Antinociceptive activity of the S1P-receptor agonist FTY720

FTY720 is a novel immunosuppressive drug that inhibits the egress of lymphocytes from secondary lymphoid tissues and thymus. In its phosphorylated form FTY720 is a potent S1P receptor agonist. Recently it was also shown that FTY720 can reduce prostaglandin synthesis through the direct inhibition of the cytosolic phospholipase A2 (cPLA2). Since prostaglandins are important mediators of nociception, we studied the effects of FTY720 in different models of nociception. We found that intraperitoneal administration of FTY720 reduced dose-dependently the nociceptive behaviour of rats in the formalin assay. Although the antinociceptive doses of FTY720 were too low to alter the lymphocyte count, prostanoid concentrations in the plasma were dramatically reduced. Surprisingly, intrathecally administered FTY720 reduced the nociceptive behaviour in the formalin assay without altering spinal prostaglandin synthesis, indicating that additional antinociceptive mechanisms beside the inhibition of prostaglandin synthesis are involved. Accordingly, FTY720 reduced also the nociceptive behaviour in the spared nerve injury model for neuropathic pain which does not depend on prostaglandin synthesis. In this model the antinociceptive effect of FTY720 was similar to gabapentin, a commonly used drug to treat neuropathic pain. Taken together we show for the first time that FTY720 possesses antinociceptive properties and that FTY720 reduces nociceptive behaviour during neuropathic pain

Consequences of altered eicosanoid patterns for nociceptive processing in mPGES-1-deficient mice

Cyclooxygenase-2 (COX-2)-dependent prostaglandin (PG) E2 synthesis in the spinal cord plays a major role in the development of inflammatory hyperalgesia and allodynia. Microsomal PGE2 synthase-1 (mPGES-1) isomerizes COX-2-derived PGH2 to PGE2. Here, we evaluated the effect of mPGES-1-deficiency on the noci-ceptive behavior in various models of nociception that depend on PGE2 synthesis. Surprisingly, in the COX-2-dependent zymosan-evoked hyperalgesia model, the nociceptive behavior was not reduced in mPGES-1-deficient mice despite a marked decrease of the spinal PGE2 synthesis. Similarly, the nociceptive behavior was unaltered in mPGES-1-deficient mice in the formalin test. Importantly, spinal cords and primary spinal cord cells derived from mPGES-1-deficient mice showed a redirection of the PGE2 synthesis to PGD2, PGF2α and 6-keto-PGF1α (stable metabolite of PGI2). Since the latter prostaglandins serve also as mediators of noci-ception they may compensate the loss of PGE2 synthesis in mPGES-1-deficient mice

Inter-strain differences of serotonergic inhibitory pain control in inbred mice

Background: Descending inhibitory pain control contributes to the endogenous defense against chronic pain and involves noradrenergic and serotonergic systems. The clinical efficacy of antidepressants suggests that serotonin may be particularly relevant for neuropathic pain conditions. Serotonergic signaling is regulated by synthesis, metabolisms, reuptake and receptors. To address the complexity, we used inbred mouse strains, C57BL/6J, 129 Sv, DBA/2J and Balb/c, which differ in brain serotonin levels. Results: Serotonin analysis after nerve injury revealed inter-strain differences in the adaptation of descending serotonergic fibers. Upregulation of spinal cord and midbrain serotonin was apparent only in 129 Sv mice and was associated with attenuated nerve injury evoked hyperalgesia and allodynia in this strain. The increase of dorsal horn serotonin was blocked by hemisectioning of descending fibers but not by rhizotomy of primary afferents indicating a midbrain source. Para-chlorophenylalanine-mediated serotonin depletion in spinal cord and midbrain intensified pain hypersensitivity in the nerve injury model. In contrast, chronic inflammation of the hindpaw did not evoke equivalent changes in serotonin levels in the spinal cord and midbrain and nociceptive thresholds dropped in a parallel manner in all strains. Conclusion: The results suggest that chronic nerve injury evoked hypernociception may be contributed by genetic differences of descending serotonergic inhibitory control

FLIm and raman spectroscopy for investigating biochemical changes of bovine pericardium upon genipin cross-linking

Biomaterials used in tissue engineering and regenerative medicine applications benefit from longitudinal monitoring in a non-destructive manner. Label-free imaging based on fluorescence lifetime imaging (FLIm) and Raman spectroscopy were used to monitor the degree of genipin (GE) cross-linking of antigen-removed bovine pericardium (ARBP) at three incubation time points (0.5, 1.0, and 2.5 h). Fluorescence lifetime decreased and the emission spectrum redshifted compared to that of uncross-linked ARBP. The Raman signature of GE-ARBP was resonance-enhanced due to the GE cross-linker that generated new Raman bands at 1165, 1326, 1350, 1380, 1402, 1470, 1506, 1535, 1574, 1630, 1728, and 1741 cm-1. These were validated through density functional theory calculations as cross-linker-specific bands. A multivariate multiple regression model was developed to enhance the biochemical specificity of FLIm parameters fluorescence intensity ratio (R2 = 0.92) and lifetime (R2 = 0.94)) with Raman spectral results. FLIm and Raman spectroscopy detected biochemical changes occurring in the collagenous tissue during the cross-linking process that were characterized by the formation of a blue pigment which affected the tissue fluorescence and scattering properties. In conclusion, FLIm parameters and Raman spectroscopy were used to monitor the degree of cross-linking non-destructively. © 2020 by the authors. Licensee MDPI, Basel, Switzerland

Diagnosing Celiac Disease : Towards Wide-Scale Screening and Serology-Based Criteria?

Celiac disease is one of the most common food-related chronic disorders in children. Unfortunately, this multifaceted disease is challenging to recognize and remains markedly underdiagnosed. Screening of either known at-risk groups or even the whole population could increase the suboptimal diagnostic yield substantially. Many recent guidelines recommend screening of at least selected risk groups, but more wide-scale screening remains controversial. The increasing prevalence of celiac disease and the development of autoantibody assays have also led to a gradual shift in the diagnostics towards less invasive serology-based criteria in a subgroup of symptomatic children. The main open questions concern whether these criteria are applicable to all countries and clinical settings, as well as to adult patients. On the other hand, widening screening and the mistaken practice of initiating a gluten-free diet before the appropriate exclusion of celiac disease increase the number of borderline seropositive cases, which may also challenge the classical histopathological diagnostics. Sophisticated diagnostic methods and a deeper understanding of the natural history of early developing celiac disease may prove useful in these circumstances.Peer reviewe

Prevalence and diagnostic outcomes of children with duodenal lesions and negative celiac serology

Background: Celiac disease diagnostics begin by measuring autoantibodies, which may fail to identify seronegative patients. Duodenal lesion in the absence of antibodies is scarcely studied, especially in children. Aims: To investigate the prevalence and diagnostic outcomes of children with seronegative duodenal lesion in two countries with different disease profiles. Methods: Medical data, including the results of histology and transglutaminase (tTGab) and endomysium (EmA) antibody measurements were collected from 1172 Finnish and 264 Romanian children with systematic duodenal sampling. Database of 509 Finnish children with celiac disease was examined to identify earlier seronegative patients. Results: Celiac disease was diagnosed in 307 Finnish and 83 Romanian children in the endoscopy cohorts. No seronegative patients were found among 899 celiac disease patients, although some were only tTGab or EmA positive. Non-celiac duodenal lesion was detected in eight Finnish and 32 Romanian children, their most common diagnoses being inflammatory bowel disease and infections, respectively. Six children with morphological lesion received no diagnosis. None of them developed celiac disease during a follow-up of 3-11 years. Conclusion: Pediatric seronegative celiac disease is exceptional in the era of modern autoantibodies. Other reasons for duodenal lesion should therefore be sought, bearing in mind possible differences across countries. (C) 2019 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.Peer reviewe

Citizens and Peace Mediations in Divided Societies: Identifying Zones of Agreement through a Conjoint Survey Experiment

How can areas of potential agreement be identified and endorsed by citizens in protracted conflicts? In an effort to answer this question, the article introduces a conjoint experiment across the ethnically and territorially split communities of Cyprus and tests a range of hypotheses about the structure of public opinion with respect to a future settlement. We test hypotheses on security and credible commitments, the legacy of past negotiations, as well as transitional justice mechanisms following United Nations plans to mediate the conflict between Greek and Turkish Cypriots. Contrary to conventional wisdom, we demonstrate that a zone of possible agreement (ZOPA) exists from a public opinion perspective. We specifically explore power-sharing in the context of security, provisions for the internally displaced, federal courts, and territorial readjustments and highlight their relative importance for public opinion interventions across conflict-ridden societies

Incorporating Citizen Preferences into the Design of Effective Peace Settlements

This paper describes the use of conjoint survey experiments to identify citizen preferences with respect to a possible peace agreement in Cyprus and a border agreement in Northern Ireland. The recommendations offered in the conclusion emphasize the flexibility of the method and its transferability to other conflict settings. Results also suggest ways of reinvigorating stalled peace negotiations (Cyprus) or improving past deals (Good Friday Agreement/Brexit-Northern Ireland) and can help contending groups and mediators identify potential zones of agreement by revealing areas where contending groups’ preferences overlap or differ and where possible trade-offs exist that could lead to greater consensus. Conjoint experiment results can be presented in the form of visual opinion maps and incorporated into interactive software applications. Such applications allow policymakers and the public to examine the elements of peace settlement packages to assess their degree of support by different communities and to evaluate communities’ readiness for peace settlements. Conjoint survey analysis thus serves as a powerful tool for identifying citizen preferences in discrete postconflict situations

Citizens and Peace Mediations in Divided Societies: Identifying Zones of Agreement through a Conjoint Survey Experiment

How can areas of potential agreement be identified and endorsed by citizens in protracted conflicts? In an effort to answer this question, the article introduces a conjoint experiment across the ethnically and territorially split communities of Cyprus and tests a range of hypotheses about the structure of public opinion with respect to a future settlement. We test hypotheses on security and credible commitments, the legacy of past negotiations, as well as transitional justice mechanisms following United Nations plans to mediate the conflict between Greek and Turkish Cypriots. Contrary to conventional wisdom, we demonstrate that a zone of possible agreement (ZOPA) exists from a public opinion perspective. We specifically explore power-sharing in the context of security, provisions for the internally displaced, federal courts, and territorial readjustments and highlight their relative importance for public opinion interventions across conflict-ridden societies