text:
|Home | About | Journals | Submit | Contact Us | Français
Conceived and designed the experiments: JD JEF LG. Performed the experiments: JD AAD VO. Analyzed the data: JD AAD VO JEF LG. Wrote the paper: JD JEF LG.
Rheumatoid Arthritis (RA) is a chronic immune mediated disease associated with deregulation of many cell types. It has been reported that different T cell subsets have opposite effects in disease pathogenesis, in particular Th17 and Treg cells.
We investigated whether non-depleting anti-CD4 monoclonal antibodies, which have been reported as pro-tolerogenic, can lead to protection from chronic autoimmune arthritis in SKG mice – a recently described animal model of RA – by influencing the Th17/Treg balance. We found that non-depleting anti-CD4 prevented the onset of chronic autoimmune arthritis in SKG mice. Moreover, treated mice were protected from the induction of arthritis up to 60 days following anti-CD4 treatment, while remaining able to mount CD4-dependent immune responses to unrelated antigens. The antibody treatment also prevented disease progression in arthritic mice, although without leading to remission. Protection from arthritis was associated with an increased ratio of Foxp3, and decreased IL-17 producing T cells in the synovia. In vitro assays under Th17-polarizing conditions showed CD4-blockade prevents Th17 polarization, while favoring Foxp3 induction.
Non-depleting anti-CD4 can therefore induce long-term protection from chronic autoimmune arthritis in SKG mice through reciprocal changes in the frequency of Treg and Th17 cells in peripheral tissues, thus shifting the balance towards immune tolerance.
Rheumatoid arthritis (RA) is a common chronic autoimmune inflammatory disease characterized by destruction of the synovial joints, leading to progressive disability, increased co-morbidity and premature mortality [1], [2]. Both genetic and environmental factors are known to contribute to the development of the disease [3]. RA is characterized by a complex immune mediated response with the participation of many cell types including CD4+ T cells [4], [5], [6], such as the IL-17 producing Th17 subset, which have been shown to play an important role in the pathogenesis of the disease [7], [8], [9]. The participation of CD4+ T cells in the pathogenesis of RA, namely by influencing other key cellular mediators of the disease (such as B cells or macrophages), has prompted the development of therapeutic strategies targeting this lymphocyte population [10], [11], [12], [13]. Monoclonal antibodies (MAbs) targeting key T cell molecules (such as co-receptor and co-stimulation) have been suggested as drugs capable of achieving long-term protection from the disease, with the potential of leading to immune tolerance, following a short treatment [14]. Indeed long-term transplantation tolerance can be induced in mice following CD4 or co-stimulation blockade [15], [16], [17].
The most commonly used mouse models for autoimmune arthritis – such as collagen-induced arthritis – have been instrumental in the development of new therapies, such as the blockade of key cytokines, such as TNF. However, arthritis in these mice is self-limited and, as such, pre-clinical studies of putative tolerogenic regimens aiming for long-term effects have been hampered by the lack of suitable animal models of chronic autoimmune arthritis that are not TCR transgenic.
SKG mice, harboring a mutation in ZAP-70 rendering T cells more resistant to activation and thus interfering with appropriate negative selection in the thymus, have been recently described as developing chronic autoimmune arthritis with several characteristics resembling RA [18]. Arthritis in SKG mice has a centripetal course starting with small finger joints, eventually leading to histological changes and bone destruction similar to RA [19]. The incidence and severity of the disease is greater in females, with most mice developing rheumatoid factor (RF), and some animals displaying extra-articular lesions similar to rheumatoid nodules and pneumonitis [18]. Although CD4+ T cells, and its Th17 subset, are important in the pathogenesis of arthritis in SKG mice, other cell populations, such as B cells, participate in the disease as suggested by the production of RF in these animals [18].
Our data reports the long-term protection from chronic autoimmune arthritis following a short course of non-depleting anti-CD4 MAb in SKG mice, associated with decreased IL-17 and increased Foxp3 expression in the synovial tissue. Furthermore, the non-depleting nature of the therapeutic MAb preserves the immune competence of treated mice.
All experiments involving animals were approved by the Animal User and Ethical Committees at the Instituto Gulbenkian de Ciencia, according with directives from Direccao Geral Veterinaria (PORT 1005/92). Mice were bred and maintained under specific pathogen free (SPF) conditions.
BALB/c, DO11.10.RAG1-/-, and SKG mice (generously provided by Professor Shimon Sakaguchi, Kyoto, Japan). Experimental animals were between 8–10 weeks of age and sex matched.
BALB/c and SKG mice were injected intraperitoneally (i.p.) with a single shot of 3mg curdlan per mouse. Treated mice were injected with 1 mg anti-CD4 on days 0 (the day of curdlan injection), 2 and 4. Mice treated at disease onset, were injected with 3 shots of 1 mg anti-CD4 every other day, from the day they have reached a clinical score of 0.5.
Joint swelling was monitored in blinded cages by two independent observers and scored as described elsewhere [18]: 0, no joint swelling; 0.1, swelling of one finger joint; 0.5, mild swelling of wrist, ankle, or base of tail; and 1.0, severe swelling of wrist, ankle or base of tail. Scores for all joints were totaled for each mouse (with a maximum score of 5 corresponding to severe swelling of the four paws and base of tail).
Curdlan (Wako, Japan) and Zymosan-A (Sigma-Aldrich, USA) were dissolved in sterile PBS at 15 mg/ml and 20 mg/ml, respectively. Non-depleting anti-CD4 (YTS177) and the isotype control anti-dog CD4 (YKIX302) MAbs were produced in our laboratory using Integra CL1000 flasks (IBS, Chur, Switzerland), purified by 50% ammonium sulfate precipitation, dialyzed against PBS, and purity checked by native and SDS gel electrophoresis. The hybridomas were generously provided by Professor Herman Waldmann (Oxford, UK).
Evaluation of serum cytokines was performed using the mouse inflammation cytometric bead array (BD Biosciences, San Diego, CA), with beads specific for IL-6, TNF, IFN-γ, monocyte chemoattractant protein-1 (MCP-1), and IL-10. IL-17 was quantified by ELISA using a kit from R&D Systems. Cytokine concentrations were measured in duplicates, and compared with standard curves, according to manufacturer instructions.
Serum levels of rheumatoid factor were measured by ELISA as previously described [18], using 5 µg/ml mouse IgG to coat the plates, and 1 µg/ml anti-mouse-IgM-HRP for detection (Southern Biotech, Birmingham, USA).
On day 30 following anti-CD4 treatment, or treatment with an isotype control, the mice were immunized with two injections two weeks apart, of 20 µg ovalbumin (OVA, grade V; Sigma, St Louis, USA), in 2.0 mg of endotoxin-free aluminum hydroxide (alum, Alu-gel-S, Serva, Heidelberg, Germany), and sacrificed one week after the last immunization. Non-immunized (naïve) mice were maintained as negative controls. The serum concentration of OVA-specific immunoglobulins was determined by ELISA using an OVA-specific IgG1 kit (SouthernBiotech, Birmingham, USA) with anti-OVA IgG1 standard from Serotec (Oxford, UK).
Ankle and metatarso-phalangical (MTP) joints were collected and cryopreserved in OCT (Sakura, NL). Cryosections were stained with hematoxilin-eosin according to standard procedures.
Cells were stained for flow cytometric analysis with the following fluorochrome-labeled monoclonal antibodies: CD3 (145-2C11), CD4 (RM4-5), CD25 (PC61.5), and Foxp3 (FJK-16s) from eBiosciences or BD Biosciences. Intracellular cytokines were investigated in lymphocytes activated for three hours in PMA-ionomycin in the presence of Brefeldin-A. Monoclonal antibodies specific for IFN-γ (XMG1.2), IL-17A (eBio17B7), and IL-10 (JES5-16E3) were used (all from eBiosciences).
OVA-specific CD4+ T cells from DO11.10.RAG1-/- mice were purified by magnetic separation with CD4 (L3T4) microbeads (Miltenyi Biotec, Germany). Cell purities were between 92–96%. The T cells were cultured for 5 days with bone marrow derived DCs, 0.1 µM OVA peptide (New England Peptide LLC, USA), and 10 µg/ml anti-CD4 (YTS177) in IMDM 5% FBS (Invitrogen), 1% Pen/Strep (GibCo), 0.1% β-Mercaptoethanol (GibCo), 1 ng/ml TGF-β (R&D systems), 20 ng/ml IL-6 (R&D systems), 10 ng/ml IL-1β (Ebiosciences), and 10 µg/ml anti-INFγ (R46A2). At the end of the culture the cells were harvested, and processed for flow cytometry.
Total RNA was extracted from synovial tissue, dissected from ankle joints, using lysis buffer, and following the tissue RNA kit instructions (Omega bio-tek, USA). Foxp3 and IL-17 were quantified by real time PCR, performed on the ABI Prism® 7000 sequence detection system (Applied Biosystems, USA). The relative mRNA levels of the target genes were normalized against CD3. CD3, Foxp3 and IL-17 primers are described elsewhere [20], [21], [22].
Statistical significance was determined using the two-tailed non-parametric Student's t test (Mann-Whitney U). P values <0.05 were deemed significant.
Although initial reports have suggested that SKG mice develop chronic autoimmune arthritis spontaneously [18], it was later confirmed that disease induction requires exposure to yeast wall extract (zymosan) or purified β-glucans, like curdlan or laminarin, acting through the pattern recognition receptor Dectin-1 [23].
We confirmed that a single intraperitoneal injection of 2 mg Zymosan (not shown) or 3 mg Curdlan is sufficient to induce chronic disease in SKG mice, but not in wild-type controls (Figure 1A). Both male and female mice developed arthritis, although the disease was more severe in females (Figure 1B). Based on these data we decided to use curdlan in female SKG mice in subsequent experiments.
To assess whether non-depleting anti-CD4 MAbs, suggested in previous studies as having tolerogenic potential, can lead to long-term beneficial effects in chronic autoimmune arthritis, female SKG mice were treated with non-depleting anti-CD4 together with curdlan. Anti-CD4 treatment was effective in preventing the development of autoimmune arthritis (n=5, P<0.001, Figure 2A). Since arthritic SKG mice are known to produce high titres of RF (IgM anti-IgG), we quantified serum RF. We found that serum RF were below the limit of detection in all mice treated with anti-CD4 (Figure 2B).
Furthermore, animals treated with anti-CD4 not only remained without clinical manifestations of the disease, but their joints were free from inflammatory cell infiltrates. Indeed, histological sections of ankle and MTP joints from anti-CD4 treated mice showed normal joint tissues, without inflammatory infiltration or bone erosions, compared to the curdlan induced arthritic mice (Figure 2C).
We also evaluated the presence of pro-inflammatory cytokines in arthritic mice compared to anti-CD4 treated animals. We observed a significant decrease in the concentration of IL-6, TNF, MCP-1 and IFN-γ in sera from anti-CD4 treated mice, suggesting that a treatment targeting T cells can have an impact on additional cell types producing those cytokines (Figure 2D). It should be noted that IL-6, which has been associated with Th17 differentiation, is known to be critical for the pathogenesis of chronic autoimmune arthritis in SKG mice [24], and was not detectable in any of the anti-CD4 treated animals. Despite the reported association of IL-17 with arthritis in SKG mice, this cytokine was not detected in sera from arthritic animals, remaining below detection level in all groups (Figure 2E). This observation is in accordance with the proposed local effect of this inflammatory mediator.
Previous studies have suggested a protective role for IL-10 in this murine model of autoimmune arthritis [25]. However, we did not find any significant difference in the serum levels of IL-10, between arthritic and anti-CD4 treated mice (n=10, P>0.05, Figure 2E).
It has been reported that the anti-CD4 MAb used in our study (YTS177) has a non-depleting isotype [26]. We confirmed the non-depleting nature of the MAb as neither the splenic frequency (Figure 3A and B) nor the total number (not shown) of CD4+ T cells were reduced in animals treated with anti-CD4.
Transplantation tolerance achieved with non-depleting anti-CD4 has been associated with the induction of Treg cells, both in the spleen and within tolerated transplants [27], [28], [29]. We investigated if changes in Treg frequency could be seen in the spleen of anti-CD4 treated mice. We found that there was no change in T cell subpopulations of anti-CD4-treated animals, namely Foxp3+ Treg cells, with a similar frequency of these cells in mice exposed to curdlan in the presence or absence of anti-CD4 treatment (Figure 3A and B). In addition, the frequency of IL-17, IFN-γ or IL-10-producing T cells, identified by intracellular cytokine staining, remained constant in all groups of animals, and below 2% of the CD4+ T cells (not shown).
As our data show that anti-CD4 treatment can prevent joint inflammation, even though T cell subpopulations in secondary lymphoid organs appear to be unaffected, we investigated whether anti-CD4 treatment was leading to alterations in the T cell subpopulations within the synovial tissue of protected animals. Given the technical limitations for the direct enumeration of individual T cells from mouse synovial tissue, we used the expression of Foxp3 and IL-17 mRNA as surrogate markers for the relative frequency of, respectively, Tregs and Th17 cells. For this purpose Foxp3 and IL-17 mRNA expression was measured by quantitative real time PCR and normalized to CD3 expression (thus controlling for different numbers of infiltrating T cells in different samples, as the arthritic synovium contains greater numbers of T cells). This method, of using CD3 expression for normalization of different numbers of infiltrating T cells in tissues with few lymphocytes has been established for other tissues with small numbers of T cells, such as skin grafts in mice [22]. We observed that while IL-17 expression among synovial T cells (i.e. IL-17/CD3 mRNA ratio) was reduced in mice treated with anti-CD4 and consequently protected from inflammatory manifestations of the disease, the expression of Foxp3 among synovial T cells was increased in the same conditions (n=4, P<0.05, Figure 3C). Thus, the Foxp3/Th17 ratio in the synovial tissue is substantially shifted following anti-CD4 treatment. In addition, the analysis of popliteal LNs, draining affected joints, showed a reduction in the frequency of IL-17+ T cells in anti-CD4-treated mice (n=8, P<0.05) while the frequency of Foxp3+ cells remained similar in both groups of animals (Figure 3D).
Although non-depleting anti-CD4 has been widely studied for the induction of transplantation tolerance its exact mechanism of action has not been fully characterized. In experiments performed with TCR-transgenic mice devoid of Foxp3+ Treg cells, it was previously shown that CD4-blockade could directly lead to peripheral conversion of T cells towards Foxp3+ Treg cells thus achieving transplantation tolerance [22]. However, it was never assessed whether CD4-blockade could directly interfere with Th17 polarization, or whether a reduction in Th17 cells (as we observed in vivo) would be secondary to Treg-mediated suppression.
To address this issue we investigated whether CD4-blockade could prevent in vitro Th17 polarization. We used OVA-specific TCR-transgenic CD4+ T cells sorted from DO11.10.RAG-/- mice. We stimulated these cells in vitro, for five days, in the presence of DCs loaded with the appropriate peptide and under culture conditions promoting optimal Th17 polarization (in presence of TGF-β, IL-6, IL-1β, and anti-IFN-γ)[30]. We observed that addition of anti-CD4 led to a significant reduction of Th17 cells (n=6, P<0.05, Figure 4). In spite of the presence of cytokines that promote Th17 polarization (cytokines that are known to prevent Foxp3 induction) the addition of anti-CD4 resulted in a significant increase in the frequency of Foxp3+ T cells (n=6, P<0.05, Figure 4).
To assess whether protection from arthritis induced with anti-CD4 treatment had a long-term effect, SKG mice initially injected with curdlan and non-depleting anti-CD4 were challenged with curdlan 60 days following the initial treatment. Animals exposed to curdlan in the presence of the putative tolerogenic anti-CD4 MAb at day 0 were protected from the induction of arthritis following curdlan administration at day 60, unlike the age-matched controls that did not receive any treatment at day 0 (n=6, P<0.05, Figure 5A).
However, it should be noted, that some anti-CD4 treated mice developed mild manifestations of arthritis following curdlan challenge at day 60, although without progressing to the severe manifestations of the disease observed in control groups.
Given the fact that non-depleting anti-CD4 treatment prevents the onset of autoimmune arthritis, we tested the effectiveness of a similar course of anti-CD4 for the treatment of established arthritis in SKG mice. Female SKG mice were immunized with curdlan and when the clinical score reached 0.5 the arthritic mice were randomly included in a group treated with anti-CD4 MAb or a control group. Mice treated with non-depleting anti-CD4 showed a long-term benefit with slower disease progression and less severe clinical scores (n=5, P<0.05, Figure 5B). However, remission was only achieved in a minority of the treated animals.
A concern of immunomodulatory or tolerogenic therapeutic strategies is their long-term impact on the overall immune response. We therefore assessed the immune competence of anti-CD4-treated BALB/c mice (same genetic background as the SKG mice, but without the ZAP70 point mutation) to mount CD4+ T cell-dependent immune responses towards an unrelated antigen. For this purpose, mice treated with anti-CD4 were sensitized with 20 µg OVA-alum 30 days following anti-CD4 treatment. The quantification of OVA-specific immunoglobulins in the serum was determined one week following sensitization. Our data show that the concentration of OVA-specific immunoglobulins was similar in immunized mice, regardless of previous anti-CD4 treatment, and considerable higher than in naive controls (n=5, P<0.05, Figure 5C). Moreover, we confirmed the same results in SKG mice, subjected to the same protocol (n=2, not shown). Of note, if OVA was administered at the time of anti-CD4 treatment in BALB/c mice, the animals became unable to produce OVA-specific immunoglobulins following subsequent OVA immunization (n=6, P<0,05, Figure 5D), thus proving that OVA-specific IgG production is CD4-dependent, and that tolerance is only imposed over the antigens present at the time of tolerance induction.
Our data show that a short course of non-depleting anti-CD4 can lead to long-term protection from the development of autoimmune arthritis, in a murine model of chronic disease. We have shown that our non-depleting antibody (clone YTS177) is not affecting T cells in the spleen, but seems to be preventing autoimmune arthritis, acting locally at the site of inflammation. It is likely that by targeting CD4+ T cells, the pathogenic cycle of events leading to synovial inflammation and progressive joint destruction is abrogated, as other cellular players are not recruited towards the articular tissue to cause inflammation. This impact of CD4-blockade on other cell types is well illustrated by the marked decrease of pro-inflammatory cytokines produced by dendritic cells (DCs) and macrophages in anti-CD4 treated animals. In addition, given Th17 cells have been described as involved in the production of autoantibodies in experimental autoimmune arthritis [31], [32], our observation that anti-CD4-treated mice do not produce RF is in line with the hypothesis that by maintaining pathogenic T cell clones under control the B cells will not receive the necessary stimuli for the production of autoantibodies. We cannot exclude, at this time, a direct effect of non-depleting anti-CD4 MAbs on innate cells expressing CD4, namely natural killer T (NKT) cells that have been reported as being able to provide "help" to B cells, and to influence autoimmune arthritis [33].
In our experiments, we found a limited efficacy for tolerance induction once the animals became overtly arthritic. Although we do not have a complete explanation for this observation, it is possible that such resistance to tolerance induction may be due to the participation of other cell types, besides CD4+ T cells, at that late time. In fact, in transplantation it is known that in pre-sensitized animals a population of Asialo GM1+ CD8+ T cells can create a barrier for tolerance induction with MAbs [34]. Thus, it may be possible to enhance the efficacy of tolerance induction in overt arthritis with reagents targeting other cell types, namely CD8+ T cells and B cells.
It remains to be established whether the long-term protection from arthritis afforded following anti-CD4 treatment, even after a new curdlan challenge at a later time, can be explained by the development of regulatory mechanisms that have been described in other animal models of anti-CD4 induced immune tolerance [28], [35]. In fact, it is now established that CD4+ T cell activation in the presence of TGF-β and IL-6 favors T cell conversion towards arthritogenic Th17 cells, while activation in the same environment devoid of IL-6 shifts the differentiation from Th17 towards Foxp3+ Treg cells [30]. SKG autoimmune arthritis development is known to be dependent on Th17 [36].
Our data suggests that protection from arthritis induced with anti-CD4 is associated with an overall decrease of infiltrating T cells in synovial tissue and, within those T cells in the synovium, with an increase in the frequency of synovial Foxp3+ Treg cells. As a consequence, the tissue is endowed with local changes that are likely to prevent the onset of arthritis directly within the local environment where inflammation would occur, even following a later exposure to curdlan at a time (day 60) where anti-CD4 MAbs are no longer present. Moreover, the reciprocal decrease of IL-17 expression at the same time that the expression of Foxp3 increases, in the joints of anti-CD4 treated mice, supports the hypothesis that indeed the balance between Treg and Th17 can determine the decision between prevention or onset of autoimmune arthritis. The observation that IL-6 decreases in the serum of anti-CD4 treated mice is also in agreement with this hypothesis. It should be noted, however, that the number of T cells is markedly reduced in the synovium of treated mice, as can be seen in the histological sections (and confirmed with greater CD3 expression in the synovia by RT-PCR – thus the need to use CD3, rather than a housekeeping gene, to normalize our gene expression studies). It was recently reported that IL-17A can be produced by mast cells in rheumatoid arthritis synovia [37]. Although we did not investigate this possible source of IL-17, the overall quantification of IL-17 transcripts was significantly reduced in anti-CD4 treated animals, where T cells were also less abundant. As a consequence, the shift in the Treg/Th17 balance in the synovial tissue is likely to be also influenced by tissue accessibility to different types of effector T cells.
We have also shown that CD4-blockade can directly inhibit T cell polarization towards an IL-17-producing Th17 phenotype, even when the most appropriate cytokine environment is provided. In addition, our data show that even in the presence of those cytokines known to inhibit Foxp3 induction (namely IL-6), CD4-blockade can facilitate the peripheral conversion of Foxp3+ Treg cells. Taken together, our data complements previous studies on the mechanism of tolerance induction in transplantation with anti-CD4 (where peripheral induction of Foxp3+ Treg cells have been shown critical), by demonstrating that CD4-blockade can also lead to a direct inhibition of Th17 polarization – a critical factor for the arthritis pathogenesis, namely in SKG mice [36].
Given the essential role of CD4+ T cells in the pathogenesis of RA, both directly and by recruiting and activating other participating cell types (such as B cells, DCs and macrophages), the therapeutic targeting of CD4+ lymphocytes has been extensively pursued [38]. Depleting and non-depleting anti-CD4 MAbs have been tested in several animal models of autoimmune arthritis [39], [40], [41], [42], and in clinical trials with RA patients [43], [44], [45]. In spite of promising results in pre-clinical studies, the therapeutic effectiveness of anti-CD4 in clinical trials was modest and short-term, possibly due to transient immunosuppression and not tolerance. In retrospect, those unimpressive results are not too surprising due to technical details related with dosing and MAb characteristics. In fact the immunogenicity of the mouse or chimeric MAb used was well documented as leading to their rapid clearance and consequent loss of efficient CD4 blockade [46]. The reduction of the number of CD4+ T cells was also associated with a concern of possible increased susceptibility to infection.
Our data show that non-depleting anti-CD4 can be effective in preventing chronic autoimmune arthritis while preserving immune competence, as treated mice remain able to mount a CD4-dependent immune response against a different antigen (OVA). OVA immunization is a well established protocol for the induction of CD4-dependent production of OVA-specific immunoglobulins. Moreover, administration of anti-CD4 together with OVA prevents the effectiveness of subsequent immunizations with the same antigen. Taken together, these data suggest that anti-CD4 prevents immune responses towards antigens present at the time of treatment, without hampering immune responses to unrelated antigens introduced in the organism at a later time, therefore preserving immunocompetence. It should be noted that these types of studies, on the long-term immunocompetence of treated mice have been difficult to perform in animal models that, unlike SKG mice, do not develop a chronic form of arthritis.
In summary, we show that therapeutic strategies leading to synovial accumulation of Treg cells and reduction of Th17 are capable of protecting from the onset of autoimmune arthritis, as well as to prevent long-term disease progression, without leading to overall immune suppression.
We thank Margarida Souto Carneiro and Marta Monteiro for helpful suggestions. We are grateful to Professor Shimon Sakaguchi (Kyoto, Japan) for providing the SKG mice, and to Professor Herman Waldmann (Oxford, UK) for providing reagents used in this study.
Competing Interests: The authors have declared that no competing interests exist.
Funding: This work was funded by SUDOE, grant number IMMUNONET-SOE1/1P1/E014, and supported by a research grant from Fundação para a Ciência e Tecnologia (FCT), Portugal (FCT/POCI/SAU-MMO/55974/2004). JD, AA-D, and VGO are funded with scholarships from FCT (SFRH/BD/23631/2005, SFRH/BD/49093/2008, and SFRH/BPD/22575/2005). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
PubMed Central Canada is a service of the Canadian Institutes of Health Research (CIHR) working in partnership with the National Research Council's national science library in cooperation with the National Center for Biotechnology Information at the U.S. National Library of Medicine(NCBI/NLM). It includes content provided to the PubMed Central International archive by participating publishers.


text:
Lamborghini for Sale
Selected Filters:Type of Ad: Vehicles for Sale Make: Lamborghini
2003 Lamborghini Murcielago
San Carlos, CA
We don't see 6 speed Murcielago's as often as we'd like but this one was worth the wait. Nero Aldebaran over Nero interior with... More
1974 Lamborghini Urraco P250
West Gosford, Australia
Up for sale is a Lamborghini Urraco P250, designed by Marcello Gandini at Bertone. The Urraco came from factory as a more affordable alternative... More
1988 Lamborghini Jalpa
West Gosford, Australia
Presenting this Australian delivered Lamborghini Jalpa 3.5 Targa. Sitting in red with cream leather interior. Only 410 units of the Jalpa were produced with an... More
1988 Lamborghini LM002
Nordrhein-Westfalen, Germany
one of only 301 examples earley version with caburrator 12 cylinder with 450 horsepower rare color combination great overall condtion This Lamborghini is delivered new to Italy at the... More
2014 Lamborghini Gallardo 2dr Car
Bryn Mawr, PA
2014 Lamborghini Gallardo LP550-2 shown in Grigio Lynx over Nero Perseus interior. This one owner vehicle is in exceptional condition inside and out and... More
2000 Lamborghini Jarama 400GT
Monterey, CA
Lamborghini Jarama 400 GT... More
Advertiser since 2012
2015 Lamborghini Huracan
Jonesboro, AR
Vehicle Description: 2015 Lamborghini Huracan LP610-4 FOR SALE!! Finished in the very rare Grigio Titans (Matte Grey) over a Nero Ade & Rosso Interior (Black and... More
1968 Lamborghini Miura P400
West Gosford, Australia
We are extremely excited to offer this 1968 Lamborghini Miura P400 LHD. This Miura P400 has undergone a fully documented, no expense spared restoration... More
1989 Lamborghini Countach
Astoria, NY
Extremely Rare RHD 1989 Lamborghini Countach: Only 3,247 km This 1989 Lamborghini Countach 25th Anniversary is an extremely rare right-hand-drive example and a very low mile car... More
Advertiser since 2005
1989 Lamborghini Countach Anniversary
Bensalem, PA
1989 Lamborghini Countach. USA Version . Black Beige with black piping. This all original Countach was recently acquired from its 3rd owner who only... More
1992 Lamborghini Diablo
Astoria, NY
1992 Lamborghini Diablo: A highly collectible modern classic super-car This 1992 Lamborghini Diablo is a beautiful original example and a California car with 26k kilometers. This first... More
Advertiser since 2005
1971 Lamborghini Jarama Jarama 400GT
Chandler, AZ
In order to comply with the increasingly stringent American safety and emissions regulations, it became necessary for Lamborghini to replace the Islero Coupe by... More
2016 Lamborghini Aventador Roadster LP700-4 Pirelli Edition
Beverly Hills, CA
2016 Lamborghini Aventador LP700-4 Roadster Pirelli Limited Edition Bianco Canop (Matte White) w/Nero Ade Interior (Black Alcantara) with Existing Factory Warranty MSRP $525k bought new... More
1966 Lamborghini 350GT
Brummen, Netherlands
Beautiful and mythical 350 GT, the first creation of Lamborghini, technically very advanced on its opponents from this period. Full Alloy Superleggera bodywork by... More
Advertiser since 2015
2009 Lamborghini Gallardo Coupe
West Palm Beach, FL
Marino Performance Motors is thrilled to announce the arrival of this amazing and one of a kind 2009 Lamborghini Gallardo LP560-4 finished in Bianco... More
Advertiser since 2013

subset: commoncrawl


text:
Welcome to GS1 US
The Global Language of Business
Join trading partners and peers and unlock the power of standards
The GS1 US® University Learning Management System, or LMS, is your personal portal to GS1 Standards education. Featuring on-demand learning modules with more being added monthly, the LMS allows you to track your learning, set up training plans for yourself or your colleagues, and view modules at your convenience. Have only a few minutes at a time to learn? You can view modules whenever you want, at your own speed, and pick up where you left off.
If you're accessing the LMS for the first time, you'll need to create an account, with your own user name (your email address). After you register, a temporary password will be emailed to you. Log into the LMS and click the "Change Password" link under Tools & Links to create a custom password. It's very important that you select your learning preferences. We're going to create a customized education plan just for you based on the selections you make. These courses will help you to gain a fast and thorough understanding of GS1 US and get you started quickly! In the LMS you can:
Looking for a list of recorded webinars that are available on demand?
Visit the Resource Library >
Check out these 3 recommended courses, instructed by Aiden, to help you get started with GS1 Standards:


text:
Hotels in Paonia
Hotel reservation
United States
Hotel rooms in Paonia
There are not so many hotel rooms in Paonia, just 1, still everyone can find an offer to suit his choice. The most common offers in this city are farm, they count 1 out of 1, and their prevalent location is central district. According to our practice, it is the most profitable to book a hotel in the south of Paonia, as it is the location of the hotels with optimal cost and quality offers along with the cheap hotels. Taking into account the small size of the city, there is no need to dwell hotel reservation on the location: the road to the city center would take less then half an hour, so one can book a hotel in any district of Paonia. The most populated with hotels district of Paonia is the south, 100% of cheap hotel rooms are concentrated here. Paonia is a truly multifaceted city, here everyone can find a hotel of his choice: a business person, a young couple or a family with little children. Apart from all these, hotels in Paonia offer their customers restaurant/cafe, parking and wi-fi in public areas. The most appreciated amenities in Paonia hotels are food. According to the visitors reviews, hotels in Paonia has delicious food. Take a look at our selection of the cheap hotel rooms in Paonia to make a well-informed choice for your reservation!
Best hotels in Paonia
Hotels in Paonia are spread around the city within the distance of 0.6 kilometers. The most popular accommodations in Paonia is
The Living Farm Cafe And Inn
located in a 0.6 kilometers from the city center.
The best hotels are here and now. Try them!
All cities in United States


text:
Twitter me this
- New series (must find this) Unicornland. following the elusive poly unicorn. sexpert.com/sex-in-the-new… 1 hour ago
- How to stay grounded in these tumultuous times. bellalavey.com/blog/stay-grou… 3 hours ago
Putting the fun back in dysfunctional.
My WIP is a big What If … book. I have a thing for "soul mates" who have been separated by time and their own misconceptions (see: Second Chance Romance) who get back together later.
And then I was surfing Facebook and came across a friend from university (I only attended one year and then dropped out) who I had a huge crush on but he was dating someone else and I sorta dated his friend (this was part of why I dropped out). And I think, I think, he liked me as well, but y'know it was what it was, and we never got together.
My mind was wandering like, what if we had dated. Not in a, I wish it were so, kind of way, but in a, what might have happened differently.
Possibly the same things that actually did happen, because I had a lot of issues that I didn't deal well with. We might have ended in just as a big a train wreck and I would have dropped out and moved home anyway.
Do you ever indulge in the "What if …." thinking/daydreaming?
|Dealing In The Face… on Tips for dealing with Seasonal…
|elisha on Canning vs Caning and it…
|asraidevin on Project Tuesday: January …
|Jae on Project Tuesday: January …
|Louise Behiel on blog priorties


text:
Maternity photo by metamorphamagi Love this - thanks for sending @ccampbellbrown :)
This written on belly dad kissing belly, boys lined up next to them Dream Photography - Maternity Shoot
Slightly more modest yet extremely beautiful couples boudoir. www.360VisionEvents.com
Baseball Maternity Photos
Pregnancy, Creative, Bump, Maternity, Baby, Photography, Photo, Volkphotography
Wow definitely one I'm going to do
<3 this pose!
Stupidly cute. Love this... pregnancy photography idea...Sweeps can take your photos! http://www.sweeps.jobs
maternity photography photoshoot shoot silhouette baby bump pregnant black and white baby announcement couple kiss poses
Christmas - #maternity ill be ready to pop at Christmas time excitinggg!! :) My favorite time of the year!


text:
> Landscaping & Planters
> Garden Planters
Choose the colour of this iQbana Low Square Garden Planter from either black or grey and create wonderful features for the garden or patio.more
iQbana Low Square Garden Planter Features:
Why not sign up to our newsletter to receive exclusive offers and news about what's happening at Internet Gardener. You'll
receive fantastic offers and seasonal gardening ideas directly to your inbox. We value your privacy, and so we promise not to share your email adresses
with anyone else.


text:
8 AM-9 PM CST. Mon-Fri
8 AM-5 PM CST. Sat-Sun
Visitors Insurance USA - Heart Attack Coverage
Many elderly visitors to USA are worried that if they get heart attack while visiting USA, whether it would be covered or not.
Q: If my visiting father gets heart attack, will that be covered?
A: There is no way to answer for sure whether that would be covered or not in advance. Once the providers (doctors, hospital etc.) submit all the medical records such as physician report, treatment records etc. to the claims department, they will look into it to determine whether it would be a covered expense or not.
Q: If a visitor gets a heart attack, what are the possible scenarios?
A: A heart attack may be caused because of many different reasons.
- If the heart attack is determined to be a completely new medical condition, it will be
covered up to the policy maximum according to the terms and conditions of the insurance you
have purchased.
- If it is determined to be an
acute onset of pre-existing condition, it will be
covered up to the limits of acute onset of pre-existing condition, provided the insurance you
have purchased has coverage for the same, depending upon your age, the chosen policy maximum
and the type of the plan purchased.
- If it is determined to be an
sudden and unexpected recurrence of pre-existing condition, it will be
covered up to the limits of sudden and unexpected recurrence of pre-existing condition, provided the insurance you
have purchased has coverage for the same, depending upon your age, the chosen policy maximum
and the type of the plan purchased.
- If it is determined to be a
pre-existing condition that is not acute onset of pre-existing
condition or the plan you have purchased does not have any coverage for an acute onset of
pre-existing conditions, it will not be covered at all.
Q: My mother never had a heart attack before. In that case, how can that be pre-existing condition?
A: If it is determined that heart attack was caused due to other pre-existing medical conditions such as high blood pressure, diabetes, prior heart disease etc., it would still be considered as pre-existing condition.
A: According to most insurance companies' opinion, if he is taking any treatment or any medications currently (including any over the counter medicines), it will be considered a pre-existing condition. If not, at the time of the claim, based on attending physician statement(APS), the claim adjuster will determine whether it will be considered as a pre-existing condition or not.
Q: I am reading the brochures for various visitors insurance plans and they say that the pre-existing condition exclusion is for 2 years or 3 years, but my mother had heart attack 5 years ago. If she gets heart attack now, how can that be pre-existing condition?
A: Obviously, the person does not continuously get heart attack every day. Actually, the heart disease is a pre-existing condition and the heart attack is an aggravated condition of the ongoing heart disease. Even though the last heart attack was 5 years ago, if the person is still taking medications regularly for the ongoing heart disease and therefore, the heart disease is still a pre-existing condition. And according to our prior experience, everyone who had a heart attack early takes regular medication for blood thinning, etc.
Q: Does it mean that if the person has high blood pressure or diabetes, the heart attacks will always be excluded?
A: That is absolutely not the case. We have seen heart attacks being covered as well as being declined. Therefore, it really depends upon the details of individual case, which can only be determined after it already happens and the Claims Department has all the medical records to look at.
Q: My friends are telling me that visitors insurance would never cover heart attack with one excuse or another. What is the point of buying visitors insurance?
A: That is not true. It is determined on a case by case basis. Based on medical records, it will be determined whether it is a covered expense or not.
Q: Why don't you answer in simple Yes or No whether the heart attack would be covered or not?
A: It is not possible to do so. Until someone looks at all the medical records of the condition that has occurred, there is no basis to make such determination in advance. It can be determined only the after fact.
Q: If I send you my father's medical records, can you tell me whether it would be covered in future when he visits USA?
A: No. The determination is not based only on the prior medical records, but more importantly, the most current medical records, the ones that will be generated if and when he gets the heart attack for which the coverage is in question. And those medical records can't be generated in advance. Therefore, until that happens, there is no way to know for sure.
Q: Could you please give an example of a heart attack that would be considered as acute onset of pre-existing condition?
A: If the person has high blood pressure and everything is stable and all of sudden a person
gets a heart attack without any prior symptoms or warnings and the person needs to take treatment
in the next 24 hours, and that may be an acute onset of pre-existing conditions.
Important: Everyone is reminded that you should not simply consider all such similar looking cases to be exactly the same and assume that such case would always fall under acute onset of pre-existing condition. It is determined on a case by case basis based on medical records received.
Q: Could you please give an example of a heart attack that would NOT be considered as acute onset of pre-existing condition?
A: If the person is having a minor chest pain for the last 4-5 days, or if the person has been complaining of the elevated blood pressure for the past 3-4 days, and then the person gets a heart attack, it was not acute, it was not all of sudden nor unexpected and therefore, it would not be considered as acute onset of pre-existing condition. And therefore, not covered.
Q: Could you please give an example of a heart attack that would be considered a sudden and unexpected recurrence of pre-existing condition?
A: A heart attack is most often an acute manifestation of the underlying medical condition of coronary artery atherosclerosis (CAD) (Please note that there are some rare causes of heart attacks that are not caused by CAD, e.g., Takotsubo Cardiomyopathy, Prinzmetal Angina, etc., but examples below deal with CAD as the primary cause of heart attacks.) If someone had a pre-existing diagnosis of CAD, she/he could have had symptoms or manifestations of CAD without having had a prior heart attack – e.g., chest pain diagnosed as Coronary Angina, stent placed in a blocked artery, or the discovery of CAD on routine physical leading to medical or surgical intervention. If the same person had that condition stabilized then suffered a heart attack after their Effective Date, that could be considered a sudden recurrence of the pre-existing condition.
Q: It seems that there is no way for visitors insurance companies to tell me in advance whether a particular heart attack would covered or not. When it happens, the medical bills have already incurred and if the visitors insurance company determines it to be non-covered expenses, it would be too late and I would be stuck with big bills. What do you suggest?
A: Your analysis is correct. There is no way to know in advance whether a particular condition would be covered. You should carefully analyze the risk before inviting elderly relatives about how you would handle non-eligible medical expenses.
Q: Do you personally know anyone whose heart attack was covered in visitors insurance when the person had other disease such as high blood pressure?
A: Yes, in addition to numerous customers being covered, our company's President/CEO's mother-in-law had a heart attack while traveling overseas and it was covered even though she had high blood pressure. But please note that each case is different and no one should assume that everyone in such a manner would be covered under all circumstances because it is determined entirely at the time of claim based on the medical records and attending physician's statement.
Safe Travels series of plans from Trawick International completely exclude cardiac disease or conditions, whether as new medical conditions or as acute onset of pre-existing conditions.
Disclaimer: The information within this article is intended as a broad summary of benefits and services and is meant for informational purposes only. The information does not describe all scenarios, coverages or exclusions of any insurance plan. The benefits and services of an insurance plan are subject to change. This is not your policy/certificate of insurance. If there is any discrepancy between the information in this article and the language of your policy/certificate wording, the language of the policy/certificate wording will prevail.


text:
I applied online. The process took 3 weeks. I interviewed at EDSA (Madison, WI) in April 2015.
Very easy going, she asked me more questions about my resume and personality rather than my portfolio. Since EDSA has an international design focus, they were interested in my experience studying abroad in China and how that influenced me as a designer and as a person. They are also involved with LAbash (student ran LA Conference) so they appreciated that I had participated in the past couple LAbash's.
Interview Questions
I applied online. The process took 4+ weeks. I interviewed at EDSA.
apply online-phone interview-on site interview
Interview Questions
I applied online. I interviewed at EDSA.
I received a phone interview with the Human Resources Generalist at EDSA. Most questions
of the interview are personality questions, such as When will you graduate from XXX
University? Why choose XXX University for your graduate school? Why choose EDSA? Why
should we employ you? The total interview last about ten minutes.
Interview Questions
Is this helpful? The community relies on everyone sharing – Add Anonymous Interview Review
I applied online. The process took 2 weeks. I interviewed at EDSA (Fort Lauderdale, FL) in March 2014.
1. HR phone interview: ask your background, why interested in EDSA, what is your goal and location preference
2. HR phone interview: ask questions related to skills: for example, hand drawing skill, computer skills and teamwork experiences etc.
Some intern were asked to come down to Fort Lauderdale but not me
Interview Questions
I applied online. The process took 3 weeks. I interviewed at EDSA (Fort Lauderdale, FL) in March 2014.
The process was smooth. The human resources department was knowledgeable and shared a lot of information on how the company works and their unique structure. I also talked to a couple of principals of the firm and they were very pleasant and interested in my skills and what I have to offer to the firm.
Interview Questions
Reasons for Declining
I received a better offer somewhere else
I applied online. The process took 4 weeks. I interviewed at EDSA.
2 phone interviews, one with HR and one with a principal. The phone interview is structured, with questions as why you choose this profession, why you apply for EDSA, what are your strengths, do you like team work, can you do public speaking, etc.
I am offered an on-site interview now, have not done that yet.
Interview Questions
I applied through college or university. The process took 2 weeks. I interviewed at EDSA (Fort Lauderdale, FL) in November 2011.
Consisted of two rounds of phone interviews. Mainly questions about how you work with others on a team, how you manage conflicts, and about projects you have worked on in the past.
Interview Questions
There was no negotiation
I applied in-person. The process took 3 weeks. I interviewed at EDSA (Fort Lauderdale, FL) in January 2008.
I have known this company because it is famous in industry; submit the resume and portfolio through company HR and got phone interview. Phone interview was more behaviarol questions. On-site interview followed, meeting with a group of managers (including future manager) for past experience and technical questions.
Interview Questions
Did not negtoaite because the offer was industry average and good enough
(Translated from English)
I applied through an employee referral. The process took 1 day. I interviewed at EDSA (Vienna (Austria)) in July 2011.
Nichts besonderes. Nur ein Gespräch mit meinem zukünftigen Boss über meinem Erfahrungen und Technologie. Kein Fähigkeitentest. Ich wurde von einem Freund empfohlen und sie haben ihm einfach vertraut.
Nothing special. Just talking with the future boss about my experiences and technologies. No skill test. I was refered by a friend of mine and they simply trsted him.
Would you like us to review something? Please describe the problem with this {0} and we will look into it.
Your feedback has been sent to the team and we'll look into it.
This will replace the current featured interview for this targeted profile. Are you sure you want to replace it?
Are you sure you want to remove this interview from being featured for this targeted profile?


text:
- Photos
- Map/Street View
- Things Nearby
img src="http://www.ardorny.com/i.aspx?t=a&s=t2&r=1642366" / Ardor Web ID: 1642366 - True 2 Bedroom -Central Park West (89th ST)A true 2 bedroom apartment with 1 bath. Apartment is spacious with a good layout. Good size living room, large master bedroom with wall to wall closet. Second bedroom is also a good size → Read More
Share this listing: Email Print


text:
Home › Forums › General Karting Discussion › Best Kart Track in USA that is open 12 months a year › Reply To: Best Kart Track in USA that is open 12 months a year
Thanks guys. I will check out some of the TX tracks.
I actually know PKRA…spent a few days there with AJ Whisler and Alan Rudolph a few years ago when I was trying to learn how to go fast. Nice layout.
Seems like the Forums have gotten pretty quiet over the years. 10 years ago, there would have been 20 replies to a topic like this.
February 24-26, 2017
Phoenix, Arizona
Challenge of the Americas
March 3-5, 2017
New Orleans, Louisiana
SKUSA Pro Tour WinterNationals
April 7-9, 2017
Sonoma, Califorina
Challenge of the Americas


text:
I am student of scu and looking for short stay with my spouse.
Peaceful property with beautiful valley views. 1 bedroom bungalow located on 12 acre horse farm near Federation University. Horse agistment available for extra charge. Pets negoitable. Strictly non-smoking property. Rent includes water and wi-fi internet. Electricity billed separately weekly. Rent is $150 pw if paying for 4 weeks upfront and no bond. Or $100 per week plus 4 week bond if going on lease for 6 months or longer. Owner lives in main farmhouse on property. Contact me for photos and more detailed information.


text:
DeVotchKa and Flobots on TV Tonight and Tomorrow Night
Just a quick reminder: Tonight and tomorrow night, two of Denver's most high profile exports will be invading the small screen. Tonight at 11:35 mountain time, DeVotchKa is slated to appear on Late Night with Conan O'Brien on NBC.
Tomorrow night, meanwhile, on the same channel at 12:35 a.m. our time, Flobots will be making their televised debut on Last Call with Carson Daly -- and that's contrary to our previous report that the group's appearance would be tonight. The confusion stems from a post on Flobot's Myspace page touting the performance as happening on Monday, May 19. As it turns out, near as we can tell from this site in which tickets can be procured, the performance is presumably being taped this evening for broadcast tomorrow (or Wednesday morning, as it were).
On a related note, tomorrow evening at 6 p.m. Los Angeles time, to commemorate Universal's re-release of Fight with Tools, the outfit will be performing in the courtyard of the Virgin Megastore on Hollywood and Highland, followed by an in-store signing at the retail outlet. Area fans who purchase a copy of the disc will reportedly receive a wristband that will earn them a signed copy of the disc.
-- Dave Herrera
Get the Music Newsletter
Keep your thumb on the local music scene each week with music news, trends, artist interviews and concert listings. We'll also send you special ticket offers and music deals.
In Case You Missed It
Upcoming Events
UNC Spring Concert Warm-Up
TicketsWed., Feb. 22, 9:00pm
TicketsThu., Feb. 23, 8:00pm
Chancey Williams & the Younger Brothers
TicketsFri., Feb. 24, 8:00pm
Stewart Copeland & The Colorado Symphony
TicketsSat., Feb. 25, 7:30pmpowered by goldstar
Sponsor Content


text:
To save this list or send to a friend, please log in or sign up
{{ loginError }}
Forgotten your password?
New to i-escape?
Sign up now
Between Bergerac and Sarlat, Dordogne, France
You have selected more than 31 nights.For long stays please contact i-escape on
+44 (0) 117 946 7072 or [email protected]
Please select the correct leaving date. (Leaving date must be later than the date of arrival)
There are no available rooms at The Watermill for some or all of your dates, please submit new dates below
(no hidden costs, credit card charges or booking fees)
5 bedrooms (from 32 to 45 sq.m.) each with ensuite bathroom with shower and tub, kitchen, lounge. Beds can be made up as twins or doubles; please state preference when you book
Features: Internet Connection, Hairdryer, Full Kitchen, fridge, Oven, Microwave, Dishwasher, Washing machine
Best Nightly Accommodation Only Rate
Currency conversion is supplied as a guide only; the exchange rate used by your bank may vary. The final payment will be charged in the property's own currency.
Restrictions: For rentals in off-season (Oct-March), please make an enquiry for your required dates and you will be provided with a quote directly by the owner
Closed: never.
Rates shown are per Whole House per night based on 6-10 people sharing unless otherwise specified
Check-in: 16:30
Check-out: 10:00
Best Weekly Accommodation Only Rate, Best Nightly Accommodation Only Rate
Non-refundable guarantee deposit is charged in United Kingdom Pounds (GBP) by i-escape upon reservation.
Outstanding balance is to be paid directly to The Watermill 30 days before arrival by bank transfer only.
The Watermill does NOT accept credit cards. Payment can be made by Bank Transfer only.
Best Weekly Accommodation Only Rate, Best Nightly Accommodation Only Rate
More than 90 days before arrival:
From 90 days to 30 days before arrival:
Less than or 29 days before arrival:
No show or early departure:
Payment and cancellation policies may vary with special offers.
Unless otherwise specified, the initial guarantee deposit is non-refundable.
We recommend that you take out insurance against cancellation due to unforeseen circumstances.
For 1 Night
Would you like to see only family-friendly places while browsing our site?


text:
Contact Technical Support at 800-966-0669 option 3. Available 24 hours a day, 7 days a week.
LUMEDX Technical Support has received the HDI Team Certified Award for commitment to service excellence through the adoption of best practices and the acquisition of enhanced skills and knowledge.
If you have a comment or question about the services and support you are receiving, please email Bill Gazda.
Product Offerings |
Newsletter Subscription |
Contact Us |
Site Map
Careers |
Events |
Partners |
Web Master |
© 2012 - 2017 Lumedx


text:
Is Db Khan incorrect or missing key business information? Update your Hotfrog listing today.
Contact details
Are these details correct?
Is Db Khan in 1ST FLOOR KOUSAR PLAZA BASHIR GUNJ, BEED Maharashtra 431122 your business? Claim your listing and attract more leads by adding more content, photos and other business details.
We have more Chartered Accountants services in BEED Maharashtra available on Hotfrog INDIA. You can update your search for BEED Chartered Accountants by location, keyword or service options.
Sonajirao Kshirsagar Homoeopathic Medical College Vidhya Nagar W Beed Maharashtra 431 122
PLOT NO 70, MIDC AREA Beed Maharashtra 431122
gut no 723 sakshal pimpri Beed Maharashtra 431122
raju nager dhanora road beed dist beed contect. salim mujawar & fahim mujawar mo.09860890398/09767780864 Beed Maharashtra 431122
Small Business Hub
Sharing tips, ideas and advice to help grow your small business.
Your profile without ads
Have you considered upgrading to Hotfrog AdVantage? No competitor advertising means exclusive focus on your business. You take centre stage.
Create your free Hotfrog business profile
Follow Hotfrog on:
Share on:
Hotfrog Small Business Hub


text:
How do people stay motivated?
Hi, this is my first post here. I am currently 92kg and need to lose about 30kg which I'm doing by the 5:2 diet. I have a long list of medical problems including mobility problems, (rheumatoid arthritis and fibromyalgia) plus OCD (which makes routine and structure a necessity with everything I do). My therapist (for the OCD) suggested I join a forum for some moral support. I want to lose weight for my health, I know it's having a really negative impact on my RA and Fibro.
I used to be a real gym bunny, 5 times a week, but I can barely walk anymore, so it puts more dependance on losing the weight via diet. I plan on trying to include a little swimming and yoga, but I certainly can't exercise like I used to. Which is part of the reason I've put 5 stone on!
One of my problems is keeping motivated after I've 'strayed' from my idea of healthy food. For example, I failed to resist the one bar of chocolate, so the whole day is wasted so I might as well have that biscuit as well, and the can of coke while I'm there. Not rational I know, but that's what I tend to think.
So, my question, what motivational tips work for you?


text:
Did you know that on average, libraries have local collections that number in the thousands? It's only through resource sharing that
residents get access to 53 million items
Read magazines on your phone or tablet with Flipster!
Available in the Apple, Google, and Kindle app stores
Click below for the app
State funding cuts are putting Library Resources AT RISK!
Learn more at the MBLC


text:
Software Development Leader Salary
A Software Development Leader earns an average salary of $99,952 per year.
Add this chart to your site:
Copy and paste this HTML:
Job Description for Software Development Leader
Software development leaders are management-level workers that shepherd programs, applications, and updates through the programming and/or updating process. These leaders work with other teams - such as design and quality assurance - to ensure that the program or application works as intended and is completed in a timely manner. The software development leader typically creates schedules for their team and assigns team members work based on design and development templates that are conceptualized by their department in conjunction with other relevant personnel.Read More...
These professionals also establish timeframe estimates and deadlines for work completion, continually monitor their team's progress toward those goals, and create working alpha and beta builds for applications, which are then typically put through a quality assurance phase. The software development leader evaluates quality assurance reports and then works with the development team to address all issues found in that process. Many companies allow the software development leader to have input, if not control, over hiring decisions, and the development leader must be capable of estimating a development budget based on time and labor involved. Leaders are held accountable for these budgets and must constantly monitor them.
Companies typically prefer to hire software development leaders from existing employees who already possess a great deal of practical experience in programming with design or development teams. In some cases, with larger, high-profile companies, an applicant for this job may be asked to show a portfolio of applications and programs already shipped. Software companies also typically prefer individuals for this job who possess at least a bachelor's degree in computer science or another relevant discipline.
Software Development Leader Tasks
- Collaborate with team members to identify strengths and weaknesses of applications and improve upon them.
- Evaluate functionality of products and remediate any lapse in functionality.
- Lead a team in the development, coding, and delivery of new software products and applications.
- Perform product and customer research and develop improvement strategies based on findings.
Software Development Leader Job Listings
Search for more jobs:
Pay by Experience Level for Software Development Leader
Median of all compensation (including tips, bonus, and overtime) by years of experience.
Related Job Salaries
Related Jobs
Key Stats for Software Development Leader
20 %
80 %
Job Satisfaction
|Highly satisfied
Rated 4 out of 5
based on 2 votes.


text:
Viewsonic XG2701 27" LED LCD Monitor - 16:9 - 1 msLCD Monitors
Adjustable Display Angle - 1920 x 1080 - 16.7 Million Colors - 300 Nit - Full HD - Speakers - HDMI - DisplayPort - USB - 35 W - Black - WEEE, ErP, RoHS, REACH, China Energy Label (CEL), EPEAT Silver, ENERGY STAR 6.0, cTUVus - View Complete Details
Product Number: SYNX4388680
Sold Out
This product is sold out and we do not know when we will be getting another shipment. We apologize for any inconvenience this may cause.
Check similar items below to see if a replacement product is available.
You May Also Like
Product Details
Viewsonic XG2701 27" LED LCD Monitor - 16:9 - 1 ms - 27" Fast action gaming monitor, incredible 144 Hz refresh rate with a blazing-fast 1ms response time, low input lag, 1920 x 1080 resolution, 80M:1 DCR, DisplayPort, HDMI, VGA inputs, integrated speakers, and compatible with FreeSync. Integrated Game Mode, SmartSync, black stabilization, eye-care technology with Flicker-Free and Blue Light Filter.View Product Specs
Still have a question? Click to ask a Question
ReviewsThere are no Customer Reviews yet.
Help out our customers.
Be the first to write a review.
Question & Answer
No questions have been posted for this product.
Have a question about this product? Please click the button below to get started. Once you have posted your question we will submit it to our community of customers and with our own staff who have recent experience with the same product for their open and honest feedback.Ask a Question


text:
For research/science purposes
- Size: 640px
- Quality: High
- Size: 12.40 MB 488.63 KB
This Gif entitled For research/science purposes was created from the youtube video 3 years ago. It uses 18 frames per second and is displayed at 640px resolution. This animated image plays for 5 seconds, was built with high quality and an estimated weight of 12.40 MB for download. This animation was originally created from the [MV] AOA - Miniskirt (짧은 치마) [ENG-SUBS + HAN|ROM FULL LYRICS] video from 00:53 to 00:58.
Flag This GifSend


text:
New Music
The Archives
New Music
Hear Teklife's
On Life
, a New 23-Track Footwork Compilation From the Chicago Crew
Today, the Chicago footwork crew Teklife released On Life, a new compilation of 23 tracks, with contributions from veterans like RP Boo and Traxman and rising stars like DJ Paypal…
Andy Cush
February 17, 2017
Watch Video
Watch Traxman's CGI-Adorned Video for 'Ever and Always'
In 2012 Chicago footwork innovator Traxman dropped his Da Mind of Traxman release; an album that was both a SPIN Essential and reminder that the…
Puja Patel
May 20, 2014
Ryan Hemsworth's Radiohead Rave, DJ Rashad's Footwork, 11 More Dance LPs in Control Voltage
ALBUM OF THE MONTH: Special Request, Soul Music (Houndstooth)Paul Woolford has been out there doing his thing — mostly a techno thing — for a long time…
Philip Sherburne
November 5, 2013
Traxman Was Shot in the Leg and Robbed in His Chicago Hometown
Traxman, a leading ambassador of Chicago's footwork style, was shot in the leg during an armed robbery in his home city. Traxman's latest album Da Mind…
Marc Hogan
June 3, 2013
Animal Collective Preview Remix EP With Worldly Gang Gang Dance Assist
On May 28, Animal Collective will release the Monkey Been to Burn Town EP featuring revisions of a pair of Centipede Hz tracks. "Monkey Riches" gets flipped…
Chris Martins
April 23, 2013
SPIN Essentials
Traxman, 'The Mind of Traxman' (Planet Mu)
"Footwork" is prime proof of a recurring truth in dance music: While the various electronic vanguards strive self-consciously to break all sound barriers, it's the…
Simon Reynolds
April 26, 2012
Prev Page
Next Page
Read More »
Review: Kingdom's
Tears in the Club
Is an Uneven Release From a Brilliant Producer
Review: On
Why Love Now
, Pissed Jeans Explore the Lighter Side of Everyday Agony
Review: David Bowie's
No Plan
Is a Fond, Final Glimpse at a Departed Master
Review: Future Suddenly Comes Alive On Surprise Album
Bull Sessions.
Sign up for the SPIN newsletter and stay in the know.
Thank you for signing up for our newsletter. You will receive a confirmation shortly.
Editor's Picks
The 50 Best Albums of 2016 So Far
The 100 Greatest David Bowie Moments
The 66 Best Songs of 2016 So Far


text:
BEAUTYPREP™ FACE TONER - beauty begins here.
the feel hydrated
Optimize the benefits of the mineral makeup you love with our high-performance daily toner, designed to restore and prepare the surface of the skin to help makeup go on smoother and last longer.
- Infused with Herbasome, a Fruit Extract water that contains organic Lemon Grass, Apple, Pear, Carrot and Coconut Water to restore the surface of the skin and balance pH. It refines pores and moisturizes to help makeup go on smoother and last longer. Ideal for daily use with BeautyPrep Face Cleanser and BeautyPrep Face Moisturizer. Awarded ECOCERT's Natural Cosmetics certification.
Aqua/Water/Eau, Leuconostoc/Radish Root Ferment Filtrate, Pyrus Malus (Apple) Fruit Water, Pyrus Communis (Pear) Water, Daucus Carota Sativa (Carrot) Root Water, Cocos Nucifera (Coconut) Water, Glycerin**, Rosa Canina (Rosehips) Fruit Extract*, Camellia Sinensis (White Tea) Leaf Extract*, Calendula Officinalis (Calendula) Flower Extract*, Chamomilla Recutita (Matricaria) Flower Extract*, Cympopagon Flexuosus (Lemon Grass) Oil*, Citrus Aurantium Dulcis (Orange) Oil*, Helianthus Annuus (Sunflower) Seed Oil*, Lecithin, Tocopherol, Lavandula Angustifolia (Lavender) Oil*, Alcohol**
100% of the total ingredients are from natural origin 5.17% of the total ingredients are from Organic Farming Natural Cosmetic certified by Ecocert Greenlife according to Ecocert Standard available at http://cosmetics.ecocert.com
jane iredale - THE SKIN CARE MAKEUP®, is a comprehensive line of makeup developed with quality minerals and skin care ingredients that are good for your skin and create a healthy, radiant glow. All of the jane iredale products adhere to the highest standard of integrity as each product is subjected to rigorous sensitivity and safety tests to ensure it is as good for the skin as it is beautiful to wear. It is a top makeup choice of skin care professionals and is recommended by plastic surgeons and dermatologists worldwide.jane iredale logo, text, graphics and photo images: Copyright © 2004 – 2016 by Iredale Mineral Cosmetics, Ltd. All rights reserved. Used by permission.
We love our products and we think you will too. We stand behind the quality of all the products we carry, and want to insure you are 100% satisfied with your order. If for any reason you are dissatisfied, please send us an email with your concern so we can be sure to make it right.
To start the return process a return our Returns Page. It's a quick and easy process.
We accept returns and exchanges within 30 days from the shipping date or the in-store purchase. Used or opened items can be returned for a store credit in the form of a gift card for the full amount paid for the item. Unused and unopened items can be returned for a full refund to original payment method. In-store returns and exchanges require a receipt.
Bella Cuore will ONLY pay for a return's shipping costs if a product arrived damaged or if we sent you the wrong item. Otherwise, the customer is responsible for the shipping costs.
You will receive an e-mail confirmation when your return is received, inspected and your refund had been processed.
We do NOT accept returns for:
Customized Sample Kits
Gift Cards
How to AVOID returns:
Let one of our Green Beauty Experts assist you! Green Beauty Experts can help with finding just the right products for you and your unique skin type, hair type, eye color, skin tone, texture color, and more! Chat with us or Call us.
We offer a great Customized Sample Kit for the majority of our products, this program allows you to sample 6 products prior to purchasing the full retail product. This is a great way to try before you buy. All sample kits ship fast and free.
If you are returning an item because it is damaged or defective or you did not receive the product ordered, we will provide a prepaid return label free of charge via email.


text:
Gorky Parks Surf Camp // 15:58
Exclusive surf training camp in the Jungle of Costa Rica Brought to you by Aaron Cormican
Exclusive surf training camp in the Jungle of Costa Rica Brought to you by Aaron Cormican
How to surf NSB, by Gorkin. How to get smashed on the rocks, by embarrassed random Highs and lows from Hurricane Leslie
Gorkin tunes you in and tunes out the haters Several chosen tracks for your weekend's festivities
It's post-Irene in the Garden State... And this is The Situation
A black and white mellow groove Contrasting the over saturated line up.
A hop, skip and a jump into some playful Puerto Rican wedges
The rum is put on ice while the contest wraps up in Neptune beach, Florida
Gorkin wins yet another East Coast comp at Wrightsville's Reef/Sweetwater Pro By Matt Walker Three things you can count on in an East Coast summer: flat spells. Tourists. And Aaron Cormican winning at least one pro event. Actually, over the past five years, Gorkin's taken nearly every East Coast money comp no matter the season,


text:
Rene Descartes' Meditations on First Philosophy in Focus
By (author) Rene Descartes
Volume editor Stanley Tweyman
Translated by G. R. T. Ross
Format: Hardback
Normal Price: $188.00
Your Price: $169.20 AUD, inc. GST
Shipping: $7.95 per order
You Save: $18.80! (10% off normal price)
Plus...earn $8.46 in Boomerang Bucks
Availability: Available, ships in 7-10 days
Rene Descartes' Meditations on First Philosophy in Focus by Rene Descartes
Book DescriptionThis volume presents the excellent and popular translation by Haldane and Ross of Descartes' Meditations on First Philosophy, an introduction by Stanley Tweyman which explores the relevance of Descartes' Regulae and his method of analysis in the Meditations, and six articles which indicate the diversity of scholarly opinion on the topic of method in Descartes' philosopy.
Buy Rene Descartes' Meditations on First Philosophy in Focus book by Rene Descartes from Australia's Online Bookstore, Boomerang Books.
Book DetailsISBN: 9780415077064
(216mm x 140mm x 17mm)
Pages: 236
Imprint: Routledge
Publisher: Taylor & Francis Ltd
Publish Date: 18-Nov-1993
Country of Publication: United Kingdom
Other Editions...
Books By Author Rene Descartes
Discourse on Method, Paperback (June 2017)
Descartes' Discourse, presented here in an engaging new translation, is a perfect point of entry into early modern philosophical and scientific thought.
Passions of the Soul and Other Late Philosophical Writings, Paperback (November 2015)
The Passions of the Soul is Descartes's greatest contribution to the understanding of the union of mind and body. It discusses the emotions and their place in human life. This volume also includes both sides of the correspondence with Princess Elisabeth of Bohemia, crucial to the genesis of the work, and Part I of The Principles of Philosophy.
Meditations on First Philosophy, Paperback (June 2013)
Complete with a new and highly readable translation, this edition makes the classic text more accessible than ever before.
Meditations, Paperback (August 2010)» View all books by Rene Descartes
Widely regarded as the father of modern Western philosophy, Descartes sought to look beyond established ideas and create a thought system based on reason. In this work, he meditates on doubt, the human soul, God, truth and the nature of existence itself.
» Have you read this book? We'd like to know what you think about it - write a review about Rene Descartes' Meditations on First Philosophy in Focus book by Rene Descartes and you'll earn 50c in Boomerang Bucks loyalty dollars (you must be a member - it's free to sign up!)
Facebook Page | Twitter | Google+ | Bulletin e-Newsletter | Blog | RSS
Become a Member | Book Lists | Recently Released | Coming Soon | Fast Delivery Books
Bestselling Books: Our Current Bestsellers | Australia's Hottest 1000 Books | Bestselling Fiction | Bestselling Crime Mysteries and Thrillers | Bestselling Non Fiction Books | Bestselling Sport Books | Bestselling Gardening and Handicrafts Books | Bestselling Biographies | Bestselling Food and Drink | Bestselling History | Bestselling Travel Books | Bestselling School Textbooks & Study Guides | Bestselling Children's General Non-Fiction | Bestselling Young Adult Fiction | Bestselling Children's Fiction | Bestselling Picture Books | Top 100 US Bestsellers
For: Schools | Organisations | Libraries | Publishers | Authors | Book Clubs | Bloggers | Affiliates
About Us | Contact Us | Help Desk | Security | Privacy | Terms of Use | Copyright
Phone: 1300 36 33 32 (9am-5pm Mon-Fri AEST) - International: +61 2 9960 7998 - Online Form
Address: Boomerang Books, 878 Military Road, Mosman Junction, NSW, 2088
© 2003-2017. All Rights Reserved. Eclipse Commerce Pty Ltd - ACN: 122 110 687 - ABN: 49 122 110 687
For every $20 you spend on books, you will receive $1 in Boomerang Bucks loyalty dollars. You can use your Boomerang Bucks as a credit towards a future purchase from Boomerang Books. Note that you must be a Member (free to sign up) and that conditions do apply.


text:
£625,000 Guide Price
3 Bedrooms Terraced House for sale
Windsor Street, Chertsey, Surrey, KT16
Located in the heart of chertsey is this splendid grade ii listed georgian townhouse thought to date back to the first quarter of the 18th century. the accommodation is spread over…
1 Bedroom Apartment Flat for sale
Windsor Street, Chertsey, Surrey
Offered to the market is this one bedroom apartment located in the heart of chertsey town centre. the property is offered with no onward chain and offers a brand new lease of 125 years.…
Free Instant Valuation
Find out if you are charging enough rent or what your property would be worth if you were to sell now


text:
It's not just strength and conditioning, but also how we tie this to soccer. The concept is to combine physicality with soccer skill abilities.
Many people will think of neck strength as something that is just for guys or just for football players. The truth is concussions happen in every sport. There are just as many concussions in girls youth soccer than in football. These exercises certainly don't guarantee safety but they can definitely help.
Find out now – FREE! Avoid Injury Created by Poor Movement Skills. Continue Your Strength Program knowing that your athletes are getting stronger, faster with minimum risk of injury.
Have you ever gone to bed on Sunday night ready to attack your goals for the week ahead only to wake up on Monday morning and feel as if you're being pulled in a thousand different directions. Before you know it the week is attacking you and you're just reacting. The one habit that has made the biggest difference in my life has allowed me to focus and attack the things that are most important in my life.I call this habit the Simple Sunday Ritual.
Soccer requires us to perform incredible amounts of running, jumping, change of direction, acceleration and deceleration – in other words it is one of the most demanding sports on the body. And, the anterior chain, or front of the body, bears the majority of the stress compared to the backside of the body.
I find that "pushing" exercises like squatting and push-ups are much easier for the majority of our female soccer players to perform than "pulling" exercises such as deadlifts and rowing variations.Therefore I counterbalance these strength imbalances by targeting 3 main areas.
What you need is lots of PATIENCE. Do not look for any 'drills' to keep children active. All soccer players including your 4-5 year olds come to practice to PLAY! So make your first goal to: KEEP the PLAYERS and the SOCCER BALL MOVING in other words KEEP THEM ACTIVE – ALL THE TIME!
Using pattern recognition training, players will be given the opportunity to understand the most effective patterns on the field, the correct spacing within those patterns, and the proper timing both on and off the ball. They will also simultaneously be training the proper techniques of passing, receiving, dribbling, turning, and shooting that are essential as well to a player and teams success.
While recovery is important for all aspects of soccer, this article is focusing on everything you need to know about optimizing your muscle recovery. Taking the techniques and tips in this article seriously will help you feel less sore, gain more muscle, practice and workout more and harder and overall improve your game.
M-2-M is a series of nine movement skill tests graded on a pass/fail basis. If the athlete fails any of the tests, they are placed on a movement skills corrective program which they do until they pass all the tests. Then the athlete can successfully start a strength and conditioning program. This muscle program must be done using correct exercise techniques and proper progressive overloading with planned recovery, to ensure the continuation of proper exercise techniques.
Understanding and combating fear within youth soccer is an integral process throughout the development of a player. As coaches/parents/mentors we must be able to take that fear out of the players'/participants' game. That's important football psychology!
Since soccer is a sport that requires explosive actions separated by periods of recovery, the best way to improve your fitness is to do just that – perform activities of high intensity followed by some rest. High intensity workouts can involve more than just running!
The real focus should be on what professional athletes did when no one was watching- before anyone knew they were going to be stars. How did they build their athleticism? How did they improve their skill and technique? These are the questions that should be getting asked.
Here are a menu of exercises that you can add to your off-season program to develop strength/power specific to soccer. They should be used as part of an overall program design to the individual needs of each player.
These 9 TED talks cover leadership, motivation, inspiring action, developing leaders, the power of belief and more. Each speaker's message is under 18 minutes in length and contains innovative ideas that can be applied to your coaching. Hopefully at least one of these gets you thinking about your ability to motivate and impact not only your team's performance but also your players' lives.
We don't practice it properly or on a regular basis so 'heading' gets relegated to the waste paper basket. Then people wonder why injuries happen. Skill is knowledge and rarely do the great headers of the ball get injured because of that awareness & know how.
And rather than banning 'heading' in the younger age groups I would suggest that governing bodies encourage the play of Futsal as the main soccer game up to U.12's…!
Today, yoga is a mainstay for professional athletes and teams. More and more people are discovering the countless ways that yoga can be used to improve athletic performance—from increasing mental concentration and improving flexibility and balance to preventing common injuries and honing skills. If you can't get outside this winter to work on your technical skills and even if you can but have some time to work in some yoga to enjoy the numerous benefits of this discipline, here are a few poses that can help you.
In this article coach Josh Brown points out a crucial differentiator when it comes to success and failure as a coach – being mentally prepared to deliver. If we demand it from players then we need to demand it from ourselves – we need to be as mentally robust as them.
Gerard Houllier, former coach of Lyon, Liverpool and Aston Villa says that "The most important moment in the modern game is when the ball is won or lost." Houllier is referring to the moment of interception of a pass, a goalkeeper's save, a tackle in free play, or the ball going out of bounds. The reason this moment has become so critical is that defenses are so well organized that many teams can only be scored upon when they are attacked before they get into their defensive shape.
Skills have to be at the top of the pyramid when it comes to the growth of an athlete, but in a lot of ways its been reversed. Young athletes are specializing in one sport, developing the skills to compete at a high level, but still incomplete as a player. They haven't developed the overall strength and agility that comes from a wide foundation of pure athleticism. For those of you who just love the game, whatever that game may be, here are 3 of my favorite corrective moves.
The varied tactical approach's of the modern game demands players who are more flexible in their thinking and willing to embrace change. Today, top teams restructure their tactical approach many times during the course of a game and "intelligent" players who can identify challenges on the field and provide effective solutions will thrive. The modern player will literally be required to "think on their feet" and embrace and thrive during change.
Your kids are registered to play soccer for the upcoming season and lets hope they are looking forward to the experience. I say that, because if you're looking forward to your son or daughter playing soccer more than they are, then there is something wrong that picture. Did your children agree to play because they were too afraid to disappoint you by saying they didn't want to play? I'm sure that is not the case with your child but be careful not to get trapped into what I like to call the parent vacuum.
Youth sports coaches sometimes feel like everything is conspiring against them. The majority of parents support these volunteers, but there's always those few who take things too seriously. Coaches may put too much pressure on themselves to win, and experience too much of an emotional letdown when their teams don't. for the most part, coaches must take the initiative to improve the experience for their teams and the players in their charge. Here are five coaching tips that every youth coach needs to hear.
I am often asked what young players, aged 9-12 should focus on. The effect of role-models is very important at this stage of development. Young players should seek out role models and identify players and teams to follow. Young players should also begin to transition from being self-centered to being self-critical. This is the "golden age of learning" and the most important age for skill development. This is also an important time to start to understand basic principles of play.
Positive mindset allows performance levels to increase because it facilitates direction and focus. The relationship between mental preparation and sport psychology therefore becomes important and there is evidence of its use in cricket, golf and tennis. It is therefore not surprising that football has also introduced sport science to their mapped programme of which sport psychology is an integral part. Given the contention that sport psychology plays an integral role within football it would be purposeful to argue of its merit for football coaches in performance settings.
We've reviewed our analytics for the past year and below we have counted down the 16 most read posts on Amplified Soccer in 2016. Thank you to all of our contributors that helped make it an amazing year. We hope everyone has a great 2017!
This program is perfect for youth coaches wanting practices to start their soccer coaching education and it is also for those more advanced and experienced coaches wanting to train their players as best they can at these wonderful open minded ages for development and education of both the mind and body. Our plan is to help all coaches at whatever level of experience they are at.
This article highlights the importance of a quick start as well as the necessary key words players must house in their mind to keep them mentally alert.
If you take time off from soccer to enjoy winter sports, you want to pay careful attention to your sports diet. Otherwise, lack of food and fluids can take the fun out of your outdoor activities. These tips can to help you fuel wisely for cold weather workouts.
In the future the best players will be those who can excel in a fast paced environment. There will be even greater demands on technique, tactical understanding and physical conditioning. Players must have fun and enjoy the learning process. The premise that players develop faster and experience more enjoyment in small side games is universally accepted and proven.
With the Fall Soccer Season finished, coaches are now organizing their off-season plans. Because of the unpredictable weather here in New Jersey, at Total Soccer Fitness & Training, we look to get into a facility or school gym to conduct our sessions during the off-season months of December, January and February. But inside or outside, off-season training has become an integral part of club soccer. Our theory at TSFT is to use the off-season to hone technical skills, review and practice tactical concepts, and most importantly, work on fitness and endurance both with and without the ball.
If you want to compete at your best at soccer, you need to commit to preseason training, so that your team's strength and cardiovascular fitness peaks at the right time. This is a moderate intensity aerobic training session. This session is designed to replicate the demands of soccer.
This is an exercise where the field is divided into several vertical channels. Initially none of the players may leave the channel they are in. The most important condition is that the ball CANNOT be played forward to a team mate in the same channel. The ball must be played into an adjacent channel. This simple condition guarantees angled passes and sideways on reception.
This session from Soccer Champions Coaches' Clinic is focused on short/intermediate passing and possession and includes a pattern series passing drill, a possession 5 v 5 + 2 game and a 6 v 6 + GKs to large goals game.
The objective of this drill is developing quick continuous attacking play. Players are breaking one way passing to an outside player and switching positions, inside player out, outside player in then attack the other side of the zone.
Work on angle of approach, cover and group defending with this transition drill from Smedley's Soccer Site. During the drill, the attackers play 4 v 3 in one half of the field, looking to change the ball over to their teammates in the other half.
The key is to integrate your goalkeeper with the team. This can be done right from the warm-up phase of training. Watch a preview and get the full outline of this team games for training goalkeepers session from Tony DiCicco & Deb Raber that was presented at the 2016 Soccer Champions Coaches' Clinic.
Here are three match day warm up activities to raise the heart rate and get in game specific movements of changing direction, passing, receiving and turning.
Receiving and turning to attack and score in the defender (A)'s goal. (2) Passes the ball into (1) who has to receive and turn and beat (A) and score a goal. Have the attacker run the ball into the goal to score or shot it in.
This set of 4 small-sided games focusing on coaching attack and defense from Brian Bliss, Director of Player Personnel Sporting Kansas City, was presented at the 2016 Soccer Champions Coaches' Clinic.
In this patterns of play drill from Smedley's Soccer Site, we are working on speed of play, changing the field and the overlap run. We want to always try to increase the speed of play with one touch passing.
Encouraging competitiveness in players in a small sided game environment and developing the best features of youth soccer as it used to be played in the parks, streets and back alleyways around the world, into the more formalized structure of the modern club soccer training program. It is about the technical and skills development of the younger player. Here's what you need to know and how to get started.
With The Triangle Training Method learn mannequin training exercises used by top European teams such as Arsenal and Bayern Munich as well as games that create environments to pass and play in triangles. Get started with triangle training by doing these basic rotations.
This technical dribbling and shooting session comes from Ian Mulliner, Technical Director, Massachusetts Youth Soccer Association, and was presented at the Soccer Champions Coaches' Clinic.
The goalkeeper begins the drill by coming off of his line and out to the 12. The first shooter hits the goalkeeper in the hands from close in, and after the goalkeeper saves, the second shooter drives a ball towards the crossbar from 30 yards out. The goalkeeper must recover back and make the save at the far post.
Use this drill with your team to improve players technique, accuracy and weight of passing..
Speed is integral to both the physical demands of soccer and the physical demands we must train in our players. Here is one speed training session from the Best of Amplified Soccer Training Volume 2.
The theme here is making diagonal runs with or without the ball to receive or create space for a teammate. When it is a forward diagonal run the player making it must avoid running offside in a game situation.
To score, the attacking team must dribble the ball across their opponent's end line. They can use the two neutral attackers playing inside the central grid to relieve pressure, but the neutrals are limited to one or two touches. After scoring, the attacking team reverses field and tries to score in the other direction. Games are played to three points, and on balls put out of touch, the Feeder re-starts play.
Use this session to review and reinforce the keys of individual defending. These drills create a competitive environment where 2 defenders coordinate & adjust def. roles by reading cues of teammate and opponents.
A good place to begin functional training is in a wide position with a flank player, mannequin (maybe) and some support players. In this instance the coach can act as the feeder (4) or have a player do it…there is no mannequin.
The Feeder begins play with a pass out to Player A (or B), and the defender releases with the Feeder's first touch. Player A plays a square ball to Player B, and runs an overlap around him. From there, play continues 2 v 1 to goal. If the defender wins the ball, he can score in the two small goals set up just outside of the penalty area. Upon completion, The Feeder re-starts play with the next set of players.
Players have the ball at their feet for approximately 5 minutes out of 90. What do they do the rest of the 85 minutes? They must learn to move off the ball and to move into open passing lanes to be open at all times to help the player on the ball or the next player on the ball. Here is a great session to teach this.
The following training session comes from 2016 Soccer Champions Coaches' Clinic Featured Presenter, Brian Bliss, from Sporting Kansas City. These drills incorporates game related components and involves the whole team in the build-up to the shot.
Soccer is a sideways on sport -- players will have much more success when they are able to receive the ball at an angle. Being sideways on allows players, in advance of the ball, to be able to see peripherally advancing defenders.
This warm up is excellent for beginning to develop this sideways on aspect of receiving and passing the ball.
The key defensive skill we are practicing here is for the defending player to always be able to see the ball and the attacker at the same time. The defender must gauge whether it is possible to intercept the ball and, if it is not, then must adopt a position behind the attacking player's receiving foot. Sometimes attacking players spill the ball when they are under pressure and the defender can, sometimes, win the ball after the attacker misplays it.
The best goalkeepers do more than just stop shots. Once the goalkeeper has the soccer ball, he or she becomes an attacking player. Just like any attacking player, the keeper wants to move the ball towards the other goal in possession if possible. This drill will help your keepers develop their distribution skills.
Fast passing and movement plays in fours in a game situation. 1 v 1 Attacking Play Using Cones to Represent Defenders forcing players to move into open passing lanes for each other.
There are twelve players set up on a split field, playing 3 v 2 with players starting from the sideline. During the game, the attacking team starts in the defending half, and the defenders may not cross over the midfield line. Play continues 3 v 2 to completion from there. On a goal or a turnover, the ball is played to the goalkeeper and the direction of play reverses.
This functional technique session comes from Mario Prata, Director of Coaching for Connecticut Junior Soccer Association and was presented at the Soccer Champions Coaches' Clinic. Functional training involves training or practicing the specific demands of a position or a role. This can be for an individual player, or for a unit (i.e. defense).
Having studied Brazilian soccer I have been impressed with two things; Their angled passing style of play and the sideways on aspect of their play. Their ability to disguise a pass by "front foot" passing These exercises are designed to incorporate each of these characteristics into our players.


text:
iPhone apps
Perennial Specimens for Colorful Gardens
Perennial Color with SpecimensThe Unique Plant-Pollyann's- Big, showy, fragrant, beautiful, different but mesmerizing. Short bloom times, wrong sizes, challenges to keep going. Oh yes, the specimens are all of these and more. These are the perennials….. Read more
iPhone Screenshots
Video Reviews
No video review..
Customer reviews
Be the first to review this app. Write a Review
Be the first question this app.
Users Community
The information may be outdated. For actual information go to iTunes
Related to «Perennial Specimens for Colorful Gardens» applications
Perennial Color for Cottage Gardens
Perennial Color for Cottage Gardens -Pollyann's-The Classic Cottage Garden sits closely to the house and contains flowers, vegetables and herbs for the at-home gardener. The biggest… [more..]
Price: $2.99 |
Perennial Color for Shade Gardens
Perennial Color for Shade GardensPollyann'sPerennial Color in Shade can be a huge challenge. There are plenty of leafy green perennials that can fill a shady landscape but the beauty of color enhances… [more..]
Price: $3.99 |
Perennials for Fragrant Gardens
Perennials for Fragrant Gardens -Pollyann's-Growing perennials can be visually stimulating - not to mention full of satisfaction - for any successful gardener or landscaper. But what about a… [more..]
Price: $3.99 |
Color Vision (for Color Blindness)
If you have a color deficiency (color blindness) this is the app for you. By using the camera in your device, Color Vision will give you a colorful view of the world - in real time!How it works:The… [more..]
Price: $1.99 |
Eye For Color - Creative Color Comparison Puzzle…
How much of an Eye for Color do you have? Try this unique and exciting puzzle game that challenges your ability to differentiate between colors of slightly varying hues and values.In Eye For Color,… [more..]
Price: $0.99 |
Eye For Color Lite - Creative Color Comparison…
How much of an Eye for Color do you have? Try this unique and exciting puzzle game that challenges your ability to differentiate between colors of slightly varying hues and values.Fill in a gradient… [more..]
Price: free |
Safelight+ Darkroom Safe Light + Notes for Indoor…
Safelight+ turns your iDevice into a mobile darkroom safelight you can write on.• optimized for iPhone, iPod touch, and iPad (iOS 4.0 or later)• make Notes while you're in your darkroom:… [more..]
Price: $0.99 |
Zen Unlimited. Nature music calming sounds for Zen…
Zen Unlimited. Nature music calming sounds for Zen gardens, meditation & relaxation is an advanced Zen guide, Relaxation music channels, nature sounds and relaxation aid.It helps you leave your… [more..]
Price: $1.99 |
iBeachhouse Books for Kids - Diving For Colors in…
Hawai'i is such a beautiful, culturally rich state. We have so much to offer. Our books, whether printed or digital, strive to share our unique local culture, environment, history, and traditions with… [more..]
Price: $1.99 |