A survey of current and past Pediatric Infectious Diseases fellows regarding training

<p>Abstract</p> <p>Background</p> <p>The objectives of this study were to characterize the satisfaction of Pediatric Infectious Diseases fellows with their training and to understand how opinions about training have changed over time.</p> <p>Methods</p> <p>Anonymous survey studies were conducted with questions designed to include areas related to the 6 ACGME core competencies. Surveys for current fellows were distributed by fellowship directors, while surveys for graduates were mailed to all individuals with Pediatric Infectious Diseases certification.</p> <p>Results</p> <p>Response rates for current fellows and graduates were 50% and 52%, respectively. Most fellows (98%) and graduates (92%) perceived their overall training favorably. Training in most clinical care areas was rated favorably, however both groups perceived relative deficiencies in several areas. Current fellows rated their training in other competency areas (e.g., systems-based practice, research, and ethics) more favorably when compared to past graduates. Recent graduates perceived their training more favorably in many of these areas compared to past graduates.</p> <p>Conclusions</p> <p>Pediatric Infectious Diseases fellowship training is well regarded by the majority of current and past trainees. Views of current fellows reflect improved satisfaction with training in a variety of competency areas. Persistent deficiencies in clinical training likely reflect active barriers to education. Additional study is warranted to validate perceived deficiencies and to establish consensus on the importance of these areas to infectious diseases training.</p

PDE-4 inhibition rescues aberrant synaptic plasticity in Drosophila and mouse models of fragile X syndrome.

Fragile X syndrome (FXS) is the leading cause of both intellectual disability and autism resulting from a single gene mutation. Previously, we characterized cognitive impairments and brain structural defects in a Drosophila model of FXS and demonstrated that these impairments were rescued by treatment with metabotropic glutamate receptor (mGluR) antagonists or lithium. A well-documented biochemical defect observed in fly and mouse FXS models and FXS patients is low cAMP levels. cAMP levels can be regulated by mGluR signaling. Herein, we demonstrate PDE-4 inhibition as a therapeutic strategy to ameliorate memory impairments and brain structural defects in the Drosophila model of fragile X. Furthermore, we examine the effects of PDE-4 inhibition by pharmacologic treatment in the fragile X mouse model. We demonstrate that acute inhibition of PDE-4 by pharmacologic treatment in hippocampal slices rescues the enhanced mGluR-dependent LTD phenotype observed in FXS mice. Additionally, we find that chronic treatment of FXS model mice, in adulthood, also restores the level of mGluR-dependent LTD to that observed in wild-type animals. Translating the findings of successful pharmacologic intervention from the Drosophila model into the mouse model of FXS is an important advance, in that this identifies and validates PDE-4 inhibition as potential therapeutic intervention for the treatment of individuals afflicted with FXS

Genotype-Phenotype Correlation in NF1: Evidence for a More Severe Phenotype Associated with Missense Mutations Affecting NF1 Codons 844–848

Neurofibromatosis type 1 (NF1), a common genetic disorder with a birth incidence of 1:2,000–3,000, is characterized by a highly variable clinical presentation. To date, only two clinically relevant intragenic genotype-phenotype correlations have been reported for NF1 missense mutations affecting p.Arg1809 and a single amino acid deletion p.Met922del. Both variants predispose to a distinct mild NF1 phenotype with neither externally visible cutaneous/plexiform neurofibromas nor other tumors. Here, we report 162 individuals (129 unrelated probands and 33 affected relatives) heterozygous for a constitutional missense mutation affecting one of five neighboring NF1 codons—Leu844, Cys845, Ala846, Leu847, and Gly848—located in the cysteine-serine-rich domain (CSRD). Collectively, these recurrent missense mutations affect ∼0.8% of unrelated NF1 mutation-positive probands in the University of Alabama at Birmingham (UAB) cohort. Major superficial plexiform neurofibromas and symptomatic spinal neurofibromas were more prevalent in these individuals compared with classic NF1-affected cohorts (both p < 0.0001). Nearly half of the individuals had symptomatic or asymptomatic optic pathway gliomas and/or skeletal abnormalities. Additionally, variants in this region seem to confer a high predisposition to develop malignancies compared with the general NF1-affected population (p = 0.0061). Our results demonstrate that these NF1 missense mutations, although located outside the GAP-related domain, may be an important risk factor for a severe presentation. A genotype-phenotype correlation at the NF1 region 844–848 exists and will be valuable in the management and genetic counseling of a significant number of individuals

Functional analyses of a human vascular tumor FOS variant identify a novel degradation mechanism and a link to tumorigenesis

MTG6Molecular tumour pathology - and tumour genetic

Mutations in the Human UBR1 Gene and the Associated Phenotypic Spectrum

Johanson-Blizzard syndrome (JBS) is a rare, autosomal recessive disorder characterized by exocrine pancreatic insufficiency, typical facial features, dental anomalies, hypothyroidism, sensorineural hearing loss, scalp defects, urogenital and anorectal anomalies, short stature, and cognitive impairment of variable degree. This syndrome is caused by a defect of the E3 ubiquitin ligase UBR1, which is part of the proteolytic N-end rule pathway. Herein, we review previously reported (n=29) and a total of 31 novel UBR1 mutations in relation to the associated phenotype in patients from 50 unrelated families. Mutation types include nonsense, frameshift, splice site, missense, and small in-frame deletions consistent with the hypothesis that loss of UBR1 protein function is the molecular basis of JBS. There is an association of missense mutations and small in-frame deletions with milder physical abnormalities and a normal intellectual capacity, thus suggesting that at least some of these may represent hypomorphic UBR1 alleles. the review of clinical data of a large number of molecularly confirmed JBS cases allows us to define minimal clinical criteria for the diagnosis of JBS. for all previously reported and novel UBR1 mutations together with their clinical data, a mutation database has been established at LOVD.German Research FoundationUniv Hosp Magdeburg, Inst Human Genet, D-39120 Magdeburg, GermanyUniv Hosp Erlangen, Inst Human Genet, Erlangen, GermanyHosp Nacl Ninos Dr Carlos Saenz Herrera, Dept Med, San Jose, Costa RicaKlinikum Bremen Mitte, Bremen, GermanyCHU Vaudois, Dept Med Genet, CH-1011 Lausanne, SwitzerlandUniv Hosp, Dept Pediat Surg, Poitiers, FranceHosp La Fe, Dept Pediat, E-46009 Valencia, SpainAMC Univ Hosp, Dept Pediat Genet, Amsterdam, NetherlandsVanderbilt Univ, Monroe Carell Jr Childrens Hosp, Div Pediat Gastroenterol Hepatol & Nutr, Nashville, TN 37235 USACleveland Clin, Genom Med Inst, Cleveland, OH 44106 USAGuys Hosp, London SE1 9RT, EnglandKariminejad Najmabadi Pathol & Genet Ctr, Tehran, IranGreenwood Genet Ctr, Greenwood, SC 29646 USAUmea Univ, Dept Med Biosci Med & Clin Genet, Umea, SwedenWomens & Childrens Hosp, SA Clin Genet Serv, Adelaide, SA, AustraliaStiftung Deutsch Klin Diagnost GmbH, Fachbereich Kinder & Jugendmed, Wiesbaden, GermanyUniv São Paulo, Dept Pediat, São Paulo, BrazilUniv British Columbia, Dept Pediat, Div Biochem Dis, BC Childrens Hosp, Vancouver, BC V6T 1W5, CanadaCtr Human Genet, Ingelheim, GermanyNanjing Med Univ, Nanjing Childrens Hosp, Dept Digest Dis, Nanjing, Jiangsu, Peoples R ChinaUniv Klinikum Bonn, Zentrum Kinderheilkunde, Bonn, GermanyUniv Tehran Med Sci, Childrens Med Ctr, Res Ctr Immunodeficiencies, Tehran, IranUniv Tehran Med Sci, Dept Immunol, Tehran, IranKing Faisal Specialist Hosp & Res Ctr, Dept Genet, Riyadh 11211, Saudi ArabiaOndokuz Mayis Univ, Dept Med, Samsun, TurkeyOndokuz Mayis Univ, Dept Pediat Genet, Samsun, TurkeyAl Thawra Teaching Hosp, Dept Pediat, Sanaa, YemenHosp Gen Mexico City, Fac Med, Dept Human Genet, Mexico City, DF, MexicoUniv Med Ctr Utrecht, Dept Med Genet, Utrecht, NetherlandsNatl Childrens Hosp, San Jose, Costa RicaSisli Etfal Res Hosp, Dept Med Genet, Istanbul, TurkeyNizams Inst Med Sci, Dept Med Genet, Hyderabad, Andhra Pradesh, IndiaMaulana Azad Med Coll, Dept Pediat, New Delhi, IndiaDeenanath Mangeshkar Hosp & Res Ctr, Dept Genet, Erandawane, IndiaMinist Hlth, Dept Pediat, Manama, BahrainUniv Fed Bahia, Fac Med, Hosp Univ Prof Edgar Santos, Pediat Endocrinol Unit, Salvador, BA, BrazilErnst Moritz Arndt Univ Greifswald, Univ Med, Dept Med A, Greifswald, GermanyTech Univ Munich, Else Kroner Fresenius Zentrum Ernahrungsmed, Freising Weihenstephan, GermanyTech Univ Munich, Zent Inst Ernahrungs & Lebensmittelforsch, Freising Weihenstephan, GermanyTech Univ Munich, Klinikum Rechts Isar, Dept Pediat, D-80290 Munich, GermanyGerman Research Foundation: DFG ZE 524/2-3Web of Scienc

Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases

Gene-disruptive mutations contribute to the biology of neurodevelopmental disorders (NDDs), but most pathogenic genes are not known. We sequenced 208 candidate genes from >11,730 patients and >2,867 controls. We report 91 genes with an excess of de novo mutations or private disruptive mutations in 5.7% of patients, including 38 novel NDD genes. Drosophila functional assays of a subset bolster their involvement in NDDs. We identify 25 genes that show a bias for autism versus intellectual disability and highlight a network associated with high-functioning autism (FSIQ>100). Clinical follow-up for NAA15, KMT5B, and ASH1L reveals novel syndromic and non-syndromic forms of disease