ABSTRACT
IL-1R antagonist (IL-1Ra) is required for adequate host defense in invasive pneumococcal disease (IPD). The minor allele of an IL1RN gene (C/T) promoter polymorphism (rs4251961) has been shown to be associated with decreased IL-1Ra production in healthy adults. We genotyped 299 children with IPD, and examined 19 IL1RN haplotype-tagging single-nucleotide polymorphisms. Human embryonic kidney HEK293(T) cells were transfected with the promoter reporter plasmid pGL3p containing either allelic variant C (pGL3pCC) or T (pGL3pTT) with or without cotransfection with an expression construct overexpressing the globin transcription factor GATA-1. Plasma IL-1Ra concentrations were significantly higher in nonsurvivors compared with survivors (p < 0.0005), and the C allele of rs4251961 was associated with a significant increase in plasma IL-1Ra concentrations (p = 0.01) during the acute illness of IPD. These findings were validated in a cohort of 276 treatment-naive HIV-infected adults, with borderline significance (p = 0.058). Functional analyses demonstrated that the activity of the promoter constructs containing the T allele increased ~6-fold as compared with basal activity, and that containing the C allele by ~9-fold (p < 0.001) in the presence of GATA-1. Our findings suggest that the IL-1Ra single-nucleotide polymorphism rs4251961 plays a key role in the pathophysiology of IPD and in other human infections.
Subject(s)
GATA1 Transcription Factor/physiology , Interleukin 1 Receptor Antagonist Protein/metabolism , Meningitis, Pneumococcal/immunology , Pneumonia, Pneumococcal/immunology , Polymorphism, Single Nucleotide/genetics , Promoter Regions, Genetic/immunology , Adult , Alleles , Child , Child, Preschool , Cohort Studies , Female , GATA1 Transcription Factor/blood , Gene Expression Regulation, Bacterial/immunology , HEK293 Cells , Humans , Infant , Interleukin 1 Receptor Antagonist Protein/biosynthesis , Interleukin 1 Receptor Antagonist Protein/blood , Interleukin 1 Receptor Antagonist Protein/genetics , Male , Meningitis, Pneumococcal/blood , Meningitis, Pneumococcal/genetics , Pneumonia, Pneumococcal/blood , Pneumonia, Pneumococcal/genetics , Young AdultABSTRACT
Epilepsy affects nearly 3 million people in the United States alone. Given the fact that many people suffer from seizures that are intractable to pharmacological intervention, research groups are investigating the use of electrical stimulation to interact with and ameliorate symptoms of epileptic seizures. In mouse cortical slices made seizuregenic through chemical means, we applied precision controlled current pulses and measured local field potentials through a four point probe system to investigate the response of seizing tissue to electrical stimulation. We have determined that the frequency of the spontaneous seizure-like events may be modified by low amplitude, current controlled stimulation (0.5 microA). Differently from previously thought, this change in frequency is however not accompanied by any alteration of the tissue permittivity or conductivity during the inter-seizure interval.
