A somatic mutation in the thyrotropin receptor gene in a patient with an autonomous nodule within a multinodular goiter

ABSTRACT Thyrotropin (TSH) is the prime regulator of thyroid cell growth and function and acts through the thyrotropin receptor (TSHR) located on the surface membrane of thyrocytes. Somatic heterozygous mutations that cause TSHR activation in the absence of TSH have been found in toxic adenomas and in hot nodules of multinodular goiters. Clinically and histologically heterogeneous nodules can share common gain-of-function mutations. Mutation prevalence varies greatly and is inversely related to iodine intake of the population. We report a Greek patient presenting with subclinical hyperthyroidism due to a fast-growing autonomous hyperplastic nodule in a long-standing multinodular goiter. Direct DNA sequencing showed that the hot nodule harbored a somatic heterozygous activating TSHR mutation: substitution of glutamine for leucine in the third transmembrane helix. This mutation (L512Q) was recently described in two solitary toxic adenomas. This report expands the spectrum of mutations shared by dissimilar hot nodules, supporting a common mechanism for nonautoimmune thyroid autonomy. The identification of the L512Q substitution demonstrates that gainof-function TSHR mutations are encountered in Greece, although iodine deficiency has been significantly corrected over the last three decades

Expression and Membrane Topology of Anopheles gambiae Odorant Receptors in Lepidopteran Insect Cells

A lepidopteran insect cell-based expression system has been employed to express three Anopheles gambiae odorant receptors (ORs), OR1 and OR2, which respond to components of human sweat, and OR7, the ortholog of Drosophila's OR83b, the heteromerization partner of all functional ORs in that system. With the aid of epitope tagging and specific antibodies, efficient expression of all ORs was demonstrated and intrinsic properties of the proteins were revealed. Moreover, analysis of the orientation of OR1 and OR2 on the cellular plasma membrane through the use of a novel ‘topology screen’ assay and FACS analysis demonstrates that, as was recently reported for the ORs in Drosophila melanogaster, mosquito ORs also have a topology different than their mammalian counterparts with their N-terminal ends located in the cytoplasm and their C-terminal ends facing outside the cell. These results set the stage for the production of mosquito ORs in quantities that should permit their detailed biochemical and structural characterization and the exploration of their functional properties

A worldwide perspective of nursing home-acquired pneumonia compared with community-acquired pneumonia

© 2014 by Daedalus Enterprises.BACKGROUND: Nursing home-acquired pneumonia (NHAP) is the leading cause of death among long-term care patients and the second most common cause of transfers to acute care facilities. The aim of this study was to characterize the incidence, microbiology, and outcomes for hospitalized patients with community-acquired pneumonia (CAP) and NHAP. METHODS: A secondary analysis of 5,160 patients from the Community-Acquired Pneumonia Organization database was performed. World regions were defined as the United States and Canada (I), Latin America (II), and Europe (III). RESULTS: From a total of 5,160 hospitalized patients with CAP, NHAP was identified in 287 (5.6%) patients. Mean age was 80 y. NHAP distribution by region was 6% in region I, 3% in region II, and 7% in region III. Subjects with NHAP had higher frequencies of neurological disease, diabetes mellitus, congestive heart failure, and renal failure than did subjects with CAP (P < .001). ICU admission was

KLF10 gene expression is associated with high fetal hemoglobin levels and with response to hydroxyurea treatment in β-hemoglobinopathy patients

In humans, fetal hemoglobin (HbF) production is controlled by many intricate mechanisms that, to date, remain only partly understood. Pharmacogenomic analysis of the effects of hydroxyurea (HU) on HbF production was undertaken in a collection of Hellenic β-thalassemia and sickle cell disease (SCD) compound heterozygotes and a collection of healthy and KLF1-haploinsufficient Maltese adults, to identify genomic signatures that follow high HbF patterns. KLF10 emerged as a top candidate. Moreover, genotype analysis of β-thalassemia major and intermedia patients and an independent cohort of β-thalassemia/SCD compound heterozygous patients that do or do not respond to HU treatment showed that the homozygous mutant state of a tagSNP in the KLF10 3'UTR is not present in β-thalassemia intermedia patients and is underrepresented in β-thalassemia/SCD compound heterozygous patients that respond well to HU treatment. These data suggest that KLF10 may constitute a pharmacogenomic marker to discriminate between response and nonresponse to HU treatmen