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This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is cited.
In patients with rheumatoid arthritis (RA), chemokine and chemokine receptor interactions play a central role in the recruitment of leukocytes into inflamed joints. This study was undertaken to characterize the expression of chemokine receptors in the synovial tissue of RA and non-RA patients. RA synovia (n = 8) were obtained from knee joint replacement operations and control non-RA synovia (n = 9) were obtained from arthroscopic knee biopsies sampled from patients with recent meniscal or articular cartilage damage or degeneration. The mRNA expression of chemokine receptors and their ligands was determined using gene microarrays and PCR. The protein expression of these genes was demonstrated by single-label and double-label immunohistochemistry. Microarray analysis showed the mRNA for CXCR5 to be more abundant in RA than non-RA synovial tissue, and of the chemokine receptors studied CXCR5 showed the greatest upregulation. PCR experiments confirmed the differential expression of CXCR5. By immunohistochemistry we were able to detect CXCR5 in all RA and non-RA samples. In the RA samples the presence of CXCR5 was observed on B cells and T cells in the infiltrates but also on macrophages and endothelial cells. In the non-RA samples the presence of CXCR5 was limited to macrophages and endothelial cells. CXCR5 expression in synovial fluid macrophages and peripheral blood monocytes from RA patients was confirmed by PCR. The present study shows that CXCR5 is upregulated in RA synovial tissue and is expressed in a variety of cell types. This receptor may be involved in the recruitment and positioning of B cells, T cells and monocytes/macrophages in the RA synovium. More importantly, the increased level of CXCR5, a homeostatic chemokine receptor, in the RA synovium suggests that non-inflammatory receptor–ligand pairs might play an important role in the pathogenesis of RA.
Rheumatoid arthritis (RA) is a chronic inflammatory condition that affects multiple joints, and it results in the accumulation of leukocytes within the synovial tissue (ST) and synovial fluid (SF). The inflammatory infiltrate consists predominantly of B lymphocytes, T lymphocytes and macrophages in the ST, whereas neutrophils are mainly found in the SF. The lymphocyte infiltration is organized in lymphoid-like microstructures in just under 50% of the RA patients; however, the patients present germinal centre reactions in only 20% of cases [1]. The pathogenesis of the RA is still largely unknown but leukocytes and their products play an important role in the development of inflammation, joint destruction and pain [2,3]. The attraction of leukocytes into the joints is controlled by chemokines, a family of small chemotactic cytokine-like molecules that act as potent mediators of inflammation [4].
Chemokine activity is dependent on the presence of and interaction with chemokine receptors on the leukocyte surface. Indeed, chemokines and their receptors are involved together in the development and perpetuation of inflammation [5]. In vitro and in vivo experiments have indicated that blocking chemokines or their receptors could potentially provide an effective treatment of inflammatory diseases [5,6]. The 19 receptors so far identified belong to a super-family of G-protein-coupled receptors with seven transmembrane domains [7]. Chemokine receptors have a regulatory effect on the maturation and traffic of leukocytes, and they are implicated in several disease states [8]. There have been several reports on chemokine receptor expression on T cells from RA ST, RA SF and RA peripheral blood (PB) [9-13]. The expression of some chemokine receptors on monocytes/macrophages, dendritic cells and neutrophils has also been reported [14-17], and the importance of the role of chemokine receptors in RA is emerging [18,19].
CXCR5 is a chemokine receptor highly expressed in recirculating B cells, in subsets of CD4+ and CD8+ T cells and monocytes [20,21]. It also has been identified on B-cell infiltrates in Sjogren's syndrome [22,23]. CXCR5 is involved in the immune-system homeostasis and in lymphoid organogenesis [24]. Several morphological and functional studies suggest that lymphoid neogenesis takes place in RA [1,25,26]. Furthermore, an important disturbance of follicle and germinal centre formation in the spleen and Peyer's patches is observed in CXCR5-deficient mice [27]. CXCL13, the unique ligand of CXCR5, is also involved in follicular homing, as observed in CXCL13-deficient mice [28].
In view of the role of chemokine receptors in leukocyte traffic, the aim of the present study was to compare their expression in inflamed and non-inflamed tissue to shed light on which chemokine receptors may be involved in the recruitment and retention of leukocytes in ST. We examined chemokine receptor expression in ST taken from RA and non-RA patients using microarray technology, RT-PCR and immunohistochemistry. The microarray and RT-PCR experiments demonstrated the differential expression of CXCR5, and immunohistochemistry showed that this receptor is expressed in B-cell and T-cell infiltrates, on macrophages and blood vessels. Our study identifies CXCR5 as a potentially interesting therapeutic target in RA and points to the use of antagonists to this receptor as a treatment strategy in the disease.
Tissue samples were obtained from patients with RA (n = 8) who fulfilled the American Rheumatism Association criteria for RA (Table (Table1).1). The patients' mean age was 59 ± 14.8 years with a male to female ratio of 1:8. The disease duration of six out of eight RA patients was over 10 years. ST was taken from these subjects at the time of total knee replacement. Non-RA patients (n = 9) had knee joint symptoms for suspected articular cartilage or meniscal damage (Table (Table1).1). Their mean age was 47.6 ± 6.8 years with a male to female ratio of 8:1. Except for one patient, the non-RA patients had knee complaints for 1 year or less. ST biopsies were obtained from these patients at the time of arthroscopy. All samples were taken with informed consent and ethical approval. The ST samples were taken from the suprapatellar pouch and the medial gutter, which is reported to provide representative sampling of synovial membrane pathology [29]. Synovia were cut into approximately 4 mm3 pieces and were either snap frozen in isopentane and stored in liquid nitrogen or formalin fixed and paraffin embedded.
Monocytes/macrophages were isolated from the PB and SF of another four RA patients (Table (Table1).1). In brief, the blood and hyaluronidase-treated SF were centrifuged over a ficoll cushion (Amersham Biosciences, Chalfont St Giles, UK). The macrophages were isolated from the buffy coat layer (lymphocytes, macrophages) by adherence onto a glass dish.
Total RNA was extracted from frozen blocks of synovia or from isolated monocytes/macrophages using TRIreagent solution (Sigma, Poole, UK) according to the manufacturer's recommendation. The quantity recovered was determined by spectrophotometry and the integrity was assessed by gel electrophoresis. For microarray experiments, equal quantities (7 μg) of RNA from each RA or non-RA patient were pooled and the messenger RNA was extracted using the mRNA GeneElute Kit (Sigma). The quantity recovered was determined by fluorometry using SYBR Green II (Molecular Probes, Leiden, The Netherlands). RNA had to be pooled since only small biopsies could be obtained from non-RA patients.
The panorama human cytokine gene array (Sigma-Genosys, Pampisford, UK) was used. This array contains 375 different cDNAs including 16 chemokine receptors and 33 chemokines, each printed in duplicate on nylon membranes.
The probe labelling and hybridization were carried out according to the manufacturer's instructions. Briefly, 33P-radiolabelled cDNA probes were prepared from 0.5 μg mRNA (see earlier) using human cytokine cDNA labelling primers (Sigma-Genosys) and AMV reverse transcriptase at 42°C, and were purified on a Sephadex® G-25 spin column (Sigma-Genosys). The arrays were hybridized for 17–18 hours at 65°C, washed and subjected to autoradiography for various lengths of time using Kodak BioMax MR X-ray film.
The intensity of hybridization signals was quantified using the ArrayVision, version 6.0, software (Imaging Research Inc., Haverhill, UK). The intensity of each spot was corrected for background levels using the 'corners between spots' (set to 3 pixels) with or without 'segmentation' protocols, and were normalized for differences in labelling using the average values of seven housekeeping genes: β2-microglobulin, β-actin, cyclophilin A, glyceraldehyde-3-phosphate dehydrogenase, HLA-A 0201 heavy chain, human hypoxanthine phosphoribosyl transferase, and α-tubulin. The remaining two housekeeping genes, L19 and transferrin R, were excluded because of signal saturation and differential expression, respectively. The software performs the normalization automatically.
Total RNA aliquots from individual patients were reverse transcribed using oligo(dT18) (MWG Biotech, Ebersberg, Germany) and MMLV reverse transcriptase (Promega, Southampton, UK) at 37°C for 1 hour. The reactions were terminated at 70°C for 10 min and were diluted to 80 μl with H2O. For two of the non-RA patients no more RNA was available for RT-PCR following microarray analysis.
The PCR reactions were normalized against the ribosomal RNA L27 using specific primers (MWG Biotech) (Table (Table2).2). Appropriate cDNA dilutions were used subsequently for the RT-PCR reactions using specific primers for CXCR5 (MWG Biotech) (Table (Table2).2). Specific primers were designed from the published sequences. The number of cycles and the annealing temperature were optimized for each primer pair. The RT-PCR conditions were one cycle at 94°C for 3 min, 57°C for 1 min and 72°C for 1 min, X cycles at 94°C for 1 min, 57°C for 1 min and 72°C for 1 min, and one cycle at 94°C for 1 min, 57°C for 1 min and 72°C for 10 min. X equals 34 cycles for CXCR5 and 24 cycles for L27.
The ST from the patients that had been examined at the transcription level was also available for protein expression analysis. Paraffin embedded sections were cut 4 μm thick on 3-aminopropyltriethoxysilane-coated slides. Sections were deparaffinized and rehydrated before blocking endogenous peroxidase activity with H2O2 (0.3%) in methanol. The slides were rinsed with PBS and incubated with normal serum (1:67 in PBS) for 10 min before applying anti-human CXCR5 monoclonal antibody (1:666; R&D, Abingdon, UK) and the respective IgG control (Dako, Ely, UK). The sections were rinsed with PBS and incubated with biotinylated secondary antibody. The antibody binding was detected using reagents in the Vectastain ABC Elite kit (Vector, Peterborough, UK) and the chromogen 3,3'-diaminobenzidine (DAB) (Vector). Sections were rinsed and counter stained in Mayer's haematoxylin.
B cells and macrophages were localized using anti-human CD20 antibodies (1:100; Dako) and CD68 antibodies (clone PG-M1, 1:75; Dako), respectively. CD20 required antigen demasking by 15 min microwaving in citrate buffer (pH 6.0), but H2O2 treatment was not necessary. CD68 antigen was demasked using 0.05% pronase in Tris-buffered saline (pH 7.2) for 10 min.
Double immunohistochemistry was performed with anti-human CD3 rabbit monoclonal antibodies (Labvision) and CXCR5 antibodies. The slides were deparaffinized, rehydrated and microwaved for 15 min in citrate buffer pH 6.0 before being treated with H2O2 in methanol. The slides were incubated with 2.5% normal swine serum for 20 min before applying CD3 diluted 1:60 in 2.5% serum for 30 min. The sections were rinsed with PBS and were incubated with swine anti-rabbit antibody linked to alkaline phosphatase (1:40; Dako). CD3 binding was detected using Vector Red substrate (Vector). Sections were rinsed and were either counter stained in Methyl Green (Vector) or subjected to a second round of immunohistochemistry. CXCR5 was used as for single immunohistochemistry except that blocking and antibody dilutions were made in 2.5% normal horse serum and CXCR5 was revealed with DAB-Nickel (Vector). No counter stain was performed for double immunohistochemistry sections.
Synovia were obtained from knee joints as this allowed the use of arthroscopic samples of non-RA (normal) as controls instead of osteoarthritic tissue, which can show more enhanced inflammatory changes. The histology of H&E-stained RA synovial sections demonstrated classic signs of inflammation. Mononuclear cell infiltrates were visible in seven out of eight patients and consisted of aggregate structures; one of these seven patients also contained more germinal-like centre structures. In addition one patient revealed a diffuse infiltration. The synovium of the non-RA patients showed minimal signs of inflammation. In eight out of nine patients no mononuclear infiltrates were observed, and in one case only a small infiltrate was seen. No thickening of the intima was observed in the non-RA compared with the RA samples.
To allow rapid preliminary screening of a large number of chemokines and their receptors in RA ST and non-RA ST, chemokine expression was investigated using microarrays.
A pair of human cytokine microarrays including 16 chemokine receptors and 33 chemokines was hybridized with labelled cDNA probes prepared from mRNAs obtained from RA and non-RA pools of synovial RNA. Figure Figure11 shows the results of hybridization of the RA and non-RA probes to the array membranes. To reduce the bias that could be introduced during the quantification, arrays showing very similar signals for the housekeeping genes were chosen and only non-saturated and non-regulated signals/genes were used for normalization. The intensity of each spot was corrected for background levels. The analysis step was repeated eight times for each pair of autoradiogram.
Of the 16 chemokine receptors present, the expression of 12 chemokine receptors was visible on the RA microarrays. These were CCR1, CCR2a, CCR5, CCR7, CCR9, CX3CR1, CXCR1, CXCR2, CXCR4, CXCR5, CXCR6 (STRL33) and Bob (Table (Table3).3). Expression of the same receptors could be observed on the non-RA membranes with the exception of Bob, CCR7 and CCR9. Bob/GPR15 is an orphan receptor that is a coreceptor for human and simian immunodeficiency viruses, and its expression in the RA synovium is a novel observation that might be worthy of further investigation. The detection of CCR7 and CCR9 in RA was only possible after extended exposure times, but at the time points used for quantification no regulation was demonstrated. Four chemokine receptors (CCR2b, CCR3, CCR4 and CCR6) could not be detected in RA samples or non-RA samples under our conditions.
The most obvious differences between RA samples and non-RA samples were for the chemokine receptors CXCR5 and CXCR2, and to a lesser extent CXCR4, which gave stronger signals in RA samples (Fig. (Fig.1).1). In order to quantify the differential expression of these receptors the densities of autoradiographic spots were measured using ArrayVision software (Table (Table3).3). The criteria we set for a gene to be considered as upregulated or downregulated were a RA/non-RA ratio higher than 3 or lower than 0.3, respectively, and a 95% confidence interval below 10% (criteria as [30]). In the present study the expression of CXCR5 and CXCR4 was 22.6 ± 0.7-fold higher and 3.5 ± 0.1-fold higher in RA tissue than in non-RA tissue, respectively. These results indicated that, of the chemokine receptors studied, CXCR5 was the most upregulated in RA (Table (Table3).3). The upregulation of CXCR2 could not be calculated for mathematical reasons because the signal intensity of CXCR2 in non-RA tissue after correction for the background was zero. CXCR2 was only visible on the non-RA autoradiogram upon prolonged exposure, at which point the housekeeping genes were saturated and were therefore unsuitable for quantification purposes.
Out of the 33 chemokines present on the arrays, 29 of these ligands were visible on the RA membranes and 21 on the non-RA membranes (Fig. (Fig.11 and Table Table3).3). These included CXCL13, CXCL12, CXCL8, CXCL1-3 and CXCL5, which are ligands for the chemokine receptors CXCR5, CXCR4 and CXCR2. Several chemokines were visible on RA microarrays but not on non-RA microarrays (namely CXCL13, CCL21 and CCL24), suggesting that these genes might be induced in the inflamed synovium. In contrast, there were no chemokine signals that were present on non-RA membranes and were absent on RA membranes. Where chemokine signals were detectable on RA and non-RA microarrays, it was possible to quantify the degree of upregulation or downregulation using the criteria described earlier for chemokine receptors. Of these chemokines, the following showed upregulation: CCL18 (4.5 ± 0.4-fold increase), CXCL9 (3.6 ± 0.1-fold increase), CXCL5 (3.5 ± 0.3-fold increase), and CXCL8 (3.3 ± 0.2-fold increase). No chemokines displayed a downregulation with a RA/non-RA ratio less than 0.3. The upregulation of CXCL9 in RA synovia is in agreement with the only microarray study of RA synovia, in which this chemokine was also shown to be increased [31]. In our study only five chemokines (CXCL7, CCL13, CCL20, CCL17 and CCL25) could not be detected at all, whether in RA or non-RA samples.
The rapid screening of several genes at once made array technology a very attractive method. Its use has revealed disadvantages, however, including the requirement for large amounts of RNA (which are not always available from human tissue biopsies), a susceptibility to experimental variability and a lack of standard optimum methods for statistical analysis [32]. Arrays also present the risk of cross-hybridization leading to false positive or negative results [31]. However, the array approach remains a valuable tool if the samples can be pooled and if it is used in conjunction with alternative methods such as RT-PCR.
To confirm the array results and to examine individual patients, RT-PCR was performed on the total RNA from each patient sample (Fig. (Fig.2).2). PCR primers were run through the BLAST program (available through the UK MRC HGMP-RC website: http://www.hgmp.ac.uk) to ensure the gene specificity of the RT-PCR results and to exclude the possibility of cross-hybridization with other genes. Overall, CXCR5 RNA was more abundant in RA patients than in non-RA patients, confirming the microarray data. CXCR5 expression was detected in the synovia of all eight RA patients and showed some degree of patient-to-patient variation. The difference in CXCR5 expression between RA patients and non-RA patients was unlikely to be due to differences in the relative amount of cDNA produced by different RT reactions since the PCR reactions were normalized using the ribosomal gene L27. RT-PCR showed that the difference between RA patients and non-RA patients was less marked for CXCR2 and CXCR4 than for CXCR5 (data not shown).
To identify the cell types expressing CXCR5, and since RNA expression and protein expression do not always correlate, the protein expression of this receptor and three specific cell markers (CD20, CD3 and CD68) was investigated by immunohistochemistry of paraffin-embedded sections.
Seven out of eight RA patients presented substantial lymphoid follicles in their synovia. The specific cell markers CD20 and CD3 confirmed the presence of B cells and T cells, respectively, in these infiltrates. In every RA patient where lymphoid follicles occurred, CXCR5+ cells were always present in these structures; this indicates a correlation between the expression of CXCR5 and the occurrence of lymphoid follicles. Serial sections indicated that CXCR5 was expressed by CD20+ B cells (Fig. 3a,3c).
It was not possible to colocalize CXCR5 and CD3 in serial sections, so a double-label immunohistochemistry technique was developed. Sections were treated with anti-CD3 followed by alkaline phosphatase and Vector red substrate. Anti-CXCR5 was added to the same sections, and the colour developed using peroxidase and DAB-Nickel. CD3 expression alone gave a light red colour (Fig. (Fig.3e)3e) and CXCR5 expression alone produced a grey–black colour (Fig. (Fig.3f).3f). Where these two proteins colocalized a dark red colour was obtained (Fig. (Fig.3f).3f). Using this technique it was evident that in the RA synovium there was a population of CD3+ T cells that expressed CXCR5 (Fig. (Fig.3f).3f). These were localized exclusively in lymphoid follicles in the synovia of five out of the eight RA patients. The patient with diffuse infiltration was negative for CXCR5+/CD3+ cells. Serial sections treated with anti-CXCR5 and the macrophage marker anti-CD68 suggested that CXCR5+ cells in the intima included macrophages (Fig. 4a,4b). The endothelial cells of synovial postcapillary venules were positive for CXCR5 in the RA synovium (Fig. (Fig.4e4e).
In non-RA tissue, CXCR5 was localized in the intima and endothelial cells (Fig. (Fig.5).5). Intimal cells were widely positive for CXCR5 and serial sections indicated that these included CD68+ macrophage-like cells (Fig. 5a,5b). No lymphocytic infiltrates were present in these synovial samples due to their non-inflamed nature. Sections treated with CD20 and CD3 antibodies were negative, showing that no B cells or T cells could be detected. In non-RA tissue and RA tissue, fibroblasts were negative for CXCR5, as were neutrophils in RA synovia, indicating selectivity in the cell types expressing this receptor.
For all immunohistochemistry experiments in this study, the use of isotype-matched immunoglobulin controls or sera instead of primary antibodies resulted in negative staining of RA sections and non-RA sections (Figs 3b,3d,3g,3h, 4c,4d,4f and 5c,5d,5f).
To further investigate whether macrophages themselves are producing CXCR5 and to confirm the results of immunohistochemistry, we performed RT-PCRs on monocytes/macrophages isolated from the PB and SF of four additional RA patients (Fig. (Fig.6).6). CXCR5 was strongly expressed in all four samples and there was little difference between PB and SF.
The major finding of the present study is that CXCR5 is upregulated in the RA synovium. The cells expressing this chemokine receptor are B lymphocytes, T lymphocytes, macrophages and endothelial cells. The increased numbers of B lymphocytes, T lymphocytes and macrophages producing CXCR5 in the RA synovium are probably responsible for the increased expression of the receptor in this chronically inflamed tissue. The majority (seven out of eight) of the RA synovia included in this study contained substantial lymphoid aggregates but only one out of nine non-RA patients presented a very small infiltrate. These cell aggregates contained CD20+ B cells that expressed CXCR5. The expression of CXCR5 has been reported in mature B cells and secondary lymphoid organs but as far as the authors are aware this is the first report of a chemokine receptor expressed by B cells in the RA synovium and its ectopic lymphoid structures.
Our findings are particularly interesting in view of the functional role of B cells in RA. This includes autoantibody production, antigen presentation, a role in lymphoid follicle and germinal centre formation, and the promising results of the anti-CD20 treatment in RA [33,34]. The microarrays showed that the mRNA for CXCL13, the only known ligand of CXCR5, was present in the RA synovium and not in the non-RA synovium. Furthermore, other reports have shown a CXCL13 message in RA synovia, together with its protein that localizes to follicular dendritic cells, endothelial cells and synovial fibroblasts, suggesting that these cells produce the chemokine [1,25]. Taken together with our data, this indicates that CXCR5 on B cells may be important in the recruitment of these cells into the RA synovium, in addition to their positioning and retention within the synovial infiltrates. In this regard, the role of CXCR5 on B cells in secondary lymphoid organs has been well documented [35,36]. CXCR5 guides B cells into the B-cell follicles and also directly promotes the recruitment of these cells into Peyer's patches via high endothelial venules [27,28,37,38]. In addition CXCR5-deficient mice exhibit impaired development of lymph nodes and Peyer's patches, and the tissue architecture of these organs is severely disturbed showing a lack of B-cell follicles [27,28].
Our double immunohistochemistry data indicate that there is a population of CXCR5+CD3+ T cells present in the RA synovium. CXCR5+ T cells have been shown in secondary lymphoid tissue where some of these cells localize within germinal centres [20,39], and it is proposed that CXCR5 enables them to enter B-cell follicles guided by CXCL13 [36]. Within these follicles they may provide B-cell help and have therefore been named follicular B helper T cells, since purified human tonsillar CD4+CXCR5+ T cells efficiently stimulate the production of immunoglobulins by B cells [39,40]. These follicular B helper T cells are CD57+, whereas the majority of the CXCR5+ T cells that are present in interfollicular and T-cell areas of the lymphoid tissue are CD57- and are poor B-cell helpers [41]. Since lymphoid neogenesis occurs in the RA synovium it is possible that the CXCR5 expression on T cells as shown in the present study is involved in the positioning of these cells within the synovium and in providing B-cell help, although further studies are required to characterize this synovial T-cell population. Whether the two populations of CXCR5+CD57+ and CXCR5+CD57- T cells are present in the RA synovium and what their role could be is still unknown. However, CD57+ T cells are reported to be present in the RA synovium and SF, where levels of this marker are elevated compared with controls [42,43]. Furthermore, an involvement of CD57+ T cells has been shown in disease activity of RA [44].
Immunohistochemical experiments indicated that CD68+ cells in the synovial intima express CXCR5. Intimal cells comprise two cell types: macrophage-like cells and fibroblast-like cells. In RA the former macrophage-like cells are numerous, comprising up to 80% of this cell layer [45]. It has been reported that in the RA synovium anti-CD68 reacts strongly with intimal macrophages, but fibroblasts also show some reactivity with this antibody [45]. Therefore, since macrophages are abundant in the RA intima and because of their strong reactivity with anti-CD68, it is likely that intimal macrophages are positive for CXCR5. In the normal non-RA intima, macrophages are positive for CD68 and fibroblasts are negative, making it more certain that macrophages express CXCR5 in this cell layer [45]. Consequently, RT-PCR was performed to verify that RA macrophages/monocytes can express CXCR5. The RT-PCR did indeed demonstrate CXCR5 mRNA in macrophages from RA SF, as well as PB monocytes from the same RA patients. Since the CXCR5 mRNA is expressed at similar levels in RA PB and RA SF it is suggested that the contribution of monocytes/macrophages to the upregulation of CXCR5 in the RA synovium is due to their increased number, rather than due to an increased abundance of CXCR5 transcripts per cell. CXCR5 mRNA has also been found in normal human PB monocytes by RT-PCR [21]. Studies by ourselves and other workers have shown that monocytes/macrophages express several other CXC chemokine receptors in RA, including CXCR1, CXCR2 and CXCR4 [15,16,46]. Furthermore, RA monocytes/macrophages express CC chemokine receptors such as CCR1, CCR2, CCR3 and CCR5 [14], illustrating their broad profile of chemokine receptor expression.
Endothelial cells are another cell type expressing CXCR5 in the synovium. There have been several reports of endothelial cells in the RA synovium expressing chemokine receptors, including CXCR3 and CXCR4, in addition to the Duffy antigen that is a non-signalling chemokine receptor [18,47-49]. In the RA synovium there is increased turnover of blood vessels with enhanced formation of new blood vessels together with enhanced vascular regression [50,51]. These mechanisms are regulated by the balance of angiogenic and angiostatic factors, and these factors include chemokines. Some chemokines are angiogenic (e.g. CXCL8, CXCL12, CCL1 and CCL2) and other chemokines are angiostatic (e.g. CXCL9 and CXCL10), and activation of their respective chemokine receptors results in the stimulation of or inhibition of endothelial cell proliferation [47,52-57]. CXCL13 has been shown to have an angiostatic function, inhibiting the angiogenic effects of FGF-2 on human umbilical vein endothelial cells [58]. In addition, the presence of CXCR5 in a variety of cultured human endothelial cells – from umbilical and saphenous veins, for example – may mediate the angiostatic effects of CXCL13 [58,59]. Our data showing the presence of CXCR5 on endothelial cells in the synovium and the presence of its ligand in this tissue [1,25]suggest that CXCR5 may play an angiostatic role in RA pathophysiology, although the angiostatic effects of CXCL13 could potentially be acting through CXCR3, which is also expressed by the RA synovial endothelium [48,60].
In the present study mRNA for other chemokine receptors were detected in the RA synovium, such as CXCR1, CXCR2, CXCR4, Bob, CCR1, CCR2a, CCR7, CCR9 and CX3CR1 (CXCR3 was not on the microarray). All of these showed variable degrees of increased mRNA expression in RA, although the upregulation was less compared with that of CXCR5. Several previous reports have shown the expression of chemokine receptors by leukocytes from RA joints. These have included CCR4–CCR6, CXCR3, CXCR4 and CX3CR1 by T lymphocytes [9,12,13,19] and CCR1–CCR5 and CXCR1–CXCR4 by monocytes/macrophages [14-16,18]. Such reports mainly focused on selected cell types and certain chemokine receptors. The present study took a different approach. Ours was primarily a whole-tissue study examining the mRNA expression of a wide range of chemokine receptors in RA and control synovia. While our study is in general accord with previous reports, differences may in part be due to the RA ST used. This tissue was highly infiltrated and, in all but one sample, had extensive lymphoid follicles bearing resemblance to those of secondary lymphoid organs. This feature may be responsible for the particular upregulation of the constitutive chemokine receptor CXCR5. In addition, our RA patients had long-standing disease (Table (Table1)1) and the patient sample may also have influenced the types of chemokine receptors expressed.
Our study demonstrates the expression of CXCR5 on B cells, on T cells, on monocytes/macrophages and on endothelial cells in the RA synovium. The expression of a marker shared by cells that are known to play a central role in the process of chronic inflammation is of particular interest and suggests that targeting CXCR5 could provide a powerful new treatment for RA.
DAB = 3,3'-diaminobenzidine; H&E = haematoxylin and eosin; PB = peripheral blood; PBS = phosphate-buffered saline; PCR = polymerase chain reaction; RA = rheumatoid arthritis; RT = reverse transcription; SF = synovial fluid; ST = synovial tissue.
The author(s) declare that they have no competing interests.
CS carried out the microarray work, the RT-PCR and the double immunohistochemisty, and drafted the manuscript. AH carried out the single colour immunohistochemistry. AB isolated the peripheral blood and synovial fluid monocytes, and isolated the RNA after adhesion. BA participated in the design of the study. CB and MS collaborated on the study or coordinated the collection of samples in Birmingham, and contributed to the writing of the manuscript. JM conceived the study, and participated in its design and in the writing the manuscript. All authors read and approved the final manuscript.
The authors are indebted to the patients who kindly agreed to take part in this study. They thank Mr C McGeoch, Mr D Rees, Mr L van Niekerk and Mr S White and the theatre teams for their help in obtaining synovial tissue. They are also very grateful to P Evans, M Pritchard and N Harness for their histological expertise and to J Menage for helpful immunohistochemistry discussion. Finally, the authors thankfully acknowledge the Henry Smith Charity, Droitwich Medical Trust Ltd and the Orthopaedic Institute Ltd for their financial support.
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.


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Director Shankar is all praises for Vishal and Mysskin iThupparivaalan
Kolkata golfer Shankar Das returned with a card of one-under-71 on the final day to emerge victories by one shot at the Kensville Open presented by PGTI on Friday.
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Fuel wrap up weekend with matinee against the Mallards
- Updated: March 19, 2017
Morellis Cleaners Game Preview: Fuel vs. Mallards
Game 63
Sunday, March 19, 2017
3:05 p.m. – Indiana Farmers Coliseum, Indianapolis
Tickets: Ticketmaster, Indiana Farmers Coliseum Box Office
Broadcast Info: CBS Sports 1430, ECHL.TV, @IndyFuel
The Indy Fuel (17-39-3-3) play their third game in as many days Sunday as the Quad City Mallards (35-23-2-2) visit for an afternoon affair at Indiana Farmers Coliseum. It's another Family Fun Day, so fans are invited to take the ice after the game for a free open skate with their favorite Fuel players. Tickets are available through Ticketmaster or by visiting the Indiana Farmers Coliseum box office.
Indy heads into the last game of their weekend tripleheader after splitting a home-and-home set with the Kalamazoo Wings. The Fuel grabbed a comeback victory Friday night at Wings Event Center, before Kalamazoo responded with a 5-1 win Saturday at Indiana Farmers Coliseum. Goaltender Eric Levine kept things close for Indy with a brilliant 40-save performance, before two late goals – one on an empty net – helped the Wings pull away. Jake Marchment accounted for the Fuel's lone goal in the third period, his second tally in as many games.
With just ten games left on their schedule, the Fuel are looking to keep moving in the right direction as they welcome Quad City Sunday. Indy has picked up points in three of its last five games overall, but have only one win from its last 10 games on home ice (1-7-1-1). Sunday is the Fuel's last test at Indiana Farmers Coliseum before the club embarks on a four game road swing, beginning next weekend in Greenville and South Carolina and wrapping up on March 31 in Toledo. As of Sunday morning, Indy is still tied for sixth in the Central Division with the Wichita Thunder with 40 points, though the Thunder have two games in hand.
On the other side, Quad City can clinch a Kelly Cup Playoff berth with a point against the Fuel, or a loss from the Tulsa Oilers. With 74 points, the Mallards are trying to hang on to the third seed in the Central, where they currently sit four points ahead of the Kalamazoo Wings. Quad City is seven points back from the Fort Wayne Komets – its first round opponent if the current standings hold – for second place in the Division.
The Mallards have just one regulation loss in their last eight games (5-1-2-0), and are coming off of a pair of home victories over the Missouri Mavericks this weekend; winning 3-2 on Friday night and 5-0 Saturday. Since Phil Axtell took over head coaching duties on Jan. 20, Quad City is 16-7-2-0. A well-balanced offensive attack is one of the primary reasons for the Mallards' recent success – Quad City has scored three or more goals in six consecutive games and now boasts six players with over 40 points on the season.
Inside the Matchup: The Fuel and Mallards square off Sunday for the ninth of ten times in 2016-17, the fifth of six meetings in Indianapolis. Quad City has won all but one of the first eight games in the season series this year, outscoring the Fuel by a total of 18-4 in the previous three. The Mallards took a 6-1 victory on March 4 in the previous encounter between the two clubs at iWireless Center, and swept a two game set from Jan. 28-29 the last time the two teams met in Indianapolis. Quad City holds a 10-8 edge in the all-time series against Indy, while the Fuel are 5-4-0-0 all time at Indiana Farmers Coliseum. However, Indy is 0-4 against the Mallards on home ice this season.
Mallards forward Chris Francis leads the season series with five goals and six assists in eight games, while Alex Wideman's nine points (3g, 6a) paces the Fuel against Quad City. In six starts against Indy, All-Star goaltender C.J. Motte has compiled a 5-1 record alongside a 2.28 goals against average and a .928 save percentage.
Who to Watch: Forward Jake Marchment (13g, 18a) has scored goals in both games this weekend, tallying the game-tying goal in Friday's win in Kalamazoo before accounting for Indy's lone marker on Saturday … Kenton Helgesen (4g, 14a) provided an assist on each of Marchment's goals, giving the forward one goal and four assists in seven total games played for the Fuel … Over his last five games, Michael Neal (7g, 4a) has racked up six goals and two assists.
Mallards forward Justin Kovacs (15g, 34a) has strung together three goals and 10 assists across his previous eight games … Josh MacDonald (23g, 29a)has marked assists in three of his last four outings, and leads Quad City in scoring with 52 points – 37 of them coming as a member of the Rapid City Rush … Goaltender Adam Vay has picked up the win in each of the Mallards' victories over Missouri this weekend, stopping 59 of 61 shots (.967 SV%).
Worth Noting: Indy enters Sunday with a 1-9-0-0 record this season when playing the the third game in as many days, and are just 1-7 on home ice when closing out a 3-in-3 … Quad City is 4-2 overall this season when playing the final game of a three-game set, including a 2-1 mark on the road … The Fuel are 7-16-1-3 this year against Central Division opponents … Mallards goaltender Adam Vay has allowed two or fewer goals in four of his last five starts … Indy's 87 third period goals allowed is second to only Rapid City (92) … Quad City forward Michael Parks (23g, 25a) ranks seventh in ECHL rookie scoring with 48 points … Forward Woody Hudson and defenseman Jack Burton each made their professional debuts for Indy Saturday night after being added to the roster earlier in the day. Each player finished with a -1 rating, while Hudson registered a shot on net.


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About Us
MantellaMan Conservation was created to help raise awareness about the speces of not just Amphibia, but all Fauna and Flora that is endemic to the island of Madagascar. It has also been created to raise awareness about the Conservation strategies and actions set in place to protect them and the habitats they dwell within.
Of course, information doesnt just cover Malagasy species of Amphibia but also worldwide from all continents.
It also makes me very proud to have the honour of annoucing that, MantellaMan Conservation (MMC) is now an Associate Partner of the International Union for the Conservation of Nature (IUCN) Amphibian Survival Alliance (ASA). It certainly is a huge honour to be able to raise awareness with the worlds largest partnership for Amphibian conservation.
What will we be doing?
- Performing educational talks to Colleges, Schools, Events and Workshop meets about the classification of Amphibia and the conservation of them.
- Providing information through blogging, photography and video documentary.
- Researching insitu in Madagascar (primarily) and various other countries.
- Contributing towards conservation strategies for Amphibians.
If you would like to contact us for the following:
- Educational Posters
- Educational Presentations/Talks
- Information regarding something more specific.
Then please, fill in the required form and we will get back to you as soon as possible.


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Pond Roofing Company Recognized
Pond Roofing Company, a family-owned residential roofing and exterior company in Fairfax, Virginia, was recognized as one of the top 100 roofing contractors in the United States for 2016 by Roofing Contractor, the premier magazine for commercial and residential roofing and insulation.
Patrick Readyhough, president and owner of Pond Roofing, attributed the inclusion of Pond Roofing as one of the country's leading roofing contractors to the demand for quality workmanship and customer loyalty that has never wavered during the company's 52-year-old history. Pond Roofing Company was established in 1964 by the late Bob Pond.
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E C E 271: Circuits Laboratory II
- Catalog Description:
Experiments cover electronic device characteristics, limitations and applications of operational amplifiers, and feedback circuits.
- Credits: 1
- Prerequisites: ECE 270; ECE 340 or con reg
- Official Course Description (pdf)
Moodle and D2L are being retired. Already, many Engineering courses are in Canvas rather than Moodle. Rather than using the Moodle links below, it is recommended that you use the Learn@UW site (learnuw.wisc.edu) to gain access to all of the LSM choices available to campus.
- Engineering Moodle Courses on the Web
- Create an Engineering Moodle Course Homepage (formerly eCOW2)


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Welcome to Patio Records, home of great music, a community of talented and caring artists, and Healing Garden Music Fests – all dedicated to the creation of natural healing environments for people undergoing the rigors of cancer treatments.
Next Up
7th Annual Toronto Healing Garden MusicFest
8:00 PM Oct 14, 2017
Lyric Theatre: Toronto Centre for the Arts
North York, Toronto, Ontario
Lyric Theatre: Toronto Centre for the Arts
5040 Yonge St.tocentre.com
North York, Toronto, Ontario
North York, Toronto, Ontario
$45.00 in advance
$50.00 at the door
$50.00 at the door
(prices in CAD)
Online at Ticketmaster.com (or via the tocentre.com site).
Also available at the TCA Box office in person or by phone: 416-250-3708
Co-Bill featuring stalwarts of great songwriting, musicianship, and performing talents
Headliners are "Tom Paxton and the Don Juans (Don Henry and John Vezner)", and Richmond Hill, Ontario's own "The Good Brothers".
Tom Paxton and the Don Juans
The Good Brothers
21st Annual Greater Waltham Healing Garden Benefit Concert
7:30 PM Oct 21, 2017
French American Victory Club
Waltham, Massachusetts
French American Victory Club
193 Elm Streetfavclub.org
Waltham, Massachusetts
United States
(781) 899-8195
Waltham, Massachusetts
United States
(781) 899-8195
$20.00 in advance
$25.00 at the door
$25.00 at the door
(prices in USD)
Tickets available online at http://www.brownpapertickets.com/event/3058749 , and soon at the French Club or Marcou Jewelers. (Stay tuned).
Cathy Fink & Marcy Marxer
Irene Kelley
Edmond Boudreau
Scott Neubert
Sam Gleaves
Kelly Hill


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Anika Dali Women's Solid Color Premium Best Quality Pashmina Shawl (20 COLORS)
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Product description
Special Sale. Limited quantities. Premium Pashmina Scarves by Anika Dali.
Luxurious and premium quality pashmina scarves / stoles / shawls perfect for all-season use (work or play).
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Wrap yourself in soft pashmina shawls during cold winter months.
100% Pashmina Viscose. Size: Approx. 28" x 70". 3" twisted fringe. Imported. By Anika Dali.
Disclosure: Authentic traditional Pashmina refers to a type of fine cashmere wool and the scarves made from it, which can sell for hundreds if not thousands of dollars per piece. In recent times, however, the term 'Pashmina' has gained popularity in the online marketplace and is being used a substitute for the soft and economical 100% Viscose fabric. Our Pashmina is 100% super soft high quality Viscose (soft like silk, warm like wool), in addition, we also carry high quality fine cashmere at a premium.
- Package Dimensions: 10.8 x 8 x 1.4 inches
- Shipping Weight: 2.4 ounces (View shipping rates and policies)
- Item model number: 121012
- Date first available at Amazon.com: August 31, 2012
- #741 in Clothing, Shoes & Jewelry > Women > Accessories > Scarves & Wraps > Wraps & Pashminas
- #365319 in Clothing, Shoes & Jewelry > Women > Shops
- Average Customer Review:
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So I wouldn't necessarily recommend this pashmina for embroidery, but it is lovely! If it didn't have 6 embroidered letters on it I'd definitely be wearing it!
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Knitters can previously build all kinds of gifts. We all have taken their vacations scarves, winter hats, and bulky fluffy sweaters. So, when it's time to gift the enduring gifted, you get worried that what is the best gift for them.
Best Gift Ideas For Knitters
So, here are the cool gifts you can give to any knitter and they will truly like your this type of gifts. For more gift ideas, visit Giftbeta.
1. Loom Set:
You should gift a plastic loom set to the knitters. Knitting is not referred to cold weather appurtenances, that you know. The fantastic plastic loom set is the perfect gift for knitters, and they will like it.
These beautiful hovers assist in the formation of dollies, doll skirts, rounded hats and whatever more that the designer can provoke. It is in featherweight and simple to grasp.
2. Weaving Bowl:
Rubberized Weaving Bowl is the best gift that you can give to any knitter. Because these knitting bowls are the necessity for families with little, enthusiastic, child hands analyzing each corner, so the pottery bowls might not be a perfect concept.
It is a trendy lightweight bowl with rubber below protecting the bowl from slipping on soft shallows. This rubberized knitting bowl is such a mindful gift for the fast knitting mommy.
3. Scissors:
You can also gift collapsible scissors to the knitters. Because a knitter requires accurately pointed scissors, but nobody needs the pointiest. Cutting scissors just secular over in their squishy, comfy knitting nest.
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Funeral held for Minister Bernadine Layton, survivor of 16th St. Baptist Church bombing
Minister Bernadine Layton, who was well-known as one of the survivors of the 1963 16th Street Baptist Church bombing in Birmingham, died Jan. 10 and a "Homegoing" service for her was held at noon Saturday.
Those who knew her say she had a forgiving spirit, even forgiving those responsible for the bombing that killed four young girls.
Layton dedicated her time as the spokesperson for the Re-digging of the Wells Ministries to introduce people to religion in a non-denominational format.
Family and friends attended her service at Living Church Ministries on Omega Street in Birmingham.
You can read Bernadine's obituary here.


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Our VALUE Process
Successful businesses require great processes – and the same is true for successful families. At Spurstone, our comprehensive approach starts by employing a diagnostic advisory process that involves establishing your family vision. Through this process, we seek to understand your unique family needs, evaluate concerns and formalize goals to serve as a basis for all future action.
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We will focus on who you are and how you envision your family's financial future. We will help identify specific family goals and arrange them by timeframe and priority.
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Wednesday, 2 August 2017
Thursday, 27 July 2017
term 2 bookreview
fat four eyed and useless
the story is about Ben how he was called fat four eyed and useless. he was never good at sport he didn't enjoy anything but then he found out that he was really good at writing he joined the writers group. as a event for the writers group he went to the juniors/ankle biters he calls then that because they are short. He had to read to them his kid stories.
i enjoyed this book because it was fun to read and it was interesting how all of this stuff happen to him
the story is about Ben how he was called fat four eyed and useless. he was never good at sport he didn't enjoy anything but then he found out that he was really good at writing he joined the writers group. as a event for the writers group he went to the juniors/ankle biters he calls then that because they are short. He had to read to them his kid stories.
i enjoyed this book because it was fun to read and it was interesting how all of this stuff happen to him
Tuesday, 4 July 2017
Monday, 3 July 2017
Current Events Term 2, 2017
- Year7/8: I can use appropriate skills and technologies to find and use a range of texts for specific purposes.
Each week we have read a short text about a current event/ topic. We then formed questions based on what we had read. After this we researched the answers to our questions and finally we gave our opinions on what we had found out.
Here is some evidence of my learning.
My Next Step is to continue to apply the reading and research skills that I have learned in a variety of other areas.
Monday, 26 June 2017
Careers Education C.V. Writing
In CAREERS EDUCATION we have been learning to write a skills based Curriculum Vitae.
A skills based C.V. focuses more on the skills that we have, rather than our work history.
Here is a link to our online Modelling Book that shows the process we have followed.
Three things that I have learned about writing a Curriculum Vitae are:
- that you have to get your punctuation, spelling, capital letters and full stops
- but respectful thing in your cv to get a good reputation
- not to write fake things about you
Here is a link to my Skills based Curriculum Vitae. (Link your C.V. here)\
Saturday, 6 May 2017
Use simple fractions and percentages to describe probabilities
Question 1:
Show your working and answer here:2/6 or ⅓ because there are 6 possibilities and 2 chances of penny getting her choice of toppimng.
Question 2:
Show your working and answers here:
2ams mataira has to use $4 by buying four bubble gum
2b ms mataira has to use $6 buying six bubble gum
2c:mr smith has to use $9 by buying 9 bubble gum
Question 3:
Show your working and answer here:
Thursday, 4 May 2017
Term 1 Book Review
fire in the sky
This story is about… the pink and white terraces that erupted in June 10, 1886, the volcano erupted and they thought it was a earthquake but it was going to long. So they didint know what it was so they run outside up the hill and saw the fire in the sky. Mud from the volcano it was up to there knees they had to get away from it. my opinion on this book is all right it takes awhile to get to the good parts. If you like long stories i would recommend it to you
Wednesday, 12 April 2017
Current Events Term 1
Current Events Term 1
In Current Events I covered these topics:
- The design of the Halswell Skate Park and I made a submission to the council.
- Donald Trump's Refugee Plan
- Christchurch Earth Memorial
- The new Ngā Puna Wai Sports Facility
- The Red Zone and Avon River Regeneration Plan with a submission to the council.
My favourite topic was The design of the Halswell Skate Park and I made a submission to the council. ...because… i like looking at designs and getting involved in them and i like skate parks
Here is a link to my learning on the Red Zone and Avon River Regeneration Plan.
The Reading National Standards I have achieved are
- Year 7 and 8
- Identifying and resolving issues that come from competing information in texts
gathering, evaluating, and synthesising information across a small range of texts
- I can use appropriate skills and technologies to find and use a range of texts for specific purposes.
Tuesday, 11 April 2017
Term 1 Novel Study
Term 1 Novel Study
This term I have been reading and studying the novel fire in the sky
I found this novel ok because… it was not as interesting as i thought
During the novel I had to complete two major assessment tasks. The first is an Explain Map which shows the consequences of a major event in the book. The second was a Describe++ Map (Inference map) which shows I how I have connected prior knowledge and other experiences to what I have been reading to make an inference.
- Link to Explain Map
National Standard this covers
- Year 7/8 Standard
- using several pieces of information to make inferences
using their prior knowledge, along with information in the text, to interpret abstract ideas, complex plots, and sophisticated themes
- I can use a range of strategies, such as inferring, to work out more complex words.
Monday, 13 March 2017
Writing Leadership Article
In writing I have been learning to:
- use all basic punctuation independently
I have been especially focussing on using parentheses and commas. I have highlighted these in green where I have used them as well as other punctuation that I changed because it was used incorrectly. Here is a piece of my writing that shows this
Leadership is a skill of being able to motivate people/teams to work towards a goal. There are 6 traits of an effective leader: Integrity, Trustworthy, Resilient, Goal focused, Active Thinker, Motivational. My key leadership role for 2017 is head pal. This means that each day i have to write who is doing there duty on that day And remind them to do their duty. In order to be a good head pal I need to show the effective leadership traits in my role.
One of the leadership effective traits is motivational means the act or process of giving someone a reason for doing something. Shane van gisbergen he wants people to me motivated to do what you love. I want people to play games and try not to get people board in games my games i will show that by doing different games each day and mix up the rules. how will i demonstrate this leadership trait in my role by getting people to make their own games at lunch time. So people don't get in trouble. You also need to be trustworthy because you can cheat and you would be biased
One of the leadership traits of an effective leader is being trustworthy. Being trustworthy means that you can be relied upon to do what is needed or right. Jamie whincup he has never cheated and a race so he is being trustworthy. I need to turn up to my duty so i have to be trusted to do that. And can not be biased because that would not be fair and people will leave. Goal Focused is A person or a group who works hard to achieve results they have set.
Goal Focused is A person or a group who works hard to achieve results they have set.
Sam johnson he started a Facebook page which evolved into the Student Volunteer Army and the Volunteer Army Foundation Charitable Trust. Both are incredible team projects. Important to be goal focussed my goal good is to make sure people enjoy the game and turn up to duty. I will demonstrate this by just turning up and choose interesting and fun games mix it up for people.
Overall to be a good leader I need to show these effective leadership traits motivational,goal focused and trustworthy. I will make sure I show these
These leadership traits to be an effective leader.
Games with minimal or no equipment.
In PE we have been participating in a variety of games that require little or no equipment.
Below is the Matrix which shows our progression in this unit of learning.
The table below shows my understanding of games with minimal or no equipment.
(Fill this table in, in as much detail as possible. )
Examples of Games that need minimal or no equipment.
What equipment would we usually need to play these games.
Why do we play games with minimal or no equipment?
|invzilbl tag
|esay to set up and do not have to find a lot of stuff
My Strengths.
Some things that I have done well during this unit of learning are getting involed …………..because………..it is fear
My Next Steps.
Some things I could improve on when playing games with minimal or no equipment are to use no equipment……. Because…………… esay to play and dont have to take a long time to get equipment
Posted by Lindsay at 17:56 No comments:
Labels: PE
Thursday, 2 March 2017
Find factors of numbers to 100 and common multiples of numbers to 10 Assessment task
WALT: Find factors of numbers to 100 and common multiples of numbers to 10
Assessment Task:
1. Find all the factors of 16
The factors of 16 are: 1 2 4 8 16
2. Find all the factors of 20
The factors of 20 are:1 2 4 5 10 20
3. Fill in the missing factors below:
Here are the 3 screenshots to my IXL activities:
My next step is: to get it done faster
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Internal Sales Consultant
Our client based in Bourne End is looking to recruit a professional, personable Internal Sales Consultant to manage new and existing accounts and work with the external sales team, concentrating on a designated territory.
This role will also be focusing on setting up appointments for the external sales team and updating CRM on a daily basis so all pipelines are completed for month end reporting
Our client offers 25 days holiday, free parking and a generous basic salary of up to £25000 plus a bonus structure after completion of 6 month probation period. Working hours of 8.30am - 5pm.
Primary responsibilities
· Identify opportunities within existing accounts to generate growth
· Manage follow up of existing customers, prospects and quotations on a systematic basis
· Build good relationships with contacts to maintain existing accounts
· Monitor the overall sales performance of the account base assigned and take corrective actions to meet the agreed sales budget requirements
· Support with incoming customer calls and assist with enquiries
· Organise trial appointments for the external sales team
· Identify new business opportunities to generate new accounts, inclusive of cold calling
· Previous experience in a similar role - B2B Telemarketing/Inside Sales
· Has a professional and friendly telephone manner
· Takes pride in ensuring exceptional customer service at all times
· Meticulously organised with the ability of managing multiple tasks simultaneously
· Ability to work well under pressure, and manage own workload
· Has an honest, respectful and diligent approach to work with a strong sense of integrity
· A positive, solutions orientated attitude is essential
Please note that we will only contact those candidates that we assess as suitable for the positions we have currently available based on their experience, training and skills that they identify. If you do not hear from us within 5 working days from your registration, please accept our apologies but we are unable to help you on this occasion.
Bucks and Berks Recruitment is an equal opportunities employment agency and employment business that is serious about its compliance with legislation. Bucks and Berks is acting as an Employment Agency in relationship to this role (if the vacancy is for a permanent position) or is acting as a Recruitment Business in relationship to this role (if the role is for a temporary position).


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series asking some of our favorite San Francisco food people about the
dish they just can't celebrate Thanksgiving without.
Knowing that Roger Feely, aka Soul Cocina, has traveled and worked all over, SFoodie suspected that, when we interviewed him about his essential Thanksgiving dish, it wouldn't be candied yams with marshmallows.
Feely: I don't really celebrate Thanksgiving on a huge scale. I'm into
traditions, but not really into the source of the holiday. But I often
celebrate Thanksgiving with family, and they demand turkey. Since I don't
like roasting turkey, I make something different. It's like the
The dish I make the most offten is relleno negro, a dark turkey mole
from the Yucatan. It's a bunch of charred chiles ― moritos, chiles
negros, puyas ― with charred seeds and nuts that are ground to make a
really dark mole. I make it with a turkey stock, and then it's basically
a thick turkey soup.
I use the dark meat to make a sausage with coagulated pork blood, and in the center of the blood sausage is boiled eggs. We poach that in the turkey stock. The white meat gets slowly cooked and shredded, and the sausage is sliced into thick disks. Then everything is served in the black mole. (You can see pictures of last year's relleno negro on Soul Cocina's blog.)
it's a dish that I read about a bunch of times, and began making. but it wasn't until Poc-Chuc opened that I had a chance to try the original dish. Just by chance, mine turned out really similar to the way they did it. I always have lots of different family members that I celebrate Thanksgiving with ― relatives from Ireland, Chicago, San Diego, South Carolina ― and they're into it. For some people, it's too spicy, but my sister in San Diego and her kids enjoy it a lot.
Other Thanksgiving essentials in this series:
-Jonathan Kauffman's Brussels sprouts with prosciutto
-Jun Belen's stuffing balls
-John Birdsall's braised turkey legs with polenta


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Nike SB Performance Trucker Hat
PacSun presents the Nike SB Performance Trucker Hat. This unique cap comes a ventilated rear, an adjustable snapback panel, and a raised Nike SB logo sewn on front of a solid color base.
- Solid trucker hat
- Raised Nike SB embroidery on front
- Mesh rear
- Embroidered eyelets
- Flat bill
- Adjustable snapback panel
- One size fits most
Sku # 0641236759243
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Ratings & Fit Summary


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Vodacom said the purchase would give it an edge on Safaricom's successful M-Pesa offering East Africa while cementing its grip on its home market for the year ended March.
Vodacom, which is majority owned by British based Vodafone, yesterday said that the deal with Safaricom would make it a dominant player in the region and provide it with access to an additional 28.1 million customers.
Read also: Vodacom launches Thetha Nathi app
Shameel Joosub, Vodacom group chief executive, said the deal would create further incremental value through close co-operation, particularly in driving M-Pesa adoption across its operations.
"This is an exciting occasion for Vodacom and a unique opportunity to diversify our revenue growth and profitability," Joosub said. "Acquiring a strategic stake in Safaricom will provide our shareholders with access to a high growth, high margin, and high cash generation business operating in a high growth market."
Vodacom is to fund the acquisition by issuing 226.8 million new ordinary shares. Under the terms of the deal Vodacom will transfer a 35 percent stake in Safaricom to its Johannesburg-based unit, getting stock in return that raises its Vodacom stake to about 70 percent.
M-Pesa is a mobile phone-based money transfer, financing and microfinancing service that was launched in 2007 by Vodafone for Safaricom and Vodacom.
Vodacom shares rose 0.24 percent on the JSE on Monday to close at R152.86.


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Children's Privacy Policy
We are dedicated to protecting your child's online privacy with respect to our handling of any personal information we may collect. This Policy is provided below to explain (1) the types of personally identifiable information we may collect with respect to children under the age of 13; (2) how we use the personally identifiable information; (3) how we notify parents that a child's personally identifiable information has been provided, and; (4) how parents can restrict their child's future participation with the ArtsRising website (the "Website").
1. Types of Personally Identifiable Information
Children under the age of 13 are free to access the Website without any personal information being collected, aside from those passive means of collecting non-identifiable information outlined in the ArtsRising Privacy Policy. The Website permits children to supply us with their first name, last name, age, and their e-mail address on a fill-in browser form for the purpose of subscribing to our newsletter or receiving other information about ArtsRising or its affiliates via e-mail. Additionally, if a child indicates that he or she is under the age of 13, the child will be required to provide an e-mail address for a parent or a guardian (the term "Parent" used hereinafter is to be inclusive of legal guardians).
2. How we use the Personally Identifiable Information
Personally identifiable information collected from a child under the age of 13 is strictly used for internal purposes and never shared with parties not related to ArtsRising or its affiliates, except as may be required to comply with the law, to enforce our Terms of Service, our Privacy Policy, or to protect the safety and security of our Website and its visitors. The child's first and last name are used to send personalized correspondence and/or newsletters via the provided e-mail address to the child with respect to ArtsRising activities and ArtsRising affiliates. The child's stated age is used to permit us to comply with this policy.
3. How We Notify Parents that a Child's Personally Identifiable Information has been Provided
If a child indicates that he or she is under the age of 13, the child will be asked to provide the e-mail address for a Parent during their registration process. We will then send an e-mail to the Parent at the given address to notify the Parent of their child's desire to receive e-mail correspondence and newsletters from ArtsRising, along with a link to this Policy. If an e-mail sent to a Parent is returned as undeliverable, we will not permit the child to receive subsequent newsletters or correspondence and we will delete the child from our mailing list so as to prevent the child from receiving subsequent e-mail from ArtsRising.
4. How Parents Can Restrict their Child's Future Participation with the ArtsRising Website
Parents can request that their child's personal information be deleted by the Website operator so that children will not receive subsequent newsletters or correspondence. Such requests can be sent via mail to ArtsRising, c/o The Philadelphia Education Fund, 1709 Benjamin Franklin Parkway, Suite 700, Philadelphia, PA 19103. Upon receipt of such request, ArtsRising will delete a child's personal information and remove him or her from any ArtsRising mailing lists. After a child's personal information is deleted, he or she will remain free to visit the Website and may elect to provide their personally identifiable information again, thereby restarting the notification procedures referenced herein.
We may amend this Policy at any time. We will provide notice on the Website and to parents via e-mail if there are any material changes in the way we intend to collect, use and/or share personal information on the Website. Parents are asked to provide us with their current e-mail address at all times. Parents are also advised to review our Terms of Service and our Privacy Policy for additional information pertaining to our Website.
The name and contact information of the Website operator collecting and maintaining personal information collected in conformity with this policy is as follows:
The Philadelphia Education Fund
1709 Benjamin Franklin Parkway, Suite 700
Philadelphia, PA 19103


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Hatha Yoga Teaches a Natural Mode of Living
Yogi does not have to get back to Nature, for he is already there, and has not been dazzled and befooled by the mad rush...
Hatha Yoga is that branch
of the Yoga Philosophy which deals with the physical body— its care— its well— being— its health— its strength- and all that tends to keep it in its natural and normal state of health.
read more
A Series of Lessons in Raja Yoga by Yogi Ramacharaka
The trained Will exhibits itself in a tenacious Attention, and this Attention is one of the signs of the trained Will...
As man advances
in development, his consciousness passes from the lower planes to the higher, and he becomes more and more aware of his higher nature. The spirit contains within it all potentialities, and...
read more
A Series of Lessons in Gnani Yoga by Yogi Ramacharaka
Each branch of Yoga is but a path leading toward the one end--unfoldment, development, and growth.
Every person who
wishes to develop by "knowing"--by studying the fundamental principles, and the wonderful truths underlying Life, follows the path of "Gnani Yoga."
read more
14 Lessons in Yogy Philosophy by Yogi Ramacharaka
Prana is not the Ego, but is merely a form of energy used by the Ego in its material manifestation...
This transfering of Prana under
the direction of the will is the underlying principle of thought transference, telepathy, etc. One may surround himself with an aura of Prana, colored with strong positive thought...
read more
An Introduction to Yoga by Annie Besant
Yoga is an applied science, a systematized collection of laws applied to bring about a definitive end.
Yoga takes up the laws of
psychology, applicable to the unfolding of the whole consciousness of man on every plane, in every world, and applies those rationally in a particular case.
read more
The Hindu-Yogi Science of Breath by Yogi Ramacharaka
Life is absolutely dependent upon the act of breathing. "Breath is Life."
Breathing may be considered
the most important of all of the functions of the body, for, indeed, all the other functions depend upon it. Man may exist some time without eating; a shorter time without...
read more
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Gasoline prices surge to $2.61 a gallon in Pittsburgh regionAugust 7, 2017 11:32 AM
The average price of gasoline in the Pittsburgh region increased 4 cents a gallon in the last week to $2.61 on Monday, according to GasBuddy's survey of more than 700 stations in southwestern Pennsylvania.
It was the third consecutive week of increasing pump prices in the region after gasoline slowly but steadily declined for much of May, June and July.
Meanwhile, the average price nationally increased 2 cents during the week to $2.34 a gallon, GasBuddy reported.
The increases are normally larger and more frequent during the summer months, when motorists usually see the most expensive fuel prices of the year. Most years, seasonal pressures push up gasoline prices during summer months as demand from motorists typically rises with warmer weather.
Each spring, average U.S. gasoline prices rise 35 cents to 75 cents, usually from February to May, according to GasBuddy's historical figures. Last year, Pittsburgh-area prices increased 73 cents from February to June.
This year, regional prices sit around about what they were at the beginning of the year.
Pittsburgh prices — as well as prices across the country — have been weighed down by slumping global oil prices, which are the biggest factor in U.S. gasoline prices. The global oil price benchmark fell as low at $42 a barrel in June.
In recent weeks, however, oil prices have staged a minor rally as oil producing countries try to cut production to bring supply back in line with demand. Political turmoil in Venezuela, a major oil producer, also contributed to boosting prices to $52 a barrel last week.
Patrick DeHaan, senior petroleum analyst for GasBuddy, said gasoline prices are likely to keep rising.
"For the third straight week, gasoline prices have accelerated with the national average at its highest level in over eight weeks, driven by rising oil prices as inventories continue to tighten and concern over Venezuela," said "We're likely to see gas prices continuing to move higher in the week ahead."
Pittsburgh-area gasoline is higher than in most of the country. Pennsylvania has the eighth-most expensive price per gallon, in part because the state has the highest fuel taxes in the country, according to GasBuddy.com.
Compared with previous years, the region's pumps are on average 31 cents more expensive than this time one year ago; 18 cents cheaper than this time in 2015; and $1.08 cheaper than this time in 2014.
Daniel Moore: firstname.lastname@example.com, 412-263-2743 and Twitter @PGdanielmoore.


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Very SAD Story which make you cry New Reading List. Vote Romance #death #destroyed #love #sad #which. Very SAD Story which make you cry 123K 189 111. What can music do for you?. Listening to different music can make you feel lots of different things, sad If you enjoyed this essay. Why Facebook Makes You Feel Bad About Yourself. By Alexandra Sifferlin @acsifferlin Jan. 24 Why You're More Likely to Remember A Facebook. Sad Short Stories That Will Make You Cry. Sad Stories That Will Make You Cry (short) By victoriarose933. 18K 548 123. Sad Stories that will Touch your heart. Tell Us What Makes You Happy. How do you look for fulfillment—and does what you do work. This is the HR interview questions and answers on "What makes you angry?". Home Aptitude Logical Reasoning Verbal Ability GK Engineering Interview Online Test.
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5 Questions to Discover Who You Are and What Will Make You Happy. What makes you genuinely happy?. you're sad because you're poor and hungry. Why Am I So Sad? KidsHealth. How sad you feel can depend on the situation that's causing the sadness and how you're coping with it A problem makes you sad. Studies suggest that browsing Facebook can make you unhappy, says Justin Mullins. Why might that be?. Can it really be possible that Facebook makes you sad. Free Essays on Essay Talks About About Thing Makes U Happy And Sad. Bullying Essay. Frightened, Weak, Sad, Unwanted. You end up not wanting. What makes you smile essay what makes you smile essay Professional Paper Writing. The next time someone is feeling sad, scared, nervous, whatever it may. Wiki How to Write a Dark or Sad Story. Two Methods: Sample Stories Writing Your Own Story Community Q&A how would you feel? Be sure that your work makes.
Self-Acceptance is the Key to Happiness. What makes you happy and what makes me happy are. F Free Essays G-L Free Essays M-Q Free Essays R-Z Essay. Why Does Music Make Us Feel?. 30 subjects were presented with a series of happy or sad musical. (The sound of running makes us wonder what we're running. Essay. sad or depressed" and "I. So maybe it's true that talk is the reason having a sister makes you. How happy are you? Test your emotional intelligence quotient. What makes people. Having a positive outlook doesn't mean you never allow yourself to feel sad. These movies don't just have a few sad moments but several studies have shown that keeping busy mentally makes you happier than just lying around on the beach. What makes you happy? I'm not talking deliriously happy, like skipping down the street, but just a general feeling of contentment with the world around you.
What makes you happy? What makes you sad? What makes you happy? What makes you sad? PollWhat makes you happyand what makes you sad. What makes you happy?. Overall thanks for a nice essay and let us know what you are writing it for. All RSS. Forum Timezone: Asia/Bangkok. Most. Touchy, sad Essay topics? yahooo Registered User Posts: 1,386 Senior Member If you write something about a sad challenge that you faced. What Article Headline Makes You Laugh Every. 10 Sad Stories That Will Make You Cry This one was just included to make you feel better about everything you. Happy and the sad causing. You can order a custom essay on Sadness now! Posted by Webmaster at 2:12 AM. Labels: college essay on sadness, essay. Why Music Makes You Happy. according to new research. When you listen to tunes that move you, the study found, your brain releases dopamine. Things that make me sad !!! 28-mar-2011 Things. Below is an essay on "Things That Make Me Sad" from. Bullying makes me sad because you see how upset the.
Tips for Scholarship Applications and Personal Essays*. you have to tell the judges what makes you a. writing a winning essay. Of course, you have to make sure. I'm Not Sad About Prince. you didn't grow up hooked on. Casey's Top 40 hit list from last Sunday night makes you an even odder duck than you. It will only lead to sad endings and you can't bring that to the bank and make you happy The people around will appreciate your work, which makes you feel proud. Why Sadness is the Key to True Happiness something written by the philosopher Anthony Grayling in an essay about. life makes you sad all the. Sad Story included in Essay?. is certainly troubling and rather sad. Make sure the essay is about how you. I think you should write about something that makes. Being rich makes you feel smarter and better than the rest of the world, and that feels good. Sometimes you don't need to write a lot to express a feeling. This category is for sad poems when just a few lines will do. Feelings are not complex.


text: Ryan A Report post Posted February 6 Hi all, Open forge at Marshall's will resume 02/13. These are every Monday at 7:00. Marshall's address is in the NJBA newsletter, or PM me for details. We hope to see you there! -Ryan Share this post Link to post Share on other sites


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Joseph P. Kennedy II
Joseph Patrick "Joe" Kennedy II is an American businessman and politician who is a member of the Kennedy family. Wikipedia*
On the C-SPAN Networks:
Joseph P. Kennedy II has 314 videos in the C-SPAN Video Library; the first appearance was a 1987 House Proceeding. The year with the most videos was 1995 with 55 videos. The year with the highest average number of views per program was 2009 with an average of 5,169 views per program. Most appearances with Ted Kennedy (16), Richard A. Gephardt (5), David E. Bonior (5). Most common tags: U.S. History, Democratic National Convention, Kennedy, John F..