Colony-stimulating-factor-1 (CSF-1) signaling through cFMS receptor kinase is increased in several diseases. To help investigate the role of cFMS kinase in disease, we identified GW2580, an orally bioavailable inhibitor of cFMS kinase. GW2580 completely inhibited human cFMS kinase in vitro at 0.06 M and was inactive against 26 other kinases. GW2580 at 1 M completely inhibited CSF-1-induced growth of mouse M-NFS-60 myeloid cells and human monocytes and completely inhibited bone degradation in cultures of human osteoclasts, rat calvaria, and rat fetal long bone. In contrast, GW2580 did not affect the growth of mouse NS0 lymphoblastoid cells, human endothelial cells, human fibroblasts, or five human tumor cell lines. GW2580 also did not affect lipopolysaccharide (LPS)-induced TNF, IL-6, and prostaglandin E2 production in freshly isolated human monocytes and mouse macrophages. After oral administration, GW2580 blocked the ability of exogenous CSF-1 to increase LPS-induced IL-6 production in mice, inhibited the growth of CSF-1-dependent M-NFS-60 tumor cells in the peritoneal cavity, and diminished the accumulation of macrophages in the peritoneal cavity after thioglycolate injection. Unexpectedly, GW2580 inhibited LPS-induced TNF production in mice, in contrast to effects on monocytes and macrophages in vitro. In conclusion, GW2580's selective inhibition of monocyte growth and bone degradation is consistent with cFMS kinase inhibition. The ability of GW2580 to chronically inhibit CSF-1 signaling through cFMS kinase in normal and tumor cells in vivo makes GW2580 a useful tool in assessing the role of cFMS kinase in normal and disease processes.CSF-1 ͉ macrophage colony-stimulating factor

No abstract

VT decrements of 5-10 points were seen for diseases known to cause fatigue. Further, differences of 5-10 points in the VT score were associated with significant increased risk of negative outcomes. We recommend an MID of 5 points for analyses of groups with VT scores below average. For follow-up of individual patients, we recommend a 10-point difference as important.

No abstract

The 13-item MSQ appears to be an appropriate measure of migraine-specific HRQoL for patients undergoing migraine prophylaxis. Moreover, given the stability of the latent structure over time, the interpretation of scores is likely to remain quite consistent throughout a clinical trial.

To propose minimal important differences (MID) for the Migraine-Specific Quality of Life Questionnaire version 2.1 (MSQ v2.1). To our knowledge (to date), no published MID values exist for the MSQ v2.1 in any population. Analyses were performed on data from two pivotal clinical trials of topiramate for migraine prevention (n = 916), as well as from the QualityMetric National Headache Survey (n = 1016). Analyses included both distribution- and anchor-based MID techniques as well as group- and individual-level MID values. Group-level anchor-based MID values ranged from 3.2 [Role Restrictive domain (RR)] to 7.5 [Emotional Functioning domain (EF)], setting the minimum level of appropriate MID (which can also aid with power analysis). Individual-level distribution-based MID values resulted in highly similar estimates from two large databases: median MID of 8.5 for RR, 9.2 for Role Preventive (RP) and 12.0 for EF. Finally, individual-level anchor-based MID values ranged from 5.0 (RR and RP domains) to 10.6 (EF). For group-level purposes of calculating power for future studies, an MID of 3.2, 4.6 and 7.5 for RR, RP and EF is recommended. For within-group analyses for analysing clinical trial efficacy of each patient's change with responder analyses, 5 points is necessary for RR. For RP and EF, ranges are recommended: 5.0 to 7.9 for RP and 8.0 to 10.6 for EF. These latter two domains tend to have more error in the MID, and thus a sensitivity analysis with both ends of the range should be used to confirm significant differences in responder analyses.

Children with psoriasis often have involvement of the face and intertriginous areas. While corticosteroids have been the mainstay of treatment for plaque-type psoriasis, the face and intertriginous areas are more sensitive to local effects of topical steroid use such as cutaneous atrophy. Topical tacrolimus has shown promise in adult patients as an alternative antiinflammatory without the cutaneous side effects of steroids. Eleven patients between 6 and 15 years of age with facial or inverse psoriasis were evaluated in a 6-month, single-center, open-label trial. Clinical evaluations were made at baseline and days 30, 90, and 180. Severity was assessed using the physician's global assessment of improvement relative to baseline, a 6-point rating scale for signs of disease (erythema, infiltration, desquamation), and an overall severity score. Within the first 30 days of treatment, every patient had cleared or achieved excellent improvement with the use of tacrolimus ointment. Statistically significant improvement was achieved in each sign of disease and the overall severity score. The only adverse event reported in 6 months of observation was significant pruritus in one patient. We therefore conclude that tacrolimus ointment is an effective treatment for psoriasis on the face or intertriginous areas in children.

The cFMS (cellular homolog of the V-FMS oncogene product of the Susan McDonough strain of feline sarcoma virus) (Proc Natl Acad Sci U S A 83:3331-3335, 1986) kinase inhibitor 5-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)pyrimidine-2,4-diamine (GW2580) inhibits colony-stimulating factor (CSF)-1-induced monocyte growth and bone degradation in vitro and inhibits CSF-1 signaling through cFMS kinase in 4-day models in mice (Proc Natl Acad Sci U S A 102:16078, 2005). In the present study, the kinase selectivity of GW2580 was further characterized, and the effects of chronic treatment were evaluated in normal and arthritic rats. GW2580 selectively inhibited cFMS kinase compared with 186 other kinases in vitro and completely inhibited CSF-1-induced growth of rat monocytes, with an IC 50 value of 0.2 M. GW2580 dosed orally at 25 and 75 mg/kg 1 and 5 h before the injection of lipopolysaccharide inhibited tumor necrosis factor-␣ production by 60 to 85%, indicating a duration of action of at least 5 h. In a 21-day adjuvant arthritis model, GW2580 dosed twice a day (b.i.d.) from days 0 to 21, 7 to 21, or 14 to 21 inhibited joint connective tissue and bone destruction as assessed by radiology, histology and bone mineral content measurements. In contrast, GW2580 did not affect ankle swelling in the adjuvant model nor did it affect ankle swelling in a model where local arthritis is reactivated by peptidoglycan polysaccharide polymers. GW2580 administered to normal rats for 21 days showed no effects on tissue histology and only modest changes in serum clinical chemistry and blood hematology. In conclusion, GW2580 was effective in preserving joint integrity in the adjuvant arthritis model while showing minimal effects in normal rats.CSF-1 promotes the survival, proliferation, and differentiation of mononuclear phagocyte lineages and regulates the response of these lineages to inflammatory challenge. CSF-1 binding to its cell surface receptor triggers autophosphorylation by receptor cFMS (cellular homolog of the V-FMS oncogene product of the Susan McDonough strain of feline sarcoma virus) (Sacca et al., 1986) kinase and a cascade of cell signaling. cFMS kinase is the cellular homolog of the v-FMS oncogene product of the Susan McDonough strain of the feline sarcoma virus (Sacca et al., 1986). The ability of CSF-1 to promote the survival, proliferation, and differentiation of bone progenitor cells, monocytes, macrophages, and osteoclasts in vitro correlates with the expression of CSF-1 receptor in these cells (for review, see Chitu and Stanley, 2006). Mice without CSF-1 (Wiktor-Jedrzejczak et al., 1990, 1992b or its receptor (Dai et al., 2002) are osteopetrotic, deficient in several macrophage populations, show decreased TNF pro-