New αIIbß3 variants in 28 Turkish Glanzmann patients; structural hypothesis for complex activation by residues variations in I-EGF domains.

Glanzmann thrombasthenia (GT) is a rare autosomal recessive bleeding disorder characterized by impaired platelet aggregation due to defects in integrin αIIbß3, a fibrinogen receptor. Platelet phenotypes and allelic variations in 28 Turkish GT patients are reported. Platelets αIIbß3 expression was evaluated by flow cytometry. Sequence analyzes of ITGA2B and ITGB3 genes allowed identifying nine variants. Non-sense variation effect on αIIbß3 expression was studied by using transfected cell lines. 3D molecular dynamics (MDs) simulations allowed characterizing structural alterations. Five new alleles were described. αIIb:p.Gly423Asp, p.Asp560Ala and p.Tyr784Cys substitutions impaired αIIbß3 expression. The αIIb:p.Gly128Val substitution allowed normal expression; however, the corresponding NM_000419.3:c.476G>T variation would create a cryptic donor splicing site altering mRNA processing. The ß3:p.Gly540Asp substitution allowed αIIbß3 expression in HEK-293 cells but induced its constitutive activation likely by impairing αIIb and ß3 legs interaction. The substitution alters the ß3 I-EGF-3 domain flexibility as shown by MDs simulations. GT variations are mostly unique although the NM_000419.3:c.1752 + 2 T > C and NM_000212.2:c.1697 G > A variations identified in 4 and 8 families, respectively, might be a current cause of GT in Turkey. MD simulations suggested how some subtle structural variations in the ß3 I-EGF domains might induce constitutive activation of αIIbß3 without altering the global domain structure.

Increased Postexercise Lipoxin A4 Levels in Exhaled Breath Condensate in Asthmatic Children With Exercise-Induced Bronchoconstriction.

BACKGROUND: Lipoxins could be potential modulators of inflammation in the lungs. To our knowledge, the role of exhaled breath condensate (EBC) lipoxin A4 (LXA4) in asthmatic children with exercise-induced bronchoconstriction (EIB) has not been investigated. OBJECTIVE: The aim of our study was to determine the involvement of EBC LXA4 in EIB. METHODS: Forty-five patients aged between 5 and 17 years were included in the study. Patients were divided into 2 groups: asthmatic children with a positive response to exercise (n = 17) and asthmatic children with a negative response to exercise (n = 28). Levels of LXA4 were determined in EBC before and immediately after the exercise challenge using ELISA. RESULTS: EBC LXA4 levels were significantly increased immediately after exercise in asthmatic children with a positive response to the exercise challenge (P = .05). No significant differences were observed in children with a negative response to exercise (P > .05). There was an inverse correlation between LXA4 levels and the percent degree of reduction in forced expiratory volume in the first second (FEV1%) postexercise in children with a positive exercise challenge (P = .05, r = -0.50). No significant differences were observed in LXA4 levels between atopic and nonatopic asthmatics (P > .05, Mann-Whitney U test). CONCLUSIONS: Levels of EBC LXA4 increased immediately after exercise in asthmatic children with a positive exercise challenge response. We hypothesize that airway LXA4 levels increase to compensate bronchoconstriction and suppress acute inflammation, and that spontaneous bronchodilatation after EIB may be due to LXA4.

Increased postexercise lipoxin A4 levels in exhaled breath condensate in asthmatic children with exercise-induced bronchoconstriction

Background: Lipoxins could be potential modulators of inflammation in the lungs. To our knowledge, the role of exhaled breath condensate (EBC) lipoxin A4 (LXA4) in asthmatic children with exercise-induced bronchoconstriction (EIB) has not been investigated. Objective: The aim of our study was to determine the involvement of EBC LXA4 in EIB. Methods: Forty-five patients aged between 5 and 17 years were included in the study. Patients were divided into 2 groups: asthmatic children with a positive response to exercise (n=17) and asthmatic children with a negative response to exercise (n=28). Levels of LXA4 were determined in EBC before and immediately after the exercise challenge using ELISA. Results: EBC LXA4 levels were significantly increased immediately after exercise in asthmatic children with a positive response to the exercise challenge (P=.05). No significant differences were observed in children with a negative response to exercise (P>.05). There was an inverse correlation between LXA4 levels and the percent degree of reduction in forced expiratory volume in the first second (FEV1%) postexercise in children with a positive exercise challenge (P=.05, r=-0.50). No significant differences were observed in LXA4 levels between atopic and nonatopic asthmatics (P>.05, Mann-Whitney U test). Conclusions: Levels of EBC LXA4 increased immediately after exercise in asthmatic children with a positive exercise challenge response. We hypothesize that airway LXA4 levels increase to compensate bronchoconstriction and suppress acute inflammation, and that spontaneous bronchodilatation after EIB may be due to LXA4 (AU)

Introducción: Las lipoxinas pueden actuar potencialmente como inmunomoduladores de la actividad inflamatoria en el pulmón. A nuestro entender, el papel de la lipoxina A4 (LXA4), determinada en condensado de aire exhalado (EBC) en niños asmáticos con broncoconstricción inducida por el ejercicio (BEI) no ha sido previamente investigado. Objetivo: El objetivo de nuestro estudio fue determinar la implicación de la LXA4 determinada en EBC, en el broncoespasmo inducido por ejercicio. Métodos: Se incluyeron en el estudio un total de cuarenta y cinco pacientes de edades comprendidas entre 5 y 17 años. Los pacientes se dividieron en dos grupos: niños asmáticos con respuestas positivas (n = 17) y negativas (n = 28) a la provocación bronquial con ejercicio. Los niveles de LXA4 en EBC se determinaron inmediatamente antes y después de la provocación bronquial mediante un método ELISA. Resultados: Los niveles de LXA4 en EBC aumentaron significativamente tras la provocación con ejercicio en aquellos niños asmáticos con respuestas positivas en la provocación (p = 0,05). Sin embargo, no pudimos encontrar ninguna diferencia estadísticamente significativa en pacientes con respuesta negativa al ejercicio (p > 0,05). Hubo una correlación inversa entre el incremento de los niveles de LXA4 y el grado de reducción porcentual del volumen espiratorio forzado en un segundo (FEV1%) en los pacientes con respuesta positiva a la provocación (p = 0,05, r = -0,50). No se observaron diferencias significativas en los niveles de LXA4 entre asmáticos alérgicos y no alérgicos (p> 0,05, prueba de Mann-Whitney). Conclusiones: Los niveles de EBC LXA4 se incrementan inmediatamente después de la broncoconstricción inducida por el ejercicio en niños asmáticos. Se postula que los niveles de las vías respiratorias aumentan LXA4 para suprimir la inflamación aguda en la vía respiratoria, y podrían ser responsables de la inducción de broncodilatación espontánea que aparece tras el EIB (AU)

Exhaled breath condensate annexin A5 levels in exercise-induced bronchoconstriction in asthma: A preliminary study

BACKGROUND AND OBJECTIVE: The pathogenesis of exercise-induced bronchoconstriction (EIB) in asthma is incompletely understood. The role of exhaled breath condensate (EBC) annexin A5, which is an anti-inflammatory mediator, has not been investigated. The purpose of this study is to evaluate EBC annexin A5 levels in EIB in asthmatic children. METHODS: Two groups of children were enrolled in this study: asthmatic children with positive (n = 11) and negative (n = 7) responses to exercise. The levels of pre- and post-exercise EBC annexin A5 were determined with using enzyme-linked immunosorbent assay (ELISA). RESULTS: We observed significant higher pre-exercise EBC annexin A5 levels in the challenge test negative children than in the challenge test positive children (p < 0.05). No significant difference was observed in the post-exercise EBC annexin A5 levels between the groups (p > 0.05). Also, no significant difference was observed between pre- and post-exercise EBC annexin A5 levels within each group (p > 0.05). There was an inverse correlation between annexin A5 levels and a reduction in forced expiratory volume at one second percent (FEV1%) (p = 0.009, r = −0.598). CONCLUSIONS: Our preliminary study showed that EBC annexin A5 may have a possible preventive role in EIB in asthma. Annexin A5 and related compounds may provide novel therapeutic approaches to the treatment of EIB in asthma

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Exhaled breath condensate annexin A5 levels in exercise-induced bronchoconstriction in asthma: A preliminary study.

BACKGROUND AND OBJECTIVE: The pathogenesis of exercise-induced bronchoconstriction (EIB) in asthma is incompletely understood. The role of exhaled breath condensate (EBC) annexin A5, which is an anti-inflammatory mediator, has not been investigated. The purpose of this study is to evaluate EBC annexin A5 levels in EIB in asthmatic children. METHODS: Two groups of children were enrolled in this study: asthmatic children with positive (n=11) and negative (n=7) responses to exercise. The levels of pre- and post-exercise EBC annexin A5 were determined with using enzyme-linked immunosorbent assay (ELISA). RESULTS: We observed significant higher pre-exercise EBC annexin A5 levels in the challenge test negative children than in the challenge test positive children (p<0.05). No significant difference was observed in the post-exercise EBC annexin A5 levels between the groups (p>0.05). Also, no significant difference was observed between pre- and post-exercise EBC annexin A5 levels within each group (p>0.05). There was an inverse correlation between annexin A5 levels and a reduction in forced expiratory volume at one second percent (FEV1%) (p=0.009, r=-0.598). CONCLUSIONS: Our preliminary study showed that EBC annexin A5 may have a possible preventive role in EIB in asthma. Annexin A5 and related compounds may provide novel therapeutic approaches to the treatment of EIB in asthma.