Polymorphisms in eicosanoid-related biosynthesis enzymes associated with acute urticaria/angioedema induced by nonsteroidal anti-inflammatory drug hypersensitivity.

BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) are the main triggers of drug hypersensitivity, with NSAID-induced acute urticaria/angioedema (NIUA) the most frequent phenotype. NSAID hypersensitivity is caused by cyclooxygenase 1 inhibition, which leads to an imbalance in prostaglandin (PG) and cysteinyl leukotriene (CysLT) synthesis. As only susceptible individuals develop NSAID hypersensitivity, genetic factors are believed to be involved; however, no study has assessed the overall genetic variability of key enzymes in PG and CysLT synthesis in NSAID hypersensitivity. OBJECTIVES: To evaluate simultaneously variants in the main genes involved in PG and CysLT biosynthesis in NIUA. METHODS: Two independent cohorts of patients were recruited in Spain, alongside NSAID-tolerant controls. The discovery cohort included only patients with NIUA; the replication cohort included patients with NSAID-exacerbated respiratory disease (NERD). A set of tagging single-nucleotide polymorphisms (tagSNPs) in PTGS1, PTGS2, ALOX5 and LTC4S was genotyped using mass spectrometry coupled with endpoint polymerase chain reaction. RESULTS: The study included 1272 individuals. Thirty-five tagSNPs were successfully genotyped in the discovery cohort, with three being significantly associated after Bonferroni correction (rs10306194 and rs1330344 in PTGS1; rs28395868 in ALOX5). These polymorphisms were genotyped in the replication cohort: rs10306194 and rs28395868 remained associated with NIUA, and rs28395868 was marginally associated with NERD. Odds ratios (ORs) in the combined analysis (discovery and replication NIUA populations) were 1·7 for rs10306194 [95% confidence interval (CI) 1·34-2·14; Pcorrected = 2·83 × 10-4 ) and 2·19 for rs28395868 (95% CI 1·43-3·36; Pcorrected = 0·002). CONCLUSIONS: Variants of PTGS1 and ALOX5 may play a role in NIUA and NERD, supporting the proposed mechanisms of NSAID-hypersensitivity and shedding light on their genetic basis.

Genetics and Epigenetics of Nasal Polyposis: A Systematic Review.

Chronic rhinosinusitis (CRS) is an inflammatory disease of the nose and paranasal sinuses that is often associated with nasal polyposis (CRSwNP) in the most severe cases. As in other complex diseases, genetic factors are thought to play an important role in the risk and development of the disease. Environment may also modulate the epigenetic signature in affected patients. In the present systematic review, we aimed to compile all published data on genetic and epigenetic variations in CRSwNP since 2000. We found 104 articles, 24 of which were related to epigenetic studies. We identified more than 150 genetic variants in 99 genes involved in the pathogenesis of nasal polyposis. These were clustered into 8 main networks, linking genes involved in inflammation and immune response (eg, MHC), cytokine genes (eg, TNF), leukotriene metabolism, and the extracellular matrix. A total of 89 miRNAs were also identified; these are associated mainly with biological functions such as the cell cycle, inflammation, and the immune response. We propose a potential relationship between genes and the miRNAs identified that may open new lines of investigation. An in-depth knowledge of gene variants and epigenetic traits could help us to design more tailored treatment for patients with CRSwNP.

Promoter Genotyping and mRNA Expression - Based Analysis of the PTGDR Gene in Allergy.

BACKGROUND AND OBJECTIVE: Prostaglandin D2 receptors are acquiring a relevant role as potential therapeutic targets in allergy. PTGDR has been described as a candidate gene in allergic disease, although functional studies on this gene are lacking. Objective: The objective of this case-control study was to investigate the potential role of PTGDR in allergy. METHODS: The study population comprised 195 allergic patients and 112 healthy controls. The PTGDR promoter polymorphisms -1289G>A, -1122T>C, -881C>T, -834C>T, -613C>T, -549T>C, -441C>T, -197T>C, and -95G>T were amplified by polymerase chain reaction (PCR) and sequenced. PTGDR expression levels were analyzed using quantitative PCR and normalized to GAPDH and TBP mRNA levels. All procedures were performed following the Minimum Information for Publication of Quantitative Real-Time PCR Experiment guidelines. RESULTS: PTGDR expression levels were significantly higher in allergic patients than in controls (P<.001). Receiver operating characteristic analysis for expression of PTGDR showed a sensitivity of 81.4% compared with 67% for IgE levels. In addition, differences in the genotypic distribution of the polymorphisms -1289G>A and -1122T>C were found in allergic patients (P=.009). CONCLUSIONS: The results indicate that PTGDR overexpression is associated with allergy. The polymorphisms -1289G>A and -1122T>C partly explain the variation in expression we observed. PTGDR expression could have a potential role as a biomarker and pharmacogenetic factor in allergy.

Origin, evolution, phylogeny and taxonomy of Pulex irritans.

The human flea Pulex irritans Linnaeus, 1758 (Siphonaptera: Pulicidae) is one of the most studied species together with the cat flea Ctenocephalides felis Bouché, 1835, because they have a cosmopolitan distribution and are closely related to humans. The present study aimed to carry out a comparative morphometric and molecular study of two different populations of P. irritans (Spain and Argentina). Accordingly, internal transcribed spacer (ITS)1 and ITS2 of rDNA and the partial cytochrome c oxidase subunit 1 (cox1) and cytochrome b (cytb) mtDNA genes of these taxa were sequenced. Furthermore, the taxonomy, origin, evolution and phylogeny of P. irritans was assessed. The morphometric data obtained did not show significant differences between P. irritans specimens from Spain and Argentina, even when these two populations were collected from different hosts; however, there was a considerable degree of molecular divergence between both populations based on nuclear and mitochondrial markers. Thus, it is proposed that P. irritans, in contrast with other generalist fleas, maintains a certain degree of morphological similarity, at least between Western Palearctic and Neotropical areas. Furthermore, two well defined geographical genetic lineages within the P. irritans species are indicated, suggesting the existence of two cryptic species that could be discriminated by a polymerase chain reaction-linked restriction fragment length polymorphism.

Bariatric surgery as a risk factor in the development of dental caries: a systematic review.

OBJECTIVES: Obesity is one of the most prevalent chronic pathologies in the world and has become a public health problem. At the present time, bariatric surgery (BS) is considered the best option and the only effective method of treatment, but it can occasionally result in a series of alterations at the oral level. This study aims to review the current literature to establish the possible association of patients who have undergone BS and a greater risk of dental caries. STUDY DESIGN: This study is a systematic review of the literature. METHODS: A search was made in the database of Medline (via PubMed), over the last 10 years, using the keywords 'bariatric surgery' OR 'gastrectomy' OR 'obesity surgery,' combined independently with the terms 'saliva' and 'dental caries' by means of the connector 'AND.' The criteria used were those described in the PRISMA® Declaration for performing systematic reviews. Inclusion criteria and study selection: (a) studies done with humans; (b) articles published in English and Spanish; (c) series of cases; and (d) clinical trials. The risk of bias was assessed independently by two authors. In both data extraction and risk of bias assessment, disagreements were resolved through discussion with a third author. RESULTS: Two independent reviewers read the titles and summaries of the 79 articles found. Finally, nine of them were included in the study. In the various articles, the parameters that had clinical relevance to the risk of dental caries were evaluated. CONCLUSIONS: Within the limitations of this study, it is plausible to think that patients who have undergone BS have a greater risk of dental caries. The oral complications associated with BS could be prevented or minimized by including in the multidisciplinary treatment of these patients a team of odontologists who would be responsible for prevention and oral assessment.

Retinoic Acid Modulates PTGDR Promoter Activity.

BACKGROUND AND OBJECTIVE: Vitamin A has been linked to the development of allergic diseases although its role is not fully understood, Retinoic acid (RA), a metabolite of Vitamin A, has been previously associated with the prostaglandin pathway, and PTGDR, a receptor of PGD2, has been proposed as a candidate gene in allergy and asthma. Considering the role of PTGDR in allergy, the goal of this study was to analyze the effect of RA on the activation of the promoter region of the PTGDR gene. METHODS: A549 lung epithelial cells were transfected with 4 combinations of genetic variants of the PTGDR promoter and stimulated with all-trans RA (ATRA); luciferase assays were performed using the Dual Luciferase Reporter System, and real-time quantitative polymerase chain reaction was used to measure the expression of PTGDR, CYP26A1, RARA, RARB, RARG, and RXRA in basal A549 cell cultures and after ATRA treatment. We also performed an in silico analysis. RESULTS: After ATRA treatment increased expression of CYP26A1 (12-fold) and RARB (4-fold) was detected. ATRA activated PTGDR promoter activity in transfected cells (P<.001) and RA response element sequences were identified in silico in this promoter region. CONCLUSIONS: RA modulated PTGDR promoter activity. Differential response to RA and to new treatments based on PTGDR modulation could depend on genetic background in allergic asthmatic patients.

Analysis of FOXP3 gene in children with allergy and autoimmune diseases.

BACKGROUND: Allergy and autoimmunity are important immunological entities underlying chronic diseases in children. In some cases both entities develop simultaneously in the same patient. FOXP3 gene codes for a transcription factor involved in regulation of the immune system. Considering that regulatory T cells are involved in controlling immunological disease development, and the relevant role of FOXP3 in this kind of T cells, the objective of this study was to analyse the FOXP3 gene in the most prevalent autoimmune diseases and/or allergies in childhood in a European population. METHODS: A total of 255 Caucasian individuals, 95 controls and 160 patients diagnosed with allergic, autoimmune or both diseases were included in this study. The molecular analysis of FOXP3 was performed by DNA sequencing following the recommendations for quality of the European Molecular Genetics Quality Network. Genomic DNA was extracted from peripheral blood of all participants and was amplified using the polymerase chain reaction. After the visualisation of the amplified fragments by agarose gel-electrophoresis, they were sequenced. RESULTS: Thirteen different polymorphisms in FOXP3 gene were found, seven of which had not been previously described. The mutated allele of SNP 7340C>T was observed more frequently in the group of male children suffering from both allergic and autoimmune diseases simultaneously (p=0.004, OR=16.2 [1.34-195.15]). CONCLUSIONS: In this study we identified for first time genetic variants of FOXP3 that are significantly more frequent in children who share allergic and autoimmune diseases. These variants mainly affect regulatory sequences that could alter the expression levels of FOXP3 modifying its function including its role in Treg cells.

Genome-wide association studies (GWAS) and their importance in asthma.

Asthma is a complex disease determined by the interaction of different genes and environmental factors. The first genetic investigations in asthma were candidate gene association studies and linkage studies. In recent years research has focused on association studies that scan the entire genome without any prior conditioning hypothesis: the so-called genome-wide association studies (GWAS). The first GWAS was published in 2007, and described a new locus associated to asthma in chromosome 17q12-q21, involving the ORMDL3, GSDMB and ZPBP2 genes (a description of the genes named in the manuscript are listed in Table 1). None of these genes would have been selected in a classical genetic association study since it was not known they could be implicated in asthma. To date, a number of GWAS studies in asthma have been made, with the identification of about 1000 candidate genes. Coordination of the different research groups in international consortiums and the application of new technologies such as new generation sequencing will help discover new implicated genes and improve our understanding of the molecular mechanisms underlying the disease.

[Epidemiological characteristics of out-of-hospital cardiorespiratory arrest recorded by the 061 emergencies system (SAMU) in the Balearic Islands (Spain), 2009-2012]. / Características epidemiológicas de las paradas cardiorrespiratorias extrahospitalarias registradas por el sistema de emergencias 061 (SAMU) de la Comunidad Autónoma de las Islas Baleares (2009-2012).

OBJECTIVE: To describe the epidemiology of out-of-hospital cardiorespiratory arrest (OHCA) and identify factors associated with recovery of spontaneous circulation (ROSC). DESIGN: Observational study of OHCA registered on a continuous basis in the Emergency Medical Services (EMS) database during 2009-2012. SETTING: The islands of Mallorca, Ibiza, Menorca and Formentera (Balearic Islands, Spain). PATIENTS: OHCA in patients ≥ 18 years of age. The main variables were: Patient sex, age, probable cause, place of arrest, bystander, witnessed, basic life support (BLS), shockable rhythm, intervention time, semi-automatic defibrillator (AED), duration of cardiopulmonary arrest (CA), and ROSC. Independent variables were defined according to the Utstein protocol, and the dependent variable was defined as ROSC. RESULTS: The EMS treated 1170 OHCAs (28/100,000 persons-year). We included 1130 CA. The mean age was 61.4 years (73.4% males). Most CA (72.3%) were of cardiac etiology, and 84.7% were witnessed. A total of 840 (74.3%) received BLS and 400 (47.6%) did so before arrival of the EMS (45 by bystander relatives). AED was available in 330 cases CA (29.2%) (96 with shockable rhythm). The interval between emergency call and BLS and between emergency call and advanced life support was 8.4 and 15.8min, respectively. Shockable rhythm was monitored in 257 CAs (22.7%). ROSC occurred in 261 (23.1%). Factors associated with ROSC were age, shockable rhythm, BLS before EMS arrival, and CA duration less than 30min. CONCLUSION: The incidence rate of the OHCA is low. The proportion of patients receiving BLS from relatives was low. Age, shockable rhythm and BSL before EMS arrival were associated with ROSC.

Phylogenetic relationship of serovar C-1 isolates of Avibacterium paragallinarum.

The bacterium Avibacterium paragallinarum is the etiologic agent of infectious coryza of chickens. Serovar C-1 has emerged in infectious coryza outbreaks in layer hens of Ecuador and Mexico. In the current study, genotyping and phylogenetic analyses of five Ecuadorian and 10 Mexican isolates of Av. paragallinarum serovar C-1 were performed. All 15 isolates share a unique enterobacterial repetitive intergenic consensus-based-PCR fingerprint and have identical 16S ribosomal RNA and hemagglutinin antigen gene sequences. Results indicate that Ecuadorian and Mexican isolates of serovar C-1 of Av. paragallinarum have a clonal relationship.

Implications of cytokine genes in allergic asthma.

Asthma is a complex disease involving numerous mediator molecules and effector cells, in combination with a range of environmental determining factors. Cytokines play a key role in the physiopathological mechanisms of asthma; the study of the structure, regulation and variations of the genes that encode for these molecules is therefore crucial. Cytokines have extremely diverse roles, and exert effects both as activators and inhibitors of the innate and adaptive immune response. Certain modifications in the expression or structure of these molecules, resulting from the presence of polymorphisms, may give rise to deregulation of the mentioned effects, and therefore to a predisposition to develop concrete asthma phenotypes.

The prostaglandin D2 receptor (PTGDR) gene in asthma and allergic diseases.

The prostaglandin D2 receptor (PTGDR) gene has been associated to asthma and related phenotypes by linking and association studies. Functional studies involving animal models and other expression studies based on in vitro cell models also point to a possible role of polymorphisms in the promoter region, in the differential binding of transcription factors, and thus in PTGDR expression, which appear to be associated to the development of asthma or of susceptibility to the disease.

Application of Medical Information Systems for the detection of high risk patients: rapid care alerts. Pilot study of the ARA-Son Llàtzer Project.

OBJECTIVE: To describe the implementation of a Medical Information System (MIS) in the Critical Care Departament (CCD). DESIGN: A prospective observational cohort study was carried out. SETTING: Clinical and Surgical wards in Son Llàtzer Hospital. PATIENTS: Patients with criteria of rapid care alert (RCA) without treatment, cardiac arrest (CA), and unexpected ward deaths (UWD), during 2010. MAIN VARIABLES: Age, sex, nursing shift, nursing alert, vital signs, unplanned admission to intensive care, CA, UWD and death. RESULTS: The MIS detected 9647 episodes with RCA signs in 4020 patients (26.4 episodes/day). A total of 8547 episodes were reviewed. Sixty-five patients required rapid response by the intensive care staff; 61.5% were detected in the afternoon shift (15:00 a 22:00), and 61.5% were admitted to the CCD. Diminished consciousness (DC) and respiratory failure were the most frequent problems. The sepsis rate was 23%. We reviewed 45 CA and 35 UWD. Of the total cases of CA, 33 patients died (73.3%) and 66.7% had criteria of untreated RCA. Monitoring (P<.05) and rhythms amenable to defibrillation (P<.002) were associated to survival. As regards the UWD, 75% had criteria of untreated RCA, and 40.6% presented diminished consciousness. In the last 6 months there was a significant reduction in UWD (P=.01) CONCLUSIONS: The MIS could be a complimentary tool in the activity of the CCD to improve the prognosis of hospitalized patients.

Tryptase: genetic and functional considerations.

Tryptase is one of the main proteases located in the secretory granules of the mast cells, and is released through degranulation. It is therefore assumed to play an important role in inflammatory and allergic processes. Four genes are known to encode for these enzymes, with different alleles that give rise to different types of tryptases. The term "tryptase" generally refers to ß-tryptase, which in vivo is a heterotetramer, possessing a structure of vital importance for enabling drug and substrate access to the active site of the molecule. Tryptase has been reported to possess antagonistic functions, since it plays an important role both in inflammatory phenomena and as a protector against infection. In allergic processes it is associated to bronchial hyperresponsiveness in asthmatic patients, where PAR-2 is of great importance as an airway receptor. Lastly, the genes that encode for tryptase are highly polymorphic and complex. As a result, it is important to establish a relationship between genotype and phenotype in disorders such as asthma, and to identify mutations that are presumably of pharmacological relevance.

Evaluation of health risk and arsenic levels in vegetables sold in markets of Dhaka (Bangladesh) and Salamanca (Spain) by hydride generation atomic absorption spectroscopy.

The main objective of this study was to determine arsenic (As) levels in vegetables collected from the markets of Dhaka, Bangladesh and for comparison from Salamanca, Spain by HGAAS under optimal conditions, and the potential health risk from consumption of these vegetables. The mean and range of the total As concentration in the vegetables from the markets of Dhaka, Bangladesh were 114 and 1.0-293 µg/kg, respectively. Total As concentration in 77% of Bangladesh vegetables measured was higher than that recommended by the standard. The mean and range of As concentrations for vegetables grown in Spain were 65 and bdl-130 µg/kg, respectively, for Salamanca, 102 and bdl-423 µg/kg, respectively, for Almeria. The As content of the Bangladesh vegetables was approximately twofold to threefold higher than those observed for the vegetables from Almeria and Salamanca (Spain), but in some cases, were similar or less. Daily consumption of As-rich vegetables may result in an additional source of As in the diet, based on the provisional tolerable intake of As for adults recommended by WHO.

[Effects of two methods of heat therapy on the acute vascular response and hemodynamics in healthy subjects]. / Efectos de dos métodos de termoterapia sobre la respuesta vascular aguda y parámetros hemodinámicos en un grupo de sujetos sanos.

OBJECTIVE: Recently, non-pharmacological resources to relieve pain like hot packs and ultrasound (US) have become common in clinical practice. However, little experimental evidence is available about the possible mechanisms through which these methods bring about pain relief. We aimed to determine the effects of hot packs and US on the acute vascular response and on hemodynamic parameters in healthy subjects. MATERIALS AND METHODS: We conducted an experimental study in 20 healthy subjects (10 men and 10 women; mean age, 22.54±1.70 years). The two interventions were randomly applied: a) hot packs (n=10): 15min at 60°C and b) US (n=10): 15min at 1Mhz. Before and after each intervention, the following vascular parameters were measured in the brachial artery using Doppler ultrasonography with a 7MHz probe: arterial compliance, elastic modulus, beta stiffness index, systolic and diastolic arterial diameters, systolic flow velocity and diastolic flow velocity, systolic/diastolic ratio, resistance index, and pulsatility index. The following hemodynamic parameters were monitored: heart rate and blood pressure (systolic, diastolic, and mean). RESULTS: After the application of hot packs, we observed changes in diastolic flow velocity and in the pulsatility index (P<05). After the application of US, we observed changes in diastolic flow velocity, systolic/diastolic ratio, resistance index, and arterial compliance (P<05). No changes in hemodynamic parameters were observed after either intervention. CONCLUSIONS: Applying hot packs or US modifies the physiology of the vascular system but does not affect hemodynamic parameters in healthy subjects.

Approximate reinforcement learning to control beaconing congestion in distributed networks.

In vehicular communications, the increase of the channel load caused by excessive periodical messages (beacons) is an important aspect which must be controlled to ensure the appropriate operation of safety applications and driver-assistance systems. To date, the majority of congestion control solutions involve including additional information in the payload of the messages transmitted, which may jeopardize the appropriate operation of these control solutions when channel conditions are unfavorable, provoking packet losses. This study exploits the advantages of non-cooperative, distributed beaconing allocation, in which vehicles operate independently without requiring any costly road infrastructure. In particular, we formulate the beaconing rate control problem as a Markov Decision Process and solve it using approximate reinforcement learning to carry out optimal actions. Results obtained were compared with other traditional solutions, revealing that our approach, called SSFA, is able to keep a certain fraction of the channel capacity available, which guarantees the delivery of emergency-related notifications with faster convergence than other proposals. Moreover, good performance was obtained in terms of packet delivery and collision ratios.

ERIC-PCR genotyping of emergent serovar C-1 isolates of Avibacterium paragallinarum from Mexico.

Between 2008 and 2010, 14 isolates of Avibacterium paragallinarum were identified as serovar C-1 in Mexico. All isolates were obtained from commercial laying hens suffering infectious coryza despite a history of vaccination. The enterobacterial repetitive intergenic consensus-based PCR genotyping showed that all isolates had a common pattern. Until recently, serovars A-1, A-2, B-1, and C-2 were the serovars prevalent in Mexico. Serovar C-1 has been identified in Japan and recently in the Americas in Ecuador. Our current study suggests that Av. paragallinarum serovar C-1 is an emerging serovar in Mexico. Our results also indicate that the Mexican isolates of Av. paragallinarum serovar C-1 may have a clonal relationship. Knowledge of the genetic diversity of Av. paragallinarum may be of value in understanding vaccine performance and identifying the best combination to achieve broader protection.

Distribution and mobility of mercury in soils of a gold mining region, Cuyuni river basin, Venezuela.

An extensive and remote gold mining region located in the East of Venezuela has been studied with the aim of assessing the distribution and mobility of mercury in soil and the level of Hg pollution at artisanal gold mining sites. To do so, soils and pond sediments were sampled at sites not subject to anthropological influence, as well as in areas affected by gold mining activities. Total Hg in regionally distributed soils ranged between 0.02 mg kg(-1) and 0.40 mg kg(-1), with a median value of 0.11 mg kg(-1), which is slightly higher than soil Hg worldwide, possibly indicating long-term atmospheric input or more recent local atmospheric input, in addition to minor lithogenic sources. A reference Hg concentration of 0.33 mg kg(-1) is proposed for the detection of mining affected soils in this region. Critical total Hg concentrations were found in the surrounding soils of pollutant sources, such as milling-amalgamation sites, where soil Hg contents ranged from 0.16 mg kg(-1) to 542 mg kg(-1) with an average of 26.89 mg kg(-1), which also showed high levels of elemental Hg, but quite low soluble+exchangeable Hg fraction (0.02-4.90 mg kg(-1)), suggesting low Hg soil mobility and bioavailability, as confirmed by soil column leaching tests. The vertical distribution of Hg through the soil profiles, as well as variations in soil Hg contents with distance from the pollution source, and Hg in pond mining sediments were also analysed.