text:
Vascular involvement in rheumatic diseases: 'vascular rheumatology'
- Zoltán Szekanecz1Email author and
- Alisa E Koch2, 3
DOI: 10.1186/ar2515
© BioMed Central Ltd 2008
Published: 10 October 2008
The vasculature plays a crucial role in inflammation, angiogenesis, and atherosclerosis associated with the pathogenesis of inflammatory rheumatic diseases, hence the term 'vascular rheumatology'. The endothelium lining the blood vessels becomes activated during the inflammatory process, resulting in the production of several mediators, the expression of endothelial adhesion molecules, and increased vascular permeability (leakage). All of this enables the extravasation of inflammatory cells into the interstitial matrix. The endothelial adhesion and transendothelial migration of leukocytes is a well-regulated sequence of events that involves many adhesion molecules and chemokines. Primarily selectins, integrins, and members of the immunoglobulin family of adhesion receptors are involved in leukocyte 'tethering', 'rolling', activation, and transmigration. There is a perpetuation of angiogenesis, the formation of new capillaries from pre-existing vessels, as well as that of vasculogenesis, the generation of new blood vessels in arthritis and connective tissue diseases. Several soluble and cell-bound angiogenic mediators produced mainly by monocytes/macrophages and endothelial cells stimulate neovascularization. On the other hand, endogenous angiogenesis inhibitors and exogenously administered angiostatic compounds may downregulate the process of capillary formation. Rheumatoid arthritis as well as systemic lupus erythematosus, scleroderma, the antiphospholipid syndrome, and systemic vasculitides have been associated with accelerated atherosclerosis and high cardiovascular risk leading to increased mortality. Apart from traditional risk factors such as smoking, obesity, hypertension, dyslipidemia, and diabetes, inflammatory risk factors, including C-reactive protein, homocysteine, folate deficiency, lipoprotein (a), anti-phospholipid antibodies, antibodies to oxidized low-density lipoprotein, and heat shock proteins, are all involved in atherosclerosis underlying inflammatory rheumatic diseases. Targeting of adhesion molecules, chemokines, and angiogenesis by administering nonspecific immunosuppressive drugs as well as monoclonal antibodies or small molecular compounds inhibiting the action of a single mediator may control inflammation and prevent tissue destruction. Vasoprotective agents may help to prevent premature atherosclerosis and cardiovascular disease.
Vessels and the vascular endothelium are involved in the pathogenesis of inflammatory rheumatic diseases. Rheumatoid arthritis (RA) serves as a prototype of these diseases as it is the most common type of arthritis and a great body of data is available regarding leukocyte recruitment into the synovium, angiogenesis, and accelerated atherosclerosis. The term 'vascular rheumatology' has been accepted by many investigators and includes both microvascular and macrovascular involvement in rheumatic diseases. Apart from RA, systemic lupus erythematosus (SLE), systemic sclerosis (SSc), the antiphospholipid syndrome (APS), and systemic vasculitides have been associated with vascular inflammation, altered angiogenesis, and increased cardiovascular morbidity and mortality. In this review, we will discuss the most relevant information on arthritis-related vascular inflammation, including the role of endothelial cells (ECs), endothelial adhesion molecules (CAMs) and chemokines, as well as the involvement of neovascularization and some aspects of accelerated atherosclerosis in rheumatic diseases. We will discuss RA in more detail, and other connective tissue diseases described above will also be mentioned. Finally, some aspects of vascular targeting in rheumatology will also be briefly summarized.
Endothelial biology and leukocyte trafficking through the vessel wall
Vascular permeability and vascular damage underlying inflammation
Some important inflammatory mediators released by vascular endothelial cells
Monocyte chemoattractant protein-1/CCL2
Growth-regulated oncogene-alpha/CXCL1
Growth factors
Endothelial cell-derived growth factor
Transforming growth factor-beta
Colony-stimulating factors
Granulocyte colony-stimulating factor
Granulocyte-macrophage colony-stimulating factor
Platelet-activating factor
Nitric oxide
Prostacyclin (PGI2)
Intercellular adhesion molecules in arthritis
Relevant members of the selectin, integrin, and immunoglobulin adhesion molecule superfamilies
Adhesion receptors
L-selectin (CD62L, LAM-1)
Sialylated carbohydrates, GlyCAM-1
E-selectin (CD62E, ELAM-1)
P-selectin (CD62P, PADGEM)
Sialyl-Lewis-X, other carbohydrates
β1 integrins
Laminin, collagen, fibronectin
α4β1 integrins
Fibronectin, VCAM-1
β2 integrins
β3 integrins
Vitronectin, von Willebrand factor, other matrix molecules
Immunoglobulin superfamily
αLβ2 (LFA-1), αMβ2 (Mac-1, CR3)
α4β1, α4β7
PECAM-1, αVβ3 integrin
Chemokines and chemokine receptors in synovial inflammation
Chemokine receptors with ligands relevant for arthritis and angiogenesis
Chemokine receptor
Chemokine ligand
CXC chemokine receptors
IL-8/CXCL8, ENA-78/CXCL5, groα/CXCL1, CTAP-III/CXCL7
IP-10/CXCL10, PF4/CXCL4, Mig/CXCL9, ITAC/CXCL11
C-C chemokine receptors
MIP-1α/CCL3, RANTES/CCL5, MCP-3/CCL7, MPIF-1/CCL23
MIP-3β/CCL19, SLC/CCL21
C chemokine receptors
C-X3-C chemokine receptors
Fractalkine/CX3CL1 has also been detected in RA synovial tissues [19]. Fractalkine/CX3CL1 has also been implicated in the development of accelerated atherosclerosis [18], a topic discussed later. Chemokines bind to their seven-transmembrane domain receptors expressed on the target cells [12, 18]. Some of these receptors have numerous chemokine ligands whereas others are specific receptors for single ligands [14]. Chemokine receptors have also been associated with various histological subtypes of inflammation. For example, whereas CXCR3 and CCR5 may be involved primarily in Th1 type diseases (such as RA), CCR3, CCR4, and CCR8 may play a role in leukocyte migration underlying Th2 type inflammation (such as asthma) [11]. Most CXC and CC chemokine receptors mentioned above as well as XCR1 and CX3CR1 are expressed in the arthritic synovium [14, 17, 18].
The process of leukocyte recruitment into inflamed tissues
Leukocyte adhesion to ECs occurs following a cascade of events. White blood cells in the bloodstream weakly adhere to the endothelium lining the inner vessel wall (tethering) followed by rolling of leukocytes on the endothelial layer. Tethering and rolling are mediated primarily by selectins and their ligands. These events are followed by leukocyte activation, which is dependent upon interactions between chemokine receptors expressed on leukocytes and proteoglycans on ECs. Activation-dependent firm adhesion occurs next, involving α4β1 integrin/VCAM-1 (vascular cell adhesion molecule-1), β2 integrin/ICAM-1, and JAM/integrin interactions. This is associated with the secretion of chemokines. These chemokines may also upregulate integrin expression on the adhering cells via PI3K (phosphatidylinositol 3-kinase)- mediated pathways. Leukocyte diapedesis through the endothelial layer involving integrins occurs when chemokines bind to endothelial heparan sulphate. Chemokines preferentially chemoattract EC-adherent leukocytes. These processes lead to the transmigration of leukocytes into the inflamed tissue [1, 8].
Targeting of cell adhesion, chemokines, and leukocyte recruitment
Inhibition of cell adhesion, chemokines, and migration using specific antibodies or purified ligands has provided an important perspective on the molecular pathogenesis of RA. In addition, some of these strategies may be included in the future therapy of arthritis [20]. Regarding anti-CAM trials, an anti-human ICAM-1 antibody (enlimomab) was tried in refractory RA with little success [2, 20]. Other antiadhesion strategies have been introduced into the treatment of other inflammatory diseases. For example, efalizumab (anti-LFA-1) and alefacept (LFA-3-Ig fusion protein) have been tried in psoriasis, natalizumab (anti-α4 integrin) in multiple sclerosis and Crohn disease, and an anti-α4β7 integrin monoclonal antibody in ulcerative colitis [2, 3, 20]. These and other anti-CAM strategies may be tried in arthritis as well [2, 3, 20]. Chemokines and chemokine receptors can be targeted in a number of ways. Disease-modifying antirheumatic drugs (DMARDs) and anti-TNF biologics, currently used in the treatment of RA, may indirectly influence chemokine production [18]. Antibodies to IL-8/CXCL8, ENA-78/CXCL5, CXCL16, MIP-1α/CCL3, MCP-1/CCL2, and fractalkine/CX3CL1 have been used to control arthritis in various rodent models [18–20]. Several oral chemokine receptor antagonists, including CXCR2, CXCR4, CCR1, CCR2, and CCR5 inhibitors, have been tried in human RA as well as in animal models of arthritis [18, 20–22].
Angiogenesis and vasculogenesis in rheumatic diseases
The processes of angiogenesis and vasculogenesis
Some angiogenic and angiostatic factors in arthritis
IL-8/CXCL8, ENA-78/CXCL5, groα/CXCL1, CTAP-III/CXCL7, SDF-1/CXCL12, MCP-1/CCL2, SLC/CCL21, MPIF/CCL23, fractalkine/CX3CL1
PF4/CXCL4, IP-10/CXCL10, Mig/CXCL9, SLC/CCL21
Matrix molecules
Type I collagen, fibronectin, laminin, heparin, heparan sulphate
Thrombospondin, RGD sequence
Cell adhesion molecules
β1 and β3 integrins, E-selectin, P-selectin, CD34, VCAM-1, endoglin, PECAM-1, vascular endothelial-cadherin, Lewisy/H, MUC18
RGD sequence (integrin ligand)
Growth factors
VEGF, bFGF, aFGF, PDGF, EGF, IGF-I, HIF-1, TGF-βa
TNF-α, IL-6a, IL-15, IL-18
IL-4, IL-6a, IFN-α, IFN-γ
MMPs, plasminogen activators
TIMPs, plasminogen activator inhibitors
Angiogenin, substance P, prolactin
DMARDs, infliximab, etanercept, angiostatin, endostatin
The major chemoattractant that drives EPCs is the SDF-1/CXCL12 chemokine and its receptor, CXCR4 [29]. In arthritis, proinflammatory cytokines stimulate the production of SDF-1/CXCL12 and thus tissue vasculogenesis by recruiting CXCR4+ EPCs [14, 17, 29].
Angiogenic mediators and inhibitors in rheumatoid arthritis
The hypoxia-VEGF-angiopoietin pathway is an essential angiogenic network in synovitis [16, 23–25, 30]. VEGF, a growth factor that binds to heparin in the synovial ECM, plays a central role in the regulation of neovascularization [23, 30]. There is hypoxia present within the joint cavity, and hypoxia as well as TNF-α and IL-1 stimulate VEGF release [16]. Hypoxia acts through the hypoxia-inducible factor heterodimer, HIF-1α/HIF-1β [16]. Several other angiogenic mediators also act indirectly via VEGF [23]. Angiopoietin-1 (Ang1) and Ang2 regulate EC functions upon stimulation by VEGF. Both Ang1 and Ang2 interact with the Tie2 endothelial tyrosine kinase receptor [16, 24]. Ang1-Tie2 interactions result in vessel stabilization. On the other hand, Ang2, an antagonist of Ang1, inhibits vessel maturation [24]. Another important player in this network is survivin, an apoptosis inhibitor, which is also involved in VEGF-induced angiogenesis and EC survival [16]. VEGF, HIF-1, Ang1, Tie2, and survivin are all expressed in the arthritic synovium [16, 25]. Growth factors other than VEGF but implicated in angiogenesis include fibroblast (FGF-1 and FGF-2), hepatocyte, platelet-derived, epidermal (EGF), insulin-like, and transforming (TGF-β) growth factors [16, 24, 25]. Among chemokines described above, CXC chemokines that contain the ELR (glutamic acid-leucine-arginine) amino acid motif promote angiogenesis [13]. ELR+CXC chemokines that stimulate angiogenesis and also synovial inflammation include IL-8/CXCL8, ENA-78/CXCL5, groα/CXCL1, and CTAP-III/CXCL7. SDF-1/CXCL12 is a unique CXC chemokine as it exerts mainly a homeostatic function, yet it has been implicated in inflammation such as in RA [13, 14, 17, 29]. Moreover, this chemokine lacks the ELR motif but is still angiogenic [14, 29]. The crucial role of SDF-1/CXCL12 in vasculogenesis is discussed above [29]. In contrast to angiogenic CXC chemokines, the ELR-PF4/CXCL4, IP-10/CXCL10, and Mig/CXCL9 suppress neovascularization [13, 14, 17]. Regarding CC chemokines, MCP-1/CCL2 promotes neovascularization induced by growth factors [14, 17]. The sole CX3C chemokine, fractalkine/CX3CL1, also promotes synovial angiogenesis [14, 17, 19]. Regarding chemokine receptors, CXCR2, which binds most ELR+ CXC chemokines described above, is a crucial chemokine receptor in angiogenesis [13, 14, 17]. CXCR4 has been implicated in SDF-1/CXCL12-induced neovascularization in arthritis [14, 17, 29]. In contrast, CXCR3, a receptor for the angiostatic IP-10/CXCL10 and Mig/CXCL9, may be involved in chemokine-mediated angiostasis [14, 17]. Numerous proinflammatory cytokines, such as TNF-α, IL-1, IL-6, IL-15, IL-17, IL-18, granulocyte and granulocyte-macrophage colony-stimulating factors, oncostatin M, and macrophage migration inhibitory factor, also induce synovial angiogenesis [16, 31]. In contrast, other cytokines, such as IFN-α, IFN-γ, IL-4, IL-12, IL-13, and leukemia inhibitory factor, suppress the production of angiogenic mediators and thus inhibit neovascularization [16, 31, 32]. ECM components, matrix-degrading proteases, and cellular adhesion molecules described above may be involved in EC emigration, sprouting, and thus angiogenesis. Among ECM components, various types of collagen, fibronectin, laminin, vitronectin, tenascin, and proteoglycans promote neovascularization [16]. Proteolytic enzymes, such as MMPs and plasminogen activators, play a role in matrix degradation underlying synovial angiogenesis [16, 25]. On the other hand, tissue inhibitors of metallo-proteinases and plasminogen activator inhibitors antagonize the angiogenic effects of proteases described above [16, 32]. Among CAMs, β1 and β3 integrins, E-selectin, glycoconjugates (including Lewisy/H), melanoma cell adhesion molecule (MUC18), VCAM-1, PECAM-1, and endoglin have been implicated in neovascularization [2, 16, 25, 33, 34]. The αVδ3 integrin is of outstanding importance as this CAM mediates both synovial angiogenesis and osteoclast-mediated bone resorption and the development of erosions in RA [34]. Other important angiogenic factors not mentioned above include endothelin-1, angiogenin, angiotropin, and many others [16, 25] (Table 4). Angiostatic mediators and compounds also include angiostatin (a fragment of plasminogen), endostatin (a fragment of type XIII collagen), thrombospondin-1, 2-methoxyestradiol, paclitaxel, osteonectin, chondromodulin-1, and others [16, 30, 32, 35] (Table 4). These molecules suppress the action of angiogenic mediators, such as VEGF, HIFs, or the αVβ3 integrin [16, 30, 32, 35].
Angiogenesis in other types of arthritis and connective tissue diseases
Differential vascular morphology may exist in the synovia of RA versus psoriatic arthritis (PsA) patients [16, 25]. Furthermore, VEGF production may be associated with increased disease activity and accelerated angiogenesis in PsA and ankylosing spondylitis [16]. In SLE, angiogenic EGF, FGF, and IL-18 as well as angiostatic endostatin have been detected in the sera of patients. Serum VEGF levels were correlated with the SLAM (systemic lupus activity measure) activity score [16, 25]. Angiogenesis in SSc is somewhat controversial. On one hand, there is significant loss of vessels in scleroderma despite severe tissue hypoxia associated with increased concentrations of the angiostatic endostatin [16, 28]. On the other hand, SSc skin biopsy explants stimulated neovascularization and there is increased production of VEGF in the sera and skin of scleroderma patients [16, 28]. Thus, hypoxia may induce angiogenesis in SSc but this is transient and the newly formed vessels are rather unstable in this disease [28]. Furthermore, sustained production of VEGF results in the formation of giant capillaries seen using capillaroscopy in SSc [16, 28]. Similarly to SSc, in inflammatory myopathies, expression of hypoxia-associated increased HIF-1, αVβ3 integrin, and VEGF receptor in muscle biopsies was not sufficient to compensate the loss of blood vessels [16, 25]. Regarding systemic vasculitides, abundant production of angiogenic VEGF and TGF-β has been associated with Kawasaki syndrome [16]. Increased serum levels of TGF-β were found in ANCA (antineutrophil cytoplasmic antibody)-associated vaculitides, including Wegener granulomatosis, Churg-Strauss syndrome, and microscopic polyangiitis [16, 25].
Targeting of angiogenesis in inflammatory rheumatic diseases
Antiangiogenic targets
Endogenous inhibitors
Interleukin-4, interleukin-13
Platelet factor-4/CXCL4 chemokine
Exogenous inhibitors
Classical disease-modifying antirheumatic drugs
Anti-tumor necrosis factor biologics
Fumagillin analogs
Vascular endothelial growth factor inhibitors
Hypoxia-inducible factor heterodimer inhibitors
Angiopoietin-1/Tie2 inhibitors
αVβ3 integrin inhibitors
Microtubule destabilizers (for example, paclitaxel)
Others (for example, glitazones)
Accelerated atherosclerosis in rheumatic diseases
The basis of atherosclerosis and increased vascular risk
Common risk factors in the pathogenesis of atherosclerosis underlying rheumatic diseases
1. Traditional
Diabetes mellitus
Sedentary lifestyle
2. Inflammatory
Acute-phase proteins (C-reactive protein, fibrinogen)
Lipoprotein (a)
Folate and vitamin B12 deficiency
Decreased paraoxonase activity
CD4+/CD28- T cells
Autoantibodies (anti-CCP, rheumatoid factor, anti-oxLDL, anti-phospholipid antibody, anti-hsp)
Proatherogenic cytokines (tumor necrosis factor-alpha, interleukin-6)
Angiogenic growth factors
Matrix-degrading metalloproteinases
Increased cell adhesion molecule expression
Defective apoptosis
3. Iatrogenic
Methotrexate – bimodal?
Corticosteroids – bimodal?
Indeed, several inflammatory and atherogenic mediators, including homocysteine, lipoprotein (a), C-reactive protein (CRP), hyperhomocysteinemia, and folate, and vitamin B12 deficiency and decreased paraoxonase-1 activity are strongly associated with atherosclerosis and CVD [36, 42, 43]. Athero-sclerotic plaques, similarly to the RA joint, are characterized by enhanced accumulation of inflammatory monocytes/macrophages and T cells. These inflammatory leukocytes abundantly produce proinflammatory cytokines, chemokines, and MMPs [42, 43]. CD4+ T cells, especially the CD4+/CD28- T-cell subset, have been associated with both arthritis and inflammation-related vascular damage [37, 38, 43]. Regarding proinflammatory cytokines, TNF-α and IL-6 play an important role in atherosclerosis as well as in RA [31, 36, 43]. Increased production of TNF-α and IL-6 has been associated with heart failure as well as with insulin resistance, dys-lipidemia, and obesity [36, 43]. In contrast, IL-4 and IL-10 may exert an anti-inflammatory role during the development of atherosclerosis by driving Th2 responses [31, 43] (Table 6).
Vascular involvement in various rheumatic diseases
In RA, age, gender, ethnicity, traditional risk factors described above as well as (among RA-related risk factors) disease duration, activity, and severity, functional impairment, rheumatoid factor and anti-CCP status, CRP, radiographic indicators, presence of the shared epitope, and treatment modalities have been implicated in the development of accelerated atherosclerosis [36–38, 44]. We have recently assessed common carotid intima-media thickness (ccIMT) indicating atherosclerosis and flow-mediated vasodilation (FMD), a marker of endothelial dysfunction in RA. Increased ccIMT and impaired FMD have been associated with age, disease duration, and anti-CCP, CRP, and IL-6 production [44]. In SLE, primary APS (PAPS) and secondary APS associated with SLE, traditional, and autoimmune-inflammatory factors are involved [40]. Among these factors, longer disease duration and cumulative corticosteroid dose seem to
be the major predictors of clinical atherosclerosis [37, 38, 40, 41]. Additional inflammatory risk factors include CRP, fibrinogen, IL-6, costimulatory molecules (CD40/CD40L), CAMs, anti-phospholipid antibodies (APAs), including anti-cardiolipin and anti-β2 glycoprotein I (anti-β2GPI), anti-oxidized low-density lipoprotein (anti-oxLDL), anti-oxidized palmitoyl arachidonoyl phosphocholine (anti-oxPAPC), anti-HDL and anti-hsp antibodies, homocysteine, and lipoprotein (a) [37, 40, 41]. APAs are of importance in both SLE and APS. APAs may bind to neoepitopes of oxLDL as well as to oxLDL-
β2GPI complexes, and both APA and anti-oxLDL antibodies have been implicated in the pathogenesis of atherosclerosis associated with SLE and APS [37, 38, 40, 41]. Autoantibodies against oxLDL-β2GPI complexes have been detected in SLE and PAPS patients [40, 41]. Both APA and anti-oxLDL may account for increased mortality in CVD [41]. The β2GPI phospholipid cofactor has been detected in the wall of large arteries in the vicinity of CD4+ T-cell infiltrates. Macrophages and ECs bind to β2GPI during the atherosclerotic process [37, 38, 41]. Atherosclerosis is the most pronounced in lupus-associated secondary APS, in which traditional and nontraditional risk factors are multiplied and atherosclerosis occurs more prematurely [40, 41]. SSc is associated with both macrovascular disease (including CVD, pulmonary hypertension, and peripheral arterial occlusion) and micro-vascular disease (including Raynaud phenomenon) [37–39, 45, 46]. Pathogenic factors involved in SSc-associated vascular damage include increased LDL, homocysteine, and CRP production [37, 39, 46]. We recently described the association of 5,10-methylene-tetrahydrofolate reductase (MTHFR) C677T polymorphism with homocysteine, vitamin B12 production, and macrovascular abnormalities in SSc [46]. Increased arterial stiffness and ccIMT as well as impaired FMD have been detected by us [39, 45] and others [37] in scleroderma.
Therapeutic considerations
Anti-inflammatory treatment used in inflammatory rheumatic diseases may be either proatherogenic or antiatherogenic [37, 47]. Corticosteroids are atherogenic by augmenting dys-lipidemia, hypertension, and diabetes mellitus [36, 47]. In autopsy studies, long exposure to corticosteroid therapy was associated with the development of atherosclerosis. However, other clinical studies could not confirm this association [36, 47]. Glucocorticoids may exert a bimodal action as they are atherogenic but, on the other hand, also anti-inflammatory. There is evidence that the above-described inflammatory factors associated with more active disease may exert higher risk for atherosclerosis than anti-inflammatory treatment [37, 47]. In contrast to corticosteroids, antimalarial drugs such as chloroquine and hydroxychloroquine may exert evident antiatherogenic properties. Antimalarials may reduce LDL cholesterol, very LDL cholesterol, and (in corticosteroid-treated patients) triglyceride production [36, 37, 47]. Methotrexate (MTX) exerts bipolar effects on atherosclerosis in RA: on one hand, MTX treatment increases plasma levels of homocysteine, but, on the other hand, MTX controls several other mediators of inflammation and thus may beneficially influence the net outcome of CVD in RA [36, 47]. Concomitant folate supplementation prevented the increase of homocysteine production and reduced CVD mortality in MTX-treated patients [36]. Among biologic agents, TNF-α blockers may have significant effects on the vasculature [48]. In RA, infliximab treatment reduced endothelial dysfunction and ccIMT [48]. We recently proposed that rituximab may also exert favorable effects on FMD, ccIMT, and dyslipidemia [49]. Atherosclerosis treatment strategies in rheumatic diseases should include an aggressive control of all traditional risk factors, including hyperlipidemia, hypertension, smoking, obesity, and diabetes mellitus. Both pharmacological treatment and changes in lifestyle should be introduced in these patients [47]. There is very little solid evidence from randomized controlled trials indicating the preventative action of any drugs in arthritis-associated CVD [47]. Drug therapy may include the use of antiplatelet agents, statins, folic acid, B vitamins, and (as described above) possibly antimalarials [36, 47]. A recommendation from the European League Against Rheumatism for the prevention and management of CVD in arthritis is about to be published [50].
In this review, we discussed the putative role of leukocyte-EC adhesion, chemokines, and angiogenesis in leukocyte recruitment underlying the pathogenesis of inflammatory synovitis. A number of CAMs are involved in this process. These CAMs interact with soluble inflammatory mediators such as cytokines and chemokines. The presence of various CAM pairs and the existence of distinct steps of rolling, activation, adhesion, and migration account for the diversity and specificity of leukocyte-EC interactions. Chemokines and their receptors drive inflammatory leukocytes into the synovium. A number of soluble and cell-bound factors may stimulate or inhibit angiogenesis. The outcome of inflammatory and other 'angiogenic diseases' such as various forms of arthritis depends on the imbalance between angiogenic and angiostatic mediators. There have been several attempts to therapeutically interfere with the cellular and molecular mechanisms described above. Specific targeting of leukocyte adhesion, CAMs, chemokines, chemokine receptors, and/or angiogenesis, primarily by using agents with multiple actions, may be useful for the future management of inflammatory rheumatic diseases.
The Scientific Basis of Rheumatology: A Decade of Progress
This article is part of a special collection of reviews, The Scientific Basis of Rheumatology: A Decade of Progress, published to mark Arthritis Research & Therapy's 10th anniversary.
Other articles in this series can be found at: http://arthritis-research.com/sbr
- β2GPI:
β2 glycoprotein I
anti-endothelial cell antibody
- Ang:
- anti-CCP:
anti-cyclic citrullinated peptide
- anti-oxLDL:
anti-oxidized low-density lipoprotein
antiphospholipid antibody
antiphospholipid syndrome
endothelial adhesion molecule
- ccIMT:
common carotid intima-media thickness
C-reactive protein
connective tissue-activating peptide-III
cardiovascular disease
disease-modifying antirheumatic drug
endothelial cell
extracellular matrix
epidermal growth factor
glutamic acid-leucine-arginine
epithelial neutrophil-activating protein-78
endothelial progenitor cell
fibroblast growth factor
flow-mediated vasodilation
- groα:
growth-regulated oncogene-alpha
high endothelial venule
hypoxia-inducible factor
intercellular adhesion molecule
interferon-gamma-inducible 10-kDa protein
junctional adhesion molecule
low-density lipoprotein
lymphocyte function-associated antigen
monocyte chemoattractant protein-1
- Mig:
monokine induced by interferon-gamma
- MIP-1α:
macrophage inflammatory protein-1-alpha
matrix metal-loproteinase
- oxLDL:
oxidized low-density lipoprotein
primary antiphospholipid syndrome
platelet-endothelial cell adhesion molecule-1
platelet factor-4
rheumatoid arthritis
stromal cell-derived factor-1
systemic lupus erythematosus
- SSc:
systemic sclerosis
- TGF-β:
transforming growth factor-beta
tumor necrosis factor
vascular cell adhesion molecule
vascular endothelial growth factor.
This work was supported by National Institutes of Health (Bethesda, MD, USA) grants AR-048267 and AI-40987 (AEK), the William D Robinson, MD, and Frederick GL Huetwell Endowed Professorship (AEK), funds from the Veterans' Administration (AEK), and grant T048541 from the National Scientific Research Fund (OTKA) (ZS).
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text:
Pangu 7 Star Hotel, Beijing
- Free WiFi
Main amenities
- 234 guestrooms
- 2 restaurants and 2 bars/lounges
- Indoor pool
- Breakfast available
- Fitness center
- Self parking
- Spa services
- Conference center
- 24-hour front desk
- Air conditioning
- Daily housekeeping
- Garden
For families
- Free cribs/infant beds
- Rollaway/extra beds (surcharge)
- Private bathroom
- Separate bathtub and shower
- Free toiletries
- Garden
What's around
- In North Chaoyang
- Beijing International Convention Center (0.9 mi / 1.5 km)
- Beijing National Stadium (1.3 mi / 2 km)
- China National Convention Center (1.6 mi / 2.6 km)
- China Town Shopping Plaza (0.8 mi / 1.3 km)
- National Aquatics Center (0.9 mi / 1.5 km)
Pangu 7 Star Hotel, Beijingfrom $250
- Executive Suite, 2 Single Beds
- Executive Twin Room
- Premium Room, 2 Single Beds
- Deluxe Room
- Premium Suite, 2 Single Beds
- Premium Suite
- Grand Deluxe with View
- Grand Deluxe Room
- Pangu Suite
- Superior Deluxe Room
- Superior Deluxe Room with View
- Deluxe Room, View
More great choices
At a glance
Key facts
Hotel size
- This hotel has 234 rooms
- This hotel is arranged over 21 floors
- Check-in time 2 PM-11:30 PM
- Check-out time is noon
- Express check-in/out
Required at check in
- Credit card or cash deposit required
- Government-issued photo ID required
- Minimum check-in age is 15
Travelling with others
- Pets not allowed
- Free WiFi in public areas
- Free WiFi in rooms
- Self parking (limited) *
Nearby Five Star Beijing hotels
In the hotel
- Buffet breakfast daily (surcharge)
- 2 restaurants
- 2 bars/lounges
- 24-hour room service
- Indoor pool
- Fitness facilities
- Spa services on site
- Number of meeting rooms - 8
- One meeting room
- Conference center
- Computer station
- 24-hour front desk
- Concierge services
- Tours/ticket assistance
- Dry cleaning/laundry service
- Luggage storage
- Wedding services
- Multilingual staff
- Porter/bellhop
- Number of buildings/towers - 1
- Year Built 2008
- Elevator/lift
- ATM/banking
- Safe-deposit box at front desk
- Designated smoking areas (fines apply)
- Garden
- Fireplace in lobby
In the room
- In-room climate control (air conditioning)
- Air conditioning
- Minibar
- Coffee/tea maker
- Bathrobes
- Slippers
- Iron/ironing board
- Pillow menu
- Down comforter
- Blackout drapes/curtains
- Turndown service
- Premium bedding
- In-room massage available
- Individually decorated
- Individually furnished
- Private bathroom
- Separate bathtub and shower
- Rainfall showerhead
- Designer toiletries
- Hair dryer
- 42-inch LED TV
- Cable TV channels
- DVD player
- Desk
- Free WiFi
- Free local calls
- Free bottled water
- Daily housekeeping
- In-room safe
Top Beijing hotels
Recently reviewed hotels in Beijing
- Renaissance Beijing Wangfujing HotelFrom
"was extremely impressed immediately upon arrival. One of the nicest hotels i have ever stayed at. The room was out of this world!! bathroom was awesome! beds were great! staff…"Jan 16, 2017
- Fairmont Beijing HotelFrom
"Great staff - extremely attentive and polite. Will go back."Jan 14, 2017
- Shichahai Shadow Art Performance HotelFrom
"Very quiet place in Old Beijing Hutong area near Houhai. Also very close to the metro station 'North Beihai' within 1000 meters. People there are very nice and welcome. Staying…"Jan 14, 2017
- Wangfujing Xin Xiang Ya Yuan ApartmentFrom
"Very nice apartment with full kitchen, living area and spacious bathroom. Clean and well maintained. Staff is friendly and extremely helpful. Apartment is located near subway…"Jan 12, 2017
Nearby hotels
Also popular with travelers from the USA
Special features
DiningWenqi - Overlooking the garden, this restaurant specializes in Asian cuisine and serves lunch and dinner. Reservations are required. Open daily.
Auspicious Garden - Overlooking the garden, this buffet restaurant specializes in international cuisine and serves breakfast, lunch, and dinner. Open daily.
Happiness Lounge - Overlooking the garden, this bar specializes in Modern European cuisine and serves light fare only. Happy hour is offered. Open daily.
Karma Lounge - This lobby lounge serves light fare only. Open daily.
Pangu 7 Star Hotel, Beijing's small print
Also known as
- Pangu Seven Star
- Pangu Seven Star Beijing
- Pangu Seven Star Hotel
- Pangu Seven Star Hotel Beijing
- Pangu 7 Star Hotel Beijing
- Pangu 7 Star Hotel
- Pangu 7 Star Beijing
- Pangu 7 Star
Only registered guests are allowed in the guestrooms.
The name on the credit card used at check-in to pay for incidentals must be the primary name on the guestroom reservation.
Optional extras
Self parking is available for an extra charge
Rollaway beds are available for CNY 600 per night
Buffet breakfast is offered for an extra charge of CNY 216 per person (approximately)
Airport shuttle service for children costs CNY 800.00
We have included all charges provided to us by this hotel. However, charges can vary, for example, based on length of stay or the room you book.
Recent reviews
Excellent 4.4 /5 from 13 reviews
He floor stink. We have two people stay and only one peeskn offered breakfast. The food sucks. Other than Swimming pool is great, he hotel worth nothing
Beautiful hotel with large rooms
It was worth staying for a night or two to say you were at a hotel with a view to the Olympic Stadium. Service was below average and inconsistent. Prices at the restaurants were too high and not a value for what it was. for this standard the service was really poor. I had to argue about the bill and there were no accommodations made. The hotel service was so disappointing. Nothing seven stars other than the view.
Really great view from the window, the bird nest and water cube is all in your eyes.and the bed is comfortable, service is good, overall it was a great stay.
Stayed there for a business trip, area is spacious and no traffic. Right next to the Olympic venue, and room is very comfortable. The down side is its far from any local convenience stores.
Is the description of this hotel not correct? Tell us

subset: commoncrawl


text:
August 13th, 2010
This is what happens when you ask the hair stylist for a "Dorothy Hamill."
(submitted by Jackie)
This is what happens when you ask the hair stylist for a "Dorothy Hamill."
(submitted by Jackie)
I don't get the Windbreakers.
I asked for the DH cut when I was in elementary school in the Eighties because I wanted my hair to do that twirly flow-thing. Instead I ended up looking like the Fifth Beatle and was mistaken for a boy. A lot.
Seriously… I actually think this is such a cute picture. Those little girls are so cute with those haircuts. I should look through my pictures, I probably have some that look like this that I think are so cute.
I would looove to be a fly on the wall in 30 or 40 years to see what people would say about pictures of you all in haircuts that you think are super cool today.
Just sayin'
I feel for these girls- my mother FORCED the Dorothy Hamill on me too! I would still kick her ass if I ever saw her on the street…..for years and years of "the Dorothy Hamill" I wonder how many girls hate her for the same reason!!!
When I lived in England, I had a co-worker who had just moved there and was totally shocked they didn't know how to give her daughter a "dorothy-do" over there. In 2002.
This should be called the Oddball!
my kingdom for a pair of skates…………
a good picture.
My sisters both had this haircut and the windsuits. I managed not to, because I wanted long hair and my dad backed me up.
I think the most awkward part is the random blonde child….I wonder what color hair the milk man has…
Lmao win! I swear I was thinking that!
Remember the Flobee hair-cutting system?
This photo is the essence of the 90's.
hahaha the first day i saw this at your house on the dresser i knew it had a place on this website
poor little justine they are all right you stick out like a sore thumb in this photo! you look like they found you outside of sears photobooth and they said hey! she has a windbreaker and haircut like us lets use her!
i love this
OMG- I had this cut as a child. The hairdresser tried to tell me that I would not look like Dorothy from the Wizard of Oz, but for some reason I did not believe her and I ended up with a strange mushroom cut ( I have very fine hair that lays flat). I was very upset. =(
I love Jackie and her windbreaker and dorothy hamill hair!
This reminds me of many, many early 90's church directory portraits.
This picture brought to you and paid for by "SuperCuts" 1982
Dad looks like he wondering how he got caught in Dante's third circle of Hamill.
Narrator: Inwardly, Dad was jealous his "Dorothy Hamill" would not hold its shape.
That's what I was thinking, "This picture would be 10 times more awesome if dad had the same haircut."
the Hair!!… how about the wind suits!!!
OMG it's Georges W Bush in the middle
before he got on alcohol and stuff
Whoa- my thoughts exactly!
We know who wears the track pants in this family!
OMG, I so wanted a Dorothy Hamill when I was 8! I ended up with a pixie cut instead and was devastated for days.
Why, why are they wearing windbreakers in what should be a nice family portrait? It looks so junky. Especially with dad in a random plaid shirt! At least if they ALL matched that would be something!
Cute picture – captures an era of Dorthy Hamill cuts perfectly!


text:
Consular Information Embassy Bilateral cooperation
12 July 2016
Minister Witold Waszczykowski on day two of NATO summit in Warsaw
A meeting of the Visegrad Group's (V4) foreign ministers, bilateral talks, and bilateral sessions were the main points of the second day of the NATO summit in Warsaw with the participation of Minister Witold Waszczykowski.
12 July 2016
Minister Witold Waszczykowski during NATO Summit's first session
"The security status of the Eastern Flank, including that of Poland, is starting to reach the same level as the security status of Western Europe. Our efforts are bearing fruit today, this is a significant change that will take place regarding the geopolitics of the Eastern Flank and the security of Poland," Minister Witold Waszczykowski said on the first day of the NATO Summit in Warsaw.
27 July 2016
Krakow hosts the World Youth Day
From 26 to 31 July pilgrims from around the world will meet in Krakow to celebrate together under the banner "Blessed are the merciful, for they will receive mercy." The World Youth Day will end with Holy Mass in Brzegi near Krakow, celebrated by Pope Francis.
News from PolandRecommended


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Chaim Gross: A Celebration
January 26, 1996 – May 13, 1996
This exhibition focuses on the birds' eye maple sculpture Acrobatic Performers by Chaim Gross.
|American Art Museum
Six Bridges and the Making of the New York Megalopolis
January 25, 1996 – April 19, 1996
Explore photographs, drawings, and maps that examine the 6 main New York City bridges designed by Othmar H. Ammann, which were erected between 1927 and 1964.
|Cooper Hewitt, Smithsonian Design Museum
Seto and Mino Ceramics
January 23, 1996 – August 8, 2001
Track 47 objects that how how ceramics have evolved from the 9th century to the present day in the adjacent Seto and Mino regions of central Japan.
|Freer Gallery
Discover Orchids
January 20, 1996 – March 3, 1996
Explore the size, shape, color, habitat, and fragrance of orchids, one of the most diverse plant families.
|Arts and Industries
USS Monitor
January 19, 1996 – April 28, 1996
This exhibition discusses the USS Monitor, one of the first ironclad battleships, built without sails and rigging for the Union Navy, and the archaeological study of the wreck.
|American History Museum
English and French Caribbean Music in Washington, D.C.
January 8, 1996 – June 16, 1996
Follow the development of Washington, D.C.'s Caribbean music community by examining the history of performance and the presence of Caribbean music on Washington radio.
|Anacostia Community Museum
Recent Acquisitions (1996)
January 5, 1996 – July 7, 1996
On view are two paintings, one print, and one drawing recently acquired by the museum.
|Portrait Gallery
The Life of a Japanese Painting
December 17, 1995 – October 8, 1996
Understand different approaches to conserving and remounting Japanese paintings and the characteristics of Japanese painting formats and mounting styles in this exhibition.
|Freer Gallery
Whispered Silences: Japanese American Detention Camps, Fifty Years Later
December 15, 1995 – January 15, 1996
Let 44 contemporary prints by photographer Joan Myers evoke the wartime experiences of Japanese Americans, as told through the weathered objects, abandoned gardens, and building fragments of World War II detention camp sites.
|Ripley Center
Gilded Age Watercolors and Pastels from the Collection
December 15, 1995 – May 27, 1996
View 60 works from the permanent collection by such as artists as Childe Hassam, John Twachtman, Winslow Homer, and Thomas Moran.
|American Art Museum
An Historic Collection from the French Revolution and Napoleonic Era
December 8, 1995 – May 15, 1997
See pre-stamp letters and historic documents that trace the French Revolution and the Age of Napoleon.
|Postal Museum
1995 Holiday Scrapbook
December 8, 1995 – January 2, 1996
This exhibition explores how families & individuals celebrate the holiday season and features decorated trees and photos of holiday activities.
|American History Museum
Three Explorations: Yoruba, Temne, and Baga
November 22, 1995 – February 25, 1996
Examine a Yoruba mask, a Temne female figure, and a Baga ritual object in the context of their creation, use, and history.
|African Art Museum
Traders and Raiders on China's Northern Frontier
November 19, 1995 – September 2, 1996
See some 100 metal buckles, chariot and harness fittings, weapons, tools, and vessels from northern China.
|Sackler Gallery
Directions: Carmen Lomas Garza
November 18, 1995 – February 18, 1996
Paintings and mixed-media works by this San Francisco-based, Texas-bred artist present a visual narrative of Chicano life.
|Hirshhorn Museum
Metropolitan Lives: The Ashcan Artists and Their New York
November 17, 1995 – March 17, 1996
Reflect on the popular culture of early 20th-century New York through 100 paintings, drawings, prints, cartoons, and ads by 6 Americans.
|American Art Museum
Landscape Kimonos by Itchiku Kubota
November 16, 1995 – April 14, 1996
See 45 kimonos by contemporary Japanese textile artist Itchiku Kubota. Thirty of these represent fall and winter landscapes and 15 depict individual themes such as Mt. Fuji, the sun, and wildflowers.
|Natural History Museum
Elihu Vedder's Drawings for the "Rubaiyat"
November 10, 1995 – June 9, 1996
View 54 of Vedder's original drawings for Rubaiyat of Omar Khayyam (1884), a book of illustrations. An archival section features various editions of the Rubaiyat and photographs of the artist.
|American Art Museum
From Nashville With Love: Tennessee Rarities from the Jeanette Cantrell Rudy Collection
November 7, 1995 – July 8, 1996
Rare stamps and covers reflect the history and culture of the state of Tennessee.
|Postal Museum
Arab Americans in Greater Detroit: A Community Between Two Worlds
November 7, 1995 – March 31, 1996
Approximately 58 photos provide a glimpse into America's largest Arab American community and portray daily life and the process of "becoming American."
|American History Museum


text:
Fix-A-Leak is rated out of 5 by 3.
Fix-A-Leak is a blended, concentrated material designed to seal leaks in virtually any material. Fix-A-Leak can be used to fix pool and spa plumbing leaks, pool leaks and spa leaks. It will seal holes up to 1/8" in diameter and form a permanent seal.
Simply remove your cartridge filter, or set your sand or DE filter to "Recirculate" - add solution to the water during filtration and allow the repair to mend. You can also pour Fix-A-Leak directly near a suspected leak in the pool. Fix-A-Leak will seek out and fill voids up to 1/8 in.
Use 8 oz per 1,000 gallons for leaks in hot tubs. Use 32 oz for pools up to 22,000 gallons. Two treatments for large leaks. Leaking Pools, Leaking pool plumbing, Leaking pool liners, all fixed with Fix-A-Leak!!
More about this product
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Rated 1 out of 5 by PeteS from It didn't work I bought this product believing that it works form all the reviews well I thought I'd try it but my pool still leaks
Date published: 2016-09-04
Rated 5 out of 5 by Elyse from It really works! I purchased this product or of desperation as I was losing water every day. I was leery but tried it and IT WORKS!
Date published: 2016-06-25
Rated 5 out of 5 by Viccruz from Works as promised! Used this to plug a leak in a crack in the wall of my pool. When applied per instructions it will stop a leak. However, even after curing, the plug can be disturbed.
Date published: 2015-08-07


text:
John Aniston net worth: John Aniston is a Greek American actor and actress Jennifer Aniston's father who has a net worth of $10 million. John Aniston was born in 1933 on the island of Crete, Greece. John Aniston's family emigrated to the United States when Aniston was two and settled in Pennsylvania. He graduated from Pennsylvania State University with a bachelor's degree in Theater Arts. John Aniston served as an intelligence officer on active duty in Panama in the United States Navy, where he had the rank of Lieutenant Commander. John Aniston is best known for his role as Victor Kiriakis on the NBC soap opera "Days of Our Lives", which he began playing in 1985 and has played continually since that date. John Aniston has acted in soap operas nearly continuously since 1969 when he had his first stint on "Days of Our Lives" as Eric Richards, which he played until 1970. He appeared on "Love of Life" from 1975-1978, "Search for Tomorrow" from 1978-1984, and "Days of Our Lives" from 1985 to the present.
John Aniston Net Worth
John Aniston
Date of Birth
Jul 24, 1933 (83 years old)
United States of America
6 ft 2 in (1.9 m)
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All net worths are calculated by applying a proprietary algorithm. The results are then fact checked and confirmed by a team of editors. We scan all publicly available data and resources and work diligently to ensure that our numbers are the most accurate and up to date net worth data you will find anywhere on the internet.


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Robert Jordan (October 17, 1948–September 16, 2007), a native of Charleston, South Carolina, was the author of the bestselling The Wheel of Time®, with millions of books in print.
Brandon Sanderson grew up in Lincoln, Nebraska. He teaches creative writing at Brigham Young University and lives in Utah with his wife and children.
Robert Jordan was born in 1948 in Charleston, South Carolina. He taught himself to read when he was four with the incidental aid of a twelve-years-older brother, and was tackling Mark Twain and Jules Verne by five. He is a graduate of The Citadel, the Military College of South Carolina, with a degree in physics. He served two tours in Vietnam with the U.S. Army; among his decorations are the Distinguished Flying Cross with bronze oak leaf cluster, the Bronze Star with "V" and bronze oak leaf cluster, and two Vietnamese Gallantry Crosses with palm. A history buff, he has also written dance and theater criticism and enjoyed the outdoor sports of hunting, fishing, and sailing, and the indoor sports of poker, chess, pool, and pipe collecting. Robert Jordan began writing in 1977 and went on to write The Wheel of Time®, one of the most important and best selling series in the history of fantasy publishing with over 14 million copies sold in North America, and countless more sold abroad. Robert Jordan died on September 16, 2007, after a courageous battle with the rare blood disease amyloidosis.
Brandon Sanderson is the bestselling author of books including Warbreaker, Elantris, The Stormlight Archive series, starting with The Way of Kings, and The Mistborn series-Mistborn, The Well of Ascension, The Hero of Ages and The Alloy of Law. He has also written Alcatraz Versus the Evil Librarians, a book for middle-grade readers, and the young adult novel, The Rithmatist. He also completed the final books in Robert Jordan's Wheel of Time® series-The Gathering Storm, Towers of Midnight and A Memory of Light-based on Jordan's notes and material. Sanderson teaches writing at Brigham Young University. He lives in Utah.


text:
Fried Squash
4 Apr 2010
|Yellow crooked neck squash
|3 Pound
|Corn meal
|1 Cup (16 tbs)
|Garlic salt
|To Taste
|Mazola oil
|2 Tablespoon
|To Taste
|To Taste
Slice squash lengthwise.
Put in bowl, salt, cover and leave for at least an hour.
Roll in corn meal seasoned with salt, pepper and garlic salt.
Fry in oil in large skillet about 10 minutes.
Rate It
Nutrition Rank
Nutrition Facts
Serving size: Complete recipe
Calories 1107 Calories from Fat 346
% Daily Value*
Total Fat 39 g59.4%
Saturated Fat 3.1 g15.4%
Trans Fat 0.1 g
Cholesterol 0 mg
Sodium 787.3 mg32.8%
Total Carbohydrates 177 g58.9%
Dietary Fiber 36.5 g145.9%
Sugars 0 g
Protein 23 g46.8%
Vitamin A 40.8% Vitamin C 190.5%
Calcium 28.6% Iron 65.7%
*Based on a 2000 Calorie diet
Fried Squash Recipe


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Our rat loves the tent and spends most of his time in there. It was well worth the money for his enjoyment, comfort, and security as he gets used to a new home.
i recomend it to small animal owner my guinea pig loves it one thing i just need to say is it may look exspensiv but at petco .com it is 14.99 but at there store it is 19.99 i love it my pet loves it to
Good addition to the various sleeping hideouts for my rats.
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West Liberty has 1,220 residents. It is located in Ohio county.
The average in-state tuition for full time undergraduate students in dental assistant schools in West Liberty during the 2009 - 2010 school year was $4,880.00. The average tuition was $11,950.00 for non-residents studying in West Virginia.
Books and supplies for dental assistant schools in West Liberty cost an average of $1,300.00. Students living on campus at dental assistant schools in West Liberty paid an average of $6,870.00 for room and board during the 2009 - 2010 school year. Students living at home incurred costs of $3,275.00. Students have a choice of one dental assistant college in West Liberty to attend. Dental Assistant programs in West Liberty reportedly graduated 59 students in the 2008 - 2009 school year.
|Average Salary
|Number Employed in City
|Dental Hygienists
|Dental Assistants


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Dec 17, 2013
Lupatech has received "manifestation of positive support" for its restructuring plan from a bondholder group, it says. The group represents 22.4% of the struggling oil parts manufacturer's 9.875% perpetual bonds. Lupatech submitted the plan to...
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If you want to work from home, have flexible hours and love interacting with people, you should check out this position. The secret is…. the people you'll be calling really want to talk to you, they just won't know it until five minutes into the call. Getting to that point is what we'll train you to do. So if you are interested in learning state-of-the-art selling, building a career (not just a paycheck) and working for one of the finest wedding publications in the world, please send us your cover letter and resume. We are eager to get to know you!
Let's fast forward one year from now and discuss what a Successful Account Executive (you!) will have accomplished at Once Wed:
1. You innovated and refined an approach to close major accounts in retail, makeup, beauty, and fashion with major brands such as Macy's, L'Oreal, and Vera Wang providing them packaged promotional campaigns including serialized social media contests, banner advertising and original styled shoots sourced and executed by the talented Once Wed creative team.
2. The incisive client feedback you provided to Once Wed Management and Development Teams lead to the creation of superior advertising services increasing client retention by 22%.
3. Your quick grasp of split testing methodologies and strong communication of the power of this approach has won you a dozen major banner ad accounts and raised average monthly banner price we charge by 17%.
4. Your efficient work, internet savvy and persuasive proposals over email, phone and social networks have moved the Vendor Guide from 60% to 85% capacity and created recurring commissions for yourself based over 200+ accounts.
5. Your clients brag to management about your customer service skills, responsiveness and attention to detail – and tell us that "whatever you pay her, it's not enough" Some clients have even tried to lure you away from Once Wed with not so subtle job offers.
6. Your dedication to your career demonstrated by your high call volume, thoughtfulness, learning from your manager and sales team, and multiple sales books you study challenge the whole sales force to improve and propel you towards six figure earnings.
We can't wait until next year.
Now Back to Today
If you'd like this story to be yours….
Please email Brett Newman (firstname.lastname@example.com) your cover letter and resume for consideration.
Desired Skills & Experience
– Appreciation of the OW style & Aesthetic
– Flexibility – Once Wed is a growing company and we will need people who can flex and adapt to change
– 2 Years of Sales or equivalent industry experience (exceptions will be made for exceptional candidates)
– Preference given to Atlanta – it's easier to train our Account Executives if they are nearby, but we also like to take our people to lunch
– Life Experience is a major bonus (though not required)
– Dedicated phone line and high speed internet
– Installation of Rescuetime Software
– CPU or Laptop
– Headset
Comments (10)
Sounds really interesting and I have nine years of experience, but… Living in Spain :-(((
I am very much Interested.
In today's world of innovative and global technology, location is anywhere, anytime and everywhere. Asynchronous communication eliminates the need for physical nearness.
The position sounds intriguing.
How soon will the candidate start?
Our busy season is the first of the year, so we are aiming for a mid October start date. Please apply so we can learn more about you!
Are you still looking for candidates?
Yes, absolutely. Please apply if you think it's a good fit.
I would LOVE to work for Once Wed! What a great opportunity! I will update my resume and get it sent over ASAP.
Oh, and I am in Atlanta. :)
DREAM JOB!! Imagine your ideal employee who has a passion for event planning, cries at any wedding (TV or real life…), and LOVES her pinterest (like, a lot) – That's me! With that said, I'm only a junior in college at UGA. Do you offer an internships, or even need any volunteer help? I would be thrilled to help set up a wedding, do your busy work, run errands – whatever, I'm your girl! I am willing to do anything to get my foot in the door. Thanks!


text:
- Owner:
- Uploaded: Jul 21 2014 10:14 AM
- Views: 323
- Category: Scrap Girls World Tour Gallery
Photos are from our visit to Chobe National Park in Botswana in 2000.
Your photos are wonderful and I love how you placed them in the photo strips. Great background and perfect embellishments too - nicely done page!
Those are great photos. It must have been an amazing trip. I like your filmstrips too.
Wonderful photos. I love the film strip frame and the grass in the background. Lovely layout.
Beautiful photos of wonderful animals, Joyce. I really like the blue bird in the corner, and the grassy border and the film strips - and everything!
Wonderful photos and I love the film strip frames!! amazing LO
What wonderful photos! That must have been a great trip. I like the film strip -- it's a great way to show off lots of pictures. Pretty background, too.
Joyce what an amazing holiday this would have been and you have scrapped it beautifully. I love the slide show
Super cool photos Joyce, wow they are wonderful! I really like how you used the filmstrips and your background and embellishments are great! Wonderful page!
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Southeast Asian Development
By (author) Andrew McGregor
Format: Hardback
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Southeast Asian Development by Andrew McGregor
Book DescriptionSoutheast Asia has long fascinated development practitioners and researchers for being one of the few regions of the world that has resisted global trends to become a successful developing region. Divided into accessible thematic chapters, this book adopts a unique perspective of equitable development to outline the strengths and weaknesses of the transformations taking place in the Southeast Asian region. Focusing on four key themes: equality and inequality; political freedom and opportunity; empowerment and participation; and environmental sustainability, these concepts are used to explore Southeast Asian development and trace the impacts that the growing popularity of market-led and grassroots approaches are having upon economic, political and social processes. Whilst the diversity of the region is emphasized so are some of the homogenizing trends such as the concentration of wealth and services in urban areas and the subsequent migration of rural people into urban factories and squatter settlements. The ongoing commercialization and industrialization of rural agriculture as well as the expansion of non-farm income earning opportunities in rural spaces, and the alarming rates of environmental degradation which threaten health and livelihoods are also exposed. In highlighting how Southeast Asian development is unevenly distributing wealth, opportunities and risks throughout the region, this book emphasizes the need for creative new approaches to ensure that benefits of development are equitably enjoyed by all. Including illustrations, case studies and further reading, this book provides an accessible up-to-date introductory text for students and researchers interested in Southeast Asian development, development studies, Asian studies and geography.
Buy Southeast Asian Development book by Andrew McGregor from Australia's Online Bookstore, Boomerang Books.
Book DetailsISBN: 9780415384162
(234mm x 156mm x 16mm)
Pages: 272
Imprint: Routledge
Publisher: Taylor & Francis Ltd
Publish Date: 10-Mar-2008
Country of Publication: United Kingdom
Other Editions...
Books By Author Andrew McGregor
Southeast Asian Development, Paperback (March 2008)» View all books by Andrew McGregor
Outlines the strengths and weaknesses of the transformations taking place in the Southeast Asian region. This book focusses on four key themes: equality and inequality; political freedom and opportunity; empowerment and participation; and environmental sustainability and, explores Southeast Asian development.
» Have you read this book? We'd like to know what you think about it - write a review about Southeast Asian Development book by Andrew McGregor and you'll earn 50c in Boomerang Bucks loyalty dollars (you must be a member - it's free to sign up!)
Author Biography - Andrew McGregor
Andrew McGregor is a senior lecturer in the Department of Geography at the University of Otago, New Zealand, and previously worked for UNICEF Australia. His research focuses on the culture, power, and geography of foreign aid programmes in Southeast Asia.
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In honor of the winter solstice and to mark a triumphant end to 2011, Outlier has created a final release with their Solstice Experiments capsule. Comprised of three pieces, they include the Hudson Pivot Sleeve Shirt, Brushback Chino and Ultrasuede Cardigan. Each piece is visually unassuming in its technology and innovation but hopes to offer a modern update that will last you well beyond 2012. Holding true to much of their line, an utmost attention to construction and materials is heavily considered. Available now directly through Outlier.


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text:
- Description
- View Full Specifications
- Year:
- 2008
- Length:
- 65'
- Engine/Fuel Type:
- Twin / diesel
- Located In:
- Palm Beach, FL
- Hull Material:
- Fiberglass
- 74714-2839841
- Current Price:
This is a one owner, captain maintained Outer Reef 65, the company's most popular hull with many significant upgrades. The vessel has been lovingly maintained by its only owner and is fully equipped, featuring upgraded 565 HP Caterpillar C9 engines that provide a top speed of over 15 knots. A full hydraulic system operates the variable speed bow and stern thrusters, windlass and oversized stabilizers. It features expanded fuel capacity, water maker, fully finished crew quarters, recently reupholstered outside cushions, a fully enclosed pilothouse with dual Dutch Doors for access to wide side decks and the Portuguese Bridge. Complete Raymarine navigation package at both helm stations and magnificent Audio/Video for entertainment. To cruise in comfort and luxury there are three staterooms with ensuite heads, a day head in the main deck, a huge flybridge and a 14' Novurania tender with 60 HP Yamaha. A superb long range cruiser for the whole family and friends!
Joel Davidson / Outer Reef Yachts
Please contact Joel Davidson at (+1) 954-687-5612
Additional Specs, Equipment and Information:
Boat Name
LOA: 65 ft 0 in
Beam: 18 ft 6 in
Maximum Draft: 5 ft 0 in
Displacement: 93500 lbs
Total Power: 1130 HP
Engine 1:
Engine Brand: Caterpillar
Engine Model: C-9 Acert
Engine Type: Inboard
Engine/Fuel Type: Diesel
Location: Port
Engine Hours: 3100
Engine Power: 565 HP
Engine 2:
Engine Brand: Caterpillar
Engine Model: C-9 Acert
Engine Type: Inboard
Engine/Fuel Type: Diesel
Location: Starboard
Engine Hours: 3100
Engine Power: 565 HP
Fresh Water Tanks: (400 Gallons)
Fuel Tanks: (2200 Gallons)
Holding Tanks: (100 Gallons)
- Hand laid-up FRP hull with PVC foam sandwich construction above water line and vinylester barrier lamination for osmosis protection
- Hand laid-up FRP deck/house and flybridge with PVC foam sandwich construction
- Full length longitudinal engine stringers and athwartship stringers
- Windows with 3/8" tempered glass in salon, 1/2" tempered in pilothouse
- Rub rails with stainless steel capping
- Bilge area finished smooth and coated with epoxy paint
- Built-in swim platform with stainless steel swim ladder and rails
- Quiet roll integrated spray rail system
- Twin Caterpillar C-9 Acert 565 HP diesel engines with 360A ZF transmissions and electronic instruments for dual stations
- Two (2) 16 kw Northern Lights generators
- ABT TRAC model 220 stabilizers with 7.5 sq. ft. fins
- ABT 25HP hydraulic bow and stern thrusters with dual station controls
- Glendinnning engine controls for dual stations
- Wet exhaust system with FRP mufflers
- Two (2) stainless steel propeller shafts and two (2) bronze propellers
- Tides packless shaft seals with one (1) spare seal for each shaft
- Fiberglass drip pans under engines
- Stainless steel struts with bearings
- Two (2) Racor 75/1OOO MAX dual filters for main engines
- Two (2) Racor 1OOO MA single fuel filters for generators
- Stainless steel rudder with bearings
- Emergency tiller
- Teleflex hydraulic steering system for dual stations
- Maxwell HWC3500 hydraulic dual capstan/chain wheels horizontal windlass and dual anchor
- 75 lb. polished stainless steel anchor with 300' 3/8" ht chain
- 105 lb. polished stainless steel anchor w/300' 3/8" ht chain
- One (1) oil change pump for engines and generators
- Ball-valve bronze seacocks on all through-hulls below waterline
- Nutone central vacuum system
- Chilled water A/C system
- Algae-X fuel polishing system
- Groco 24V #SP080R fuel transfer pump
- Second dripless shaft seal
- Northern lights uplift water exhaust for generators
- Evolution antivibration system
- 5 1/2" diameter zinc plates on rudders
- Glendinning handheld remote control with plug-in receptacle at aft deck and additional plug-ins, one (1) at flybridge, one (1) at Portuguese bridge
- Main electric distribution panel with gauges and circuit breakers for 230/115v AC and 24/12 v DC system (AC panel can be used with either 50 AMPS or 100 AMPS)
- Glendinning 50 AMP cablemaster with 75' of cable on transom
- 50 AMP shore power inlet aft
- Charles lsoboost isolation transformers
- Two (2) engine battery banks with two (2) AGM 80-204AH batteries per bank
- Two (2) house battery banks with 2 AGM 8D-204AH batteries per bank
- Two (2) generator banks with one (1) AGM 30H-105AH battery each
- Engine battery interconnection system
- Two (2) battery isolators
- One (1) 24v and one (1) 12v battery chargers
- Shoreline power transfer rotary switches
- 24v DC overhead halogen light fixtures throughout
- 24v DC rope style valance lights at salon and staterooms
- 24v DC step lights throughout and automatic wardrobe lights
- 115v AC outlets throughout, GF outlets for heads and exterior
- Four (4) engine room blowers and three (3) head vent blowers
- 115v AC fluorescent lights and 24v DC lights for engine room
- One (1) 24v DC chart light
- Five (5) Aqua Signal navigation lights
- Three (3) Exalto dual speed self-parking windshield wipers with washdown system
- One (1) Kahlenberg D-OA dual-trumpet air horn with compressor
- One (1) tel/cable TV inlet on transom
- Two (2) Danforth 5" magnetic compasses
- One (1) DC-DC converter (24V to 12V)
- Two (2) shaft brushes in engine room
- One (1) Trace 4kw inverter (24v DC to 115v AC)
- Accessible wiring raceway throughout
- Copper bonding system to all underwater fittings with zinc anodes
- Four (4) automatic 24v DC bilge pumps and emergency bilge suction on engine
- Two (2) automatic 24v DC shower pumps
- One (1) manual bilge pump in engine room
- High water bilge alarm system with warning panel in pilothouse
- 400 gallon stainless steel water tank
- 24v DC Headhunter fresh water pump, model XR-124, with accumulator tank
- 115v AC 18 gallon water heater with heat exchanger
- Grohe single level mixing taps for sinks at galley, head and shower
- Fresh water faucet in engine room
- Shore water inlet on transom
- Five (5) Tecma electric marine toilets withy-valves and sanitary hose for all discharge plumbing
- 300 gallon FRP holding tank with macerator pump
- Three (3) aluminum fuel tanks of total capacity 2200 gallons
- Tank gauge for fuel and water tanks
- Stainless steel fuel manifold system (supply and return)
- Hot and cold transom shower in recessed box
- Fresh water washdown outlet on fore deck, aft deck, and flybridge
- One (1) salt water washdown pump with outlet on foredeck
- Rigid fresh water pipes and color coded copper fuel lines
- Cleanout and sight gauge for tanks
- Headhunter back up fresh water pump, X-caliber 24v DC
- Cruisair 230v AC back up sea water pump for AC system
- Village Marine Tec 1200 gpd watermaker
- White gel coat on hull & deck house side
- White gel coat deck with white non-skid
- Two (2) coats of black antifouling bottom paint over (5) coats of epoxy primer
- Eight (8) stainless steel hawser holes with cleats
- Single stainless steel anchor chute/roller at bow
- Stainless steel framed Plexiglas hatch on fore deck
- Flush FRP hatches over chain locker
- Stainless steel framed tempered glass portlights with screens
- Stainless steel railing on main deck
- FRP bench seats with storage beneath on aft deck
- Built-in stairway to swim platform
- FRP gate doors at fore, side and aft deck
- Removable stainless steel U-rails and swim ladder on swim platform
- Water tight Dutch doors on both sides of pilothouse
- Cantalupi exterior lighting
- ACR search light with remote, model RCL-1000, with controls for dual stations
- Stainless steel handrails on all bulkwarks (port, starboard and Portugese bridge)
- Sunbrella furniture fabric for aft deck and Portuguese seats
- Stainless steel breast plate on bow
- Two (2) additional lights over aft deck
- Swim platform extended by 12"
- Stainless steel ladder and hatch to access flybridge from aft deck
- Canvas covers for seats, tables, BBQ grill, windlass, instrument console on flybridge, foredeck seat, aft deck seat and table and pilothouse windows
- Textiline sunshade for pilothouse and side windows
- Port and starboard wing doors on aft deck
- Two (2) additional shore power inlets with rotary switches fore and aft
- Shore water inlet and TV/TEL inlet on fore deck
- Teak on swim platform and steps
- Marquipt Tide-Ride boarding steps
- Full beam width flybridge all the way forward above the pilothouse
- Molded FRP instrument console
- L-shape FRP bench seats with storage beneath and two (2) FRP fixed tables
- Cabinets for wash basin, ice maker and BBQ grill behind seats
- Venturi windscreen with stainless steel grab rails
- FRP radar switch
- Sliding hatch with stairway access to pilothouse
- Stainless steel safety rails on flybridge/boat deck
- Stainless steel destroyer-type steering wheel
- Hard top over flybridge
- Brower Systems 1500 lb. hydraulic rotation davit
- Two Stidd helm seats, model 500-200, low back admiral with powder coated base and naugahyde
- Sunbrella flybridge cushions
- Stainless steel trim around BBQ grill and stainless steel cover for LPG hose (outside of cabinet)
- 14' Novurania tender with 60 HP Yamaha
- Teak veneer panel/vinyl coverings on bulkhead
- Teak cabin doors and cabinet doors
- Teak/holly cabin sole throughout
- Removable foam backed vinyl headliner
- Muslin cushion covers for berths and seats
- Granite countertop in galley (including backsplash)
- Off-white FRP panel on wall in shower
- Drawers finished with Formica, including guides and steps
- Hanging lockers with automatic lighting
- Light valance in salon and staterooms
- Teak framed mirrors
- Satin varnish on interior teak
- One (1) Stidd helm seat, model 500-XL, low back luxury admiral with chrome base and Ultraleather upholstery
- Cantalupi stainless steel lighting in all showers
- Cantalupi chrome reading lights in master stateroom, VIP, guest and crew staterooms
- Grohe Europlus II pull-out chrome spray faucet in galley sink
- Grohe Chiara center-set chrome faucet in head sinks
- Grohe Relexa Plus chrome pulsator hand shower with 24" shower bar, hose and soap dish
- Entertainment center, one (1) hi/lo coffee table and one (1) end table in salon
- L-shaped settee in salon with 5" foam seats
- Swing door between pilothouse and galley
- Shoji screens over porthole area in master stateroom
- Seat in master shower
- Hinges and pneumatic lifting arm for floor hatch forward on the fuel tank in master
- Dual sinks in master stateroom
- Upgraded toilet to match bisque sinks
- Maple burl accents and window mullions in salon
- Hull height cabinet storage beside washer and dryer
- Dimmer switches to all light switches
- Acoustically insulated engine room lined with sound absorbing material
- Two watertight bulk heads
- Watertight aluminum engine room doors with sight sounds
- Edura coin dot flooring
- Stainless steel safety rails
- 115v AC fluorescent lights and 24v DC lights
- Shelves for parts and equipment
- Fresh water faucet
- Fireboy fire suppression system including both intake and outlet air shutdown system with aluminum louvers
- Sea chest
- Two (2) additional valves to oil change system for engine transmissions
- Raymarine 15M radar
- Raymarine Ray 240 VHF system
- Raymarine Raystar GPS
- Raymarine SR 100 Sirius weather satellite
- Raymarine ST60 depth finder
- Raymarine ST60 rudder angle indicator
- Raymarine ST60 speed indicator
- Raymarine ST60 wind speed indicator
- Speco loud hailer/horn
- Simrad AP 25 auto pilot
- KVH Tracvision M7 Sat TV
- GE Profile Energy Star 22.6 cu.ft. side by side refrigerator /freezer
- GE Profile 27 built-in single convection wall oven
- GE profile 30 built-in clean design electric cooktop
- GE monogram 12" black built-in compactor with reversible Fisher & Paykel dish drawer
- GE 1 hp garbage disposal
- Amana 26-bottle wine vault
- Bosch Axxis washer
- Bosch Aaxxis vented dryer
- Bosch stacking kit with pull out tray
- U-line combo ice maker/refrigerator
- DCS 30" professional BBQ grill
GE Spacemaker compact refrigerator
Sharp microwave oven
- Scooter
- Owner's personal effects
- Extra burgundy leather chairs in salon
- Tools
- Life raft
The Company offers the details of this vessel in good faith but cannot guarantee or warrant the accuracy of this information nor warrant the condition of the vessel. A buyer should instruct his agents, or his surveyors, to investigate such details as the buyer desires validated. This vessel is offered subject to prior sale, price change, or withdrawal without notice.
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text:
Welcome to 4550 Palm Beach Blvd, home to Domino's and the best pizza delivery in Florida! We're the restaurant to beat, offering you millions of ways to create your pizza and delivering them to you! Everyone can find something they like on the Domino's pizza menu, from vegetarian delights to carnivorous creations.
And we go beyond pizza. For example, when it comes to delivery wings, Domino's takes chicken to new heights of deliciousness. You can count on wings that are always fresh out of our ovens, baked-to-order.
What are your options? You could stick with a classic: our oven-baked bone-in wings. When our morsels of goodness come out of the oven, we cover them in one of our sublime sauces in all kinds of flavors. Or try our boneless wings, which are lightly breaded with savory spices for a satisfying flavor. Want even more flavor? Dip into one of our sauces to customize your order. Order any of our saucy treats, from sweet (think Sweet Mango Habanero Sauce) to spicy (our classic Buffalo Wings Kicker Hot Sauce) to tangy (bold BBQ sauce). We serve deliciousness however you like it. That's because wing delivery from Domino's is all about serving the best. We're also proud to offer entrées like chicken wings and oven-baked sandwiches, as well as sides like salads, drinks, and our stuffed cheesy breads. And don't forget about dessert! Why do we offer so many choices? That's easy: we want you to have the best experience.
And Domino's is about more than just deliciousness; we make it convenient for you to order from your neighborhood location! Pick up the phone and call our store, use our website to order, or get the free Domino's smartphone app and order from anywhere. Because we operate over 11,700 locations in more than 75 countries, we put the customer first to provide you with quality, value, and customer service. With more than 34 million options to customize your pizza, plus convenient online and mobile ordering for delivery or carryout, it's all about you here at Domino's.
For truly delicious choices ranging from savory pizzas to sweet treats, try Domino's! From side sauces to your choice of crusts to dozens of toppings, you can get creative and customize your pizza any way you want. And Domino's has more than just pizza! Choices of pasta, sandwiches, breads, chicken, and dessert are all available in the area. Whether you're a student at Fort Myers Institute of Technology, or just nearby, or you're ordering from around Lee County Alc Central Middle or near Life Skills Center, Domino's can do it. With specials running all the time, your neighborhood Ft Myers Domino's is dedicated to bringing you the best. Pick up the phone, go online, or stop by today!
Mon-Thu: 10:30 a.m. to 12 a.m.
Fri-Sat: 10:30 a.m. to 1 a.m.
Sun: 10:30 a.m. to 12 a.m.
(239) 693-1600