Detection of C1 inhibitor (SERPING1/C1NH) mutations in exon 8 in patients with hereditary angioedema: evidence for 10 novel mutations

Hereditary angioedema (HAE) is caused by mutations in the C1 inhibitor gene (SERPING1, C1NH) and the result is C1 inhibitor deficiency, either in levels or function. We have searched exon 8 for mutations by direct sequencing and analyzed the rest of the exons by SSCP in 87 Spanish families affected by HAE. Out of 87 screened families, we have detected exon 8 mutations in 26. Among these, 17 different mutations were identified: 14 point mutations and 3 frameshift. Seven of the point mutations and the three frameshift were not previously reported. Mutations were: S438P; R444P; V451G; W460X; V468D; G471E; X479R; S417fsX427; I440fsX450; E429fsX450. The rest of the families presented previously reported mutations, 5 missense and two nonsense. In none of the 26 families was an additional change identified in the rest of the exons by SSCP, and, in 20 out of the 22 families with point mutation, we verified that the mutation did not affect a healthy relative. Seven of these families had no history of the disease, and in five of them we were able to verify that the progenitors did not have the mutation. Therefore, they were de novo mutations

Impulse oscillometry reference values and bronchodilator response in three- to five-year old children living at high altitude

Q2Q1Introduction: Impulse oscillometry (IOS) is used to measure airway impedance. It is an effective tool for diagnosing and treating respiratory diseases, and it has the advantage that it does not require forced respiratory maneuvers. IOS reference values are required for each population group. Objective: This study aimed to determine the IOS reference values and bronchodilator response in healthy preschool children living in Bogotá, Colombia. Methods: We performed a cross-sectional study in preschool children who had no history of respiratory disease; 96 children fit the parameters for testing to determine normal values according to the American Thoracic Society and European Respiratory Society criteria. Results: Values for respiratory resistance (Rrs) and reactance (Xrs) at 5, 10, and 20 Hz, respiratory impedance (Zrs, and resonance frequency (Fres) were established. Height was the most influential independent variable for IOS values; an increase in height led to a reduction in Rrs5 and Rrs20 and an increase in Xrs5. After the administration of 400 mcg of salbutamol the values for Rrs5(-17.48%), Rrs20(-8.63%), Fres (-10.68%), and area of reactance (-35.44%) were reduced, meanwhile Xrs5 (15.35%) was increased. Conclusions: Normal IOS values before and after the administration of 400 mcg of salbutamol were determined for a population of children aged 3-5 years at 2,640 m. Reference IOS equations for these children are presented. A relative change of up to -28% and 36% after the use of salbutamol for respiratory resistance and reactance, respectively, should be considered as an upper limit of the normal range, and possible appropriate cut-off values for defining significant response for evaluating therapeutic interventions. Keywords: children; cross-sectional studies; high altitude; oscillometry; reference values; respiratory function tests.N/

Four variants in transferrin and HFE genes as potential markers of iron deficiency anaemia risk: an association study in menstruating women

Abstract Background Iron deficiency anaemia is a worldwide health problem in which environmental, physiologic and genetic factors play important roles. The associations between iron status biomarkers and single nucleotide polymorphisms (SNPs) known to be related to iron metabolism were studied in menstruating women. Methods A group of 270 Caucasian menstruating women, a population group at risk of iron deficiency anaemia, participated in the study. Haematological and biochemical parameters were analysed and 10 selected SNPs were genotyped by minisequencing assay. The associations between genetic and biochemical data were analysed by Bayesian Model Averaging (BMA) test and decision trees. Dietary intake of a representative subgroup of these volunteers (n = 141) was assessed, and the relationship between nutrients and iron biomarkers was also determined by linear regression. Results Four variants, two in the transferrin gene (rs3811647, rs1799852) and two in the HFE gene (C282Y, H63D), explain 35% of the genetic variation or heritability of serum transferrin in menstruating women. The minor allele of rs3811647 was associated with higher serum transferrin levels and lower transferrin saturation, while the minor alleles of rs1799852 and the C282Y and H63D mutations of HFE were associated with lower serum transferrin levels. No association between nutrient intake and iron biomarkers was found. Conclusions In contrast to dietary intake, these four SNPs are strongly associated with serum transferrin. Carriers of the minor allele of rs3811647 present a reduction in iron transport to tissues, which might indicate higher iron deficiency anaemia risk, although the simultaneous presence of the minor allele of rs1799852 and HFE mutations appear to have compensatory effects. Therefore, it is suggested that these genetic variants might potentially be used as markers of iron deficiency anaemia risk.This study was supported by Project AGL2009-11437. R.Blanco-Rojo was supported by a JAE-predoc grant from CSIC and European Social Found, S.Bertoncini by Grupo Santander 2009 (Estancia doctores y tecnologos UCM), and J.M.Soria by "Programa d'Estabilització d'Investigadors de la Direcció d'Estrategia i Coordinació del Departament de Salut".Peer Reviewe

Impaired CpG Demethylation in Common Variable Immunodeficiency Associates With B Cell Phenotype and Proliferation Rate

Common Variable Immunodeficiency (CVID) is characterized by impaired antibody production and poor terminal differentiation of the B cell compartment, yet its pathogenesis is still poorly understood. We first reported the occurrence of epigenetic alterations in CVID by high-throughput methylation analysis in CVID-discordant monozygotic twins. Data from a recent whole DNA methylome analysis throughout different stages of normal B cell differentiation allowed us to design a new experimental approach. We selected CpG sites for analysis based on two criteria: one, CpGs with potential association with the transcriptional status of relevant genes for B cell activation and differentiation; and two, CpGs that undergo significant demethylation from naive to memory B cells in healthy individuals. DNA methylation was analyzed by bisulfite pyrosequencing of specific CpG sites in sorted naive and memory B cell subsets from CVID patients and healthy donors. We observed impaired demethylation in two thirds of the selected CpGs in CVID memory B cells, in genes that govern B cell-specific processes or participate in B cell signaling. The degree of demethylation impairment associated with the extent of the memory B cell reduction. The impaired demethylation in such functionally relevant genes as AICDA in switched memory B cells correlated with a lower proliferative rate. Our new results reinforce the hypothesis of altered demethylation during B cell differentiation as a contributing pathogenic mechanism to the impairment of B cell function and maturation in CVID. In particular, deregulated epigenetic control of AICDA could play a role in the defective establishment of a post-germinal center B cell compartment in CVID

Monozygotic twins discordant for common variable immunodeficiency reveal impaired DNA demethylation during naı¨ve-to-memory B-cell transition

Common variable immunodeficiency (CVID), the most frequent primary immunodeficiency characterized by loss of B-cell function, depends partly on genetic defects, and epigenetic changes are thought to contribute to its aetiology. Here we perform a high-throughput DNA methylation analysis of this disorder using a pair of CVID-discordant MZ twins and show predominant gain of DNA methylation in CVID B cells with respect to those from the healthy sibling in critical B lymphocyte genes, such as PIK3CD, BCL2L1, RPS6KB2, TCF3 and KCNN4. Individual analysis confirms hypermethylation of these genes. Analysis in naive, unswitched and switched memory B cells in a CVID patient cohort shows impaired ability to demethylate and upregulate these genes in transitioning from naive to memory cells in CVID. Our results not only indicate a role for epigenetic alterations in CVID but also identify relevant DNA methylation changes in B cells that could explain the clinical manifestations of CVID individuals

Complement component 3 as biomarker of disease activity and cardiometabolic risk factor in rheumatoid arthritis and spondyloarthritis.

Funder: Europeo de Desarrollo Regional de la Unión EuropeaFunder: Rheumatic Diseases NetworkOBJECTIVE: To analyze the relationship between complement component 3 (C3) and the prevalence of cardiometabolic risk factors and disease activity in the rheumatic diseases having the highest rates of cardiovascular morbidity and mortality: rheumatoid arthritis (RA), psoriatic arthritis (PsA) and axial spondyloarthritis (axSpA). METHODS: This is a cross-sectional study including 200 RA, 80 PsA, 150 axSpA patients and 100 healthy donors. The prevalence of cardiometabolic risk factors [obesity, insulin resistance, type 2 diabetes mellitus, hyperlipidemia, apolipoprotein B/apolipoprotein A (apoB/apoA) and atherogenic risks and hypertension] was analyzed. Serum complement C3 levels, inflammatory markers and disease activity were evaluated. Cluster analysis was performed to identify different phenotypes. Receiver operating characteristic (ROC) curve analysis to assess the accuracy of complement C3 as biomarker of insulin resistance and disease activity was carried out. RESULTS: Levels of complement C3, significantly elevated in RA, axSpA and PsA patients, were associated with the prevalence of cardiometabolic risk factors. Hard clustering analysis identified two distinctive phenotypes of patients depending on the complement C3 levels and insulin sensitivity state. Patients from cluster 1, characterized by high levels of complement C3 displayed increased prevalence of cardiometabolic risk factors and high disease activity. ROC curve analysis showed that non-obesity related complement C3 levels allowed to identify insulin resistant patients. CONCLUSIONS: Complement C3 is associated with the concomitant increased prevalence of cardiometabolic risk factors in rheumatoid arthritis and spondyloarthritis. Thus, complement C3 should be considered a useful marker of insulin resistance and disease activity in these rheumatic disorders

A genetic modifier screen identifies chromosomal intervals harboring potential midline interacting genes

This work investigates the growth of B-C-N layers by chemical vapor deposition using methylamine borane (MeAB) as single-source precursor. MeAB has been synthesized and characterized, paying particular attention to the analysis of its thermolysis products, which are the gaseous precursors for B-C-N growth. Samples have been grown on Cu foils and transferred onto different substrates for their morphological, structural, chemical, electronic and optical characterizations. The results of these characterizations indicate a segregation of h-BN and Graphene-like (Gr) domains. However, there is an important presence of B and N interactions with C at the Gr borders, and of C interacting at the h-BN-edges, respectively, in the obtained nano-layers. In particular, there is significant presence of C-N bonds, at Gr/h-BN borders and in the form of N doping of Gr domains. The overall B:C:N contents in the layers is close to 1:3:1.5. A careful analysis of the optical bandgap determination of the obtained B-C-N layers is presented, discussed and compared with previous seminal works with samples of similar composition.Comment: 35 pages, 7 figure

Chemical vapor deposition growth of boron-carbon-nitrogen layers from methylamine borane thermolysis products

This is the Accepted Manuscript version of an article accepted for publication in Nanotechnology. IOP Publishing Ltd is not responsible for any errors or omissions in this version of the manuscript or any version derived from it. The Version of Record is available online at https://doi.org/10.1088/1361-6528/aa9c07This work investigates the growth of B-C-N layers by chemical vapor deposition using methylamine borane (MeAB) as the single-source precursor. MeAB has been synthesized and characterized, paying particular attention to the analysis of its thermolysis products, which are the gaseous precursors for B-C-N growth. Samples have been grown on Cu foils and transferred onto different substrates for their morphological, structural, chemical, electronic and optical characterizations. The results of these characterizations indicate a segregation of h-BN and graphene-like (Gr) domains. However, there is an important presence of B and N interactions with C at the Gr borders, and of C interacting at the h-BN-edges, respectively, in the obtained nano-layers. In particular, there is a significant presence of C-N bonds, at Gr/h-BN borders and in the form of N doping of Gr domains. The overall B:C:N contents in the layers is close to 1:3:1.5. A careful analysis of the optical bandgap determination of the obtained B-C-N layers is presented, discussed and compared with previous seminal works with samples of similar compositio

QUIJOTE scientific results -- XIII. Intensity and polarization study of supernova remnants in the QUIJOTE-MFI wide survey: CTB 80, Cygnus Loop, HB 21, CTA 1, Tycho and HB 9

We use the new QUIJOTE-MFI wide survey (11, 13, 17 and 19 GHz) to produce spectral energy distributions (SEDs), on an angular scale of 1 deg, of the supernova remnants (SNRs) CTB 80, Cygnus Loop, HB 21, CTA 1, Tycho and HB 9. We provide new measurements of the polarized synchrotron radiation in the microwave range. For each SNR, the intensity and polarization SEDs are obtained and modelled by combining QUIJOTE-MFI maps with ancillary data. In intensity, we confirm the curved power law spectra of CTB 80 and HB 21 with a break frequency $\nu_{\rm b}$ at 2.0$^{+1.2}_{-0.5}$ GHz and 5.0$^{+1.2}_{-1.0}$ GHz respectively; and spectral indices respectively below and above the spectral break of $-0.34\pm0.04$ and $-0.86\pm0.5$ for CTB 80, and $-0.24\pm0.07$ and $-0.60\pm0.05$ for HB 21. In addition, we provide upper limits on the Anomalous Microwave Emission (AME), suggesting that the AME contribution is negligible towards these remnants. From a simultaneous intensity and polarization fit, we recover synchrotron spectral indices as flat as $-0.24$, and the whole sample has a mean and scatter of $-0.44\pm0.12$. The polarization fractions have a mean and scatter of $6.1\pm1.9$\%. When combining our results with the measurements from other QUIJOTE studies of SNRs, we find that radio spectral indices are flatter for mature SNRs, and particularly flatter for CTB 80 ($-0.24^{+0.07}_{-0.06}$) and HB 21 ($-0.34^{+0.04}_{-0.03}$). In addition, the evolution of the spectral indices against the SNRs age is modelled with a power-law function, providing an exponent $-0.07\pm0.03$ and amplitude $-0.49\pm0.02$ (normalised at 10 kyr), which are conservative with respect to previous studies of our Galaxy and the Large Magellanic Cloud.Comment: 33 pages, 15 figure, 15 tables. Submitted to MNRAS. QUIJOTE data maps available at https://research.iac.es/proyecto/quijot