Is selective 5-HT1F receptor agonism an entity apart from that of the triptans in antimigraine therapy?

Migraine is a neurovascular disorder that involves activation of the trigeminovascular system and cranial vasodilation mediated by release of calcitonin gene-related peptide (CGRP).The gold standard for acute migraine treatment are the triptans, 5-HT1B/1D/(1F) receptor agonists. Their actions are thought to be mediated through activation of: (i) 5-HT1B receptors in cranial blood vessels with subsequent cranial vasoconstriction; (ii) prejunctional 5-HT1D receptors on trigeminal fibers that inhibit trigeminal CGRP release; and (iii) 5-HT1B/1D/1F receptors in central nervous system involved in (anti)nociceptive modulation. Unfortunately, coronary arteries also express 5-HT1B receptors whose activation would produce coronary vasoconstriction; hence, triptans are contraindicated in patients with cardiovascular disease. In addition, since migraineurs have an increased cardiovascular risk, it is important to develop antimigraine drugs devoid of vascular (side) effects.Ditans, here defined as selective 5-HT1F receptor agonists, were developed on the basis that most of the triptans activate trigeminal 5-HT1F receptors, which may explain part of the triptans' antimigraine action. Amongst the ditans, lasmiditan: (i) fails to constrict human coronary arteries; and (ii) is effective for the acute treatment of migraine in preliminary Phase III clinical trials. Admittedly, the exact site of action is still unknown, but lasmiditan possess a high lipophilicity, which suggests a direct action on the central descending antinociceptive pathways. Furthermore, since 5-HT1F receptors are located on trigeminal fibers, they could modulate CGRP release.This review will be particularly focussed on the similarities and differences between the triptans and the ditans, their proposed sites of action, side effects and their cardiovascular risk profile

Association of Motivational Climate With Addictive Behaviors Depending on Type of Sport in University Students: Structural Equation Analysis

This research study aims at contrasting a structural model of the associations between the alcohol consumption, tobacco dependence, and the problematic use of video games with motivational climate toward sport depending on the category of sports practiced in a sample of Physical Education university students. The sample consisted of 775 university students from the Autonomous Community of Andalusia (Spain), aged between 21 and 35 (22.22 ± 3.76) years. The instruments used were the Perceived Motivational Climate in Sport Questionnaire (PMCSQ-2), the Alcohol Use Disorders Identification Test (AUDIT), the Fagerström Test for Nicotine Dependence (FTND), and the Questionnaire of Experiences Related to Video Games (QERV) questionnaires. A path model that fitted properly in the multigroup analysis for both categories of sports was used, χ2 = 19.843; gl = 8; p = .011; comparative fit index (CFI) = 0.911; normed fit index (NFI) = 0.903; incremental fit index (IFI) = 0.912; root mean square error approximation (RMSEA) = 0.085. An inverse association was shown between task climate and tobacco consumption in individual sports, being weaker in collective sports. This association is not significant for collective sports, but it is for individual sports for ego climate. However, a positive association was found between ego climate and the use of video games in individual sports, not being significant in the case of collective sports. The importance of promoting motivational climates oriented toward tasks that are based on the practice of collective sports is established, because they could act as protective factors against the development of addictive behavior in university students.This research study has been supported by the Education Innovation Project PID 16-45, named “Implementation of digital resources in the classroom for the development of psychosocial and motivational factors in students of the degree in Primary Education with the speciality in Physical Education,” funded by the University of Granada. Education Innovation Project PIBD Advanced 470, named “Program of teaching intervention in students of the degree in primary education and early childhood education through the use of new technologies for the improvement of the psychosocial factors of the students,” funded by the University of Granada. Project I+D+I “DISPERSA,” with code number TIN2015-67149-C3-R, named “Design of Pervasive Games Based on Learning Experiences Sensitive to Context” funded by the Ministry of Economy and Competitiveness. Precompetitive Research Projects for Young Researchers (PPJI_B-05); Self-plan Research of the University of Granada

Diferencias clínicas y hematimétricas en pacientes con trombocitemia esencial y mutación para el gen de la calreticulina

Abstract [PB-090] Introducción: La identificación de la mutación somática en el gen CALR ha supuesto un avance diagnóstico en las neoplasias mieloproliferativas crónicas. Una cuarta parte de los pacientes (ptes) con trombocitemia esencial (TE) presenta dicha mutación, diferenciando dos variantes: la CALR tipo 1 (deleciones) y tipo 2 (inserciones). La TE mutada por CALR podría tratarse no solo de una entidad distinta a nivel molecular, sino también a nivel clínico-analítico. Métodos: Estudio descriptivo y prospectivo unicéntrico. Se incluyen 95 pacientes con TE diagnosticados en el Hospital Miguel Servet. Se analizan variables demográficas, características clínicas y hematimétricas en función de la biología molecular del paciente, establecimiento las diferencias observadas entre los pacientes con mutación JAK-2 y CALR (tipo 1 y tipo 2). Resultados: 35 eran hombres y 60 mujeres. Del total de pacientes, 55 presentaban la mutación JAK-2 (57, 89%), 22 la mutación CALR (23, 15%) (tipo 1: 12 ptes (46, 15%) y tipo 2: 10 ptes (38, 46%)), 5 la mutación MPL (5, 2%) y 9 eran triples negativos (9, 4%). Los ptes con TE mutada con CALR eran más jóvenes que los JAK-2, mediana de edad 65 años (29-84) y 72 años (40-96) respectivamente. Al diagnóstico, las cifras de hemoglobina y leucocitos en ptes JAK-2 eran superiores (mediana 14, 6 g/dL y 9, 30. 10³/µL) frente a CALR tipo 1 (mediana 14, 1 g/dL y 7, 78.10³/µL) y tipo 2 (14, 4 g/dL y 7, 80.10³/µL) y presentaban un recuento menor de plaquetas (mediana 744.10³/µL) frente a CALR tipo 1 (mediana 836. 10³/µL) y tipo 2 (mediana 916.10³/µL). Todos los pacientes CALR presentaban niveles normales de eritropoyetina mientras que un 18% JAK-2 presentaban niveles descendidos. 17 ptes (12, 72%) JAK-2, 3 ptes (25%) CALR tipo 1 y 1 pte (10%) CALR tipo 2 presentaban esplenomegalia. Presentaron episodio trombótico previo al diagnóstico: 5 ptes JAK- 2 (9%), de éstos 5 ptes eran hipertensos y 2 dislipémicos, 1 pte CALR tipo 1 (8, 3%), era hipertenso, dislipémico y fumador y ninguno CALR tipo 2, 1 pte era hipertenso. Tras el diagnóstico 1 pte JAK2 presentó nuevo episodio trombótico posteriormente. Al diagnóstico, 41 pacientes JAK-2 se les realizó biopsia ósea (74, 5%) con reticulina grado 1: 11 ptes (26, 82%), grado 2: 3 ptes (7, 3%) y grado 3: 0 ptes; a 11 ptes CALR tipo 1 (91, 6%) con reticulina grado 1: 3 ptes (27, 27%) y grado 2-3: 0 ptes; a 7 pacientes CALR tipo 2 (70%) con reticulina tipo 1: 3 ptes (44, 85%) y grado 2-3: 0 ptes. Conclusiones: La TE con mutación CALR parece comportarse de manera diferente en térmicos de características biológicas, hematológicas y clínicas frente a la mutación JAK2. Afecta a individuos relativamente jóvenes y se caracteriza por un recuento de plaquetas mayor pero con un riesgo trombótico inferior, especialmente los pacientes CALR tipo 2. Aunque en nuestra serie no encontramos grandes diferencias entre los subtipos de CALR, probablemente por el escaso número de ptes, creemos que ampliando la muestra existan diferencias entre ambos subgrupos que podrían implicar diferentes algoritmos terapéuticos

A genome-wide association study follow-up suggests a possible role for PPARG in systemic sclerosis susceptibility

Introduction: A recent genome-wide association study (GWAS) comprising a French cohort of systemic sclerosis (SSc) reported several non-HLA single-nucleotide polymorphisms (SNPs) showing a nominal association in the discovery phase. We aimed to identify previously overlooked susceptibility variants by using a follow-up strategy.<p></p> Methods: Sixty-six non-HLA SNPs showing a P value <10-4 in the discovery phase of the French SSc GWAS were analyzed in the first step of this study, performing a meta-analysis that combined data from the two published SSc GWASs. A total of 2,921 SSc patients and 6,963 healthy controls were included in this first phase. Two SNPs, PPARG rs310746 and CHRNA9 rs6832151, were selected for genotyping in the replication cohort (1,068 SSc patients and 6,762 healthy controls) based on the results of the first step. Genotyping was performed by using TaqMan SNP genotyping assays. Results: We observed nominal associations for both PPARG rs310746 (PMH = 1.90 × 10-6, OR, 1.28) and CHRNA9 rs6832151 (PMH = 4.30 × 10-6, OR, 1.17) genetic variants with SSc in the first step of our study. In the replication phase, we observed a trend of association for PPARG rs310746 (P value = 0.066; OR, 1.17). The combined overall Mantel-Haenszel meta-analysis of all the cohorts included in the present study revealed that PPARG rs310746 remained associated with SSc with a nominal non-genome-wide significant P value (PMH = 5.00 × 10-7; OR, 1.25). No evidence of association was observed for CHRNA9 rs6832151 either in the replication phase or in the overall pooled analysis.<p></p> Conclusion: Our results suggest a role of PPARG gene in the development of SSc

Characterization of binding, functional activity, and contractile responses of the selective 5-HT1F receptor agonist lasmiditan

Background and Purpose: Triptans are 5-HT1B/1D receptor agonists (that also display 5-HT1F receptor affinity) with antimigraine action, contraindicated in patients with coronary artery disease due to their vasoconstrictor properties. Conversely, lasmiditan was developed as an antimigraine 5-HT1F receptor agonist. To assess the selectivity and cardiovascular effects of lasmiditan, we investigated the binding, functional activity, and in vitro/in vivo vascular effects of lasmiditan and compared it to sumatriptan. Experimental Approach: Binding and second messenger activity assays of lasmiditan and other serotoninergic agonists were performed for human 5-HT1A, 5-HT1B, 5-HT1D, 5-ht1E, 5-HT1F, 5-HT2A, 5-HT2B, and 5-HT7 receptors, and the results were correlated with their potency to constrict isolated human coronary arteries (HCAs). Furthermore, concentration–response curves to lasmiditan and sumatriptan were performed in proximal and distal HCA, internal mammary, and middle meningeal arteries. Finally, anaesthetized female beagle dogs received i.v. infusions of lasmiditan or sumatriptan in escalating cumulative doses, and carotid and coronary artery diameters were measured. Key Results: Lasmiditan showed high selectivity for 5-HT1F receptors. Moreover, the functional potency of the analysed compounds to inhibit cAMP increase through 5-HT1B receptor activation positively correlated with their potency to contract HCA. In isolated human arteries, sumatriptan, but not lasmiditan, induced contractions. Likewise, in vivo, sumatriptan decreased coronary and carotid artery diameters at clinically relevant doses, while lasmiditan was devoid of vasoconstrictor activity at all doses tested. Conclusions and Implications: Lasmiditan is a selective 5-HT1F receptor agonist devoid of vasoconstrictor activity. This may represent a cardiovascular safety advantage when compared to the triptans

Cross-disease Meta-analysis of Genome-wide Association Studies for Systemic Sclerosis and Rheumatoid Arthritis Reveals IRF4 as a New Common Susceptibility Locus

Objectives: Systemic sclerosis (SSc) and rheumatoid arthritis (RA) are autoimmune diseases that share clinical and immunological characteristics. To date, several shared SSc- RA loci have been identified independently. In this study, we aimed to systematically search for new common SSc-RA loci through an inter-disease meta-GWAS strategy. Methods: We performed a meta-analysis combining GWAS datasets of SSc and RA using a strategy that allowed identification of loci with both same-direction and opposingdirection allelic effects. The top single-nucleotide polymorphisms (SNPs) were followed-up in independent SSc and RA case-control cohorts. This allowed us to increase the sample size to a total of 8,830 SSc patients, 16,870 RA patients and 43,393 controls. Results: The cross-disease meta-analysis of the GWAS datasets identified several loci with nominal association signals (P-value < 5 x 10-6), which also showed evidence of association in the disease-specific GWAS scan. These loci included several genomic regions not previously reported as shared loci, besides risk factors associated with both diseases in previous studies. The follow-up of the putatively new SSc-RA loci identified IRF4 as a shared risk factor for these two diseases (Pcombined = 3.29 x 10-12). In addition, the analysis of the biological relevance of the known SSc-RA shared loci pointed to the type I interferon and the interleukin 12 signaling pathways as the main common etiopathogenic factors. Conclusions: Our study has identified a novel shared locus, IRF4, for SSc and RA and highlighted the usefulness of cross-disease GWAS meta-analysis in the identification of common risk loci

GWAS for Systemic Sclerosis Identifies Multiple Risk Loci and Highlights Fibrotic and Vasculopathy Pathways

Systemic sclerosis (SSc) is an autoimmune disease that shows one of the highest mortality rates among rheumatic diseases. We perform a large genome-wide association study (GWAS), and meta-analysis with previous GWASs, in 26,679 individuals and identify 27 independent genome-wide associated signals, including 13 new risk loci. The novel associations nearly double the number of genome-wide hits reported for SSc thus far. We define 95% credible sets of less than 5 likely causal variants in 12 loci. Additionally, we identify specific SSc subtype-associated signals. Functional analysis of high-priority variants shows the potential function of SSc signals, with the identification of 43 robust target genes through HiChIP. Our results point towards molecular pathways potentially involved in vasculopathy and fibrosis, two main hallmarks in SSc, and highlight the spectrum of critical cell types for the disease. This work supports a better understanding of the genetic basis of SSc and provides directions for future functional experiments.Funding: This work was supported by Spanish Ministry of Economy and Competitiveness (grant ref. SAF2015-66761-P), Consejeria de Innovacion, Ciencia y Tecnologia, Junta de Andalucía (P12-BIO-1395), Ministerio de Educación, Cultura y Deporte through the program FPU, Juan de la Cierva fellowship (FJCI-2015-24028), Red de Investigación en Inflamación y Enfermadades Reumaticas (RIER) from Instituto de Salud Carlos III (RD16/0012/0013), and Scleroderma Research Foundation and NIH P50-HG007735 (to H.Y.C.). H.Y.C. is an Investigator of the Howard Hughes Medical Institute. PopGen 2.0 is supported by a grant from the German Ministry for Education and Research (01EY1103). M.D.M and S.A. are supported by grant DoD W81XWH-18-1-0423 and DoD W81XWH-16-1-0296, respectively