Targeted therapies to improve CFTR function in cystic fibrosis.

Cystic fibrosis is the most common genetically determined, life-limiting disorder in populations of European ancestry. The genetic basis of cystic fibrosis is well established to be mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that codes for an apical membrane chloride channel principally expressed by epithelial cells. Conventional approaches to cystic fibrosis care involve a heavy daily burden of supportive treatments to combat lung infection, help clear airway secretions and maintain nutritional status. In 2012, a new era of precision medicine in cystic fibrosis therapeutics began with the licensing of a small molecule, ivacaftor, which successfully targets the underlying defect and improves CFTR function in a subgroup of patients in a genotype-specific manner. Here, we review the three main targeted approaches that have been adopted to improve CFTR function: potentiators, which recover the function of CFTR at the apical surface of epithelial cells that is disrupted in class III and IV genetic mutations; correctors, which improve intracellular processing of CFTR, increasing surface expression, in class II mutations; and production correctors or read-through agents, which promote transcription of CFTR in class I mutations. The further development of such approaches offers great promise for future therapeutic strategies in cystic fibrosis.

Needle temperature effect on pain ratings after injection.

OBJECTIVES: Little research regarding appropriate immunization administration technique for adults has been carried out. Pain is a leading cause of self-deferral from immunizations. The purpose of this study was to determine whether administering intramuscular injections using cold needles would decrease patients' perceived pain and have an effect on the immune response elicited by the vaccine. METHODS: Eighty participants received an injection of influenza vaccine in 1 arm and a saline injection in the other using a cold or room temperature needle in a double-blind fashion assigned at random. Participants rated their pain after each injection using a standard visual pain scale bounded by no pain and most painful injection ever. Vaccine antibody response was measured using hemagglutination inhibition assays. RESULTS: Overall, pain scores after influenza vaccine administration were quite low (34.2+/-2.5 mm). The mean pain score for influenza vaccine was not different using cold or room temperature needles (cold 32.2 mm+/-3.20 vs. room temperature 36.0 mm+/-3.80; t=0.76; P=0.450). The mean pain scores for saline injections did not differ (room temperature 23.7 mm+/-3.19 vs. cold 25.2+/-2.95; t=-0.34; P=0.73). Individuals receiving injections with cold needles had less bruising (0/40 vs. 5/40; P<0.02) at the injection site, but incidences of pain and erythema were similar. The use of cold needles for vaccine administration had no effect on antibody response. CONCLUSIONS: Pain after influenza vaccine administration is generally mild. Use of cold needles may not be worth pursuing for injections associated with mild pain. However, it may be worthwhile to explore using cold needles as an analgesic with more painful injections.

Pathways of carbon assimilation and ammonia oxidation suggested by environmental genomic analyses of marine Crenarchaeota.

Marine Crenarchaeota represent an abundant component of oceanic microbiota with potential to significantly influence biogeochemical cycling in marine ecosystems. Prior studies using specific archaeal lipid biomarkers and isotopic analyses indicated that planktonic Crenarchaeota have the capacity for autotrophic growth, and more recent cultivation studies support an ammonia-based chemolithoautotrophic energy metabolism. We report here analysis of fosmid sequences derived from the uncultivated marine crenarchaeote, Cenarchaeum symbiosum, focused on the reconstruction of carbon and energy metabolism. Genes predicted to encode multiple components of a modified 3-hydroxypropionate cycle of autotrophic carbon assimilation were identified, consistent with utilization of carbon dioxide as a carbon source. Additionally, genes predicted to encode a near complete oxidative tricarboxylic acid cycle were also identified, consistent with the consumption of organic carbon and in the production of intermediates for amino acid and cofactor biosynthesis. Therefore, C. symbiosum has the potential to function either as a strict autotroph, or as a mixotroph utilizing both carbon dioxide and organic material as carbon sources. From the standpoint of energy metabolism, genes predicted to encode ammonia monooxygenase subunits, ammonia permease, urease, and urea transporters were identified, consistent with the use of reduced nitrogen compounds as energy sources fueling autotrophic metabolism. Homologues of these genes, recovered from ocean waters worldwide, demonstrate the conservation and ubiquity of crenarchaeal pathways for carbon assimilation and ammonia oxidation. These findings further substantiate the likely global metabolic importance of Crenarchaeota with respect to key steps in the biogeochemical transformation of carbon and nitrogen in marine ecosystems.