43). Snail1 and Snail2 are known as repressors of E-cadherin and can upregulate mesenchymal markers such as vimentin (44,45). Previous research showed that Snail expression was associated with tissue fibrosis (42). In addition, Scarpa et al reported that Snail1 plays a pivotal role in HSC activation (46). Similarly, in this study, Snail1 and Slug were upregulated in PSC activation.
Based on the results of this study and previous studies, it is clear that PSCs complete an EMT-like process that promotes the development of a migratory, mesenchymal phenotype from a quiescent phenotype. Therefore, the EMT process is a key event in PSC activation. It follows that reversing the EMT process could be a potential therapeutic strategy for chronic pancreatitis and pancreatic cancer. However, little is known about the reverse process of EMT, which is called mesenchymal-epithelial transition (MET). The process of MET is well known in kidney formation, and multiple genes are involved, including BMP7 (47–49). Similarly, BMP7 has been reported to act as a positive regulator of MET in mice (35). BMP-7 antagonizes TGF-β1-induced fibrotic effects in vitro and reverses fibrosis in various organs such as the kidney, heart and colon (50). Therefore, reducing the expression of BMP7 is likely to restore quiescence in activated PSCs. However, further work is required to clarify the molecular mechanisms underlying the signaling pathways involved in EMT and MET processes.
One pathway known to be involved in EMT is the Hedgehog pathway. This pathway promotes formation of mesenchymal cells and has been shown to participate in HSC transdifferentiation from quiescent HSCs to myofibroblastic HSCs in vitro (51–53). Similarly, in vivo studies have indicated that Hedgehog pathway activation is associated with EMT, myofibroblast proliferation and liver fibrosis while inhibition of this pathway attenuates EMT, myofibroblast accumulation and fibrosis in mouse models (29,54,55). For this reason, genes related to the Hedgehog pathway were examined by qRT-PCR in the present study (data not shown). We found the in the activated PSCs, Gli1, Gli2 (i.e., Hedgehog target genes) and sonic hedgehog (i.e., the Hedgehog ligand) were all upregulated, and HHIP (i.e., a Hedgehog ligand antagonist) was downregulated. However, additional research is needed to confirm whether the Hedgehog signaling pathway modulates the process of PSC transdifferentiation.
In conclusion, the present study supports that the transition of quiescent PSCs to activated myofibroblastic PSCs involves an EMT-like process in vitro. This knowledge improves our understanding of the pathogenesis of pancreatic fibrogenesis, and offers a potential theoretical basis for future research on the treatment of PDAC and chronic pancreatitis.
This study was supported in part by the National Natural Science Foundation of China (81272239, 81170336, 81272382, 81300351), the Natural Science Foundation of Jiangsu Province (BK2012881), the Program for Development of Innovative Research Team in the First Affiliated Hospital of NJMU, the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD, JX10231801), and the Translational Research of Early Diagnosis and Comprehensive Treatment in Pancreatic Cancer (The research Special Fund For Public Welfare Industry of Health, 201202007).
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Many immigrants in my country end up broke and mired in debt because of their mindset, similarly people who move to another relationship without changing their mindset don't solve any of their problems
When I entered my relationship with a Filipina one of the very first things I did, to become acquainted with her culture, was watching Filipino movies.
One of the first ones I watched is entitled "All My Life".
The lyrics of the theme song of this famous Filipino movie say something along the lines of "I'll never forget how you brought the sun to shine in my life…there was an empty space in my heart".
These are not just the lyrics of a song, this is actually how most people who wish to be in a relationship or wish to be in a better one think.
A lot of people in our society, not just in the Philippines, believe that on a sunny day the ideal partner will show up and "bring the sun to shine" in their hearts, there where there is an "empty space" to fill, as the song goes.
I believe that this is a myth and that entering a relationship or moving from one relationship to another doesn't quite bring the sun to shine in an empty heart.
It has been said many times and in many ways that one of the hallmark characteristics of a healthy relationship is giving, so if one has an "empty space" to fill the solution is inner work not someone else who will do it for us.
I believe that if our current partner is not causing the "sun to shine" in our heart the solution is not another partner, rather it is fixing our own crap and no one can do it for us unless we do it.
Unless one is in a relationship with a partner who has become abusive, violent, irresponsible, extremely lazy or otherwise unbearable to the point that there is no way to continue the relationship, moving from one relationship to another is not the answer in my modest opinion.
I think the condition of many Filipino immigrants in my country is an interesting metaphor to illustrate this point.
In much the same way as many people move from one relationship to another, Filipinos who live in Italy have moved from one country to another looking for greener grass.
The problem is that while some have indeed fixed their financial problems most are just as broke as if they would be if they had never left the Philippines. Why?
Because of the bahala-na approach to life (or "casual" approach to life), which is part of the "Pinoy mentality" that often doesn't change when Filipinos move to another country.
For example, one of the reasons why Filipino people leave their country and move here is because here in Italy health care is free. The problem is that despite having access to free medical care most Filipinos keep drinking way too much alcohol, eating way too often at KFC, Mc Donald's, most exercise very little if they exercise at all and, as a result of this mindset, they are just as ill as if they lived in a country that has no free health care (my wife is Filipina and I love Filipino people flaws and all, I am just trying to make a point here).
So my point is that wherever we go we bring us with us. Unless we shift our mentality no place, situation or person will ever fix our problems.
A famous motivational speaker said that "it is not the blowing of the wind, rather it's the setting of the sail" that determines where we wind up in life.
It is true that, just as there are people who cannot help but flee from dangerous and abusive relationships, there are also people who cannot help but flee from countries that are plagued by war, extremely difficult economical situations, persecution and so on.
The problem is when one runs away from a difficult situation that is the result of a messed up mindset and expects to find the solution to his or her problems by moving to another environment without changing anything about his or her mentality
Many Filipinos, as soon as they move to my country have kids before they even find adequate work, many buy a fancy car and the latest electronic gadgets and give very little thought to cultivating smart financial habits and, as a result of this bahala-na approach, many end up having spent years or even decades in this country without having changed anything about their situation.
The same principle applies to relationships: if we have an "empty space" in our heart we need to fix it by doing the hard work that is necessary to change our mindset and if we do our homework in this area chances are that "the sun" will start to shine in our heart of its own accord and it is highly likely that by doing so we will not need to rely on someone else and change partner to fill the "empty space in our heart" but rather we will be able to make our present relationship work.
If we do nothing to improve ourselves and expect a new partner to fix us we will keep chasing "the same person only in a different body" as Dr. Wayne Dyer wisely said and the empty space in our heart" will remain empty.
The bottom line is: it is way better in my opinion to work on our mindset and fix our weaknesses, thereby making our present relationship work, than run away from the relationship in search of the elusive goal of finding the perfect match who can make the sun shine in an empty heart.

subset: commoncrawl


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Let's Take a Break with Some Stuff that is Easy to Listen To
Ah, yeah! Gonna kick back and relax a bit after that last couple of wild ones. And when I relax, I like to do it in a soft leather chair, with a cool drink and an album of music that's easy to listen to.
Sorta like this one. Carmen Cavallaro was known as "The Poet of the Piano" and followed closely in the footsteps of Eddie Duchin to release albums of flashy, zingy piano stylings of both popular music and "classical pop". As a matter of fact, it's actually Carmen playing the piano for Tyrone Power in "The Eddie Duchin Story" (probably playing better than Duchin himself could have).
Carmen also released another Cocktail album, entitled "Cocktails with Cavallaro". I don't have it, though. I have this one.
- The Second Time Around
- This Could Be the Start of Something
- If Ever I Would Leave You
- Mine
- The Happiest Girl in the World
- Love Is Here to Stay
- When I Fall in Love
- Never on Sunday
- Love Letters
- Make Someone Happy
- My Sentimental Heart
Were you to come back with "WAY South of the Border!" I would have to say that I'd like to sink back with a well made Caipirinha while listening to the soothing sounds of 101 Strings playing "Fire and Romance of South America" played.
Don't believe me? Grab yourself a bottle of Cachaca and a few limes and give this a spin.
- Brazil
- La Cumparsita
- Ay Ay Ay
- Desafinado
- Inca Theme
- Tico Tico
- El Choclo
- Encanto del Caribe
- Carnival do Rio
- Adios Muchachos


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Security researcher xylitol, has submitted on 28/08/2008 a cross-site-scripting (XSS) vulnerability affecting www2.equal-mayday.org.pl, which at the time of submission ranked 22877142 on the web according to Alexa.
We manually validated and published a mirror of this vulnerability on 03/10/2008. It is currently unfixed.
If you believe that this security issue has been corrected, please send us an e-mail.
Vulnerable URL: http://www2.equal-mayday.org.pl/knowledgeTree/login.php?errorMessage=%3Cscript%3Ealert(1337)%3C/script%3E%3E%3Cmarquee%3E%3Ch1%3EXSS%20by%20Xylitol%3C/h1%3E%3C/marquee%3E


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Welcome to the webpage of the group "Mesoscopic Physics and Thermoelectricity"! The group was formed in late 2010 in order to better understand the theoretical aspects of thermoelectricity, at a fundamental level. It is part of the strategy of the CEA to develop its research activities on renewable energies.
We are a small group of theorists, working all together on the emergent field of thermoelectricity. The group, headed by Jean-Louis Pichard, is made up of three CEA researchers and typically one PhD student and one or two post-docs.
If you are interested in our activities and want to work in our group, do not hesitate to contact us. We have typically one open position per year for a postdoctoral student and from time to time, a position for a PhD student (CEA funding is sometimes possible). Graduate and undergraduate students are also welcomed to visit the lab!
Antoine Georges, professor at Collège de France and researcher at Ecole Polytechnique, gave a series of lectures on thermoelectricity at Collège de France in March and April 2013. Audio/video recordings of the lectures are available online. Another session "mesoscopic thermoelectricity" will take place in november-december 2013 (more details).
We organized in september 2012 a conference on thermoelectricity. The talks given by the participants are available on the website of the conference. It gives an idea of the group's research interests.
Vous devez préciser l'id_ast dans la table des unités.


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Leeza Store Women's Banarasi Silk Weaving Zari wrok Saree With Blouse Piece (Patola-21_Pink Color_Free Size)
₹ 1,099 ₹ 2,999
Look Trendy by wearing this Amazing Fancy Saree From House of "Leeza Store". It comes with a unstitched blouse Piece. Designed using the best quality fabric, along with best combination of colours, ensures that it should never fail to be the perfect eye magnet. An awesome combination of vibrant colours of this saree will add a level up to your graceful attitude. We quality check the products twice before dispatch. NOTE: Actual product may or may not have slight shade change due to flash effect of camera while taking photograph. Patterns and Colors will be same as shown in the image.Provided blouse piece will be an unstitched blouse piece attached with saree.
- Care Instructions: Dry Clean Only
- Blouse Fabric : Banarasi Silk, Blouse Colour : Maroon, Blouse Length : 0.8 mtr,Type : Running Unstitched Blouse(Included In Saree Length 5.5 mtr + 0.8 mtr)
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Testing 1,2,3
Or it's my ball you can't play with it..
When people say they play tested a game, what does that mean? Is it that they run all the possibilities did they can check and then double check. So we can say, do the rules work?
Playtesting the game is work and frustrating (very,) not just for the writers, and the creators and in all honestly for the play testers as well. Because things change and change creates a hurricane of havoc..
In simple terms if I present a game to you guys and through your feedback it results in four weeks major changes happened, however the play testers that were playing liked the way the game played as it worked in their favor. Then we run into other obstacles and problems down the road. I have been designing homebrewed games now for a while, in fact for over 10 years I've made 20 different games with unique game systems, and obviously in different settings.
Each time the play testers were satisfied I was never satisfied I wanted to make the perfect game that was my quest and I spent my younger years pursuing a quest on a fool's errand. Now that I'm older and more wiser and I understand there's no perfect game it's great to pursue it but I'll never get a product on the market if I pursue that ideal of the perfect game. So that being said I thought I was very close to having a game that is fun moves fast easy to play and understand. For a game designer and a player that is in a way the definition of a good game.
That was 2015, we did have a dice crunch where, we use similar mechanics to any multiple D10 system. But it was based on successes in each die rolled over the target number was a success. When the comments came in
on the first kickstarter and people saw the gameplay, i realize it's not your basic skirmish game. Now I was okay with it in the beginning but you know as time progresses I realized that some of the comments were right, and I was maybe wrong (playtesters work along a fine line between player and backseat designer, so of the feedback is very relevant, others try to influence the design and some people have the quantitative ability to get where you are trying to go and make very direct, constructive yet objective observations to what they are seeing when playing the game.)
The system we used was based on a role-playing game that I've made earlier in 2012, and like any other game role-playing games and skirmish miniature games don't quite go hand-in-hand with the same type of mechanics, it's hard to have a game to do both very well. And that's why we talked about in the previous blogs about the one dice. And believe me it was hard to go from the D10's I invested money into the D10 system I believe that it that it was going to work.
Sometimes it's better to let your pride go and go with something that works for the masses than a system that is designed for slower combat and skill driven RPG game. (Matt's note, when one was chatting to Derek early on after the second KS, this very point came up and it is very difficult as again it comes back to not wanting to be a back seat designer but at the same time wanting to try and be honest without 'being a bit of a di*k'. Thankfully one has been a playtester for others and after chatting to a couple of industry friends they both said just be the one that's honest. So one's response was 'Is this a rpg or skirmish game?')
So for me the biggest difference between an RPG game that uses miniatures and a skirmish game using miniatures is that in RP games the players are united against a common enemy or foe ran by the referee, GM or dungeon Master. And therefore so what if combat takes few hours to resolve, no one really cares though they have a good time with their friends.
Now the seriousness of skirmish games is, one cannot just only think of speed, simplicity or being invested in a system you know that works well for role-playing games. When you forget one important aspect of the skirmish game tournaments and competitive play.
Sky Relics is now a driven game not just with skirmish rules, but to be eventually set up to have tournaments at conventions, that's important. See the first kickstarter, I didn't care about point values because you're choosing a captain, you are going to play against a GM, not against your friends so it's not head-to-head matches. Then we realized that the skirmish side of things is what a lot of the players wanted and we understand that like anything else Wargames need to set up right to be successful.
Now board games really have taken over on kickstarter too but this isn't just a board game, it's so much more than that, and I will get to that later in another blog. So later in 2015 my brother and I went back to the drawing board we had to make a game that had point spending fairness, that can be easily used tournaments, at conventions in essence to be a contender in the game space. So we rolled up our sleeves and went to work, in the last six months I've playtested, playtested and play tested. But were not done yet and as you read soon in our next blog on how we're improving our next range of play testing groups.
Hopefully you keep reading and learning more about our wonderful world of Targus and Sky Relics


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So the show season has started with a bang! I've just spent the last six days at Three Counties Malvern, two of them setting up with the Hereford Guild of Craftsmen where we are joined by our neighbouring guilds, Cotswold and Worcester every year then four days of the actual show.
Category: News
Gifts for someone special
How about spoiling the special person in your life with something a little different for that special occasion? Valentine's Day, Birthdays, Christmas, Anniversaries, Retirement? Continue reading Gifts for someone special
Garden art studio video tour!
If you're anything like me, I love to have a good old nose around! So welcome to my art studio!Continue reading Garden art studio video tour!
Happy New Year everyone!
So we are now approaching the end of the year! Where has it gone? I blinked and missed it I think!
Continue reading Happy New Year everyone!
Merry Christmas to my blog readers!
As you read this I will be sat in front of my television, full of Christmas munchies and enjoying some feet up time and not in my artist studio!
Continue reading Merry Christmas to my blog readers!
Eco Friendly as possible! Going green!!!
So the environment is in need of our help. It's changing rapidly, and not always for the better. Continue reading Eco Friendly as possible! Going green!!!


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EBS Mind Trip
EBS Mind Trip (5.26.16)
Latest episode of EBS Mind Trip with another epic mix!
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Yuma, Ariz. – Time to plan your family's spring and summer: The City of Yuma's semi-annual Parks and Recreation activities guide is now available at City facilities and online.
The 42-page guide features the times, dates, places and information for all the programs, classes and co-sponsored sports leagues offered through Yuma Parks and Recreation.
The online PDF document can be saved to desktop computers or printed for future reference.
For spring and summer 2017, featured activities include the ever-popular swimming lessons, this year's Fairy Party, Camp Awesome, Family Fish Fiesta, Back to School Rodeo, Art Smart Camp, and more.
There is also information regarding the City's 4th of July All-American BBQ and Fireworks Spectacular, back now for a third year.
Registration for the programs listed within begins March 27, exclusive to City of Yuma residents. Registration for those living outside the city limits, and online registration, will begin April 3.
The guide can be accessed via links provided on the article announcing the guide's online preview under the City News section on the homepage of the City's website, www.yumaaz.gov, or via the Activities Guide page.
Printed copies of the guide will be available in upcoming weeks at all Parks and Recreation facilities, including the Yuma Civic Center, Yuma Art Center, Desert Hills Golf Course, the North End Community Center, and the main office on the first floor of City Hall. The print edition will also be included in the Sunday, March 26 issue of the Yuma Sun.


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The mushroom-shaped Ambienta lamp has two settings (grow light and ambient light) and, like a paint palette, has compartments for six plants. Seagreenlife's soil-free plants grow on water, nutrients and a hydroponic growth medium located at the base of the lamp; simply pour water through the top hole when needed. Not only does the lamp feel alive, it allows you to have plants away from the window. It should especially brighten up those dismal bedrooms, basements or other closed-off spaces that don't have a portal to the outside world. They'd also look pretty sweet in dimly lit bars.
Ambienta Plant Lamp


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April 12, Monday was Yom HaShoah, which is Hebrew for Holocaust Remembrance Day. It's a day when many remember the deaths of six million Jews in Nazi concentration camps as well as pausing to remember the other victims of the Nazi regime, some three million civilians, maybe more, who were slaughtered for no other reason than who they were. I am late on writing about this as it's a difficult topic to discuss. How can you rationally talk about the slaughter of 1.5 million children, some of whom were infants. How can you rationally talk about how entire villages and communities were wiped off the map. The scope and size of what happened is enormous. And yet, every year, we always like to say we are better than that now and say that was the past. Well, Maybe not. Consider:
This by no means is a complete list but it's a sad list. So why the post beyond just a lament against genocide which most can agree is barbaric. Well, at the Capitol today, Gen. David Petraeus, and others honored several American GIs who were among those who helped to liberate the death camps. Here's the link to the ABC story. Here are the lines in the story that got me to post this up so others could see it.
Sgt. Robert Patton, 88, served in the 65th ID, 3rd Army and helped liberate the Mauthausen-Gusen concentration camp on May 6, 1945.
"The odor of death could be detected outside the camp," Patton said. "Once you smell that odor, you will never forget it."
Patton saw hundreds of bodies piled onto pallets outside the gas chambers, "stacked like cord wood."
Imagine the nightmares those men had and remember, many of them were battle hardened vets. I can't imagine, and frankly, I don't want to. Here's another post by the milblogger and journalist, Spencer Ackermann.


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Location: Japan
Born in Saitama Prefecture in 1973, Satosato is an illustrator who creates her pieces based on the theme of kachofugetsu (traditional aesthetic nature themes) using familiar animals and plants as subject. She aims for pieces which enable the viewer to experience the joy of being alive. Satosato specializes in semi-realistic depictions of plants, and her pieces are characterized by a depth and texture created using digital media.
Web site: www.ysatosato.sakura.ne.jp
Pen, CG
Pen, CG


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This year at the World Science Fiction Convention, two works will be honored with Prometheus Awards for best works of libertarian futurism. And the winners are . . .
The Libertarian Futurist Society has announced:
The winner of the Best Novel award is "The Unincorporated Man", by Dani and Eytan Kollin (TOR Books). The Hall of Fame award was won by "No Truce with Kings," a story by Poul Anderson, written in 1964. The Kollin Brothers will each receive a plaque and a one-ounce gold coin, while a smaller gold coin and a plaque will be presented to Anderson's estate.
"The Unincorporated Man" is the first novel publication by the Kollin brothers. [Read the io9 review of the book here.] It is the first novel in a planned trilogy to be published by Tor. "The Unincorporated Man" presents the idea that education and personal development could be funded by allowing investors to take a share of one's future income. The novel explores the ways this arrangement would affect those who do not own a majority of the stock in themselves. For instance, often ones investors would have control of a person's choices of where to live or work. The desire for power as an end unto itself and the negative consequences of the raw lust for power are shown in often great detail. The story takes a strong position that liberty is important and worth fighting for, and the characters spend their time pushing for different conceptions of what freedom is.
Poul Anderson's novels have been nominated many times, and have won the Prometheus Award (in 1995, for "The Stars are also Fire"), and the Hall of Fame Award (1995 for "The Star Fox" and 1985 for "Trader to the Stars"). He also received a Special award for lifetime achievement in 2001. This was the first nomination for "No Truce With Kings".
Poul Anderson's "No Truce with Kings" was first published in 1963. Like many science fiction stories of that era, it was set in a future that had endured a nuclear war. Anderson's focus is not on the immediate disaster and the struggle to survive, but the later rebuilding; its central conflict is over what sort of civilization should be created. The story's title comes from Rudyard Kipling's poem "The Old Issue," which describes the struggle to bind kings and states with law and the threat of their breaking free. Anderson's future California is basically a feudal society, founded on local loyalties, but it has a growing movement in favor of a centralized, impersonal state. As David Friedman remarked about this story, Anderson plays fair with his conflicting forces: both of them want the best for humanity, but one side is mistaken about what that is. This story is classic Anderson and, like many of his best stories, reveals his libertarian sympathies.
The other finalists for Best Novel were Hidden Empire, by Orson Scott Card (TOR Books); Makers, by Cory Doctorow (TOR Books); Liberating Atlantis, by Harry Turtledove (ROC/Penguin Books); and The United States of Atlantis, by Harry Turtledove (ROC/Penguin Books). Eleven novels published in 2009 were nominated for the 2010 award.
The other finalists for the Hall of Fame award were "As Easy as A.B.C.," a story by Rudyard Kipling (1912); Cryptonomicon, a novel by Neal Stephenson (1999); and "'Repent, Harlequin!' Said the Ticktockman," a story by Harlan Ellison (1965).


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Per Gessle on tour – finally!
STOCKHOLM (UPDATED) - It may have been the pressure from the media or from the fans, or Per Gessle's own lust for touring, or the mix of all of it, but in the end, Per has managed to arrange a tour around the end of July to mid-August. The "around 14-gig" tour will take Per at least to Stockholm and Sofiero Slott in Helsingborg where Gyllene Tider started Återtåget tour in 1996. This time, however, the premier will be in Brottet, Halmstad on July 29th.
Per's band will be the same as at the release party: Helena Josefsson (backing vocals), Jonas Isacsson (guitars), Jens Jansson (drums), Christoffer Lundquist (guitars & backing vocals), Anders Herrlin (bass guitar) and Clarence Öfwerman (keyboards). TDR will publish more dates as they become available.
"I never could've imagined this reception for my little mazarin," says a happy Per Gessle, "and a tour was never in the cards. But we had so much fun in Halmstad and I can't resist the possibility to take these songs out in the Swedish summer. They are sort of made for parks and picnics, and I hope the audience agrees with me… and wants to end the summer in a green park with a mazarin."
Technical errors may occur.
June 16th, 2003
Internal reference code for TDR's Good Reporters: [tdr 112190]
This article was posted here on TDR in these categories:
Archive, TDR:Exclusive, vintage.


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What I Wore: Sister Style
Wednesday, April 3, 2013
What I Wore: Shirt (Tulle via The White Cupboard), Jeans and Belt (Gap), Shoes (Old Navy), Necklace (Gift)
26 comments
- AnonymousApril 3, 2013 at 9:29 AM
Awesome!!! <3ReplyDelete
You two are so fun! Love these shots-what a great location and a great set of photos! Gorgeous girls :)ReplyDelete
you girls are adorable!! love the casual chic outfits and the bridge!!ReplyDelete
This is fun. My sisters would NEVER do an outfit post with me. You are a lucky lady :)ReplyDelete
The Nautical Owl
Aww I didn't know you had a sister! This shoot was awesome, it's cool to see how your style is pretty similar. I only have brothers but I noticed them wanting to wear suits more and bow ties...even a pocket watch! So my vintage style is definitely rubbing off on them, too haha. These are really pictures- that bridge location is great. Also, thanks for your kind words on my blog, it's great to feel that someone's in your corner :)ReplyDelete
xo Marlen
Messages on a Napkin
You girls are adorable! I love your jeans look Kristian, I could never pull it off. I hope we see more sister style posts :)ReplyDelete
Southern (California) Belle
- AnonymousApril 3, 2013 at 7:24 PM
How fun that you get to do photos with your sister!! I love these shots on the bridge:)ReplyDelete
Aw this is too cute!ReplyDelete
Wyoming only has one University? wow!
ah, sister style! i love it! the bridge was a great location for these photos!ReplyDelete
lindsey louise
I LOVE FORT COLLINS. Please go to Snooze and Big City Burrito for me. I miss it dearly. You both look wonderful and these photos are so fun! I wish my sister still lived in Fort Collins. I miss it.ReplyDelete
what a fun shoot w/ your sis! you do both seem to have similar style, although I have to say I was expecting to see some of her pretty yarn works in this post. but oh well : ) oh and I do love her hair as well! I love this bridge location for a photoshoot and glad you had such a fun weekend! i'll take busy like that over studying 24/7 any day!ReplyDelete
You and your sister look so similar but in a different way! Just found your blog its really cute!! i will have to stop by again!ReplyDelete
herlux fashion
I'm really loving both of your tops! great post!ReplyDelete
Nice post dear (happy family), I hope I could get some pictures with my sister too..ReplyDelete
keep blogging dear, see you next time
Such a strong bond you two sistersReplyDelete
having! Love the second pictures c:
SISTAHS!!! Both beautiful! love the poses.ReplyDelete
Awww! What a great photo shoot! That is so awesome, sisters are just the best things ever! You both look amazing!ReplyDelete


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Principles of Wound Care
- Wound Learning Academy! FREE PREVIEW
- Wound Course Objectives FREE PREVIEW
- The Importance of Wound Care FREE PREVIEW
- Anatomy and Physiology of Skin and Soft Tissues
- Phases of Wound Healing
- Identify & manage risk factors affecting skin integrity, extrinsic vs intrinsic factors
- Wound Evaluation/Assessment
- Acute vs Chronic Wounds
- Types of Wounds
- Pressure Ulcers
- Diabetic Foot Ulcers
- Venous Stasis Ulcers
- Peripheral Artery Disease
- Lymphedema
- Infected Pressure Ulcers
- Osteomyelitis
- Cellulitis
- Burns
- Rash
- Ostomy Care
- Debridement, Indications, types of debridement & contraindications to debridement
- Wound Dressings
- Risk factors for impaired wound healing and wound complications
- Wounds at a Glance FREE PREVIEW
- Hypergranulation
- Nutrition
- G-Tube replacement
- You're Almost There!!!
- Credentialing Questionnaire
The Wound Learning Academy by SNF Wound Care is a comprehensive online wound care management educational platform designed to prepare health care professionals to perform at the highest level of care in all settings, including Skilled Nursing Facilities, hospitals, home health, hospice, and private practice.
Our online educational content was developed based on years of daily clinical experience and is updated regularly based on thousands of treated patients. We offer the most up-to-date and relevant wound care education to help nurses and healthcare professionals provide unparalleled quality of care for wound care patients.
All programs and curriculums are approved Nationwide by California Board of Registered Nursing & California Board of Vocational/Practical Nursing, and meet nursing license renewal requirements in all 50 states.
SNF Wound Care
Provider Approved by the California Board of Registered Nursing
Provider # CEP17378
& California Board of Vocational Nursing
Provider # BVNPT V10949
Please refer to our FAQs to learn more about our program offerings, including our:
Wound Care Certification Program - consisting of an online course in wound management (30 CEUs) + certification exam
Wound Care Management Course (30 CEUs) - consisting of an online curriculum in wound management (30 CEUs) for RNs & LVNs/LPNs.


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THE Hyundai i10 may be the smallest car in the Korean company's range but don't let its neat dimensions fool you.
For while it looks small from the outside, clever packaging results in this Hyundai being one of the best city cars on the market and it also offers good value for money.
The i10 range starts from £9540 and you can choose from two petrol engines – a new 1.0-litre three cylinder unit that pumps out 66PS or a 1.2-litre delivering 87PS to provide a bit more punch.
You can also select from four trim levels and that means there are combinations to suit most pockets. I tried out the flagship of the range – the 1.2 Premium SE, which costs £13,110 to get on the road – and a further £550 if you opt for metallic or pearl-finish paint.
That amount of cash gets you alloy wheels, a rear spoiler, side body mouldings, door mirror integrated indicators, fog lights, LED running lights and other nice exterior touches.
Inside, you get heated front seats, split rear seats, climate control, a sunroof, privacy glass, cruise control, electric windows front and rear, heated steering wheel, parking sensors, power outlets and a proper space saver wheel.
On the tech front, you get a seven-inch colour touchscreen with navigation and Mapcare Live services, Bluetooth, DAB radio and audio and phone controls on the wheel as well as a trip computer.
And the little Hyundai also features most of the latest safety and security measures as well as the company's valuable five-year/unlimited mileage warranty.
Every model comes with the likes of electronic stability control and vehicle stability management, plus a tyre pressure monitoring system, seatbelt reminders and automatic central locking.
All this helps to make the i10 feel like a much bigger car and this variant offers levels of equipment only found in larger vehicles costing thousands more.
There is room for four adults to travel in good comfort as long as the rear passengers are not very tall. The instruments and controls are well laid out, easy to read and use and there is good all-round visibility.
Fitted with the 1.2 powerplant linked to a nice five-speed gearbox, the i10 is good for 109mph and takes 12.1 seconds to reach 62mph. The claimed combined mpg figure is 57.6 but expect to get around 50mpg in real world driving conditions, with emissions of 114g/km.
The i10 is very nimble and great for town and city living but it is also good on longer journeys and has no difficulty keeping up with motorway traffic. It cruises quietly at the legal limit and it is easy to forget that you are in a small car.
Stylish to look at and fine to drive, it is one of the best small cars on the market and takes everything in its stride.
- Model: Hyundai i10 Premium SE
- Engine: 1.2-litre petrol
- Power 87PS
- Top speed: 109mph
- 0-62mph: 12.1 seconds
- Average mpg: 57.6
- CO2 emissions: 114g/km
- Warranty: Five years/unlimited mileage
- Price: £13,110


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Back in October American Airlines announced two new exciting international routes out of Dallas, to both Hong Kong and Shanghai.
The new Hong Kong service was especially exciting to me, given that Hong Kong is one of my favorite cities in the world, it would be American's longest route, and it would be the only route to Asia operated by American's 777-300ERs, which feature their new first and business class products. The new Hong Kong flight became bookable as of mid-December, and as of mid-January they began releasing a ton of business class upgrade and award space, which is somewhat surprising given how tough it will be for them to turn a profit on an ultra longhaul flight like this.
Anyway, over the weekend American's new route from Dallas to Shanghai became bookable as well. This will be American's third route to Shanghai, complementing their daily service out of Chicago and Los Angeles. It will be operated by a 777-200, which is the same plane they fly to all their other destinations in Asia.
Anyway, American's new Dallas to Shanghai route is now on sale for travel starting June 11, 2014 (June 12, 2014 for Shanghai to Dallas). The schedule for the flight looks as follows:
American 127 Dallas to Shanghai departing 10:55AM arriving 2:55PM (+1 day)
American 128 Shanghai to Dallas departing 4:50PM arriving 6:10PM
This definitely qualifies as an ultra longhaul flight, as it's blocked at 15hr westbound, and 14hr20min eastbound.
Now here's what's really interesting about the new Dallas to Shanghai route. American is releasing virtually no business class upgrade or award space, but they're releasing an unreal amount of first class award space. The first class cabin has 16 seats, and they're releasing at least seven first class saver award seats on a majority of dates.
For example, in looking at first class award space for six people in first class for the first month of service (over peak summer dates), here's the availability I see:
As you can see, in both directions all but two dates have at least six first class award seats.
American also has extremely reasonable first class redemption rates for travel to Asia, as they charge just 67,500 AAdvantage miles one-way.
American 777 first class seat
American 777 first class cabin
So it's not too late to book a first class award for a family to Asia this summer. While there are ultimately better first class products out there, it's tough to compete with the price and amount of first class award space they've released. I don't necessarily expect this will last, so if you're interested I'd recommend locking in space as soon as possible.
If you'd like to read more about American's international first class service, check out my first class reviews of Los Angeles to Tokyo Narita and Tokyo Narita to Los Angeles.
(Tip of the hat to Brian)


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Students pack the house at annual Rush game
Most school kids go to a museum or a greenhouse for a field trip, but on Wednesday Rapid City kids played hooky at a hockey game.
Students from Custer, Lead-Deadwood and Hill City also participated in the Rush's annual kids game. Nearly 4,800 students attended the morning competition.
All of the tickets were provided by the Rush Foundation. Organization representatives say it's an effort to get kids the opportunity to attend a game who may not otherwise have the ability.
Two kids were selected to help out our Kayleigh Schmidt as in game hosts.
"It's very thrilling to hear your friends say 'oh I saw you on tv'," said Emilia Woodruff, a fourth grade student from Corral Drive Elementary. "I like not doing math."
"It's fun," said Leighton Allgier, also a fourth grade student from Corral Drive Elementary. "It's a good break."
They both said their favorite part was meeting Rush - the team puppy.
It wasn't all fun and games. Educational elements were sprinkled in during the breaks and each kid left with a booklet about the math and science of hockey.


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"Specification Of Medicine Management"
Are you seeking a house treatment online? As well as you are curious regarding their services supplied? Well, that might be the reason why you began this page. This page has to do with about the solutions offered by Queen City skilled care competent care.
Yet before that, I wish to inform you that my objective is to provide you the precise as well as appropriate information concerning your issue. Additionally to provide you trusted as well as official info, so allow's currently begin our conversation.
House Treatment Services
A home care is a sort of house that permits skilled nursing care individuals with disabilities and also special should remain in their residence. This health house treatment is for individuals who are aging, has a chronical ailment, recuperated from a surgery, or impaired individual. It additionally offers individual care such their day-to-day regimen such as cleaning, bathing, consuming, food preparation and also etc.
In-home care, you are in fact getting all the home care provider assistance you want and needs in your very own home. Really, there are numerous various other sorts of solutions like it could a neighborhood or given away solutions.
Nursing Care Offered By Experienced Nurses That Treatment
Even if you have to have a long-lasting care due to ailment or injury, or short-term, concentrated recovery while recuperating from a procedure or severe clinical problem. Skilled nursing care can supply you that finest treatment that is required for your health because they educated their things to become gladly passionate regarding functioning.
From Helped Living to Skilled Nursing Treatment and also Back
It resembles working with the help of a doctor, a registered nurse or specialist that will do the placement as case supervisor of the client's home treatment. So the nurse or the therapist will most likely to the house of the person to review him/her according to the demands of the person. Via visiting the client on a regular basis the registered nurse or the therapist, together with the team, will certainly address the demands of the client.
They give sophisticated nursing and also our objective is always to maintain our elderly locals as independent as well as healthy as feasible, and also in the case of temporary recovery, our goal is to return locals to their initial living situation as soon as possible.
Work-related Therapy
They, in fact, focus on aiding the individuals to do a wide range of daily activities of everyday living, including their reclaiming abilities such as dressing, bathing, food preparation and basic house tasks.
Speech Therapy
Additionally, the Speech and also language therapists function to recover and also correct the physical and cognitive problems that have actually triggered you to have a trouble with your communication and/or swallowing.
House Wellness Aide
They are the one that assistants as well as offer consistent quality of personal care including pet grooming, hygiene, clothing, strolling, placing in bed as well as meal aid. Their objective is to advertise you and also family/caregiver self-reliance and engagement.
Medicine Management
Expert medicine management calls for regular oversight and instruction in medicine usage. We work together with doctors to make sure that patients have the medicines they need and also recognize them correctly.
Exactly how Does It Function?
The present study suggests the quality of life and also personal satisfaction are directly related to having the ability to stay at the residence and also get healthcare embellished especially for you. You keep a sense of control as well as self-reliance. You take part in your plan of treatment
Being residence with family and friends is essential throughout recovery durations. Queen City Proficient Treatment recognizes the environment that promotes your ideal healing. It is your home. It works for you and also your medical professional to develop a therapeutic strategy that matches your needs.
The Very Best SELECTION FOR YOUR RECOVERY
- Transitional Care- Its time will be base promptly, adhering to release from the hospital is an essential time for healing. The skilled medical professionals will certainly guarantee its modern recovery as well as provide an advancement to prevent re-hospitalization of the client.
- Medicine Administration- the registered nurses will immediately supply oversight and also instruction in medicine use. They will certainly also collaborate with the help of medical professionals to guarantee that they were offered the specific as well as proper medicine that they require.
- Specialized Injury Care- they are an expert that are well-trained in supplying a therapy to all type of wound even if it is acute or persistent wounds.
- Cognitive Rehabilitation- this is where the client goes through relearning skills which were shed or being changed from the brain damage. The speech therapist is extremely needed on this trip.
- Orthopedic Rehabilitation- this is a kind of recovering task, strength as well as motion after injury, surgery or illness. They are specializing to develop the person's level of features.
Perspective On Queen City Skilled Care
If you wish to have the home take care of your health and wellness Queen City proficient care is the most effective to select! They have all services for your demand all you should do is sign up for Queen City skilled Care!
Source: https://queencityskilled.com/


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Tynie Kickers (3-5 years) is a great way to introduce pre-school children to both football and physical activity.
The session will develop your child's motor skills, balance, co-ordination and, most importantly, their football skills in a fun and friendly environment.
- When: Sundays
- Where: The Hearts Football Academy, Oriam Performance Centre, Riccarton.
- Time: 9.00am - 10.00am
- Cost: Annual membership of £19.00 per month must be set up via standing order. Forms will be made available to you. A fee of £6.00 per session will be required until the standing order is set up. Setting up this standing order secures your place at this session.
To book or for more information, please email Calum at email@example.com or call 0131 200 7218.
For terms and conditions please click here.
Please note that moulded studs must be worn by all young players during academy sessions. This is due to the new playing surface at Riccarton. Parents are kindly requested to stay off the playing surface before, during and after the session.
You may also be interested in Academy Soccer Centres, open to kids aged 5 to 13 to provide youngsters with an exciting and developmental coaching experience.


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Price: £7.50
Quantity: 1 available
Book Condition: Very Good+ with no dust jacket
mn. Gilt titling to spine. Boards bright. Black and white frontis. 191 pp. Illustrated with black and white photographs. Clean tight and bright.; 001454; 8vo
Title: Fighting with the Guards
Categories: Older/Uncatalogued,
Edition: Cadet Edn
Publisher: London, Evans Brothers Ltd: 1960
Binding: Hardcover
Book Condition: Very Good+ with no dust jacket
Item: 1.00 Item
Seller ID: 001454
Keywords: Soldiers Guards Fighting Battle History Household Cavalry.


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Hi all
I have just completed my 16 week trial of the xolair injection, and unfortunately it hasn't worked for me. I still have asthma attacks once a week and in the past month i have had 2 hospital admissions, not to mention the 4 last year, on top of the other weekly attacks!!
I was just wondering if there was any body else whom the xolair hadn't worked for, and what your next steps were? It is getting very frustrating now not finding a treatment that works for me, as I have been signed off work since last July and it is starting to get me down!
Anybody else with a smiliar story? I would be extrememly grateful to hear from you x


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Metro breaks down the Jets draft and grades their performance.
Muhammad Wilkerson, DE, Temple
Round 1, Pick 30
The scoop: This was the ideal player and pick for the Jets, who were in desperate need of adding some bulk and speed on the defensive line help. Wilkerson is a big body and boasts an 85-inch wing span meaning he can both stuff the run burst into the backfield in a hurry. He'll be handful for O-lines.
The prediction:
» Short-term: With his engine and low center of gravity, he's the perfect end in the 3-4. "I see him as a possible three-down contributor for us," head coach Rex Ryan said.
» Long-term: Collected 16.5 sacks the last two seasons, should be an elite rusher off the edge.
Kendrick Ellis, DT, Hampton
Round 3, Pick 30
The scoop: The massive space-eater faces 20 years of jail time stemming from a felony
assault charge. Still, at 6-foot-5, 330 pounds, Ellis reminds us of former Jet Pro Bowler Kris Jenkins, who was released shortly after the season.
The prediction: Perhaps after being on "Hard Knocks," the Jets are auditioning for HBO's prison drama "Oz." If he beats his charge, expect Ellis to create plenty of jailbreaks as a starter at nose tackle.
Bilal Powell, RB, Louisville
Round 4, Pick 29
The scoop: Another guy with character issues who was stabbed while "hanging out with the wrong crowd." He had just one productive year at Louisville and there were plenty of more proven backs to take take in this spot, although filling this position was a head-scratcher to begin with for many fans.
The prediction: Powell can spell Shonn Greene but backs like him seem to be a dime a dozen. He's powerful and with a bit more muscle can be built like Baltimore's Ray Rice; a good short yardage back
Jeremy Kerley, WR, Texas Christian
Round 5, No. 22
The Scoop: Given three free agent wide receivers, not a reach that the Jets would look at Kerley. Injured for a chunk of last year, definite added value that he returns punts. An all-around good, solid athlete who makes the catches he's supposed to but doesn't excel in any one area. Citing that Kerley can play in the Wildcat, general manager Mike Tannenbaum compared the draft pick to current Jets free agent Brad Smith.
Prediction: Kerley played in a system that liked to spread the ball and put a heavy emphasis on timed routes. There should be competition at wide receiver this year for the Jets and Kerley could end up battling practice squad player Patrick Turner for a spot on the team. The Jets are short on real athlete-types and they got that in Kerley, who can make defenders miss in the open field.
Greg McElroy, QB, Alabama
Round 7, No. 5
The Scoop: A two-year starter for the Crimson Tide including their 2010 national championship season, McElroy is a winner in ever sense of the word. He tied a record scoring 48 out of 50 in the Wonderlic.
Prediction: A quarterback to be groomed as Mark Sanchez's understudy or for trade bait. He has good size and decent enough arm strength and certainly proved that he could handle the rigors of the SEC. Has a real chance to eventually be No. 2 behind Sanchez.
Scotty McKnight, WR, Colorado
Round 7, No. 24
The Scoop: McKnight's name is written near the top of nearly every receiving record at Colorado. He's a solid, smart player who was hand-timed running a 4.46 and a 4.48 time in the 40 on his Pro Day, surprising many scouts.
Prediction: Sanchez and McKnight grew up together; in fact Sanchez threw at McKnight's Pro Day in Boulder. Given the uncertainties at wide receiver, McKnight should make the roster or practice squad, but he's probably not a long term solution for the Jets.
Draft grade: C
Report card
The Jets addressed their biggest area of concern by drafting two stud defensive linemen. GM Mike Tannenbaum, though, dropped the ball on Day 3. Needing a safety and an outside linebacker, the Jets got neither, focusing instead to pad the offense with average talent. Fifth-rounder Jeremy Kerley is the only player we see having a shot to breakout. The TCU WR can be a Brad Smith clone.
After two straight AFC championship appearances, the Jets needed to add immediate impact players.
For the second straight year, general manager Mike Tannenbaum selected a player in the first round with New Jersey ties from a non-BCS program. The hope is that Temple defensive end Muhammad Wilkerson, largely considered the second best defensive end in the draft, can immediately step into the rotation and provide pass-rush support.
The Jets next pick in the third round, Kenrick Ellis, is a FCS player who is a true nose tackle and has outstanding athleticism for his 330-pound frame. But Ellis comes with character issues and could face 20 years in prison for felony assault when he stands trial this summer. Team management is confident Ellis will play this year but for a team plagued with questionable behavior, the pick seems somewhat tainted.
In Rex Ryan's previous two drafts, the Jets selected just one defensive player, picking six players on the offensive side of the ball. After taking a defensive end and a nose tackle in the first and third rounds, the Jets went offense again with their final four selections. It looks like a case of the team drafting a best player available almost to a fault, perhaps ignoring serious areas of need.


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The Feels is a film about a bachelorette party with a twist, and it was one of the films I wanted to very much see at this years BFI Flare, as it had such a great female cast, subject matter and sometimes ill admit it you need a good laugh at BFI Flare.
The film's director, co writer and actor JenEe LaMarque (who plays Nikki, Lu's sister) has achieved an amazing feet of bringing all these actors together to give a knock-out performance.
Co-writer Lauren Parks (who also stars as Vivien, Andi's friend) is great as the friend who is not over her previous relationship with Andi's best friend, Josh; who has his sights set on someone else...
The upbeat soundtrack just so happens to be the creation of LaMarque' composer husband, Julian Wass, with additional songs by Singer songwriter/actor Karin Tatoyan who plays KArin who performs for the bachelorette party.
Being a group of friends sometimes can have its dramas, as we see throughout the film - but also a lot of fun.
Any scene with Regular Helen, played by Ever Mainard, stand-up, actor, writer, improviser and all rounder will have you gasping and laughing out loud at the words that come out of her mouth. One of my favourite lines was:
"You were hard to find on social media. I tried to look you up"
in a cringe worthy stalker moment towards Karin, who is the star singer/songwriter friend of Andi. The bachelorette party comes to an abrupt halt when a drunken/drug endused Lu admits she hasn't had an orgasm ever! This sparks the Orgasm confessionals by the group in a kind of Harry met Sally way.
The cast were en to improvise some of the scenes, which comes across as flawless as this is such a strong casting.
The Feels Trailer
The Feels Synopsis
Andi and Lu are excited to celebrate their upcoming wedding with a joint bachelorette weekend in wine country. On the first night, things get off to a rocky start when one of the brides admits that she's never had an orgasm.
- Initial release: 9 June 2017
- Director: Jenée LaMarque
- Producer: Steven J. Berger
- Screenplay: Jenée LaMarque, Lauren Parks
The full 2018 BFI Flare programme is available here, but highlights of additional activities to the film screenings include:
- Talks with established film and television professionals who are leading the way in LGBTQ+ representation on screen.
- Workshops and Labs focusing on creating LGBTQ+ media with specific sessions around challenges in development, funding and exhibition.
- Networking opportunities throughout the Festival with a range of receptions with film and television professionals included in the Delegate Package.
About BFI Flare
BFI Flare: London LGBT Film Festival, formerly known as the London Lesbian and Gay Film Festival, is the biggest LGBT film festival in Europe. It takes place every spring in London, England


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Our comfortable bean bags come in many stylish colours
So you want a beanbag. Not just any beanbag, but a beanbag that will satisfy your insatiable sense of comfort, style and functionality. You have come to the right place. What are beanbags, you ask? Textbook answer:
Beanbags are essentially a bag structured in different shapes and made of various fabric or vinyl or a combination of fabric and vinyl. The beanbag is usually filled with polystyrene beads (or any other matter such as shoes, pillows, left over laundry - not recommended though by us)
Its unique attributes are that the beanbag can support a person's bodyweight while it is almost featherweight (roughly being 4-7kg, easily moved around the house to the nearest tv and entertainment venue).
This provides the perfect combination of support and comfort.
Comfort is our business.
Our beanbag designs are ergonomical - which in plain speak means our beanbags are designed to fit your body like a glove without gaps - total support.
Style never came in so many colors. All our beanbags are customizable to your desires - the size, material, texture, and colours is limited only by your imagination.
(Unless your imagination is limited, then we can do some of the imagining for you - just ask our friendly staff in our showroom at Park Mall)
Functionality is core.
Ever try ripping off the cover of a sofa set? We invite you to rip the covers off your beanbag - all our beanbags are double layered, so as to facilitate easy maintenance. Just unzip, remove, and deposit in your washing machine. Some models also come with the washable top cover attached via Velcro - so you can remove the washable quilted top easily for cleaning.
A little bit of history never hurt anyone (no one I know of anyway)
Beanbagmart was founded in 1993, 20 years ago, and we do the production, supply and retail. So you are getting your beanbag first-hand from the factory, no middle men - you know you are getting great value.
We have in our long history supplied our beanbags to many educational institutions, private clubs and those of the dancing kind (see MOS in picture gallery), hospitals and old folks' homes, and lastly to many homes in Singapore. We pride ourselves on being experts in the trade as there is no beanbag too big or too small that
we cannot do.
Visit us today at our showroom located at Park Mall, #B1-17 and let us create your personal beanbag!


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By Trend
Chairman of the Italy-Armenia Friendship Group in the Italian parliament, treasurer of the Northern League party, MP Giulio Centemero, is in a difficult situation due to a corruption scandal, Trend reports.
The name of Centemero, accused by the Milan city prosecutor's office of illegal financial transactions in the amount of 40,000 euros, is mentioned in the latest breaking news in the Italian press these days.
Reportedly, Centemero abused his authority in the Piu voci Association and conspired with Bernardo Caprotti, the founder of the group of "Esselunga SpA" supermarkets, operating in Italy's northern and central regions in 2015-2016, with the aim of illegally transferring 150,000 euros that have been allocated to the Association to the Radio Padania's accounts.
Radio Padania belongs to the Northern League party. In general, 40,000 euros were transferred to the Radio Padania's accounts. The Milan city prosecutor's office appealed to the court with a demand to choose arrest as a measure of restraint for Centemero.
Moreover, Centemero is mentioned in other financial scandals. Reportedly, he was involved in the process of illegal transfer of 250,000 euros to the Piu voci Association by Italian businessman Luca Parnasi.
Centemero is known in the Italian parliament as an ardent propagandist of the Armenian interests. His marriage to a Lebanese woman of Armenian descent is apparently connected with his Armenian fanaticism.
Follow us on Twitter @AzerNewsAz


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Roses, Book 2
Photographic Reference for Artists
- $4.99
- $4.99
Publisher Description
This is an extraordinary resource for both the "Young at Art " - or the Experienced Pro. This clip-art collection of photographs by Judith Hope Brown can both inspire and help artists of all mediums enjoy the creative use of photographic reference material. Grab a screen shot and enjoy! "It isn't cheating to use a photograph - it is just common sense to use every available tool to make good art." 212 pages.