Gene deficiency in activating Fcγ receptors influences the macrophage phenotypic balance and reduces atherosclerosis in mice

Immunity contributes to arterial inflammation during atherosclerosis. Oxidized low-density lipoproteins induce an autoimmune response characterized by specific antibodies and immune complexes in atherosclerotic patients. We hypothesize that specific Fcγ receptors for IgG constant region participate in atherogenesis by regulating the inflammatory state of lesional macrophages. In vivo we examined the role of activating Fcγ receptors in atherosclerosis progression using bone marrow transplantation from mice deficient in γ-chain (the common signaling subunit of activating Fcγ receptors) to hyperlipidemic mice. Hematopoietic deficiency of Fcγ receptors significantly reduced atherosclerotic lesion size, which was associated with decreased number of macrophages and T lymphocytes, and increased T regulatory cell function. Lesions of Fcγ receptor deficient mice exhibited increased plaque stability, as evidenced by higher collagen and smooth muscle cell content and decreased apoptosis. These effects were independent of changes in serum lipids and antibody response to oxidized low-density lipoproteins. Activating Fcγ receptor deficiency reduced pro-inflammatory gene expression, nuclear factor-κB activity, and M1 macrophages at the lesion site, while increasing anti-inflammatory genes and M2 macrophages. The decreased inflammation in the lesions was mirrored by a reduced number of classical inflammatory monocytes in blood. In vitro, lack of activating Fcγ receptors attenuated foam cell formation, oxidative stress and pro-inflammatory gene expression, and increased M2-associated genes in murine macrophages. Our study demonstrates that activating Fcγ receptors influence the macrophage phenotypic balance in the artery wall of atherosclerotic mice and suggests that modulation of Fcγ receptor-mediated inflammatory responses could effectively suppress atherosclerosis

European retrospective study of real-life haemophilia treatment

IntroductionHaemophilia treatment varies significantly between individuals, countries and regions and details of bleed rates, factor consumption and injection frequency are often not available.AimTo provide an overview of the FVIII/FIX treatment practice and outcome for patients with haemophilia A (HA) or haemophilia B (HB) across Europe.MethodsNon‐interventional, 12‐month retrospective study where anonymized data were retrieved from haemophilia centres/registers in Belgium, France, Germany, Italy, Spain, Sweden and the United Kingdom. Male patients (all ages) receiving coagulation factor treatment 24 months prior to the study, with basal FVIII/FIX levels ≤5 IU dL−1, without inhibitors, were included. Data were summarized descriptively.ResultsIn total, 1346 patients with HA and 312 with HB were included in the analysis; 75% and 57% had severe disease (FVIII/FIX < 1 IU dL−1) respectively. Prophylaxis was most common for severe haemophilia, especially for children, whereas on‐demand treatment was more common for moderate haemophilia in most countries. The mean (SD) prescribed prophylactic treatment ranged from 67.9 (30.4) to 108.4 (78.1) (HA) and 32.3 (10.2) to 97.7 (32.1) (HB) IU kg−1 per week, across countries. Most patients on prophylaxis were treated ≥3 times/week (HA) or two times/week (HB). The median annual bleeding rate (ABR) for patients on prophylaxis ranged from 1.0 to 4.0 for severe HA, and from 1.0 to 6.0 for severe HB, while those with moderate haemophilia generally had slightly higher ABRs. Median ABRs for on‐demand‐treated severe HA ranged from 4.5 to 18.0, and for HB, 1.5 to 14.0.ConclusionTreatment practice varied greatly between centres and countries and patients treated on‐demand and prophylactically both experienced bleeds, emphasizing the need for further optimization of care

Analysis of conglutin seed storage proteins across lupin species using transcriptomic, protein and comparative genomic approaches

Background - The major proteins in lupin seeds are conglutins that have primary roles in supplying carbon, sulphur and nitrogen and energy for the germinating seedling. They fall into four families; α, β, γ and δ. Interest in these conglutins is growing as family members have been shown to have beneficial nutritional and pharmaceutical properties. Results - An in-depth transcriptome and draft genome from the narrow-leafed lupin (NLL; Lupinus angustifolius) variety, Tanjil, were examined and 16 conglutin genes were identified. Using RNAseq data sets, the structure and expression of these 16 conglutin genes were analysed across eight lupin varieties from five lupin species. Phylogenic analysis suggest that the α and γ conglutins diverged prior to lupin speciation while β and δ members diverged both prior and after speciation. A comparison of the expression of the 16 conglutin genes was performed, and in general the conglutin genes showed similar levels of RNA expression among varieties within species, but quite distinct expression patterns between lupin species. Antibodies were generated against the specific conglutin families and immunoblot analyses were used to compare the levels of conglutin proteins in various tissues and during different stages of seed development in NLL, Tanjil, confirming the expression in the seed. This analysis showed that the conglutins were expressed highly at the mature seed stage, in all lupin species, and a range of polypeptide sizes were observed for each conglutin family. Conclusions - This study has provided substantial information on the complexity of the four conglutin families in a range of lupin species in terms of their gene structure, phylogenetic relationships as well as their relative RNA and protein abundance during seed development. The results demonstrate that the majority of the heterogeneity of conglutin polypeptides is likely to arise from post-translational modification from a limited number of precursor polypeptides rather than a large number of different genes. Overall, the results demonstrate a high degree of plasticity for conglutin expression during seed development in different lupin species

Sap Transporter Mediated Import and Subsequent Degradation of Antimicrobial Peptides in Haemophilus

Antimicrobial peptides (AMPs) contribute to host innate immune defense and are a critical component to control bacterial infection. Nontypeable Haemophilus influenzae (NTHI) is a commensal inhabitant of the human nasopharyngeal mucosa, yet is commonly associated with opportunistic infections of the upper and lower respiratory tracts. An important aspect of NTHI virulence is the ability to avert bactericidal effects of host-derived antimicrobial peptides (AMPs). The Sap (sensitivity to antimicrobial peptides) ABC transporter equips NTHI to resist AMPs, although the mechanism of this resistance has remained undefined. We previously determined that the periplasmic binding protein SapA bound AMPs and was required for NTHI virulence in vivo. We now demonstrate, by antibody-mediated neutralization of AMP in vivo, that SapA functions to directly counter AMP lethality during NTHI infection. We hypothesized that SapA would deliver AMPs to the Sap inner membrane complex for transport into the bacterial cytoplasm. We observed that AMPs localize to the bacterial cytoplasm of the parental NTHI strain and were susceptible to cytoplasmic peptidase activity. In striking contrast, AMPs accumulated in the periplasm of bacteria lacking a functional Sap permease complex. These data support a mechanism of Sap mediated import of AMPs, a novel strategy to reduce periplasmic and inner membrane accumulation of these host defense peptides

The Pierre Auger Observatory III: Other Astrophysical Observations

Astrophysical observations of ultra-high-energy cosmic rays with the Pierre Auger ObservatoryComment: Contributions to the 32nd International Cosmic Ray Conference, Beijing, China, August 201

Highlights from the Pierre Auger Observatory

The Pierre Auger Observatory is the world's largest cosmic ray observatory. Our current exposure reaches nearly 40,000 km$^2$ str and provides us with an unprecedented quality data set. The performance and stability of the detectors and their enhancements are described. Data analyses have led to a number of major breakthroughs. Among these we discuss the energy spectrum and the searches for large-scale anisotropies. We present analyses of our X$_{max}$ data and show how it can be interpreted in terms of mass composition. We also describe some new analyses that extract mass sensitive parameters from the 100% duty cycle SD data. A coherent interpretation of all these recent results opens new directions. The consequences regarding the cosmic ray composition and the properties of UHECR sources are briefly discussed.Comment: 9 pages, 12 figures, talk given at the 33rd International Cosmic Ray Conference, Rio de Janeiro 201

Measurement of the Depth of Maximum of Extensive Air Showers above 10^18 eV

We describe the measurement of the depth of maximum, Xmax, of the longitudinal development of air showers induced by cosmic rays. Almost four thousand events above 10^18 eV observed by the fluorescence detector of the Pierre Auger Observatory in coincidence with at least one surface detector station are selected for the analysis. The average shower maximum was found to evolve with energy at a rate of (106 +35/-21) g/cm^2/decade below 10^(18.24 +/- 0.05) eV and (24 +/- 3) g/cm^2/decade above this energy. The measured shower-to-shower fluctuations decrease from about 55 to 26 g/cm^2. The interpretation of these results in terms of the cosmic ray mass composition is briefly discussed.Comment: Accepted for publication by PR

Emergency hospital services utilization in Lleida (Spain): A cross-sectional study of immigrant and Spanish-born populations

<p>Abstract</p> <p>Background</p> <p>The use of emergency hospital services (EHS) has increased steadily in Spain in the last decade while the number of immigrants has increased dramatically. Studies show that immigrants use EHS differently than native-born individuals, and this work investigates demographics, diagnoses and utilization rates of EHS in Lleida (Spain).</p> <p>Methods</p> <p>Cross-sectional study of all the 96,916 EHS visits by patients 15 to 64 years old, attended during the years 2004 and 2005 in a public teaching hospital. Demographic data, diagnoses of the EHS visits, frequency of hospital admissions, mortality and diagnoses at hospital discharge were obtained. Utilization rates were estimated by group of origin. Poisson regression was used to estimate the rate ratios of being visited in the EHS with respect to the Spanish-born population.</p> <p>Results</p> <p>Immigrants from low-income countries use EHS services more than the Spanish-born population. Differences in utilization patterns are particularly marked for Maghrebi men and women and sub-Saharan women. Immigrant males are at lower risk of being admitted to the hospital, as compared with Spanish-born males. On the other hand, immigrant women are at higher risk of being admitted. After excluding the visits with gynecologic and obstetric diagnoses, women from sub-Saharan Africa and the Maghreb are still at a higher risk of being admitted than their Spanish-born counterparts.</p> <p>Conclusion</p> <p>In Lleida (Spain), immigrants use more EHS than the Spanish born population. Future research should indicate whether the same pattern is found in other areas of Spain and whether EHS use is attributable to health needs, barriers to access to the primary care services or similarities in the way immigrants access health care in their countries of origin.</p