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•Patient Information Sheet (PIS) used in MS clinical trials may not be understandable.•User testing (UT) highlighted critical issues in two PIS from clinical trials in MS.•UT is a useful tool for verifying the comprehensibility of PIS.•Developing PIS should involve different stakeholders with specific experience.

Protein tyrosine phosphatase receptor type Z (Ptprz) is widely expressed in the mammalian central nervous system and has been suggested to regulate oligodendrocyte survival and differentiation. We investigated the role of Ptprz in oligodendrocyte remyelination after acute, toxin-induced demyelination in Ptprz null mice. We found neither obvious impairment in the recruitment of oligodendrocyte precursor cells, astrocytes, or reactive microglia/macrophage to lesions nor a failure for oligodendrocyte precursor cells to differentiate and remyelinate axons at the lesions. However, we observed an unexpected increase in the number of dystrophic axons by 3 days after demyelination, followed by prominent Wallerian degeneration by 21 days in the Ptprz-deficient mice. Moreover, quantitative gait analysis revealed a deficit of locomotor behavior in the mutant mice, suggesting increased vulnerability to axonal injury. We propose that Ptprz is necessary to maintain central nervous system axonal integrity in a demyelinating environment and may be an important target of axonal protection in inflammatory demyelinating diseases, such as multiple sclerosis and periventricular leukomalacia.

•PROMS is a global multi-stakeholder initiative that makes MS patients’ change scientifically relevant experiential knowledge•We envision a PROMs ecosystem in which all stakeholders are co-responsible of the impact of patient engagement, from research to care•We aim to integrate a PROMs core data set from practice to care, to be included in registries•We aim to rethink research, trials, and practice via e-PROMs to enable a holistic, comprehensive and personalized care•We aim to develop a PROMs ecosystem that could be adapted and uptaken to other neurological diseases

Leukocyte trafficking to inflammatory sites is a gradual process, which is dominated in its early phases by chemokine- and cytokine-mediated neutrophil recruitment. The chemokine regulated on activation normal T cell expressed and secreted (RANTES) has been shown to be highly expressed in the joints of patient with rheumatoid arthritis and to promote leukocyte trafficking into the synovial tissue. In this study, we investigated the effect of RANTES in a murine model of peritoneal chemotaxis, and we found that RANTES dose-dependently induces neutrophil recruitment. Then, through morphological and histological analyses, we observed that activated neutrophils represent the major infiltrating population in response to RANTES chemotactic stimulus. Furthermore, we demonstrated that oral administration of either nonisoform-specific phosphoinositide 3-kinase (PI3K) inhibitor LY294002 (morpholin-4-yl-8-phenylchromen-4-one) or selective PI3Kgamma inhibitor AS041164 (5-benzo[1,3]dioxol-5-ylmethylene-thiazolidine-2,4-dione) blocks RANTES-induced chemotaxis and reduces the level of AKT phosphorylation. Because the two compounds showed a similar pharmacokinetic profile in terms of bioavailability and half-life after oral route administration, the selective inhibition of the PI3Kgamma-isoform pathway through AS041164 was three times more potent in reducing neutrophil recruitment. Finally, to confirm the blockade of neutrophil infiltration that occurs in the early phase of the inflammatory response, AS041164 was also tested in a model of carrageenan-induced paw edema in rats. Therefore, the PI3Kgamma pathway plays an important role in controlling neutrophil chemotaxis during early steps of inflammation.

(-)-cis-1-Methyl-7-[[4-(2,6-dichlorophenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol (SB-612111) is a novel human opiate receptor-like orphan receptor (ORL-1) antagonist that has high affinity for the clonal human ORL-1 receptor (hORL-1 K(i) = 0.33 nM), selectivity versus mu-(174-fold), delta-(6391-fold), and kappa (486-fold)-opioid receptors and is able to inhibit nociceptin signaling via hORL-1 in a whole cell gene reporter assay. SB-612111 has no measurable antinociceptive effects in vivo in the mouse hot-plate test after intravenous administration but is able to antagonize the antimorphine action of nociceptin [ED(50) = 0.69 mg/kg, 95% confidence limit (CL) = 0.34-1.21]. SB-62111 administration can also reverse tolerance to morphine in this model, established via repeated morphine administration. In addition, intravenous SB-612111 can antagonize nociceptin-induced thermal hyperalgesia in a dose-dependent manner (ED(50) = 0.62 mg/kg i.v., 95% CL = 0.22-1.89) and is effective per se at reversing thermal hyperalgesia in the rat carrageenan inflammatory pain model. These data show that an ORL-1 receptor antagonist may be a useful adjunct to chronic pain therapy with opioids and can be used to treat conditions in which thermal hyperalgesia is a significant component of the pain response.

Murine NGD5 is a gene identified from NG108-15 cells which is postulated to be involved in opioid receptor function. Here we report the cloning and characterization of a cDNA C20orf9-003 (ACI-1) encoding the human orthologue of the mouse NGD5. Analysis of the genomic structure revealed that C20orf9-003 (ACI-1) contains 13 exons and 12 introns, spanning 52.5 kb of genomic DNA and is a variant of C20orf9. Chromosomal localization of human C20orf9-003 (ACI-1) assigned this gene to chromosome 20q13.12. Genes at this locus have been associated with the progression and possibly the development of various cancers. In addition several linkage studies support the possibility that one or more genes affecting obesity are located in 20q13. No function can be clearly assigned to C20orf9-003 (ACI-1), however, the protein has a cytoplasmic subcellular location and the secondary structure contains a Rossman fold like feature which is found in many nucleotide binding proteins.

The specific involvement of the delta-opioid receptor in the control of nociception was explored by investigating the pharmacological activity in vivo of a selective, orally active, and centrally penetrant delta-opioid agonist. [8R-(4bS*,8aalpha,8abeta,12bbeta)]7,10-dimethyl-1-methoxy-11-(2-methylpropyl)oxycarbonyl 5,6,7,8,12,12b-hexahydro-(9H)-4,8-methanobenzofuro[3,2-e]pyrrolo[2,3-g]isoquinoline hydrochloride (SB-235863) is a new pyrrolomorphinan with high affinity (Ki = 4.81 +/- 0.39 nM) for the delta-opioid receptor, full agonist activity, and binding selectivity versus the mu- and kappa-opioid receptors of 189-fold and 52-fold, respectively. Perorally administered SB-236863 was inactive in the rat tail-flick and hot-plate tests of acute pain response, but potently reversed thermal hyperalgesia in rats resulting from a carrageenan-induced inflammatory response. This activity could be blocked by the delta-opioid antagonist naltrindole (3 mg/kg s.c.), but selective mu- and kappa-opioid antagonists were ineffective. Naltrindole (1 microg i.c.v.) also blocked the activity of 10 mg/kg (p.o.) SB-235863, showing that the compound activates delta-opioid receptor sites in the central nervous system. SB-235863 was additionally effective at reversing chronic hyperalgesia in the Seltzer rat model of partial sciatic nerve ligation after peroral administration. These data show that the delta-opioid receptor plays a selective role in regulating evoked and lasting changes in nociceptive pain signaling. Classical side effects of mu- and kappa-opioid receptor activation (slowing of gastrointestinal transit and motor incoordination, respectively) were not observed after administration of 70 mg/kg (p.o.) SB-235863, nor was evoked seizure activity affected. These results suggest a selective and limited role of delta-opioid receptors in the modulation of nociception.

We hypothesized that the up-regulated expression of one or more members of the regulator of G protein signaling (RGS) family can cause an attenuation of signaling via Gi/Go-coupled opioid receptors, and thereby play a role in the development of hyperalgesia and accompanying insensitivity to morphine observed in animal models of neuropathic pain. Accordingly, we examined the mRNA expression of several RGS genes in a rat model of chronic neuropathic pain induced by partial ligation of the sciatic nerve. During the development of hyperalgesia, RGS4 was the only isoform examined whose mRNA levels increased significantly (up to 230%) in the lumbar spinal cord. In situ hybridization studies confirmed that RGS4 is present in the dorsal horn of the spinal cord where mu-opioid receptors (MORs) are also expressed. Overexpression of RGS4 in human embryonic kidney 293 cells stably expressing mu-opioid receptors predictably attenuated opioid agonist-induced inhibition of adenylyl cyclase. This inhibitory effect was overcome partially at high agonist concentrations, supporting the view that morphine insensitivity is promoted by RGS4 overexpression. These studies provide evidence that the up-regulation of RGS4 expression may contribute to changes in pain signal processing that lead to the development of hyperalgesia, and further affect its modulation by morphine.

OBJECTIVE: Angiopoietin- I (Ang-1) and Ang-2 are ligands for the receptor tyrosine kinase, Tie-2. Ang-1, a Tie-2 agonist, may have a vascular stabilizing role in angiogenesis, while Ang-2, an endogenous antagonist of Tie-2, may have an early role in angiogenesis, destabilizing existing vasculature. We show that these ligands are expressed by rheumatoid synovial fibroblasts (RSF) and investigate whether their expression was modulated by proinflammatory cytokines present in the joint in rheumatoid arthritis (RA). METHODS: Using quantitative PCR we determined the level of expression of these 2 ligands in RSF and chronic inflamed synovial tissue. The level of expression of these ligands after treatment with proinflammatory cytokines and hypoxia was also determined. RESULTS: We observed constitutive expression of Ang-1 and Ang-2 in RSF and chronic inflamed synovial tissue. Ang-1 was the most highly expressed ligand in late stage RA synovial fibroblasts; however, in chronic inflamed synovial tissue, Ang-2 was predominant and was expressed at strikingly high levels (70 to 120-fold increase). We observed that tumor necrosis factor-alpha (TNF-alpha) and transforming growth factor-beta (TGF-beta), but not interleukin 1beta or hypoxia, stimulated Ang-1 gene expression in RSE This was confirmed at the protein level as media from TNF-alpha treated RSF resulted in increased autophosphorylation of Tie-2. In contrast, TNF-alpha and TGF-beta had no effect on Ang-2 expression in RSF, but augmented expression of Ang-2 in normal synovial fibroblasts. CONCLUSION: The angiopoietins are important angiogenic factors constitutively present in RA, and their expression is modulated by certain cytokines. Ang-2 may have an important role in rheumatoid tissue where vigorous angiogenesis is occurring.

•Latent class analysis to identify predominant cognitive phenotypes in PwMS•Combination of both cognitive and mood information from patient-centered outcomes•Classification of four phenotypes based on model fit and parsimony criteria•Taxonomy as a continuum of deterioration of cognition as the disease progresses

•Logistic regression models were applied to evaluate the association between potential demographic, clinical and self-reported predictors and the clinically significant anxiety at one-year follow up.•Educational level, relapsing-remitting form, anxiety, depression and fatigue at baseline were significant predictors for clinically significant anxiety.•Disability level, disease duration and cognitive functioning did not correlate with clinically significant anxiety.

For Abstract see ChemInform Abstract in Full Text.