Cyclooxygenase-2 Inhibition Enhances Activation of T Helper Type 1 Responses During Salmonella Infection

Production of IL-12 and IFN-γ secretion are important components of the protective host response against the intracellular bacterial pathogen, Salmonella typhimurium. While infection with Salmonella does elicit this T helper type 1 response, its magnitude does not appear to be sufficient to prevent infection or limit pathogenesis. Therefore we have investigated factors which might limit a T helper type 1 response following infection. Previously we found that infection of antigen presenting cells with Salmonella dramatically increases cyclooxygenase-2 (COX-2) activity, resulting in high levels of prostaglandin E2 (PGE2). Since PGE2 production can have profound effects on initiation of T helper type 1 responses, we questioned whether this mediator might limit antigen-specific T cell activation. Here we show that blockage of COX-2 activity with the selective inhibitor celecoxib leads to enhancement of the T helper type 1 components stimulated by Salmonella infection. In vitro studies demonstrate the induction of IL-12 and IFN-γ upon Salmonella exposure, which are further increased following COX-2 inhibition. Taken together these in vitro studies suggest that COX-2 activity can limit a salmonella-initiated T helper type 1 response

Reevaluation of the South Asian MYBPC3Δ25bp Intronic Deletion in Hypertrophic Cardiomyopathy

Background: The common intronic deletion, MYBPC3Δ25, detected in 4% to 8% of South Asian populations, is reported to be associated with cardiomyopathy, with ≈7-fold increased risk of disease in variant carriers. Here, we examine the contribution of MYBPC3Δ25 to hypertrophic cardiomyopathy (HCM) in a large patient cohort. Methods: Sequence data from 2 HCM cohorts (n=5393) was analyzed to determine MYBPC3Δ25 frequency and co-occurrence of pathogenic variants in HCM genes. Case-control and haplotype analyses were performed to compare variant frequencies and assess disease association. Analyses were also undertaken to investigate the pathogenicity of a candidate variant MYBPC3 c.1224-52G>A. Results: Our data suggest that the risk of HCM, previously attributed to MYBPC3Δ25, can be explained by enrichment of a derived haplotype, MYBPC3Δ25/−52, whereby a small subset of individuals bear both MYBPC3Δ25 and a rare pathogenic variant, MYBPC3 c.1224-52G>A. The intronic MYBPC3 c.1224-52G>A variant, which is not routinely evaluated by gene panel or exome sequencing, was detected in ≈1% of our HCM cohort. Conclusions: The MYBPC3 c.1224-52G>A variant explains the disease risk previously associated with MYBPC3Δ25 in the South Asian population and is one of the most frequent pathogenic variants in HCM in all populations; genotyping services should ensure coverage of this deep intronic mutation. Individuals carrying MYBPC3Δ25 alone are not at increased risk of HCM, and this variant should not be tested in isolation; this is important for the large majority of the 100 million individuals of South Asian ancestry who carry MYBPC3Δ25 and would previously have been declared at increased risk of HCM

Ionospheric spread-F occurence associated with tropospheric atmospheric gravity waves

Ground-level atmospheric gravity waves (GL-AGWs) recorded at Brisbane (Australia) from 1963 to 1966 using microbarographs have been investigated for possible associations with ionospheric spread-F at certain locations, particularly those with longitudes not displaced significantly from the longitude of Brisbane. Of the 121 well-defined events identified, 54 were found to be associated with tropospheric cold fronts which passed through Brisbane 1 day and particularly 2 days after these GL-AGWs were recorded. For the 67 non-frontal events some significant associations were found with spread-F recorded at some high mid-latitude stations situated at longitudes to the west of Brisbane in the northern hemisphere. No associations were found for stations (including Brisbane) close to the longitude of Brisbane. However the paper draws attention to and illustrates some of the results reported by Khan (A study of ionosphere structures with direction finding equipment, M Sc. thesis, The University of Queensland, Brisbane, Australia, 1973) which show that on some occasions for quiet conditions at Brisbane when travelling ionosphere disturbance (TID) wave amplitudes are so low that spread-F is not recorded, associations can be found between these TID wave oscilations and those at ground level recorded by microbarographs. No associations were recorded with spread-F for the events associated with the fronts