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Perkins J.R.,University College London | Perkins J.R.,Laboratorio Of Investigacion | Antunes-Martins A.,King's College London | Calvo M.,King's College London | And 9 more authors.
Molecular Pain | Year: 2014

Background: The past decade has seen an abundance of transcriptional profiling studies of preclinical models of persistent pain, predominantly employing microarray technology. In this study we directly compare exon microarrays to RNA-seq and investigate the ability of both platforms to detect differentially expressed genes following nerve injury using the L5 spinal nerve transection model of neuropathic pain. We also investigate the effects of increasing RNA-seq sequencing depth. Finally we take advantage of the " agnostic" approach of RNA-seq to discover areas of expression outside of annotated exons that show marked changes in expression following nerve injury.Results: RNA-seq and microarrays largely agree in terms of the genes called as differentially expressed. However, RNA-seq is able to interrogate a much larger proportion of the genome. It can also detect a greater number of differentially expressed genes than microarrays, across a wider range of fold changes and is able to assign a larger range of expression values to the genes it measures. The number of differentially expressed genes detected increases with sequencing depth. RNA-seq also allows the discovery of a number of genes displaying unusual and interesting patterns of non-exonic expression following nerve injury, an effect that cannot be detected using microarrays.Conclusion: We recommend the use of RNA-seq for future high-throughput transcriptomic experiments in pain studies. RNA-seq allowed the identification of a larger number of putative candidate pain genes than microarrays and can also detect a wider range of expression values in a neuropathic pain model. In addition, RNA-seq can interrogate the whole genome regardless of prior annotations, being able to detect transcription from areas of the genome not currently annotated as exons. Some of these areas are differentially expressed following nerve injury, and may represent novel genes or isoforms. We also recommend the use of a high sequencing depth in order to detect differential expression for genes with low levels of expression. © 2014 Perkins et al.; licensee BioMed Central Ltd.


Ayuso P.,University of Extremadura | Blanca M.,Hospital Carlos Haya | Cornejo-Garcia J.A.,Laboratorio Of Investigacion | Torres M.J.,Hospital Carlos Haya | And 11 more authors.
Pharmacogenomics | Year: 2013

Aim: Histamine plays an important role in the pathogenesis of allergic diseases. Genetic variations in histamine receptors (HRH) may influence the expression of allergic diseases. This study analyzes the association between HRH variants and NSAID hypersensitivity reactions. Patients & methods: The authors analyzed copy number variations (CNVs) and common functional SNPs in genes HRH1, HRH2 and HRH4 in 442 unrelated patients with hypersensitivity to NSAIDs and in 414 healthy unrelated controls. Results: The authors identified, both in patients and control subjects, individuals carrying CNVs in HRH genes. The most common genotype corresponded to two copies of each gene, but carriers of one or three copies of HRH1 (5% of individuals), HRH2 (1.1%) and HRH4 genes (0.9%) were also identified. Conclusion: For the first time, we describe CNVs in human HRH genes. Neither common functional SNPs in HRH genes nor CNVs influenced the risk of developing hypersensitivity to NSAIDs. © Future Medicine Ltd.


Agundez J.A.G.,University of Extremadura | Ayuso P.,University of Extremadura | Cornejo-Garcia J.A.,Laboratorio Of Investigacion | Blanca M.,Hospital Carlos Haya | And 11 more authors.
PLoS ONE | Year: 2012

Non-steroidal anti-inflammatory drugs (NSAIDs) are the drugs most frequently involved in hypersensitivity drug reactions. Histamine is released in the allergic response to NSAIDs and is responsible for some of the clinical symptoms. The aim of this study is to analyze clinical association of functional polymorphisms in the genes coding for enzymes involved in histamine homeostasis with hypersensitivity response to NSAIDs. We studied a cohort of 442 unrelated Caucasian patients with hypersensitivity to NSAIDs. Patients who experienced three or more episodes with two or more different NSAIDs were included. If this requirement was not met diagnosis was established by challenge. A total of 414 healthy unrelated controls ethnically matched with patients and from the same geographic area were recruited. Analyses of the SNPs rs17740607, rs2073440, rs1801105, rs2052129, rs10156191, rs1049742 and rs1049793 in the HDC, HNMT and DAO genes were carried out by means of TaqMan assays. The detrimental DAO 16 Met allele (rs10156191), which causes decreased metabolic capacity, is overrepresented among patients with crossed-hypersensitivity to NSAIDs with an OR = 1.7 (95% CI = 1.3-2.1; Pc = 0.0003) with a gene-dose effect (P = 0.0001). The association was replicated in two populations from different geographic areas (Pc = 0.008 and Pc = 0.004, respectively). Conclusions and implications: The DAO polymorphism rs10156191 which causes impaired metabolism of circulating histamine is associated with the clinical response in crossed-hypersensitivity to NSAIDs and could be used as a biomarker of response. © 2012 Agúndez et al.


Sanz M.L.,University of Navarra | Blazquez A.B.,Laboratorio Of Investigacion | Garcia B.E.,Complejo Hospitalario Of Navarra
Current Opinion in Allergy and Clinical Immunology | Year: 2011

Purpose of review: The determination of specific IgE (sIgE) against allergenic components fixed in a solid support that is provided as a microarray of high capacity and allows a more precise evaluation in the food allergy diagnosis. In this review, we will analyze the results obtained to date with this technology applied to the component-based diagnosis of food allergy. Recent findings: Microarrays of proteins or glycoproteins allow us to know the profile of sensitization of a patient with food allergy. At present, a commercially available technique exists which allows sIgE to be detected against 103 allergenic molecules. Several laboratories worldwide have explored and optimized this technique for few allergen extracts and the results have been promising with high reliabilities and sensitivities and above all, good correlations with previous existing conventional assays. Summary: In recent years, as a result of advances in molecular biology, together with the development of new technologies of producing high-capacity solid-phase matrices such as microarrays, the diagnosis of food allergy has improved and the basic situation of analyzing sIgE against an allergenic source has now become real the possibility of analyzing sIgE against an allergenic protein or glycoprotein. This change has not only led to a more precise diagnosis of sensitization, but can also be used to explain the different hazards of certain molecular sensitizations, crossreactivity phenomena in many cases and can even change the clinical management according to the information provided. Further studies are clearly needed to evaluate more precisely the scope of this new technique. © 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins.


Vargas-Rojas M.I.,Instituto Nacional Of Enfermedades Respiratorias Ismael Cosio Villegas Iner | Solleiro-Villavicencio H.,Instituto Nacional Of Enfermedades Respiratorias Ismael Cosio Villegas Iner | Solleiro-Villavicencio H.,National Autonomous University of Mexico | Soto-Vega E.,UPAEP University | Soto-Vega E.,Laboratorio Of Investigacion
Journal of Maternal-Fetal and Neonatal Medicine | Year: 2016

Introduction: Preeclampsia is one of the major causes of maternal and neonatal mortality. During pregnancy, the immune system must maintain the tolerance to the fetus, thus changes in the cytokine balance may result in a disturbed pregnancy. T helper cells play an important role in modulation of the immune system and are involved in this cytokine balance.Objective: Many studies have been performed to study the T cell composition in different compartments during pregnancy, although this is the first study in which T cells are evaluated in umbilical cord blood.Study design: Intracellular expression of INF-gamma, IL-17, IL-4 and forkhead foxP3 in CD4+ T cells was evaluated in umbilical blood from healthy pregnant and preeclamptic women using a flow cytometer.Results: Th2 and Treg cells levels were significantly diminished in preeclamptic compared to the healthy women, but no difference in Th1 and Th17 levels were found between both groups.Conclusions: Our data suggest that the cytokine balance is broken, encouraging the development of an exacerbated inflammatory response. Our results show that there is a shift, in the Th1/Th2, and the Th17/Treg balance, favoring skewness towards a proinflammatory status in the umbilical cord blood in preeclampsia. © 2015 Informa UK Ltd.


PubMed | Laboratorio Of Investigacion
Type: Journal Article | Journal: Reumatologia clinica | Year: 2011

Rheumatoid arthritis (RA) is a systemic, chronic and inflammatory disease of unknown aetiology with a genetic predisposition. The advent of new biological agents, as well as the more traditional disease-modifying anti rheumatic drugs, has resulted in highly efficient therapies for reducing the symptoms and signs of RA; however, not all patients show the same level of response regarding disease progression to these therapies. These variations suggest that RA patients may have different genetic regulatory mechanisms. The extensive polymorphisms revealed in non-coding gene-regulatory regions in the immune system, as well as genetic variations in drug-metabolizing enzymes, suggest that this type of variation is of functional and evolutionary importance and may provide clues for developing new therapeutic strategies. Pharmacogenetics is a rapidly advancing area of research that holds the promise that therapies will soon be tailored to an individual patients genetic profile.


Contreras-Romo M.C.,Autonomous University of Aguascalientes | Correa-Basurto J.,National Polytechnic Institute of Mexico | Padilla-Martinez I.,National Polytechnic Institute of Mexico | Martinez-Archundia M.,National Polytechnic Institute of Mexico | And 4 more authors.
Medicinal Chemistry Research | Year: 2014

In this work, the synthesis of 1-[(4-methylphenyl)sulfonyl]-5-oxo-2,3,4,5- tetrahydro-1H-1-benzazepine-4-carbonitrile (C9) and the study of its biological activity as a new putative antagonist of vasopressin receptors are described. The chemical identification of the compound C9 was confirmed using 1H and 13C nuclear magnetic resonance. This compound contains a moiety core similar to those of vaptans; therefore, we decided to study the compound's binding on vasopressin receptors (V1aR and V2R), whose models were built, refined by molecular dynamics simulations, and validated through docking studies. The biological effects of C9 on vascular smooth muscle (VSM) contractility and aquaresis were also tested. Rat aortic rings were used to test the inhibitory effect of C9 (0.0, 5.9, 59, and 590 μM) on AVP-induced VSM contraction (10 μM). The inhibition of the antidiuretic effect of vasopressin (50 μU/kg) by C9 (100 μg/kg) was determined using a water load test in rats. The results showed that C9 inhibits aortic rings' contraction in a concentration-dependent manner, whereas C9 exhibited an aquaretic effect on urine flow. Docking studies showed that C9 reaches the vaptan binding site via the V1a and V2 receptors, which explains the similarity in their biological effects. The results indicate that C9 functions as an antagonist on both V1aR and V2R. © 2013 Springer Science+Business Media New York.

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