Methylphenidate (Ritalin) use and abuse

No Abstrac

FXR1 splicing is important for muscle development and biomolecular condensates in muscle cells

© The Author(s), 2020. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Smith, J. A., Curry, E. G., Blue, R. E., Roden, C., Dundon, S. E. R., Rodríguez-Vargas, A., Jordan, D. C., Chen, X., Lyons, S. M., Crutchley, J., Anderson, P., Horb, M. E., Gladfelter, A. S., & Giudice, J. FXR1 splicing is important for muscle development and biomolecular condensates in muscle cells. Journal of Cell Biology, 219(4), (2020): e201911129, doi: 10.1083/jcb.201911129.Fragile-X mental retardation autosomal homologue-1 (FXR1) is a muscle-enriched RNA-binding protein. FXR1 depletion is perinatally lethal in mice, Xenopus, and zebrafish; however, the mechanisms driving these phenotypes remain unclear. The FXR1 gene undergoes alternative splicing, producing multiple protein isoforms and mis-splicing has been implicated in disease. Furthermore, mutations that cause frameshifts in muscle-specific isoforms result in congenital multi-minicore myopathy. We observed that FXR1 alternative splicing is pronounced in the serine- and arginine-rich intrinsically disordered domain; these domains are known to promote biomolecular condensation. Here, we show that tissue-specific splicing of fxr1 is required for Xenopus development and alters the disordered domain of FXR1. FXR1 isoforms vary in the formation of RNA-dependent biomolecular condensates in cells and in vitro. This work shows that regulation of tissue-specific splicing can influence FXR1 condensates in muscle development and how mis-splicing promotes disease.We thank the A.S. Gladfelter and J. Giudice laboratories, Nancy Kedersha, and Silvia Ramos for critical discussions; Eunice Y. Lee for technical help; Dr. Stephanie Gupton (University of North Carolina at Chapel Hill, Chapel Hill, NC) for donation of WT C57BL/6J mouse embryos; and Marcin Wlizla and National Xenopus Resource (RRID:SCR_013731) for their help in maintaining adult frogs and other important technical support. This work has been funded by a University of North Carolina at Chapel Hill Junior Faculty Development Award (to J. Giudice); a Nutrition and Obesity Research Center, University of North Carolina at Chapel Hill, Pilot & Feasibility Research grant (P30DK056350 to J. Giudice); University of North Carolina at Chapel Hill startup funds (to J. Giudice); the March of Dimes Foundation (5-FY18-36, Basil O’Connor Starter Scholar Award to J. Giudice); and NCTraCs Pilot Grant (550KR181805) from the National Center for Advancing Translational Sciences (NCATS), National Institutes of Health, through Grant Award Number UL1TR002489 (to J. Giudice), National Institutes of Health National Institute of General Medical Sciences grants (R01-GM130866 to J. Giudice, R01-GM081506 to A.S. Gladfelter, R35-GM126901 to P. Anderson, K99-GM124458 to S.M. Lyons, R25-GM089569 and 2R25-GM055336-20 to E.G. Curry); Howard Hughes Medical Institute Faculty Scholars program (A.S. Gladfelter), and National Institute of Health grants R01-HD084409 and P40-OD010997 (to M.E. Horb). The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding agencies.2020-09-1

Calcipotriol and Betamethasone Dipropionate Cream Based on PAD Technology for the Treatment of Plaque Psoriasis: A Narrative Review

Abstract Topical treatment plays a crucial role in psoriasis management, with non-adherence being a major barrier to treatment success. The fixed-dose combination of calcipotriol (CAL) and betamethasone dipropionate (BDP) represents the first-line choice in topical psoriasis treatment. A CAL/BDP cream based on polyaphron dispersion (PAD) Technology has emerged as a novel formulation for a more convenient topical treatment of psoriasis. This article aims to summarize the most relevant published evidence about CAL/BDP PAD-cream and its underlying PAD Technology. The PAD Technology enables CAL and BDP stability in an aqueous cream through a multimolecular shell structure, as well as it increases the penetration of both active ingredients into the epidermis and dermis. This technology also demonstrated to increase the cosmetic acceptability and to provide the desirable sensory properties for a topical psoriasis treatment. Two phase III clinical trials have been conducted so far with CAL/BDP PAD-cream. Findings from both trials revealed high efficacy with a fast onset of action, a favourable safety and tolerability profile and convenience for CAL/BDP PAD-cream compared to CAL/BDP gel. In the trial including patients with psoriasis affecting the scalp (MC2-01-C7), results support the use of CAL/BDP PAD-cream in scalp psoriasis. An anchored matching-adjusted indirect comparison (MAIC) was conducted to compare CAL/BDP PAD-cream and CAL/BDP foam, as both products had been previously compared to CAL/BDP gel. CAL/BDP PAD-cream and CAL/BDP foam showed equivalent efficacy and quality of life at their recommended treatment duration, whereas greater treatment satisfaction for CAL/BDP PAD-cream was found after one week of treatment. Overall, the high patient acceptability and treatment satisfaction observed with CAL/BDP PAD-cream in clinical trials may lead to improved adherence and hence higher efficacy in clinical practice

Interleukin-13 (IL-13)/IL-13 Receptor α1 (IL-13Rα1) Signaling Regulates Intestinal Epithelial Cystic Fibrosis Transmembrane Conductance Regulator Channel-dependent Cl− Secretion*

Interleukin-13 (IL-13) has been linked to the pathogenesis of inflammatory diseases of the gastrointestinal tract. It is postulated that IL-13 drives inflammatory lesions through the modulation of both hematopoietic and nonhematopoietic cell function in the intestine. To delineate the relevant contribution of elevated levels of intestinal IL-13 to intestinal structure and function, we generated an intestinal IL-13 transgenic mouse (iIL-13Tg). We show that constitutive overexpression of IL-13 in the small bowel induces modification of intestinal epithelial architecture (villus blunting, goblet cell hyperplasia, and increased epithelial proliferation) and epithelial function (altered basolateral → apical Cl− ion conductance). Pharmacological analyses in vitro and in vivo determined that elevated Cl− conductance is mediated by altered cystic fibrosis transmembrane conductance regulator expression and activity. Generation of iIL-13Tg/Il13rα1−/−, iIL-13Tg/Il13rα2−/−, and iIL-13Tg/Stat6−/− mice revealed that IL-13-mediated dysregulation of epithelial architecture and Cl− conductance is dependent on IL-13Rα1 and STAT-6. These observations demonstrate a central role for the IL-13/IL-13Rα1 pathway in the regulation of intestinal epithelial cell Cl− secretion via up-regulation of cystic fibrosis transmembrane conductance regulator, suggesting an important role for this pathway in secretory diarrhea

Surgical outcomes of gallbladder cancer: the OMEGA retrospective, multicentre, international cohort study

Background Gallbladder cancer (GBC) is rare but aggressive. The extent of surgical intervention for different GBC stages is non-uniform, ranging from cholecystectomy alone to extended resections including major hepatectomy, resection of adjacent organs and routine extrahepatic bile duct resection (EBDR). Robust evidence here is lacking, however, and survival benefit poorly defined. This study assesses factors associated with recurrence-free survival (RFS), overall survival (OS) and morbidity and mortality following GBC surgery in high income countries (HIC) and low and middle income countries (LMIC).Methods The multicentre, retrospective Operative Management of Gallbladder Cancer (OMEGA) cohort study included all patients who underwent GBC resection across 133 centres between 1st January 2010 and 31st December 2020. Regression analyses assessed factors associated with OS, RFS and morbidity.Findings On multivariable analysis of all 3676 patients, wedge resection and segment IVb/V resection failed to improve RFS (HR 1.04 [0.84-1.29], p = 0.711 and HR 1.18 [0.95-1.46], p = 0.13 respectively) or OS (HR 0.96 [0.79-1.17], p = 0.67 and HR 1.48 [1.16-1.88], p = 0.49 respectively), while major hepatectomy was associated with worse RFS (HR 1.33 [1.02-1.74], p = 0.037) and OS (HR 1.26 [1.03-1.53], p = 0.022). Furthermore, EBDR (OR 2.86 [2.3-3.52], p < 0.0010), resection of additional organs (OR 2.22 [1.62-3.02], p < 0.0010) and major hepatectomy (OR 3.81 [2.55-5.73], p < 0.0010) were all associated with increased morbidity and mortality. Compared to LMIC, patients in HIC were associated with poorer RFS (HR 1.18 [1.02-1.37], p = 0.031) but not OS (HR 1.05 [0.91-1.22], p = 0.48). Adjuvant and neoadjuvant treatments were infrequently used.Interpretation In this large, multicentre analysis of GBC surgical outcomes, liver resection was not conclusively associated with improved survival, and extended resections were associated with greater morbidity and mortality without oncological benefit. Aggressive upfront resections do not benefit higher stage GBC, and international col-laborations are needed to develop evidence-based neoadjuvant and adjuvant treatment strategies to minimise surgical morbidity and prioritise prognostic benefit.Funding Cambridge Hepatopancreatobiliary Department Research Fund.Copyright & COPY; 2023 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)