Intrathecal Injection of Spironolactone Attenuates Radicular Pain by Inhibition of Spinal Microglia Activation in a Rat Model

Microglia might play an important role in nociceptive processing and hyperalgesia by neuroinflammatory process. Mineralocorticoid receptor (MR) expressed on microglia might play a central role in the modulation of microglia activity. However the roles of microglia and MR in radicular pain were not well understood. This study sought to investigate whether selective MR antagonist spironolactone develop antinociceptive effects on radicular pain by inhibition neuroinflammation induced by spinal microglia activation.Radicular pain was produced by chronic compression of the dorsal root ganglia with SURGIFLO™. The expression of microglia, interleukin beta (IL-1β), interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-α), NR1 subunit of the NMDA receptor (t-NR1), and NR1 subunit phosphorylated at Ser896 (p-NR1) were also markedly up-regulated. Intrathecal injection of spironolactone significantly attenuated pain behaviors as well as the expression of microglia, IL-1β, TNF-α, t-NR1, and p-NR1, whereas the production of IL-6 wasn't affected.These results suggest that intrathecal delivery spironolactone has therapeutic effects on radicular pain in rats. Decreasing the activation of glial cells, the production of proinflammatory cytokines and down-regulating the expression and phosphorylation of NMDA receptors in the spinal dorsal horn and dorsal root ganglia are the main mechanisms contributing to its beneficial effects

Relative contributions of crust and mantle to generation of Campanian high-K calc-alkaline I-type granitoids in a subduction setting, with special reference to the Harsit Pluton, Eastern Turkey

We present elemental and Sr-Nd-Pb isotopic data for the magmatic suite (similar to 79 Ma) of the Harsit pluton, from the Eastern Pontides (NE Turkey), with the aim of determining its magma source and geodynamic evolution. The pluton comprises granite, granodiorite, tonalite and minor diorite (SiO(2) = 59.43-76.95 wt%), with only minor gabbroic diorite mafic microgranular enclaves in composition (SiO(2) = 54.95-56.32 wt%), and exhibits low Mg# (<46). All samples show a high-K calc-alkaline differentiation trend and I-type features. The chondrite-normalized REE patterns are fractionated [(La/Yb)(n) = 2.40-12.44] and display weak Eu anomalies (Eu/Eu* = 0.30-0.76). The rocks are characterized by enrichment of LILE and depletion of HFSE. The Harsit host rocks have weak concave-upward REE patterns, suggesting that amphibole and garnet played a significant role in their generation during magma segregation. The host rocks and their enclaves are isotopically indistinguishable. Sr-Nd isotopic data for all of the samples display I(Sr) = 0.70676-0.70708, epsilon(Nd)(79 Ma) = -4.4 to -3.3, with T(DM) = 1.09-1.36 Ga. The lead isotopic ratios are ((206)Pb/(204)pb) = 18.79-18.87, ((207)Pb/(204)Pb) = 15.59-15.61 and ((208)Pb/(204)Pb) = 38.71-38.83. These geochemical data rule out pure crustal-derived magma genesis in a post-collision extensional stage and suggest mixed-origin magma generation in a subduction setting. The melting that generated these high-K granitoidic rocks may have resulted from the upper Cretaceous subduction of the Izmir-Ankara-Erzincan oceanic slab beneath the Eurasian block in the region. The back-arc extensional events would have caused melting of the enriched subcontinental lithospheric mantle and formed mafic magma. The underplating of the lower crust by mafic magmas would have played a significant role in the generation of high-K magma. Thus, a thermal anomaly induced by underplated basic magma into a hot crust would have caused partial melting in the lower part of the crust. In this scenario, the lithospheric mantle-derived basaltic melt first mixed with granitic magma of crustal origin at depth. Then, the melts, which subsequently underwent a fractional crystallization and crustal assimilation processes, could ascend to shallower crustal levels to generate a variety of rock types ranging from diorite to granite. Sr-Nd isotope modeling shows that the generation of these magmas involved similar to 65-75% of the lower crustal-derived melt and similar to 25-35% of subcontinental lithospheric mantle. Further, geochemical data and the Ar-Ar plateau age on hornblende, combined with regional studies, imply that the Harsit pluton formed in a subduction setting and that the back-arc extensional period started by least similar to 79 Ma in the Eastern Pontides.Geochemistry & GeophysicsMineralogySCI(E)33ARTICLE4467-48716

Assessing treatment outcomes in multiple sclerosis trials and in the clinical setting

Increasing numbers of drugs are being developed for the treatment of multiple sclerosis (MS). Measurement of relevant outcomes is key for assessing the efficacy of new drugs in clinical trials and for monitoring responses to disease-modifying drugs in individual patients. Most outcomes used in trial and clinical settings reflect either clinical or neuroimaging aspects of MS (such as relapse and accrual of disability or the presence of visible inflammation and brain tissue loss, respectively). However, most measures employed in clinical trials to assess treatment effects are not used in routine practice. In clinical trials, the appropriate choice of outcome measures is crucial because the results determine whether a drug is considered effective and therefore worthy of further development; in the clinic, outcome measures can guide treatment decisions, such as choosing a first-line disease-modifying drug or escalating to second-line treatment. This Review discusses clinical, neuroimaging and composite outcome measures for MS, including patient-reported outcome measures, used in both trials and the clinical setting. Its aim is to help clinicians and researchers navigate through the multiple options encountered when choosing an outcome measure. Barriers and limitations that need to be overcome to translate trial outcome measures into the clinical setting are also discussed