text:
Cytokines in chronic rheumatic diseases: is everything lack of homeostatic balance?
- Carlo Chizzolini1Email author,
- Jean-Michel Dayer2 and
- Pierre Miossec3
DOI: 10.1186/ar2767
© BioMed Central Ltd 2009
Published: 14 October 2009
Biological systems have powerful inbuilt mechanisms of control intended to maintain homeostasis. Cytokines are no exception to this rule, and imbalance in cytokine activities may lead to inflammation with subsequent tissue and organ damage, altered function, and death. Balance is achieved through multiple, not mutually exclusive, mechanisms including the simultaneous production of agonist and antagonistic cytokines, expression of soluble receptors or membrane-bound nonsignaling receptors, priming and/or reprogramming of signaling, and uncoupling of ligand/receptor pairing from signal transduction. Insight into cytokine balance is leading to novel therapeutic approaches particularly in autoimmune conditions, which are intimately linked to a dysregulated cytokine production.
To explore the complex regulation of cytokine activities it may be of help to bear in mind the example of rheumatoid arthritis (RA). A major step forward in RA treatment was achieved when it became possible to control disease manifestations such as joint destruction by blocking TNF. This could indicate that a single cytokine, in this case TNF, drives unopposed a series of events that lead to inflammation and destruction. The situation is less simple inside the joint, however, where proinflammatory cytokines co-exist alongside their endogenous inhibitors. This is a consequence of ongoing processes in which proinflammatory stimuli induce their anti-inflammatory counterparts and the imbalance between the two results in disease.
Balance in cytokine activities according to biological processes
IL-1/IL-1 receptor antagonist, IL-1 receptor II, soluble IL-1 receptor I, soluble IL-1 receptor II
TNF/soluble TNF receptor I, soluble TNF receptor II
IL-6/soluble gp130
IL-18/IL-18 binding protein
IL-22/IL-22 binding protein
IL-13/IL-13 receptor alpha
Several proinflammatory chemokines (CXC and CC)/Duffy antigen receptor for chemokines
Several proinflammatory chemokines (CC not CXC)/D6
Chemerin 9/chemerin 15
Immune cell responses
Th1 cells/Th2 cells
Th17 cells/Th2 cells
Th17 cells/T cells with regulatory function
T cells with regulatory function/Th1, Th2, Th17 cells
Tissue repair and remodeling
Transforming growth factor beta/TNF
CD4 T-cell differentiation
Transforming growth factor beta/IL-6 + T-cell growth factor beta
Tissue destruction
Adiponectin/leptin, vistatin, resistin
Balance in cytokines
Balance between IL-1 and IL-1 natural antagonists
Cytokine roles categorized according to their contribution to inflammation in rheumatoid arthritis
IL-1 receptor antagonist
Transforming growth factor beta
Phosphatidylinositide 3 kinase is among the most important signaling pathways involved in the control of the IL-1/IL-1Ra balance in human monocytes, in so far as inhibition of phosphatidylinositide 3 kinase delta markedly decreases IL-1 while increasing IL-1Ra [6, 7]. A further example of the plasticity of the IL-1/IL-1Ra balance in human monocytes is the increase in IL-1Ra but decrease in T-cell-induced IL-1β in the presence of glatiramer acetate, a therapeutic agent used in multiple sclerosis [8].
Balance in TNF and IL-6 activities
TNF and IL-6 have become successful targets of biological therapies in a variety of inflammatory conditions starting with RA, thus underling their pivotal role in inflammation. Several excellent reviews have been devoted to these two cytokines and their relevance in human diseases [9–13]. Therefore we shall here overview only the basic mechanisms involved in the regulation of their biological activities, in particular stressing differences in the activity of their respective soluble receptors. Trimeric TNF, mostly produced by activated macrophages and T cells, acts by binding to two distinct TNF receptors: TNF-RI (p55), which is widely expressed; and TNF-RII (p75), mostly present on cells of the immune system (Figure 2). Both receptors can be enzymatically shed from the surface of the cells and, once in the body fluids, both can bind TNF and neutralize its biological activity [14]. The receptors therefore act as natural inhibitors of TNF, and their production is regulated by several stimuli including TNF itself.
At variance with TNF, IL-6 acts by binding to a heterodimeric receptor composed of the common gp130 chain, shared with oncostatin M, IL-11, ciliary neurotrophic factor-1, cardiotropin-1, and leukemia inhibitor factor, and to its specific IL-6 receptor alpha (IL-6Rα). The signaling chain is gp130, affinity of which for IL-6 is increased in the presence of IL-6Rα. Of interest, IL-6Rα exists as a cell-bound form expressed on few cell types - particularly hepatocytes, phagocytes, and some lymphocytes - but also in a soluble form abundantly present in body fluids. Soluble IL-6Rα (sIL-6Rα) has the capacity of binding to IL-6 and to increase its affinity for gp130. Since gp130 is ubiquitously expressed, sIL-6Rα offers the opportunity to cells that do not express IL-6Rα to become responsive to IL-6, a phenomenon called trans-signaling. In transgenic mice sIL-6Rα functions as a carrier protein for its ligand, thereby markedly prolonging the plasma half-life of IL-6, indicating that IL-6 signaling is increased by sIL-6Rα [15]. The agonistic properties of sIL-6Rα by enhancing IL-6 signaling are well documented. There are results indicating also antagonistic properties of sIL-6Rα, however, which may explain why IL-6 may in some circumstances acts as an anti-inflammatory mediator [16].
Besides a soluble form of IL-6Rα, a soluble form of gp130 (sgp130) has been detected in healthy human sera with antagonistic properties. Of interest, the antagonistic activity of sgp130 is markedly enhanced in the presence of sIL-6Rα [17]. Cell responses to IL-6 are therefore finely tuned by the ratios between-cell bound gp130 and IL-6Rα on the one side, and on the other by available IL-6, sIL-6Rα and sgp130.
Balance generated by soluble osteoprotegerin
Another cytokine whose biological activities are modulated by soluble receptors or natural antagonists is osteoprotegerin, which is a secreted member of the TNF receptor family that binds OPGL and blocks its activity. Genetic (including gene-targeting) studies and functional studies in vitro and in vivo indicate that osteoprotegerin is a pure, soluble decoy receptor [18]. Osteoprotegerin also binds and neutralizes TNF-α-related apoptosis-inducing ligand [19].
Additional cytokines whose biological activities are regulated by the balance of agonist and soluble nonsignaling receptors include IL-18/IL-18 binding protein, IL-22/IL-22 binding protein, and IL-13/IL-13 receptor alpha. These will not be discussed in the present review, however, owing to the shortage of space.
Balance in chemokine responses
A balance in chemokine responses is generated via several distinct, but not mutually exclusive, operational mechanisms. As previously shown for other cytokines, distinct chemokines may fulfill opposing functions for a given task. A classical example is the propensity of CXC chemokines sharing the ELR motif (CXCL1, CXCL3, CXCL5, CXCL6, and CXCL8) to exert angiogenic properties, while CXC chemokines lacking the ELR motif (CXCL9, CXCL10, CXCL11) are more angiostatic [20]. Similarly, chemokines may play opposing roles in proliferation and apoptosis susceptibility. In addition, a peculiarity of some chemokine receptors is that they bind chemokines but fail to signal [21]. Chemokines signal through seven-transmembrane domain, G-protein-coupled receptors, of which 19 have been molecularly defined. These receptor families reflect the two major (CC and CXC) chemokine families and two minor (C and CX3C) chemokine families [22]. In addition, chemokine receptors whose structural features are inconsistent with signaling functions have been described. By binding to chemokines, non-signaling receptors act as a decoy, scavenge receptors, and regulate inflammatory and immune responses. The family of silent chemokine receptors comprises Duffy antigen receptor for chemokines (DARC), D6 (also known as CC chemokine binding protein 2), and CCX-CKR (also known as CCRL1). It is noteworthy that the silent chemokine receptors, which lack the key residues needed for coupling with G-proteins, have unusual expression patterns and a wide range of chemokine-binding properties.
DARC is expressed on erythrocytes and endothelial cells of postcapillary veins in many organs - including, amongst others, high endothelial venules in lymphoid organs [23]. DARC binds 11 proinflammatory (both CC and CXC) but not homeostatic chemokines, and preferentially angiogenic but not angiostatic chemokines [24]. Chemokines injected in DARC-/- mice rapidly disappear from circulation, indicating a role of erythrocyte DARC as a sink or reservoir. Endothelial DARC, however, appears to have a downregulating effect on inflammation. Overexpression of endothelial DARC in animal models is therefore associated with both decreased angiogenesis and tumor growth, while a lack in DARC is associated with increased tumor growth, metastasis formation and increased concentrations of CXCL1 and CXCL3 [25, 26].
D6 binds most inflammatory CC chemokines, but not CXC and homeostatic CC chemokines. D6 is expressed at high concentrations on lymphatic and venular endothelium, particularly in the skin, gut, lung, and placenta [27]. D6 mediates chemokine degradation, being constitutively internalized through clathrin-coated pits. D6-/- mice are prone to exaggerated inflammatory responses induced by phorbol ester myristate acetate application to the skin or subcutaneous injections of complete Freund's adjuvant [28, 29]. Lack of D6 expression in syncytiotrophoblast increases the susceptibility to inflammation-induced fetal loss [30]. In contrast, transgenic expression of D6 in keratinocytes dampens cutaneous inflammation and reduces tumor growth [31].
CCX-CKR appears to have a more limited chemokine-binding repertoire that includes CCL19, CCL21, CCL25, and CXCL13, and it is expressed exclusively by stromal cells in the thymus and lymph nodes, by lymph vessels in the intestine and by the epidermis [32]. In CCX-CKR-/- mice, trafficking of dendritic cells to lymph nodes under steady-state conditions appears to be decreased, as well as the recruitment of hematopoietic precursors to the thymus.
Pathogen-encoded decoys also affect chemokine activities. Indeed, molecular mimicry of chemokines and their receptor is an important immune-evasion strategy used by pathogens, of which numerous examples are known. Viral chemokine binding protein and Schistosoma mansonii chemokine binding protein have been described.
The receptor functions of some chemokines appear to vary according to the context in which they operate. For instance, IL-10 uncouples CCR2 binding from signaling, and therefore CCR2 functionally becomes a decoy receptor [33]. An additional example is the high level of CCR5 expressed in response to lipoxin A4 on apoptotic neutrophils and T cells. Lipoxin A4 is produced late during the inflammatory response when significant tissue damage has already occurred. By increasing the expression of CCR5 on dying cells, lipoxin A4 contributes to scavenging CCR5 ligands, which therefore are no longer available for recruiting new cells, which in turn reduces inflammation.
An additional mechanism regulating chemokine activities is related to modifications of their primary structure. For instance, the N-terminal natural deletion variant of monocytes chemotactic protein-1/CCL2 (called 7ND) inhibits chemotaxis mediated by monocytes chemotactic protein-1, and the extension of RANTES/CCL5 by a single methionine (met-RANTES) creates a potent and selective RANTES antagonist.
The particular example of chemerin
Chemerin is a plasma protein known for its proinflammatory properties exerted upon binding to the G-protein coupled receptor ChemR23/CMKLR1 - expressed on macrophages and plasmacytoid dendritic cells - where it induces cell migration. Chemerin is secreted as an inactive precursor and is processed by proteases before becoming an active mediator. As for conventional chemokines, the biologically active chemerin binds to ChemR23 with its COOH-terminal portion.
Of interest, different proteases generate different chemerin peptides, which possess opposite functions. Serine proteases mainly produced by activated neutrophils - early mediators in inflammation - therefore generate chemerin 9 (9 AA peptide), which is an agonist in the nanomolar range. Cysteine proteases - mainly produced by macrophages - which arrive later at the inflammatory site, however, generate chemerin 15 (15 AA peptide). This peptide in the picomolar range acts as an antagonist, expressing potent anti-inflammatory activities and contributing to reduce inflammation [34].
A further layer of complexity has been added recently with the description of an additional chemerin receptor named CCRL2, selectively expressed on mouse mast cells. Upon binding to this receptor, chemerin induces neither cell migration nor calcium flux. CCRL2 is therefore supposed to scavenge chemerin. The experimental test of this hypothesis led to the opposite result, however, indicating enhanced inflammation in a rodent model of IgE-mediated passive cutaneous anaphylaxis. A possible explanation could be that mast cells bind the N-terminal portion of chemerin with CCRL2 and present the COOH-terminal portion to cells expressing ChemR23, which are thus potently activated [35].
The Th1/Th2 balance
In the late 1980s Mosmann and colleagues described the Th1/Th2 balance when studying a large series of mouse CD4+ T-cell clones [36]. They observed that some clones would produce IFNγ but not IL-4, while others would do the opposite. Therefore, based on the dicotomic production of two key cytokines, it was possible to classify T-cell clones into two groups, which were named Th1 and Th2. The same concepts were verified by studying human T-cell clones [37]. Naïve T cells could be induced to become Th1 or Th2 simply by modifying the cytokine present in the milieu during priming, although the dose of antigen, the amount of co-stimulation, and the age of antigen-presenting cells could also affect polarization.
Of major importance, Th1 cytokines were shown to inhibit Th2 cytokine production and function, and vice versa. This observation included cytokines important for priming: IL-12 and IFNγ for Th1 cells, and IL-4 for Th2 cells. Starting investigations with mouse models of human diseases, it was found that models of multiple sclerosis - such as the antigen-induced experimental acute encephalomyelitis (EAE) - or of RA - such as type II collagen arthritis - were associated with the overexpression of IFNγ but not of IL-4. In sharp contrast, models of allergic diseases such as asthma were associated with IL-4 without IFNγ expression. In these models, forced expression of counteracting T-helper cytokines could in many instances abrogate disease expression [38, 39].
Addition of the Th17 pattern
The Th1/Th2 paradigm was then revisited; key observations were made based on the murine EAE model [43]. This model was previously associated with Th1 responses. Th1 cells are induced by IL-12 produced by monocytes and dendritic cells. IL-12 is a heterodimer composed of p35 and p40 subunits. Protection from EAE was afforded when IL-12 was blocked with anti-IL-12p40. IL-23 is also a heterodimer, however, composed of the IL-12/IL-23 common p40 subunit and the specific p19 subunit. When inhibitors specific to IL-23 or p19-deficient mice were used, it was recognized that IL-23 and not IL-12 was responsible for EAE induction by assisting the expansion of Th17 cells. Many chronic inflammatory diseases previously thought to be associated with Th1 have therefore been reclassified as Th17 diseases [44]. The opposing roles of Th2 and Th17 responses are now clear, since IL-4 strongly inhibits IL-17 differentiation. For Th1 and Th17 cells, a more balanced view is now accepted [45]. In both human and murine conditions, a large proportion of T cells can express simultaneously IFNγ and IL-17. This is clearly seen with T-cell clones from peripheral blood. The simultaneous production of the two cytokines appears uncommon, however, in inflammatory tissues where T cells producing cytokines take on a plasma cell-like appearance, possibly indicating full differentiation with a fixed phenotype [46].
In addition to the production of IL-17 (now referred to as IL-17A), Th17 cells can produce other cytokines - including IL-17F (a close member of the IL-17 family), IL-21, and IL-22. IL-21 acts as an endogenous amplifier of the Th17 lineage [41]. IL-22 appears more specifically associated with skin defense [47]. IL-17A and IL-17F share a large number of functions, with a strong correlation between the genes induced in RA synoviocytes by the two cytokines, IL-17F being less potent [48]. In addition, synergistic activities are seen when combining TNF with IL-17A or IL-17F. IL-17A and IL-17F may, however, have different roles in mouse models of inflammation and host defense [49].
IL-17E (also termed IL-25) is a very different member of the IL-17 family. IL-17E is more a Th2 cytokine, involved in allergic reactions and inhibiting the Th17 pathway [50]. Consequently, there is another balance between the effects of IL-17A and IL-17F and those of IL-17E/IL-25.
Balance between Th17 and T cells with regulatory function
Th1, Th2, and Th17 cells are effector cells contributing to key functions of the immune response. An additional heterogeneous subset of T cells with regulatory function (Tregs) has recently been identified. Some Tregs occur naturally, whereas others are induced in response to antigens. Characteristically, Tregs express the transcription factor Foxp3, as well as CD4 and CD25. The immunomodulating effects of Tregs are mediated by membrane molecules (for example, cytotoxic T-lymphocyte-associated protein 4, glucocorticoid-induced TNF receptor, and OX40) and by cytokines including IL-10 and TGFβ.
TGFβ is key to the induction of Foxp3-positive regulatory T cells. Indeed, mice defective in TFGβ die quickly from a massive uncontrolled inflammatory disease [51]. Contrasting with the effect of TGFβ alone, the simultaneous presence of TGFβ and IL-6 favors the emergence of Th17 cells alongside the inhibition of the Tregs [52]. IL-6 - a cytokine with pleiotropic inflammatory effects - therefore plays a pivotal part, at least in the mouse, in directing the differentiation of T cells toward the Th17 or Treg pathways. TNF, IL-1, and IL-17 interact together to induce massive amounts of IL-6. Increased inflammation therefore has a positive effect on the Th17 pathway and a negative effect on its regulation.
The inhibitory functions of IL-27 and IL-35
Some recently identified cytokines such as IL-27 and IL-35 appear to be more involved in dampening the immune response. IL-27 belongs to the IL-12 cytokine family that also comprises IL-23 and IL-35, all involved in the regulation of T-helper cell differentiation. IL-27 is unique in that it induces Th1 differentiation while simultaneously suppressing immune responses. The immunosuppressive effects of IL-27 depend on inhibition of the development of Th17 cells and induction of IL-10 production [53]. IL-27 exerts potent anti-inflammatory effects in several infectious and experimental autoimmune models. In particular, suppressive effects on helper T cells - which are implicated in the pathogenesis of multiple sclerosis - suggest that IL-27 may be therapeutically relevant in multiple sclerosis. While exciting discoveries have been made, however, these are still at an early stage and further studies are required to understand the pathophysiological roles of IL-27 and its therapeutic potential in humans [54].
The inhibitory cytokine IL-35 contributes to regulatory T-cell function, being specifically produced by Tregs and required for maximal suppressive activity [55]. Ectopic expression of IL-35 confers regulatory activity on naive T cells, whereas recombinant IL-35 suppresses T-cell proliferation. The role of Tregs in RA has been established in both patients and animal models. The Tregs increase in patients who are responding to anti-TNFα therapy. Of the current hypotheses, Treg expansion or transfer may hold promise for the treatment of RA [56].
Cytokines, hormones, vitamins, arachidonic acid metabolites and lipoproteins
A further layer of control at the level of expression of cytokines, cytokine inhibitors and acute-phase proteins is provided by hormones. Estrogens as well as androgens inhibit the production of IL-1β and TNFα by monocytes-macrophages. Androgens antagonize stimulatory effects of estrogens. Some studies suggest that estradiol is more inhibitory to Thl cytokines (for example, IFNγ, IL-2) while testosterone is inhibitory to Th2 cytokines (for example, IL-4). On the other hand, cytokines control the hypothalamic-hypophyseal-adrenal gland axis as well as the sex hormones [57]. Vitamins may also affect cytokine production by influencing the polarization of effector CD4+ T cells. For instance, retinoic acid enhances Treg expansion while simultaneously inhibiting Th17 cells [58]. Conversely, vitamin D favors Th2 polarization and diverts Tregs from their regulatory function [59, 60]. Finally, prostaglandin E2 - a metabolite of arachidonic acid - may also affect cytokine production by favoring the expansion of Th17 cells [61].
Destruction/repair balance
Chronic inflammatory diseases such as RA are so severe because the disease process affects matrix metabolism. Although RA is seen as a destructive disease, it is not well appreciated that the main problem is in fact the inhibition of repair activity. Any type of chronic joint inflammation, whether infectious, inflammatory, or autoimmune, will result in joint destruction within months or, at best, within a few years, but it will take decades to observe some kind of joint repair - even in conditions like osteoarthritis where repair activity is maintained. In a model of cell interaction between synoviocytes and T-cell clones, it was found that Th1 and Th17 clones induced defects in collagen synthesis in vitro, indicating an inhibition of their repair activity (Figure 1). In sharp contrast, Th2 cells induce collagen synthesis, indicating their beneficial role in repair activity [62]. Very similar conclusions were obtained when monocytes were incubated with Th1 or Th2 clones. The interaction with a Th1 clone led to the production of IL-1, a key marker of destructive inflammation, whereas the use of a Th2 clone led to production of IL-1Ra along with its anti-inflammatory and anti-destructive properties [63].
Wingless integration site (Wnt) proteins make up a family of secreted growth factors, identified in virtually every organism; they regulate key aspects of cellular functions such as growth, differentiation, and death. Several members of the Wnt pathway play an important part in bone remodeling. Dickkopf-1, a soluble inhibitor of the Wnt pathway, controls bone remodeling. Increased Dickkopf-1 levels are linked to bone resorption, and decreased levels are linked to new bone formation. Low-density lipoprotein receptor-related protein 5, the main receptor that mediates Wnt signaling, plays a critical role in bone mass regulation. Gain-of-function mutations of lipoprotein receptor-related protein 5 cause high bone mass phenotypes, whereas loss-of-function mutations are linked to severe osteoporosis [64].
Adipose tissue in inflammation: a protective role via IL-1 receptor antagonist?
Adipokines are beginning to emerge as mediators of inflammation. Knowledge of their precise activities remains in its infancy, however, and is still controversial [65]. Many of the adipokines appear to have proinflammatory properties. In general, adiponectin is considered anti-inflammatory, and leptin, vistatin and resistin are considered proinflammatory. The formation of adipose tissue could be due to abnormal metabolic processes and, at the local level, due to chronic inflammatory processes such as those occurring in the synovium in RA or osteoarthritis, or in the peritoneal cavity in various inflammatory processes of the digestive system.
Adipocytes are said to produce many hormones and pro-inflammatory mediators. White adipose tissue in humans, however, is assumed to be the main source of IL-1Ra, and also contains IL-10. Furthermore, IFNβ was found to be the principal cytokine inducing IL-1Ra in various white adipose tissues, such as that present in the synovium. It is possible that, in addition to other functions, adipose tissue may be part of a mechanism limiting local inflammation and that fibroblasts in the vicinity may further induce IL-1Ra in adipocytes via the production of IFNβ [66].
Influence of signal transduction in cytokine balance
IL-10 contributes to homeostatic responses in proinflammatory conditions. For instance, in human monocytes, Toll-like receptor 2 ligation results in NFκB-dependent TNF production and simultaneously in activator protein-1-dependent IL-10 production [69]. Upon binding to its receptor, IL-10 decreases TNF production in a STAT-3-dependent manner, thus exerting a negative feedback. Pre-exposure of monocytes to IFNα, however, results in IL-10 gaining pro-inflammatory functions. Of interest, this process is STAT 1 dependent. It has therefore been shown in human monocytes primed with IFNα that IL-10 not only fails to reduce the subsequent production of TNF in response to lipopolysaccharide, which may simply indicate a loss of function of the anti-inflammatory activity of IL-10, but in addition primes monocytes to transcribe genes in response to IL-10 usually induced by IFN. It appears that, due to the effect of type I interferons, the balance of IL-10 signaling shifts from STAT 3 (anti-inflammatory) to STAT 1 (proinflammatory) signals. Furthermore, IL-10 induces chemokine production in IFNα-primed macrophages, resulting in recruitment of activated T cells; aberrant IL-10 signaling may therefore contribute to inflammation in conditions with high interferon levels (systemic lupus erythematosus) [70].
The suppressors of cytokine signaling (SOCS) family of intracellular proteins - which encompasses eight members, sharing a central Src homology domain 2 and a C-terminus SOCS box - act as negative regulators of intracellular signaling of the Jak-STAT pathway used by several cytokines. They act by inhibiting the kinase activity, by competing with substrates needed for signal transduction, and by targeting associated proteins to proteasome degradation. Beside negative regulation, SOCS proteins can also affect the quality of signaling. For instance, in the absence of SOCS 3, IL-6 induces a wider transcriptional response, which includes interferon-like gene expression owing to increased STAT 1 phosphorylation. SOCS proteins therefore impact on a number of important mechanisms regulating inflammation and the immune response [71].
Cytokine activities affect most, if not all, biological processes involved in homeostasis as well as in host defense and auto-aggression. A continuous, finely tuned, crosstalk between cytokines, receptors, agonist and antagonist ligands, as well as with mediators belonging to other families of molecules, regulates cytokine biological activities. Furthermore, the context in which cytokines are available, including the temporal sequence of events preceding the availability of a given cytokine, very much impact on their capacity to favor or inhibit inflammation and other biological processes. During the past three decades we have learned that an imbalance in cytokine activities is associated with autoimmune and autoinflammatory disorders. More important, our knowledge of the many levels of cytokine balance has led to the generation of important tools to control inflammatory and destructive diseases. The future will no doubt witness additional major achievements in this area of medicine.
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
CC-family chemokine receptor
Duffy antigen receptor for chemokines
experimental allergic encephalomyelitis
- Foxp3:
forkhead box p3
IL-1 receptor
- IL-6Rα:
IL-6 receptor alpha
- IL-1Ra:
IL-1 receptor antagonist
nuclear factor
rheumatoid arthritis
regulated on activation, normal T-cell expressed and secreted
single immunoglobulin IL-1-related receptor
- sIL-6Rα:
soluble IL-6Rα
suppressors of cytokine signaling
signal transducer and activator of transcription
- TGFβ:
transforming growth factor beta
- Th:
T-helper type
tumor necrosis factor
- Treg:
T cell with regulatory function
- Wnt:
wingless integration site.
The field of cytokine balance is very large and imprecisely defined. The authors would like to apologize to the many authors having contributed to this fascinating field whose work has not been quoted in the present review. CC was supported in part by grant No 31003A_124941/1 from the Swiss National Science Foundation.
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text:
Many of your descriptions of fall weather sound like my own. Right now, the leaves are full of color...a full month late and surprising more colorful than I expected after such a wretched summer and early fall. This week, we had several frosts which did in most of my tomatoes and the squash vines. I finally got some garlic planted and a couple of beds mulched. Do you know about this new website on drought? http://www.drought.gov/portal/server.pt The precipation input from COCORAHS is being shared since it also indicates no precipation. The information on this site is still very experimental but good that the data is beginning to be collected and studied.
For those of you collecting family history information, don't despair. My husband researched and gathered information for years when he was younger. The only ones interested at that time were the older folks who were amazed that he was interested. A few years ago, we copied all the pertinent information and made it available at a family reunion. The younger folks had finally become so interested that he ran out of copies (we had made around 50).
I started much later and went to my parent's home town where I interviewed several great aunts. Unfortunately, I had only a week and didn't get all the information I needed. Then, when we adopted and I was still working, I put the history aside. We are still trying to gather more information. I have two members back to Europe (most of my family came in the mid-1800s) and am still working, occasionally, on the others.
Bonnie Holmes
ETN Zone 7
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The administration of Karl Dönitz, head of state and supreme commander of Germany's armed forces following Hitler's suicide, marks a key period in World War II. Author Walter Lüdde-Neurath served at Dönitz's side through the final, chaotic weeks of fighting, the infighting among the Nazi elite as they tried to save themselves, and the negotiations for surrender. With this memoir Lüdde-Neurath provides an insider's view of what happened as the Third Reich collapsed around them.
Walter Lüdde-Neurath served as adjutant to Karl Dönitz, the commander in chief of the German navy and charged by Hitler to be the head of state upon his death.
None found for this author.


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With Tom Cruise filming his upcoming movie Wichita in Boston, it's become a TomKat family affair. On Sunday, Tom took wife Katie Holmes, daughter Suri and teen son Connor out for a day of shopping in Beantown.
PHOTOS: The TomKat Crew Hits Boston
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Announcing plans for reform of utility regulation, Dr Jack Cunningham, the shadow trade and industry secretary, also revealed that he is to meet Sir Richard Greenbury, chairman and chief executive of Marks and Spencer, this week to propose new measures to prevent abuses "on salary hikes and share option packages which are completely unrelated to individual or corporate performance".
Sir Richard chairs the committee on top pay which is due to announce plans for greater disclosure of board-level earnings and a clearer link between executive pay and performance.
At the meeting, Dr Cunningham is expected to urge the toughest possible measures to ban boardroom pay increases unrelated to performance. Labour sees the Greenbury recommendations, if they come up to scratch, as a possible benchmark for good practice in any new legislation.
Tony Blair, the Labour leader, called for an end to the "unseemly racket" of price rises by the privatised utilities in angry clashes with the Prime Minister in the Commons.
Mr Blair staked out the privatised utilities as one of the main battlegrounds for the General Election campaign.Hesought to make his party the defender of the consumers' interests. He condemned the latest "pay-and-perks scandal" over the disclosure that three board members of the National Grid had cashed in £600,000 worth of options on shares not yet available to the public.
"These utilities have degenerated into an unseemly racket and the sooner you order a thorough overhaul of their system of regulation the better," Mr Blair said.
Mr Major, the Prime Minister, has promised legislation to back the recommendations of the Greenbury Committee, but this is expected to be much less comprehensive than the new act Labour is examining.
Some of the Greenbury recommendations are likely to be incorporated in the Stock Exchange rule book and a new version of the Cadbury rules on corporate governance.
The core of Labour's utility reform plan is to make shareholders in privatised utilities share "excess" profits with customers - including what Dr Cunningham called a consumer dividend.
In a speech to a London conference organised by the left-of-centre Institute of Public Policy Research and Unison, the public sector workers' trade union, Dr Cunningham said this would work automatically to curb the excess profits from which the salary and share option bonanzas of utility directors have been generated. But he made no mention of using the regulators to curb pay directly.
Qualified backing for change came from Clare Spottiswoode, the gas regulator, who told the conference that she was looking at possible reform of the price-setting formula and the introduction of profit sharing. She promised a consultative paper in the next month.
Opening the conference, Mr Blair said the present system for regulating gas, water, electricity and the other privatised utilities was not working and a new approach was required.
Dr Cunningham also said that Labour wanted to link automatic price cuts to high profits without destroying incentives towards efficiency.
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Hi Ben and George,
I believe either of these two naming conventions is acceptable to
the ICNCP, which leaves the ICRA with the choice on these. The ICNCP does
now ban the lone use of Latin, English, and other language color or pattern
descriptives for a hosta name, hence the plant cannot simply be called
'Nakafu'. The choice then is to add the species epithet (Ben), convert the
species epithet to Japanese and make it part of the cultivar name (George),
or to rename or ask that it be renamed to an acceptable cultivar name. If
keeping the 'Nakafu' and simply adding a species epithet is illegal under
the code, then it is no longer an option. In the future we will probably be
discussing American Hosta Society naming rules, but there are none as of
this writing. This is one of many issues that we will probably be taking up
at that time.
I am in favor of discontinuing for any newer plants the practice of
using the species name first, especially of only followed by a color or
pattern descriptive. There are several reasons why I think this is the best
course, which I will outline below.
1. It is too simplistic to cover hostas, which sport far more frequently
than other plants. For example, there are several white margined plants of
pure montana lineage in the market today as well as several more
lesser-known ones in Japan. Possibly there are as many as a dozen in
existance now. The most famous of these is 'Frosted Jade', with 'Mountain
Snow' a close second. If a new one is found in Japan, or sports elsewhere
for that matter, should we allow it to be named montana 'Albomarginata' or
montana 'Shirofukurin' (same thing in Japanese instead of Latin)? The real
problem with names like that is that they only work if there is only one
white-margined montana. They can cause significant confusion if there are
several, and the purpose of the ICNCP is to reduce confusion, not increase
it. To allow a plant to be named in essence Hosta montana 'White Margined'
when there are numerous white-margined montanas clearly causes a problem in
the records.
2. Existing names. As in the above example, the word "montana" is used in
the names of some white-margined montana forms but not all. To accept
further names along these lines when many already lack the species epithet
continues adding unnecessary confusion. There are a large number of plants
of pure species lineage that do not carry the species epithet already in the
trade, especially sieboldianas. It adds to confusion to have some with the
species and some without, especially if there is no other difference between
the plants as far as species backgound goes.
3. The somewhat fluid nature of hosta species. Do we know which hostas are
species and which are not? Georges redefinition of the species is largely
accepted today, but what if in the future Ben's version holds sway? In the
examples in #1, what happens if, as Ben wishes, montana ceases to be a
species? The difference in George's naming convention is that it will not be
an issue because the species epithet is converted to a part of the cultivar
name and changed to Japanese form. While a better solution is to use a name
that fits the code for English usage and does not include the species name
in any form, the problem is that we cannot change the name without the
originator's permission.
4. The difficulty in determining if a plant is truly of a given species and
is not a hybrid with a similar appearance. This came up in the past with
such plants as kikutii 'Kifukurin', since determined to be either longipes
or a hybrid and renamed. There would be quite a bit of renaming if we just
let anyone register plants as species examples when their background is
uncertain. Remember that these plants can be registered by anyone without
any scientific examination to determine their species background.
Overall, I feel the best solution would be to disallow the use of a
species epithet altogether, even to the extent of renaming old plants like
montana 'Aureomarginata' to common names like 'Mountain Sunset'. These names
mostly came into existance before we realized the sheer number of sports we
would eventually see. At best we should slowly transfer the use of such
names to the past with quaint old names like Funkia. True, these epithets
can be useful, but only if they are accurate, but I feel they are more
confusing than useful however accurate and should be abandoned entirely at
some point. Unfortunately, I don't think this is a practical approach at
this time, and agree with George's approach as being an acceptable
transition phase.
..........Bill Meyer
> THis is a classic example for creating a problem first and then find
> a brilliant solution. If we leave the species name kiyosumiensis
> with the cultivar name Nakafu there is no problem However if the
> very informative species name is left out, without any argument,
> we have a problem that is "solved" by adding at the end the same
> species name in japanese! So if I want to use the species name
> anyway we have H. kiyosumiensis 'Nakafu kiyosumiense' I think
> the original name H. kiyosumiensis Nakafu must be adhered to.
> Ben J.M.Zonneveld
> Institute of Biology,Leiden University, Clusius lab
> Wassenaarse weg 64, 2333 AL Leiden, The Netherlands
> email@example.com
> Fax: +31-71-5274999. min temp -10C (15F)
> ---------------------------------------------------------------------
> To sign-off this list, send email to email@example.com with the
> message text UNSUBSCRIBE HOSTA-OPEN
Hi All,
Please let me correct this: It is H. kiyosumiensis not H. kyosumiensis. The
ICNCP does not allow the use of a descriptive (adjectival) name as the sole
cultivar name, hence H. kiyosumiensis 'Nakafu' is illegitimate per article
19D.1. of the ICNCP. The ICNCP article 19.4 does allow a cultivar name in
its Japanese form by adding the Japanese vernacular species name so the
correct name is H. 'Nakafu Kiyosumi' which is also the vernacular Japanese
name. H. 'Busen' could be used as a synonym and is permissible by the ICNCP
but was apparently withdrawn. George
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Five ingredient soup
Nutritional Info
- Servings Per Recipe: 6
- Amount Per Serving
- Calories: 150.9
- Total Fat: 1.0 g
- Cholesterol: 1.0 mg
- Sodium: 875.2 mg
- Total Carbs: 31.0 g
- Dietary Fiber: 6.5 g
- Protein: 7.4 g
View full nutritional breakdown of Five ingredient soup calories by ingredient
Submitted by: CHADJEN152
Introductionvery filling low cal soup very filling low cal soup
Number of Servings: 6
1 can fat free refried beans
1 can corn
1 can chopped tomatoes
1 can chicken broth
1 can black beans
Mix all ingredients together and simmer for 30 minutes. Makes 5 servings and freezes well.
Number of Servings: 6
Recipe submitted by SparkPeople user CHADJEN152.
Number of Servings: 6
Recipe submitted by SparkPeople user CHADJEN152.
Rate This Recipe
Member Ratings For This Recipe
I needed something quick with ingredients I had on hand. I decided to try this soup, but didn't have high expectations. When I added the ingredients, it really did not look very good. The end result however, was much better than I anticipated. Quite good and filling, I'll be making often! - 10/18/13


text:
Many Web services provide open source teams with an infrastructure for collaborative development, but what if you're a small team of developers with little funding wanting to develop closed source software? Can you still engage in collaborative development while keeping your costs minimal? Yes, of course. We show you how.
Collaborative development has become ingrained in the minds and practices of software developers everywhere, to the point it's no longer a buzzword. A large part of the software being developed today has been completely or partially done by programmers over a network across long distances.
Three things have greatly contributed to this: the Internet ubiquity and the advancements in bandwidth offerings, the rapid development of specialized tools and services for programmers wanting to share work across long distances, and the increasing complexity of the software required by users.
It's unquestionable that the great motivator and contributor to this software development paradigm has been the open source community. Most of the advancements in tooling and development practices concerning collaborative development has come from that group. This activity stems from the fact that open source development is almost exclusively done by large groups of developers across the globe. The Apache project includes developers from five continents, all contributing source code from their homes or work places.
However, collaborative development has also become an integrated part of closed source development. Not to the same scale, for sure. But it's been a practice among hobbyist and small developers in pursuit of creating free and commercial products. Likewise, companies large and small have been collaborating on all types of projects, either through contractual partnerships or through subcontracting. Interestingly enough, the current landscape of collaborative software tools and services presents a problem to small teams of developers wishing to collaborate over closed source projects.
A good portion of the collaboration services available on the Internet are free. These primarily include revision control and bug-tracking tools. However, these websites do not generally allow the hosting of closed source projects – when they do, it involves paying a monthly fee. These groups of programmers are often ad-hoc partnerships between individuals, with very little monetary resources, no investors to speak of and no company formed, wishing only to create a product before they commit to the legal and fiscal unpleasantness of creating a company and a brand name. Essentially, individuals with no money to speak of, but still wishing to give it a try like everyone else.
What this article presents is a complete solution for collaborative development of small team projects at no cost, past what is already there with the Internet access bill.
Explaining every step of the procedure is unnecessary and outside the scope of this article. The aim is to expose the available options. It's assumed that the reader knows what revision control, bug-tracking or Apache is and how they need to be set up (or at least know how to learn from the many online manuals and tutorials). There is however, a comments section to this article linked at the end, and I will be more than happy to answer any questions there.
The core of the whole setup is the local installation of revision control, bug-tracking and database management services that will serve the team through the Internet. An ad-hoc website will also be installed and a communications solution presented. Most of this will be server software. ADSL Internet connections aren't ideal for this type of setup, considering the great limitations they usually impose on the upload link. Ideally, one will want a DSL, cable or fiber connection, and any team member having such a connection should be considered as the prime candidate for installation.
With small teams (2 or 3, maybe 5 programmers at most) it can work reasonably well if installed over ADSL. In any case, it is recommend that the team share responsibilities instead of everything being installed on a single member machine. One member is responsible for hosting and maintaining the revision control service, another bug-tracking, another the database, et cetera.


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Vol. 46, No. 3
Fall 2002
Editor: Bruno Nettl
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Tropical Fish Keeping - Aquarium fish care and resources (http://www.tropicalfishkeeping.com/forum.php)
- Cyprinids and Atherinids (http://www.tropicalfishkeeping.com/cyprinids-atherinids/)
- - I know I'm a barb...but what kind? (http://www.tropicalfishkeeping.com/cyprinids-atherinids/i-know-im-barb-but-what-12456/)
I know I'm a barb...but what kind?
Can I be friends with other barbs?
Gold barb, maybe?
Now I'm thinking a Rosey Barb since they only have one black spot. http://elmersaquarium.com/10barb_rosy.htm I like that web site..I forgot about it. They have lotsa pics. Thanks Bob
looks alot like my neon rosy barb but dont take my word for it im not entirely shore what mine is either :wink:
Looks a LOT like my rosy barbs. Prolly a neon rosy like dr heckle said.
Zippy little buggers are hard to photograph aren't they? All my barb pics are like that. Little torpedoes with flashy trailers :)
I think neon rosey barbs wins it. They are much redder than any other rosey barb I've ever seen and yes, they are very quick and hard to photograph!!
it's a rosy barb.
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- Product Details
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This is a nylon fishnet with a subtle stretch and soft hand, comes in a variety of colors.
Color: Turquoise
Width: 74"
Content: LYCRA, NYLON
Industry Weight: 15.10 oz/yd
Learn about fabric careHOW TO CARE FOR POLYESTER FABRICS:Machine wash warm or cold, tumble-dry low. If ironing is needed, iron on a low temperature.Mood strongly recommends test-laundering a swatch, if you plan to wash your garment or home furnishings yourself.
PLEASE NOTE: The above numbers are estimations only. Please take into account garment size, lining and fabric width.


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19430 Surnames | 123747 Records | 2647 Reunions
Dead Fred asks:Are you a Desperate Genealogist?
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14 photos in database by this submitter.
Order The Desperate Genealogist's Idea Book: Creative Ways to Outsmart Your Elusive Ancestors (eBook).You can also order The Desperate Genealogist's Idea Book in hardcopy format by clicking here.
Photo #30285
Last Name: lawson
First Name : neville (jack
Middle Name: ac
Subject's City: senath
Subject's State: mo
Subject's County: dunklin
Subject's Country: usa
Date: 1941-1960
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Type** :
Comments: neville (jack ac lawson (Nee: ) | senath mo usa | 1941-1960 | Comments: father was henry crossno and mother was gemima magee. there are different spellings of the crossno name, crossnoe, crosno, crossnore.
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Newegg.com - A great place to buy computers, computer parts, electronics, software, accessories, and DVDs online. With great prices, fast shipping, and top-rated customer service - once you know, you Newegg.
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This review is from: AZZA Solano 1000 Black Japanese SECC Steel/Metal mesh in front MicroATX/ATX/Full ATX Computer Case
Pros: This AZZA case pretty much does everything for you.
1. Tons of fans.
2. Big work space.
3. Good dust filters.
4. fan controller on the back.
Cons: After about one year with this case, I have become more and more annoyed by it's issues.
1. There is no room for an aftermarket CPU cooler: the tops of the cooler collide with the side fan on the AZZA case when the side panel is on all the way. I haven't been able to keep the side panel on, except while moving the case. And if I forget to take it off again, when I turn on my computer I will be greeted by one of the loudest, more terrible noises a computer could make.
If anyone can help me with that it would be much appreciated.
2. This case isn't the most cable friendly. The back of my case bulges out due to the power supply cords, and was also very hard to put on after doing cable management behind the case.
3. Not much room for customization.
by that I mean, you can't add more fans without removing old ones.
4. Pretty loud.
Other Thoughts: Azza really should have thought to test their case with an aftermarket cooler. I am using the hyper 212, one of the most common on the market.
If you can, go with a fractal R4 or h440. Those cases are very common for a reason.


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Whether it's 50-knot gusts or rolling ocean swell, rain coming in sideways or thunder booming in the distance, there's no question: sailing in storms in the true test of seamanship. Check out our gallery of incredible storm sailing on everything from massive ocean-going race boats to simple sailboards.
Storm sails
What we don't know: where this is or who's steering that boat. What we do know: those are stormy seas, and small sails. This is the time to batten down the hatches, reef the main, and get out the blade sails.
Close to the wind
Forget Alex Thomson and Pepe Ribes charging through big seas off the British coast on Hugo Boss. Spare a thought for sailing photographer Mark Lloyd who was shooting from a helicopter. "It was right on the limits," he says.
Pointing power
Emirates Team New Zealand pierces through the surf during the AUDI MedCup. We're going to guess the crew got wet.
Towering Tazzy waves
Dany Bruch at the Mission 2 of the Red Bull Storm Chase in Temma Harbour, Tasmania. It took a storm with force 10 winds to produce waves this size.
Cold cruncher
Dany Bruch, again, at the Red Bull Storm Chase at the Bluff in Cornwall, England. Wetsuit required – this was in February!
Storm strategy
A Volvo Ocean Race boat isn't your average lake-side dinghy. Nearly every manoeuvre on the boat – tacking, jibing, or raising the sails – requires a rehearsed, choreographed effort from the crew. When the weather goes awry, the stakes get much higher.
Non-optimal conditions
Storms don't only happen on the sea. A racer in the Optimist class waits out some weather during a regatta in Trieste, Italy.
Foam and fun
Rough seas and whitewater during the America's Cup Final near Queensland.
Just a little bow spray
The bow of a race boat pierces through surf at the Portofino Rolex Trophy.
Point break
Starting from Malta and going around Sicily and its islands, the Rolex Middle Sea Race passes two active volcanos. The conditions at the time of the photo taken were extreme – blowing around 35 knots (65kph) with big seas.
Rain coming over the deck sideways during the Abu Dhabi Ocean Racing in Cascais, Portugal.
Soloing a storm
This is the only way to the train for the Vendée Globe – a solo-skippered regatta around the world, and one of the most difficult races in sailing.
White water
French sailor François Gabart during a 24-hour, bad-weather training sail in Brittany. Good thing most storms don't last all day.
Who's the Boss? For skipper Alex Thomson, there's only one answer, Hugo Boss, an Open 60. The boat has an impressive history including a fourth place in the 2012-2013 Vendee Globe after losing its keel, first in the 2010-2011 Barcelona World Race, second place in the 2011 Rolex Fastnet, and first place in the 2010 Transat Jacques Vabre. Looks just the job.
Want to experience the best of RedBull.com on the move? Get the mobile app at RedBull.com/app.


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This hotel was built in the 1960s. It has a good location and is reasonably priced. In room facilities include a fridge, AC and satellite TV. Hotel facilities include restaurant, salon, 24 hour room service, laundry service and dry cleaning.
Address: 12 Plotnikov Pereulok
Tel: 095-244- 7628
Website: -
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2-Power Batteries - 2-Power CBI1086A, Not sure this is the correct battery for your laptop? Enter your laptop brand and model into our laptop battery finder to make sure. You may even find a cheaper alternative. Asus A9
Thank you for visiting Asus A9 on shoppingfind.co.uk
We bring the products from many websites to one website for you to search, save and compare.


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These are fantastic conclusions about "playing the game" of the Citadel and heading bad ideas off at the pass. Great stuff
Go to Comment
It must be said that this has been in my work folder for a very, very long time and is not in response to any recent submissions.
Also, Moonhunter has a wide range of excellent advice columns you can peruse, especially if you are seeking the Golden Standard.
Go to Comment
These are also my own Opinions, not hard and fast rules, and come from my observations looking at thousands of submissions.


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Based on a 2,000 calorie dietSee full nutrition
Ready In
Well, it's lacking a lot. Be sure to buy the albacore tuna. The cheaper tuna is impossible to get dry enough! The rice vinegar also makes it too wet. I would suggest using Miracle Whip for the t...
I normally use jalapenos in my tuna and when I saw this I thought I'd give it a try. The rice vinegar gives it a flavor kind of like Miracle Whip. A great blend of flavors.
I also added some celery and used tahini instead of mayo. Overall, a nice twist on tuna salad.


text:
Newegg.com - A great place to buy computers, computer parts, electronics, software, accessories, and DVDs online. With great prices, fast shipping, and top-rated customer service - once you know, you Newegg.
If you are reading this message, Please click this link to reload this page.(Do not use your browser's "Refresh" button). Please email us if you're running the latest version of your browser and you still see this message.
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This review is from: OCZ Z Series 1000W Modular 80PLUS Gold High Performance Power Supply compatible with Intel Haswell Core i3/i5/i7 and AMD Phenom
Pros: Using this on a i7 3930k and GTX 770. Very stable voltages coming out. I was a little nervous since this model was put out a few years ago, but it still is excellent compared to today's technology. Kill-A-Watt confirms I'm getting around 90% power efficiency for pretty much any use, other than some hard video editting where it drops down a few %'s. All the cords are high quality, and plenty were given for a xfire/sli setup.
Cons: NoneREAD FULL REVIEW
This review is from: SAMSUNG 840 Series 2.5" 120GB SATA III Internal Solid State Drive (SSD) MZ-7TD120BW
Pros: Been working great for past 6 months
Surpasses benchmark speeds as secondary drive
Was really inexpensive compared to competition
Cons: None so farREAD FULL REVIEW
This review is from: Kingston 16GB DataTraveler SE9 USB 2.0 Flash Drive (DTSE9H/16GBZ)
Pros: Small. Has a hole to put on my keychain, and no cap to lose.
I bought 3 of these about a year ago and they all work great. I put shows on them and watch on my tablet every day on the train, so they've seen a lot of wear from read/write/erase, on the order of 100s of GB since I bought them.
Cons: They are deceivingly dense/heavy for how small they areREAD FULL REVIEW


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Technorati Is Trying, and It's Counting for Something
Just about a week ago Technorati launched 'Topics', a new service aimed at keeping you up to date at the latest posts coming in from the blogosphere. While some downplayed it as a simple TechMeme wanna-be, others rightly noted it as a meandering DiggSpy (in my opinion it's almost an exact combination of both). One week into its existence I've definitely noticed one thing: it's generating a lot more incoming links back to my site than Technorati was doing without it. Interestingly it's actually even not that far off of the incoming traffic numbers from TechMeme.
Now this data could very well be skewed because the Topics service is so new, and a lot of people have no doubt loaded up the site to check it out after reading about it on sites like the aforementioned TechMeme. But after a severe drop-off in traffic after day 1, the amount of incoming traffic has remained fairly constant for the rest of the week. It is by no means a large chunk of visitors, but it is something, and that's a start.
Technorati has been under a lot of fire recently around the Internet – and for some justifiable reasons. After becoming the go-to name in blog ranking, the service has been plagued by some lackluster service launches (WTF) and more importantly, site outtages and overall poor performance. Love it or hate it, Topics is at least a sign that Technorati is willing to listen to the ideas of its users and trying to and come up with ways to better showcase the massive amount of information about blogs they possess.
They do still need to do a better job policing their own site however as not only are there fraudulent blogs out there created just to boost another blog's authority, it also appears that WTF has turned into little more than a game-a-thon. It's like what Digg would look like if Digg never kicked out users and didn't ban URLs.
In the post announcing the Topics launch, Technorati themselves describe this as just a first step towards greater things. That's encouraging to hear as I do think there is definitely a place for Technorati in the future of the Blogosphere.


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Welcome to the Resolution Guide
Promises, promises. Its almost the end of January. How many resolutions have you broken so far in 2009? This year, we resolved to tell you only the stories of personal promises kept.
Ill begin with my own. Last August, I resolved to complete a marathon. Id never done such a thing, so I tried to make this goal doable. I didnt resolve to run. I didnt even consider the 26-miler. Instead, I told myself (and a few friends that part was key) that Id attempt to walk a half-marathon. A few of us signed up for the P.F. Changs Rock n Roll Arizona Marathon, printed out a training schedule, and for the most part actually stuck to it.
The day of the race, I was miserable. My feet hurt before wed even started. But I forced myself to get out there. And I did it. I made it to the end before the cops swept the streets of late finishers. I didnt get a medal (I was just a bit over three minutes past the four-hour mark) and it wasnt at all graceful, but I completed a half-marathon.
Resolution Guide
Mission accomplished, promise kept. And someday, Im sure, those blisters will heal.
Upcoming Events
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TicketsSun., Mar. 5, 6:00pm
Frank Ferrante in An Evening with Groucho
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Finding Neverland
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TicketsSat., Mar. 25, 7:30pm
In our 2009 Resolution Guide, were bringing you more stories of promises kept. Allyce Hargrove knew she was spending too much money. Instead of ripping up all her credit cards or putting herself on a budget, she did something simpler (but possibly even more difficult!) and swore off Target for a year. Benjamin Leatherman wanted to get in shape, so he gave up meat. Kimberly Kunasek found the one item she needed to get herself to a more spiritual place. A biting comment finally made it easy for Anne Smith to swear off cheating.
And some found it necessary to give up something: drinking at a favorite bar, women with questionable taste in music, patronizing Circle K, and a fear of flying.
Sure, there have been some lapses along the way, but lots of lessons learned (most notably, Wynter Holdens, in which she tells the true tale of the year she swore off lying). After all, some promises are easier to keep than others.
Like the one I made to myself, about a mile into my own amazing race: I will never again sign up for a marathon, half or otherwise.
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