Deficiency of Huntingtin Has Pleiotropic Effects in the Social Amoeba Dictyostelium discoideum

Huntingtin is a large HEAT repeat protein first identified in humans, where a polyglutamine tract expansion near the amino terminus causes a gain-of-function mechanism that leads to selective neuronal loss in Huntington's disease (HD). Genetic evidence in humans and knock-in mouse models suggests that this gain-of-function involves an increase or deregulation of some aspect of huntingtin's normal function(s), which remains poorly understood. As huntingtin shows evolutionary conservation, a powerful approach to discovering its normal biochemical role(s) is to study the effects caused by its deficiency in a model organism with a short life-cycle that comprises both cellular and multicellular developmental stages. To facilitate studies aimed at detailed knowledge of huntingtin's normal function(s), we generated a null mutant of hd, the HD ortholog in Dictyostelium discoideum. Dictyostelium cells lacking endogenous huntingtin were viable but during development did not exhibit the typical polarized morphology of Dictyostelium cells, streamed poorly to form aggregates by accretion rather than chemotaxis, showed disorganized F-actin staining, exhibited extreme sensitivity to hypoosmotic stress, and failed to form EDTA-resistant cell–cell contacts. Surprisingly, chemotactic streaming could be rescued in the presence of the bivalent cations Ca2+ or Mg2+ but not pulses of cAMP. Although hd− cells completed development, it was delayed and proceeded asynchronously, producing small fruiting bodies with round, defective spores that germinated spontaneously within a glassy sorus. When developed as chimeras with wild-type cells, hd− cells failed to populate the pre-spore region of the slug. In Dictyostelium, huntingtin deficiency is compatible with survival of the organism but renders cells sensitive to low osmolarity, which produces pleiotropic cell autonomous defects that affect cAMP signaling and as a consequence development. Thus, Dictyostelium provides a novel haploid organism model for genetic, cell biological, and biochemical studies to delineate the functions of the HD protein

Dosing of sublingual immunotherapy for allergic rhinitis: evidence-based review with recommendations

BACKGROUND: Since the mid 1980s, the clinical use of sublingual immunotherapy (SLIT) has dramatically increased. However, 1 of the primary barriers to providing SLIT is lack of a published dosing recommendations. The purpose of this work is to provide a range of effective SLIT dosing based upon a rigorous review of the existing evidence base. An appendix with SLIT dosing recommendations is also included. METHODS: A comprehensive search of the past 25 years of the medical literature using PubMed was performed for specific antigens. Inclusion criteria for articles included: randomized, placebo-controlled studies of SLIT, studies with clinical allergic rhinitis outcomes, and dosing units available to determine the micrograms per month of major allergen administered. The extracted data was used to compile a range of effective SLIT dosing for individual antigens. RESULTS: Seventy-five articles met the inclusion criteria, providing a range of effective dosing for some allergens. There was commonly a wide range in doses for particular antigens between the individual studies. For some antigens, there was significant overlap in dosage amount between studies showing efficacy and lack of efficacy. Clinical trials meeting inclusion criteria are not available for many allergens. CONCLUSION: This study provided a comprehensive review of the published sublingual dosing ranges for specific antigens. The review provided a range of effective sublingual doses for some allergens, whereas for other allergens there was insufficient published data to determine specific doses. Recommendations for SLIT dosing were produced based on the data revealed in the review and expert opinion

International consensus statement on allergy and rhinology : rhinosinusitis

Background: The body of knowledge regarding rhinosinusitis (RS) continues to expand, with rapid growth in number of publications, yet substantial variability in the quality of those presentations. In an effort to both consolidate and critically appraise this information, rhinologic experts from around the world have produced the International Consensus Statement on Allergy and Rhinology: Rhinosinusitis(ICAR:RS). Methods: Evidence-based reviews with recommendations(EBRRs) were developed for scores of topics, using previously reported methodology. Where existing evidence was insufficient for an EBRR, an evidence-based review (EBR)was produced. The sections were then synthesized and the entire manuscript was then reviewed by all authors for consensus. Results: The resulting ICAR:RS document addresses multiple topics in RS, including acute RS (ARS), chronic RS (CRS)with and without nasal polyps (CRSwNP and CRSsNP), re-current acute RS (RARS), acute exacerbation of CRS (AE-CRS), and pediatric RS. Conclusion: As a critical review of the RS literature, ICAR:RS provides a thorough review of pathophysiology and evidence-based recommendations for medical and surgical treatment. It also demonstrates the significant gaps in our understanding of the pathophysiology and optimal management of RS. Too often the foundation upon which these recommendations are based is comprised of lower-level evidence. It is our hope that this summary of the evidence in RS will point out where additional research efforts may be directed.188 page(s

International Consensus Statement on Allergy and Rhinology: Rhinosinusitis

Isam Alobid, MD, PhD(1) , Nithin D. Adappa, MD(2) , Henry P. Barham, MD(3) , Thiago Bezerra, MD(4) , Nadieska Caballero, MD(5) , Eugene G. Chang, MD(6) , Gaurav Chawdhary, MD(7) , Philip Chen, MD(8) , John P. Dahl, MD, PhD(9) , Anthony Del Signore, MD(10) , Carrie Flanagan, MD(11) , Daniel N. Frank, PhD(12) , Kai Fruth, MD, PhD(13) , Anne Getz, MD(14) , Samuel Greig, MD(15) , Elisa A. Illing, MD(16) , David W. Jang, MD(17) , Yong Gi Jung, MD(18) , Sammy Khalili, MD, MSc(19) , Cristobal Langdon, MD(20) , Kent Lam, MD(21) , Stella Lee, MD(22) , Seth Lieberman, MD(23) , Patricia Loftus, MD(24) , Luis Macias-Valle, MD(25) , R. Peter Manes, MD(26) , Jill Mazza, MD(27) , Leandra Mfuna, MD(28) , David Morrissey, MD(29) , Sue Jean Mun, MD(30) , Jonathan B. Overdevest, MD, PhD(31) , Jayant M. Pinto, MD(32) , Jain Ravi, MD(33) , Douglas Reh, MD(34) , Peta L. Sacks, MD(35) , Michael H. Saste, MD(36) , John Schneider, MD, MA(37) , Ahmad R. Sedaghat, MD, PhD(38) , Zachary M. Soler, MD(39) , Neville Teo, MD(40) , Kota Wada, MD(41) , Kevin Welch, MD(42) , Troy D. Woodard, MD(43) , Alan Workman(44) , Yi Chen Zhao, MD(45) , David Zopf, MD(46) CONTRIBUTING AUTHOR AFFILIATIONS: (1) Universidad de Barcelona; (2) University of Pennsylvania; (3) Louisiana State University Health Sciences Center; (4) Universidade de São Paulo; (5) ENT Specialists of Illinois; (6) University of Arizona; (7) University of Oxford; (8) University of Texas; (9) University of Indiana; (10) Mount Sinai Beth Israel; (11) Emory University; (12) University of Colorado; (13) Wiesbaden, Germany; (14) University of Colorado; (15) University of Alberta; (16) University of Alabama at Birmingham; (17) Duke University; (18) Sungkyunkwan University; (19) University of Pennsylvania; (20) Universidad de Barcelona; (21) Northwestern University; (22) University of Pittsburgh; (23) New York University; (24) Emory University; (25) University of British Columbia; (26) Yale University School of Medicine; (27) Private Practice; (28) Department of Otolaryngology, Hôtel-Dieu Hospital, Centre de Recherche du Centre Hospitalier de l'Université de Montréal; (29) University of Adelaide; (30) Pusan National University; (31) University of California, San Francisco; (32) University of Chicago; (33) University of Auckland; (34) Johns Hopkins University; (35) University of New South Wales, Australia; (36) Stanford University; (37) Washington University; (38) Harvard Medical School; (39) Medical University of South Carolina; (40) Singapore General Hospital; (41) Taho University; (42) Northwestern University; (43) Cleveland Clinic Foundation; (44) University of Pennsylvania; (45) University of Adelaide; (46) University of Michigan.status: publishe