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Background The treatment of CRPS remains controversial, but multidisciplinary and interdisciplinary approaches is mandatory to prevent long-standing or permanent disability. Bisphosphonates, apart from their antiresorptive activity, have been shown to have an analgesic or anti-inflammatory effect. Bisphosphonate therapy has been suggested for the therapy for CRPS. Objectives to evaluate the efficacy of intravenous bisphosphonates in reducing pain in patients with CRPS. Methods 52 patients (14 males and 38 females; mean age 64.3±8 years) diagnosed with CRPS of carpal and metacarpals bones (confirmed by clinical, x-ray and MRI) from two to six weeks, previously treated with non-steroidal anti-inflammatory drugs (NSAID), calcium, Vitamin D, physical therapy. All patients were treated with iv clodronate 300 mg/day for 2 weeks, followed by im clodronate 200 mg/weekly for 3 months. Pain scale (VAS 0-100) and joint examination were performed before, after two weeks and after 3 months of clodronate therapy. X-ray and MRI were performed at the diagnosis and after 3 months. Results Clodronate reduced pain significantly (p=0.0001) after two weeks of therapy (87.7±8 mm vs 15.7±4 mm). After 3 months, a further reduction of pain (10.4±3 mm) was found (p<0.001). After two weeks of therapy reduction of pain was associated also to a reduction of hyperhidrosis, edema and joint stiffness. X-ray showed a stability of radiological features, and MRI a significant reduction of bone oedema. No adverse events were reported. Conclusions Iv clodronate achieves a rapid reduction of pain in patients with CRPS. Early intervention and reduction of pain is associated with a rapid clinical and imaging improvement, may prevent long-standing disability. References Tran de QH, Duong S, Bertini P, Finlayson RJ. Treatment of complex regional pain syndrome: a review of the evidence. Can J Anaesth. 2010 Feb;57(2):149-66. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.4175

Background Rheumatoid Arthritis (RA) is an autoimmune disease characterised by chronic inflammation and synovial hyperplasia caused by influx of inflammatory cells and by a reduced rate of programmed cell death. In RA synoviocytes seem to be resistant against apoptosis and not sensitive to TNF-induced apoptosis; by contrast, TNF induces them to proliferate. In this contest TNF- α strongly interfere with Fas (CD95)–Fas ligand (FasL, CD178) death receptor pathway. Biological drugs seem to be able to induce synovial apoptosis by inhibiting TNF-α functions. With the present study we want to investigate possible links between serum sFas and sFasL and anti-TNF therapy. Objectives to investigate whether sFas and sFasL serum levels can be associated to therapeutic response to TNF antagonists (anti-TNF) Infliximab and Adalimumab in patients with RA; to correlate these values with disease activity variables. Methods circulating levels of sFas and sFasL were investigated by specific immunosorbent assay on serum samples (52 RA patients: 36 female, 16 male; mean age: 45.7±12.2 years). The variables of disease activity (analyzed by DAS28, HAQ, CRP), physical function and sFas/sFasL serum levels were determined before and after 3 months of anti-TNF therapy (32 Adalimumab and 20 Infliximab). All patients were naïve to anti-TNF therapy. 40 (28 female, 12 male) age- and sex-matched healthy controls were used as controls. The sFas/sFasL levels are expressed as means ± standard deviations (SD) and compared by Student’s t-test and Mann-Whitney Test. Spearman rank correlation test (Rs) were employed to examine relationships between serum levels and disease activity variables (analyzed by DAS28, CRP). The differences are considered significant for p values <0.05. Results disease activity of patients was severe (baseline DAS28 5.6±1, HAQ of 3.5 (2.3 to 4.1 interquartile range) CRP 12 mg/l (IQR: 9 to 16). Before anti-TNF therapies sFas and sFasL levels were not different between RA patients and controls (5278.44±271.1 vs 5869.09±256.1 pg/ml for sFas; 56.72±20.32 vs 48.74±12.22 pg/ml for sFasL). After 3 months of Infliximab and Adalimumab therapy, RA patients showed higher concentration of serum sFas (9343.61±2356.6 p<0.01 for Infliximab; 7281±1123.3 p<0.05 for Adalimumab). Clinical response correlated with serum sFas levels after 3 months of anti-TNF treatment (Infliximab/DAS28: Rs= -0,681; Infliximab/PCR: Rs= -0,643; Adalimumab/DAS28: Rs= -0,743; Adalimumab/PCR: Rs= -0,746) as demonstrated by significantly reduction of CRP (0,6 mg/l; IQR 0,3 to 2,8) and DAS28 (2,8±0,5) (p<0,05). No differences were about serum sFasL levels before starting biological treatment and after 3 months of therapies (50.53±33.3 for Infliximab; 51.47±43.5 for Adalimumab). Conclusions after Infliximab and Adalimumab therapy RA patients showed higher serum levels of sFas, but no sFasL. This results also correlate with variables of disease activity. This may suggest that Infliximab and Adalimumab blocking TNF-α functions are able to reduce disease activity at least in part by promoting synovial apoptosis, particularly by interfering with Fas apoptotic pathway, as demonstrated by higher serum levels of sFas of RA patients after biological treatment. These data suggest that in patients receiving anti-TNF treatment higher levels of sFas may serve to predict remission. Disclosure of Interest None Declared

The insulin-like growth factor-1 receptor (IGF-IR) and the human polyomavirus JCV protein, T-antigen cooperate in the transformation of neuronal precursors in the cerebellum, which may be a contributing factor in the development of brain tumors. Because it is not clear why T-antigen requires IGF-IR for transformation, we investigated this process in neural progenitors from IGF-IR knockout embryos (ko-IGF-IR) and from their wild-type nontransgenic littermates (wt-IGF-IR). In contrast to wt-IGF-IR, the brain and dorsal root ganglia of ko-IGF-IR embryos showed low levels of the antiapoptotic protein Survivin, accompanied by elevated numbers of apoptotic neurons and an earlier differentiation phenotype. In wt-IGF-IR neural progenitors in vitro , induction of T-antigen expression tripled the expression of Survivin and accelerated cell proliferation. In ko-IGF-IR progenitors induction of T-antigen failed to increase Survivin, resulting in massive apoptosis. Importantly, ectopic expression of Survivin protected ko-IGF-IR progenitor cells from apoptosis and siRNA inhibition of Survivin activated apoptosis in wt-IGF-IR progenitors expressing T-antigen. Our results indicate that reactivation of the antiapoptotic Survivin may be a critical step in JCV T-antigen-induced transformation, which in neural progenitors requires IGF-IR.

Background The screening for LTB before anti-TNF therapy is mandatory. Tuberculin Skin Test (TST) and QFT Gold in tube (QFT-GIT) may help in the detection of LTB patients who submitted a prophylactic treatment. Objectives Evaluate the role of by QFT-GIT in the evaluation of the efficacy of the LTB prophylaxis in patients affected by rheumatic disease Methods Out of 561 patients (263 Rheumatoid Arthritis (AR), 126 Psoriatic Arthritis (PsA) and 73 Spondiloarthropaty (SpA), 5 Inflammatory Bowel Disease (IBD) and 94 with other immunomediated chronic disease), we performed TST and QFT as screening tests and QFT was performed at the end the prophylaxis. Results After screening, LTB was diagnosed in 87 patients who were submitted to prophylaxis (Isoniazid for 9 months or Isoniazid plus Rifampicin for 3 months).We compared by analysis of variance the value of QFT index at the beginning and at the end the therapy (QFT-GIT medium value at the beginning 5.39 and 4.0 at the end). This comparison showed no statistically significant differences (significance value 0.31). Conclusions QFT-GIT is helpful to identify LTB but our data show that QFT-GIT index is not useful to asses the efficacy of the TB prophylaxis and rule out during the follow up the TB re-infection. QFT may be useful in identifying the TB infection during the follow up of patients who were negative at the screening. Disclosure of Interest None Declared

Background The treatment of CRPS remains controversial, but multidisciplinary and interdisciplinary approaches seem to be inevitable to prevent long-standing or permanent disability (1). Bisphosphonates, apart from their antiresorptive activity, could also have other properties through a specific analgesic or anti-inflammatory effect.Bisphosphonate therapy has been shown to be effective in single cases of CRPS (2). Objectives to evaluate the efficacyof intravenous compared with intramuscular bisphosphonates in reducing pain in patients with CRPS. Methods 14 patients (one male and 13 females; mean age 64.3±8 years) diagnosed with CRPS of carpal and metacarpals bones (confirmed by clinical and MRI) from two weeks, were treated with non-steroidal anti-inflammatory drugs (NSAID), supplemental calcium and Vitamin D, physical therapy and clodronate. Seven patients were treated with iv (Group A) and seven with im clodronate (Group B) for 2 weeks. Then all patients were subjected to im clodronate 100 mg/weekly for 3 months. Pain scales (VAS 0-100) and joint examination were performed before, after one week and after 3 months of clodronate therapy. Results pain was 92.7±12 mm in group A and 91±7.5 mm in group B, before starting clodronate (t0). Clodronate reduces pain significantly (p=0.0001) in both groups after one week of therapy, but reduction of pain was significantly higher (p=0.0001) in patients treated with iv clodronate (VAS 21.8±7 mm in group A vs 48.2±9.1 mm in group B). After 3months, nostatistical significant difference (p=0.7) in painwas found. Rapid reduction of pain in group A is associated also to a rapid reductionof hyperhidrosis, edema and joint stiffness after one week of therapy.No adverse effects were reported during therapy. Conclusions Iv clodronate achieves a rapid reduction of pain compared to im formulation, in patients with CRPS. Early intervention and reduction of pain is also associated with a rapid clinical improvement that might help in the prevention of long-standing disability. References Tran de QH, Duong S, Bertini P, Finlayson RJ. Treatment of complex regional pain syndrome: a review of the evidence. Simm PJ, Briody J, McQuade M, Munns CF. The successful use of pamidronate in an 11-year-old girl with complex regional pain syndrome: response to treatment demonstrated by serial peripheral quantitative computerised tomographic scans. Bone 2010 Apr;46(4):885-8. Epub 2009 Dec 5. Disclosure of Interest None Declared

LNCaP cells are human prostatic cancer cells that have a frame-shift mutation of the tumor suppressor gene PTEN and do not express the insulin receptor substrate-1 (IRS-1), a major substrate of the type 1 insulin-like growth factor receptor (IGF-IR). Ectopic expression of IRS-1 in LNCaP cells increases cell adhesion and decreases cell motility by an IGF-I-independent mechanism. We show now that these effects of IRS-1 are accompanied by serine phosphorylation of IRS-1 and are inhibited by inhibitors of phosphatidylinositol 3-kinase (PI3K). We have confirmed the requirement for PI3K activity and serine phosphorylation by the use of IRS-1 mutants, expressed in LNCaP cells. Serine phosphorylation inhibits IGF-I-induced tyrosyl phosphorylation of IRS-1, which is restored by the expression of wild-type PTEN or by inhibition of PI3K activity. Finally, IRS-1 in LNCaP cells co-immunoprecipitates with integrin alpha 5 beta 1, and the association is again IGF-I-independent. We conclude that in LNCaP cells, IRS-1 is serine phosphorylated by PI3K, generating effects that are different, and even opposite, from those generated by IGF-I.

HIV-1 Tat is a potent transcriptional activator of the viral promoter with the ability to modulate a number of cellular regulatory circuits including apoptosis. Tat exerts its effects through interaction with viral as well as cellular proteins. Here, we studied the influence of p73, a protein that is implicated in apoptosis and cell cycle control, on Tat apoptotic function in the central nervous system. We recently demonstrated the ability of Tat to associate with p73, and that this association modulates Tat transcriptional activity (Amini et al., Mol Cell Biol 2005; 18: 8126-8138). We demonstrated that p73 interferes with Tat-mediated apoptosis by preventing the up-regulation of Bax and down-regulation of Bcl-2 proteins in astrocytes. Thus, the interplay between Tat and p73 may affect Tat contribution to apoptotic events in the brain, limiting its involvement in the neuropathology often observed in the brains of HIV-1 patients.

We have developed a self-inactivating retroviral vector system with an internal, inducible Drosophila HSP70 promoter. This vector system delivers the desired transgene into cells rapidly and efficiently. It generates mixed populations of transduced cells where the transgene is inducible, and does not require the isolation of specific clones. Since the transgene is not expressed (or poorly expressed) at the restrictive condition (34 degrees C), mixed populations can be selected in which tumor suppressors or other inhibitory genes can be strongly induced upon changing the conditions (39 degrees C or the plant amino acid L-canavanine). This retroviral vector should be very useful for the expression of sequences that are poorly tolerated by cells, and is also active in animals.

Insulin-like growth factor I receptor (IGF-IR) has been implicated in the normal and malignant growth of many cell types including cells from the central nervous system. In the cerebellar cortex IGF-IR mRNA is found in granular cells and IGF-I stimulation is mitogenic and protects cells from low-potassium-induced apoptosis. Since primitive neuroectodermal tumors/medulloblastomas (PNETs/medulloblastomas) are suspected to originate from the external cerebellar granular layer, it is reasonable to postulate that IGF-IR and/or its signaling molecules may contribute to the transformation of these poorly differentiated cells. To study activation of the IGF-IR system in medulloblastomas, we have utilized an antibody (anti-pY1316) that specifically recognizes the phosphorylated (active) form of the IGF-IR. Medulloblastoma biopsy specimens were positive when examined immunohistochemically with anti-Y1316 antibody. Further analysis of the IGF-IR system was performed in three human (Daoy, TE-671, D283 Med) and four mouse (BsB8, BsB13, Bs-1b, Bs-1c) medulloblastoma cell lines. All the murine cell lines examined express IGF-IR and PI3-kinase at relatively normal levels, and grossly overexpress IRS-1, when compared with normal mouse cerebellum. Within 15 min following IGF-I stimulation both mouse and human cell lines phosphorylate the beta subunit of the IGF-IR, IRS-1, Akt, and MAP kinases. They respond with cell proliferation when stimulated solely with IGF-I and are strongly inhibited when challenged with a dominant negative mutant of the IGF-IR (486/STOP), or with antisense oligonucleotides against the IGF-IR mRNA.

The type 1 insulin-like growth factor receptor (IGF-IR) is known to protect cells from a variety of apoptotic injuries. In several instances, the anti-apoptotic effect of the wild type IGF-IR is more evident under conditions of anchorage-independence than in cells in monolayer cultures. We have investigated IGF-IR signaling in cells in anoikis, a form of apoptosis that occurs when cells are denied attachment to the extra-cellular matrix. IGF-I protects mouse embryo fibroblasts (MEF) from anoikis caused by withdrawal of growth factors. Survival is dependent on the concentration of IGF-I and a sufficient number of functional IGF-I receptors. In this model, IGF-I protection correlates best with ras activation and cell-to-cell aggregation, while PI3-kinase, Akt and MAP kinases seem to play a lesser, alternative role.