TY - JOUR A1 - Pritchard, Rory A. A1 - Falk, Lovissa A1 - Larsson, Mathilda A1 - Leinders, Mathias A1 - Sorkin, Linda S. T1 - Different phosphoinositide 3-kinase isoforms mediate carrageenan nociception and inflammation JF - Pain N2 - Phosphoinositide 3-kinases (PI3Ks) participate in signal transduction cascades that can directly activate and sensitize nociceptors and enhance pain transmission. They also play essential roles in chemotaxis and immune cell infiltration leading to inflammation. We wished to determine which PI3K isoforms were involved in each of these processes. Lightly anesthetized rats (isoflurane) were injected subcutaneously with carrageenan in their hind paws. This was preceded by a local injection of 1% DMSO vehicle or an isoform-specific antagonist to PI3K-α (compound 15-e), -β (TGX221), -δ (Cal-101), or -γ (AS252424). We measured changes in the mechanical pain threshold and spinal c-Fos expression (4 hours after injection) as indices of nociception. Paw volume, plasma extravasation (Evans blue, 0.3 hours after injection), and neutrophil (myeloperoxidase; 1 hour after injection) and macrophage (CD11b+; 4 hour after injection) infiltration into paw tissue were the measured inflammation endpoints. Only PI3K-γ antagonist before treatment reduced the carrageenan-induced pain behavior and spinal expression of c-Fos (P <= 0.01). In contrast, pretreatment with PI3K-α, -δ, and -γ antagonists reduced early indices of inflammation. Plasma extravasation PI3K-α (P <= 0.05), -δ (P <= 0.05), and -γ (P <= 0.01), early (0-2 hour) edema -α (P <= 0.05), -δ (P <= 0.001), and -γ (P <= 0.05), and neutrophil infiltration (all P <= 0.001) were all reduced compared to vehicle pretreatment. Later (2-4 hour), edema and macrophage infiltration (P <= 0.05) were reduced by only the PI3K-δ and -γ isoform antagonists, with the PI3K-δ antagonist having a greater effect on edema. PI3K-β antagonism was ineffective in all paradigms. These data indicate that pain and clinical inflammation are pharmacologically separable and may help to explain clinical conditions in which inflammation naturally wanes or goes into remission, but pain continues unabated. KW - c-Fos KW - Edema KW - Macrophage KW - Neutrophil KW - Plasma extravasation KW - Pain KW - PI3K isoforms Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-191312 VL - 157 IS - 1 ER - TY - JOUR A1 - Politei, Juan M. A1 - Bouhassira, Didier A1 - Germain, Dominique P. A1 - Goizet, Cyril A1 - Guerrero-Sola, Antonio A1 - Hilz, Max J. A1 - Hutton, Elspeth J. A1 - Karaa, Amel A1 - Liuori, Rocco A1 - Üceyler, Nurcan A1 - Zeltzer, Lonnie K. A1 - Burlina, Alessandro T1 - Pain in fabry disease: practical recommendations for diagnosis and treatment JF - CNS Neuroscience & Therapeutics N2 - Aims: Patients with Fabry disease (FD) characteristically develop peripheral neuropathy at an early age, with pain being a crucial symptom of underlying pathology. However, the diagnosis of pain is challenging due to the heterogeneous and nonspecific symptoms. Practical guidance on the diagnosis and management of pain in FD is needed. Methods: In 2014, experts met to discuss recent advances on this topic and update clinical guidance. Results: Emerging disease-specific tools, including FabryScan, Fabry-specific Pediatric Health and Pain Questionnaire, and Wurzburg Fabry Pain Questionnaire, and more general tools like the Total Symptom Score can aid diagnosis, characterization, and monitoring of pain in patients with FD. These tools can be complemented by more objective and quantifiable sensory testing. In male and female patients of any age, pain related to FD can be an early indication to start disease-specific enzyme replacement therapy before potentially irreversible organ damage to the kidneys, heart, or brain occurs. Conclusion: To improve treatment outcomes, pain should be diagnosed early in unrecognized or newly identified FD patients. Treatment should include: (a) enzyme replacement therapy controlling the progression of underlying pathology; (b) adjunctive, symptomatic pain management with analgesics for chronic neuropathic and acute nociceptive, and inflammatory or mixed pain; and (c) lifestyle modifications. KW - Enzyme replacement therapy KW - Small fiber dysfunction KW - System involvement KW - Outcome survey KW - Fabry disease KW - Randomized controlled-trial KW - Chronic neuropathic pain KW - Agalsidase beta KW - Screening questionnaire KW - Dose reduction KW - Adult patients KW - Diagnosis KW - Pain KW - Peripheral nervous system Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-188127 VL - 22 IS - 7 ER - TY - JOUR A1 - Bert, Bettina A1 - Chmielewska, Justyna A1 - Bergmann, Sven A1 - Busch, Maximilian A1 - Driever, Wolfgang A1 - Finger-Baier, Karin A1 - Hößler, Johanna A1 - Köhler, Almut A1 - Leich, Nora A1 - Misgeld, Thomas A1 - Nöldner, Torsten A1 - Reiher, Annegret A1 - Schartl, Manfred A1 - Seebach-Sproedt, Anja A1 - Thumberger, Thomas A1 - Schönfelder, Gilbert A1 - Grune, Barbara T1 - Considerations for a European animal welfare standard to evaluate adverse phenotypes in teleost fish JF - The EMBO Journal N2 - No abstract available. KW - Danio-rerio KW - Zebrafish KW - Pain Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-188783 VL - 35 IS - 11 ER - TY - JOUR A1 - Oder, Daniel A1 - Vergho, Dorothee A1 - Ertl, Georg A1 - Wanner, Christoph A1 - Nordbeck, Peter T1 - Case report of a 45-year old female Fabry disease patient carrying two alpha-galactosidase A gene mutation alleles JF - BMC Medical Genetics N2 - Background X-chromosomal inheritance patterns and generally rare occurrence of Fabry disease (FD) account for mono-mutational hemizygous male and heterozygous female patients. Female mutation carriers are usually clinically much less severely affected, which has been explained by a suggested mosaicism in cell phenotype due to random allele shutdown. However, clinical evidence is scarce and potential additional effects in female gene carriers, which might account for specific clinical characteristics such as less severe chronic kidney disease, are yet unknown. Case presentation This article reports on a 45 year old female patient carrying the two alpha-galactosidase A gene mutations c.416A > G, p.N139S in exon 3 and c.708G > C, p.W236C in exon 5, but still showing only mild organ manifestations. Conclusion This current case highlights the importance of careful clinical characterization in patients with Fabry disease, who may show additional rare constellations and, therefore, are in need of personalized medicine. The impact of potential additional protective effects exceeding the presence of a non-pathogenic GLA allele in female gene carriers requires further investigation. KW - Fabry disease KW - cryptogenic stroke KW - Pain KW - hypertrophic cardiomyopathy KW - chronic kidney disease Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-146617 VL - 17 IS - 46 ER -