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Pirfenidone (5 methyl-1-phenyl-2(1H)-pyridone) is a novel anti-fibrotic agent, which has been shown to decrease collagen deposition in a variety of animal models in vivo, and recently in hepatic fibrosis also. At cellular level, we have recently demonstrated that pirfenidone is able to inhibit proliferation of hepatic stellate cells induced by platelet-derived growth factor, as well as collagen type I accumulation and alpha1(I) procollagen mRNA expression.', 'To evaluate if pirfenidone maintains its anti-fibrotic properties also when administered after the induction of hepatic damage and to further investigate the molecular mechanisms leading to the anti-fibrotic effect of pirfenidone.', 'Rats treated with dimethylnitrosamine (10 mg/kg) for 5 weeks received a liquid diet containing 0.5% pirfenidone starting from the third week. Pirfenidone treatment reduced the degree of liver injury, as determined by alanine aminotransferase values and necro-inflammatory score, which was associated with reduced hepatic stellate cells proliferation and collagen deposition. Treatment with dimethylnitrosamine increased transcripts levels for transforming growth factorbeta1, procollagen alpha1(I), tissue inhibitors of metalloproteinase-1 and matrix metalloproteinase-2 by 7-, 7-, 4- and 15-fold, respectively. Pirfenidone administration downregulated elevated levels of those transcripts by 50-60%, and this was associated with a 70% reduction in collagen deposition.
Is the anti-fibrotic effect of pirfenidone in rat liver fibrosis mediated by downregulation of procollagen alpha1 ( I ) , TIMP-1 and MMP-2?

Bruton's tyrosine kinase (Btk) is required for B lymphocyte and myeloid cell contributions to pathology in murine models of arthritis. Here, we examined the potential contributions of synovial Btk expression and activation to inflammation in rheumatoid arthritis (RA).", 'Btk was detected by immunohistochemistry and digital image analysis in synovial tissue from biologically naive RA (n=16) and psoriatic arthritis (PsA) (n=12) patients. Cell populations expressing Btk were identified by immunofluorescent double labelling confocal microscopy, quantitative (q-) PCR and immunoblotting. The effects of a Btk-specific inhibitor, RN486, on gene expression in human macrophages and RA synovial tissue explants (n=8) were assessed by qPCR, ELISA and single-plex assays.', 'Btk was expressed at equivalent levels in RA and PsA synovial tissue, restricted to B lymphocytes, monocytes, macrophages and mast cells. RN486 significantly inhibited macrophage IL-6 production induced by Fc receptor and CD40 ligation. RN486 also reduced mRNA expression of overlapping gene sets induced by IgG, CD40 ligand (CD40L) and RA synovial fluid, and significantly suppressed macrophage production of CD40L-induced IL-8, TNF, MMP-1 and MMP-10, LPS-induced MMP-1, MMP-7 and MMP-10 production, and spontaneous production of IL-6, PDGF, CXCL-9 and MMP-1 by RA synovial explants.
Does btk inhibition suppress agonist-induced human macrophage activation and inflammatory gene expression in RA synovial tissue explants?

In vitro biomechanical study using a programmable testing apparatus that replicated physiologic flexion/extension cervical spine motion and loading mechanics.', 'To determine the influence of anterior plating on multilevel cervical strut-graft mechanics in vitro.', 'The addition of anterior instrumentation does not prevent construct failure in multilevel cervical corpectomy.', 'Six fresh human cadaveric cervical spines (C2-T1) were tested in the four following sequential conditions: harvested, C4-C6 corpectomy, strut-grafted, and strut-grafted with an anterior cervical plate. A force-sensing strut-graft was used to measure compression/tension, flexion/extension and lateral bending moments, and axial torsion. Parameters of stiffness, vertebral motion, and strut-graft loads were compared to determine differences between the four spine conditions.', 'Application of the anterior plate significantly increased the global stiffness (P < 0.01) and decreased the local motion (P < or = 0.01) of the instrumented levels (C3-C7). Flexion of the strut-grafted spine loaded the strut-graft, whereas extension unloaded the strut-graft. With the anterior plate, flexion of the plated spine unloaded the strut-graft. Extension significantly loaded the strut-graft more than similar degrees of flexion in the strut-grafted condition (P = 0.01). Strut-graft loading end limits of 225 N were reached with a mean 7.5 degrees extension in the plated spines.

Does anterior cervical plating reverse load transfer through multilevel strut-grafts?