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L'objectif de ce travail est d'évaluer l'impact du programme de dépistage néonatal universel chez de l’anémie falciforme (AF) chez les enfants. Méthode : Nous avons procédé à une étude de cohorte rétrospective sur 600 dossiers d’enfants atteints d’AF suivis au CHU Saint-Justine sur une période de janvier 2000 à décembre 2019. Nous avons divisé la durée de suivi en deux grandes périodes, avant 2013 (pré-dépistage néonatal, pré-DN) et après 2013 (post-dépistage néonatal, post-DN) et avons retenu 410 enfants et le logiciel R version 4.2.1 a été utilisé pour les analyses de différentes variables retenues. Résultats : Alors que 42.6% des enfants avant novembre 2013 étaient diagnostiqués pour une première manifestation de l’AF, tous les enfants nés au Québec après 2013 qui nous ont été référés ont bénéficié d’une prise en charge précoce. Nous observons ainsi une diminution de l’âge médian lors du diagnostic de 10.8 mois (EI, 1.2-52.8) en pré-DN à 1.2 mois (EI, 1.2-43.2) en post-DN, p< 0.006) et à la 1ère visite de 14.4 mois (EI, 2.4-72) en pré-DN à 1.2 mois (EI, 1.2-57.6) en post-DN, p< 0.001). La prise en charge précoce s’est traduite par une diminution de l’âge médian à l’introduction de l’hydroxyurée (HU) passant de 5 ans à 9 mois (p<0.001) pour des patients SS et Sβ0, alors que l’âge médian d’introduction n’a que peu varié chez des patients non SS (7.9 pré-DN et 7.7 ans post-DN, p>0.9). De même, le délai moyen d’introduction de l’HU depuis la première visite a diminué de 4.5 ans avant 2013 à 0.8 mois après 2013 (p<0.001). Le taux moyen d’hospitalisation par patient année (hospit/pt-an) a diminué en post-DN de moitié passant de 2 hospit/pt-an pré-DN (1st Qu.1.0 et 3rd Qu.3.0) à 1.0 hospit/pt-an (1st Qu.0.6 et 3rd Qu.1.4) avec un p (<0.001). Conclusion : L’universalisation du programme de dépistage néonatal de l’AF a permis une détection et une référence précoces des enfants dans les centres de prise en charge, associée à une diminution du taux d’hospitalisation. / The aim of this work is to evaluate the impact of the universal neonatal screening program with sickle cell disease (SCD) in children Method: We conducted a retrospective cohort study of 600 records of children with SCD followed at the CHU Saint-Justine over a period from January 2000 to December 2019. We divided the duration of follow-up into two main periods, before 2013 (pre-neonatal screening, pre-DN) and after 2013 (post-neonatal screening, post-DN) and retained 410 children. R software version 4.2.1 was used for the analyses of different retained variables. Results: Whereas 42.6% of children before November 2013 were diagnosed with a first manifestation of SCD, all children born in Quebec after 2013 who were referred to us benefited from early management. We observed a reduction in median age at diagnosis from 10.8 months (AR, 1.2-52.8) pre-DN to 1.2 months (range, 1.2-43.2) post-DN, p< 0.006) and at 1st visit from 14.4 months (range, 2.4-72) pre-DN to 1.2 months (range, 1.2-57.6) post-DN, p< 0.001). Early management resulted in a decrease in the median age at introduction of hydroxyurea (HU) from 5 years to 9 months (p<0.001) for SS patients, whereas the median age at introduction didn’t vary significantly in non-SS and Sβ0 patients (7.9 pre-DN and 7.7 years post-DN, p>0.9). Similarly, the median time to introduction of HU since the first visit decreased from 4.5 years pre-2013 to 0.8 months post-2013 (p<0.001). The mean hospitalization rate per patient year (hosp/pt-year) decreased post-DN by half from 2 hosp/pt-year pre-DN (1st Qu.1.0 and 3rd Qu.3.0) to 1.0 hosp/pt-year (1st Qu.0.6 and 3rd Qu.1.4) with a p (<0.001). Conclusion: Universalization of the neonatal SCD screening program has resulted in early detection and referral of children to care centers, associated with a decrease in the rate of hospitalization

By examining barriers to care, health professionals can better understand what disparities exist between groups and who may be at greater risk for poor primary care. Researchers have highlighted the need for additional research that focuses on the extent of unmet needs for U.S. children with sickle cell disease (SCD). The purpose of this quantitative study was to compare the differences between parents who are in a SCD support group and those who are not. The theoretical framework of this study is based on the chronic care model and social support theory. A total of 128 parents of children with SCD completed the study survey. The sampling occurred by e-mail, phone, and face-to-face conversations. Selection criteria for potential participants in both groups were based on their children being diagnosed with SCD. Seventy-four participants (57.8%) were members of a SCD support group, and 54 participants (42.4%) were not members of a SCD support group. In this study, the independent variables were parents attending or not a SCD support group. The t test and MANCOVA was used to assessed the association between perceptions of barriers to care and support group status. However, statistical analysis showed no significant results. The null hypothesis was not rejected. Therefore, the positive social change implication is to further explore potential factors that may shape perceptions of barriers to care for those with SCD so that perceived barriers to care can be overcome.

By examining barriers to care, health professionals can better understand what disparities exist between groups and who may be at greater risk for poor primary care. Researchers have highlighted the need for additional research that focuses on the extent of unmet needs for U.S. children with sickle cell disease (SCD). The purpose of this quantitative study was to compare the differences between parents who are in a SCD support group and those who are not. The theoretical framework of this study is based on the chronic care model and social support theory. A total of 128 parents of children with SCD completed the study survey. The sampling occurred by e-mail, phone, and face-to-face conversations. Selection criteria for potential participants in both groups were based on their children being diagnosed with SCD. Seventy-four participants (57.8%) were members of a SCD support group, and 54 participants (42.4%) were not members of a SCD support group. In this study, the independent variables were parents attending or not a SCD support group. The t test and MANCOVA was used to assessed the association between perceptions of barriers to care and support group status. However, statistical analysis showed no significant results. The null hypothesis was not rejected. Therefore, the positive social change implication is to further explore potential factors that may shape perceptions of barriers to care for those with SCD so that perceived barriers to care can be overcome.

The major physiological function of hemoglobin (Hb) is to bind, transport and deliver oxygen to tissues; made efficient by endogenous effectors, such as protons and 2,3-diphosphoglycerate. Synthetic allosteric effectors of Hb (AEHs) are also known to modulate Hb oxygen affinity, showing potential for the treatment of sickle cell disease (SCD) and ischemic-related diseases. In this project, AEHs which increase Hb affinity for oxygen, including derivatives of the anti-sickling compounds, 5HMF and benzaldehydes, as well as an AEH that decreases Hb affinity for oxygen, RSR-13, were synthesized for their effects on Hb oxygen binding property and their capability to release NO from substituted nitrate ester moieties. Compounds that were found to increase Hb affinity for oxygen were further tested for their anti-sickling activities. Structural studies were carried out to gain insight into the compound’s mode of action. Development of these agents could be a therapeutic strategy for SCD or ischemic-related diseases.

The rapid growth in opioid therapy for non-cancer pain has occurred without an adequate appreciation of the consequences of this growth. Few studies provide patient-centered evidence that can be used to inform the current proposed standards for efficacious (safe and effective) opioid prescribing in non-cancer pain. Furthermore, different terms may be used interchangeably in the literature to refer to opioid-taking behaviors, resulting in imprecise or vague interpretation of existing evidence. We therefore sought to explore patterns of opioid-taking behavior and their biopsychosocial-spiritual determinants in African-American adults with sickle cell disease (SCD). Many questions surround opioid use for non-cancer pain, but little has been published about behavioral patterns of taking opioids in these conditions. The main objective of this study was to develop a disease-specific scale for describing prescribed opioid taking in patients with sickle cell disease (SCD). As part of a multiphase, mixed-methods study, we used an adaptation of several published methods to construct 9 sequential, chronological steps for developing a new scale. We report here wide-ranging quantitative and semi-structured, qualitative interviews of 13 male and 11 female African-American adults with SCD, average age 36 years, from various socioeconomic and educational levels. We used grounded theory, priori and posteriori procedures to analyze the qualitative data, and to conduct an appraisal of translational validity. Scale development results have led to inclusion in the draft scale of new concepts namely momentary medication-taking behavior. The scale also captures concrete patterns of adherence for as-needed and scheduled medication and allows for several discovered conceptual domains that explain observed opioid-taking behaviors. These concepts challenge the current theories and models of medication-taking behavior and adherence. In summary, we found that contextual factors may drastically affect opioid-taking behaviors. Together, These uncovered phenomena raise new hypotheses that may challenge current theories and models of medication-taking behaviors and methods of assessing adherence. These hypotheses call for a new round of research on opioid-taking behavior, and need to be rigorously tested in future research

As Anemias Hemolíticas compreendem um grupo de doenças em que há redução acentuada na sobrevivência dos glóbulos vermelhos circulantes e a medula óssea não é capaz de compensação, mesmo aumentando sua produção, o que causa anemia desde os primeiros anos da vida da pessoa. Dentre as doenças deste grupo, a Anemia Falciforme (SCA) e a Esferocitose Hereditária (HS) destacam-se por se tratarem de enfermidades com defeitos genéticos intrínsecos das células vermelhas (RBCs) que geram complicações multissistêmicas agudas e crônicas em seus portadores. Por vias patofisiológicas distintas, reticulócitos e respectivas hemácias defeituosas de tais doenças, falciformes e esferócitos, são continuamente aprisionados e fagocitados no baço, importante órgão de destruição de células velhas e/ou defeituosas via hemólise extravascular, o que leva progressivamente à disfunção e eventual perda da função esplênica. O objetivo desse trabalho é avaliar o papel do baço em relação à habilidade e ao fenótipo adesivos de reticulócitos (ret) e eritrócitos (erit) em pacientes com SCA e HS, com e sem função esplênica preservada. Amostras de sangue de 37 pacientes (22 SCA and 15 HS) com função esplênica e 19 pacientes (13 SCA e 6 HS) sem ela foram avaliadas. Ainda, sangue de 22 crianças com SCA foi coletado em estudo longitudinal dos 6 e 29 meses de vida. Todas as amostras de sangue foram analisadas quanto à função esplênica (Contagem de células PIT e de corpúsculos de Howell-Jolly - HJB), quanto ao perfil imunofenotípico celular (em % e em média de intensidade de fluorescência - MFI) e quanto à habilidade de adesão das células vermelhas à laminina e à linhagem celular endotelial HMEC-1. A análise da transição da perda de função esplênica demonstrou que a mesma se intensificou a partir dos 3 anos de idade (PIT: r=0,8; p<0,0001; HJB: r=0,7; p<0.0001). Quanto à imunofenotipagem celular, a contagem PIT se correlacionou positivamente, principalmente com os marcadores CD147 (%ret: r=0,6; p<0,0001; MFIret: r=0,6; p<0,0001; %erit: r=0,7; p<0,0001; MFIerit: r=0,6; p<0,0001), LuBCAM (%ret: r=0,5; p=0,004; MFIret: r=0,6; p<0,0001; %erit: r=0,6; p<0,0003; MFIerit: r=0,4; p<0,004) and CD58 (%ret: r=0,4; p=0,006; MFIret: r=0,5; p<0,0013; %erit: r=0,4; p<0,009; MFIerit: r=0,6; p<0,0001). Na comparação entre ausência ou presença do baço, a perda de sua função exerceu influência no aumento da expressão de adesão de RBCs em SCA, principalmente CD147 (%ret: p=0,002; MFIret: p=0,003; %erit: p<0,0001; MFIerit: p=0,005), LuBCAM (%ret: p=0,0001; MFIret: p<0,0001; %erit: p<0,0001; MFIerit: p<0,0001) e CD58 (%ret: p=0,007; MFIret: p=0,006; %erit: p=0,003; MFIerit: p=0,0004), embora a adesão celular tenha diminuído em pacientes HS esplenectomizados. Na comparação entre as doenças, pacientes HS com o baço apresentaram maior freqüência de adesão celular em relação aos SCA, notavelmente em relação ao LuBCAM (%ret: p=0,0008; MFIret: p=0,03; %erit: p<0,0001; MFIerit: p=0,0002), CD58 (%ret: p=0,0009; %erit: p=0,003) e CD44 (%ret: p=0,009; %erit: p<0,003). No entanto, as amostras SCA sem função esplênica tiveram maior expressão de adesão celular para CD147 (%ret: p=0,006; MFIret: p=0,02; %erit: p=0,02), LuBCAM (%ret: p=0,004; MFIret: p<0,0001), CD36 (%ret: p=0,0002; MFIret: p=0,01), CD242 (%ret: p=0,0008; %erit: p=0,05) e CD49d (%ret: p=0,04). Em relação ao Ensaio de Adesão in vitro, na ausência de baço, os RBCs SCA apresentaram maior adesividade à laminina do que os RBCs SCA com função esplênica preservadaem todas as taxas de fluxo de tensão de cisalhamento empregadas (0,5 dyne/cm2: p=0,01; 1 dyne/cm2: p=0,02; 2 dynes/cm2: p=0,03; 3 dynes/cm2: p=0,03; 5 dynes/cm2: p=0,04 e 7 dynes/cm2: p=0,03). Especialmente, reticulócitos de pacientes sem baço apresentaram maior adesividade à HMEC-1 em baixas tensões de cisalhamento (1 dyne/cm2) em ambas as doenças (SCA: p=0,03; HS: p=0,03). Por fim, reticulócitos apresentaram maior habilidade adesiva à células endoteliais em indivíduos SCA do que em pacientes HS, com (0,5 dyne/cm2: p=0,04; 1 dyne/cm2: p=0,03) ou sem baço (0,5 dyne/cm2: p=0,02; 2 dynes/cm2: p=0,01; 3 dynes/cm2: p=0,03; 5 dynes/cm2: p=0,02 e 7 dynes/cm2: p=0,03). Nossos resultados indicam que embora pertençam ao grupo de Anemias Hemolíticas, as patofisiologias e evoluções clínicas distintas de SCA e de HS levam a padrões imunofenotípicos diferentes de expressão da adesão celular. Na SCA, a ausência de função esplênica teria direta relação com o aumento do fenótipo pró-adesivo e com a adesividade de RBCs SCA, o que traz sérias consequências clínicas aos pacientes, enquanto na HS sem baço, de maneira geral, os eventos de adesão celular são minimizados, embora ainda apresentem reticulócitos e eritrócitos adesivos circulantes após a esplenectomia. / Hemolytic Anemias comprise a group of diseases in which there is marked reduction in the survival of circulating erythrocytes and the bone marrow is not capable of compensation, even by increasing its production, which causes anemia from the first years of the person\'s life on. Among the diseases of this group, Sickle Cell Anemia (SCA) and Hereditary Spherocytosis (HS) stand out for being diseases with intrinsic genetic defects of red blood cells (RBCs) that generate acute and chronic multisystemic complications in their patients. By distinct pathophysiological pathways, reticulocytes and these disease\'s respective defective erythrocytes, sickle and spheroid ones, are continuously trapped and phagocytosed in the spleen, important organ of destruction of old and/or defective cells via extravascular hemolysis, which progressively leads to dysfunction and eventual loss of splenic function. The objective of this study was to evaluate the role of the spleen in relation to the reticulocyte (ret) and erythrocyte (eryt) adhesive ability and adhesion phenotype in patients with SCA and HS, with and without preserved splenic function. Blood samples from 37 patients (22 SCA and 15 HS) with splenic function and 19 patients (13 SCA and 6 HS) without it were evaluated. Still, blood from 22 children with SCA was collected in a longitudinal study from 6 to 29 months of age. All blood samples were analyzed for splenic function [pitted cells (PIT) and Howell-Jolly bodies (HJB) counting], for the cellular immunophenotypic profile (in % and in mean fluorescence intensity - MFI) and for the adhesive ability of RBCs to laminin and to endothelial cell line HMEC-1. Analysis of the splenic function loss transition showed that it intensified from 3 years of age on (PIT: r=0.8, p<0.0001; HJB: r=0.7, p<0.0001). Regarding the cellular immunophenotyping, PIT count correlated positively, mainly with CD147 markers (%ret: r=0.6, p<0.0001; MFIret: r=0.6, p<0.0001; %eryt: r=0.7, p<0.0001; MFIeryt: r=0.6, p<0.0001), LuBCAM (%ret: r=0.5, p=0.004; MFIret: r=0.6, p<0.0001; %eryt: r=0.6, p<0.0003; MFIeryt: r=0.4, p<0.004) and CD58 (%ret: r=0.4, p=0.006; MFIret: r=0.5, p<0.0013; %eryt: r=0.4, p<0.009; MFIeryt: r=0.6, p<0.0001). In the comparison between spleen absence or presence, the loss of its function exerted influence on the increase of RBCs adhesion expression in SCA, mainly on CD147 (%ret: p=0.002; MFIret: p=0.003; %eryt: p<0.0001; MFIeryt: p=0.005), LuBCAM (%ret: p=0.0001; MFIret: p<0.0001; %eryt: p<0.0001; MFIeryt: p<0.0001) e CD58 (%ret: p=0.007; MFIret: p=0.006; %eryt: p=0.003; MFIeryt: p=0.0004), although cell adhesion has been decreased in splenectomized HS patients. In the comparison between diseases, HS patients with spleen showed higher cell adhesion frequency compared to SCA, notably in relation to LuBCAM (%ret: p=0.0008; MFIret: p=0.03; %eryt: p<0.0001; MFIeryt: p=0.0002), CD58 (%ret: p=0.0009; %eryt: p=0.003) and CD44 (%ret: p=0.009; %eryt: p<0.003). However, SCA samples without splenic function had higher cell adhesion expression for CD147 (%ret: p=0.006; MFIret: p=0.02; %eryt: p=0.02), LuBCAM (%ret: p=0.004; MFIret: p<0.0001), CD36 (%ret: p=0.0002; MFIret: p=0.01), CD242 (%ret: p=0.0008; %eryt: p=0.05) and CD49d (%ret: p=0.04). Concerning the in vitro Adhesion Assay, in the spleen absence, SCA RBCs showed greater adhesiveness to laminin than SCA RBCs with preserved splenic function did at all shear stress flow rates applied (0.5 dyne/cm2: p=0.01, 1 dyne/cm2: p=0.02, 2 dynes/cm2: p=0.03, 3 dynes/cm2: p=0.03, 5 dynes/cm2: p=0.04 and 7 dynes/cm2:p=0.03). Especially, reticulocytes from patients without spleen showed higher adhesiveness to HMEC-1 at low shear stresses (1 dyne/cm2) in both diseases (SCA: p=0.03; HS: p=0.03). Finally, reticulocytes showed greater adhesion ability to endothelial cells in SCA subjects than in HS patients, with (0.5 dyne/cm2: p=0.04 and 1 dyne/cm2: p=0.03) or without spleen (0.5 dyne/cm2: p=0.02, 2 dynes/cm2: p=0.01, 3 dynes/cm2: p=0.03, 5 dynes/cm2: p=0.02 and 7 dynes/cm2: p=0.03). Our results indicate that although both diseases belong to the Hemolytic Anemias group, SCA and HS distinct pathophysiologies and clinical evolution lead to different immunophenotypic patterns of cell adhesion expression. In SCA, the absence of splenic function may have a direct relation with the increase of SCA RBCs proadhesive phenotype and adhesiveness, which brings serious clinical consequences to the patients, whereas in HS without spleen, in general, cellular adhesion events are minimized, although they still present adhesive circulating reticulocytes and erythrocytes after splenectomy.

A doença falciforme constitui um grupo de hemoglobinopatias hereditárias caracterizadas por uma mutação de ponto na cadeia da globina ?, que resulta em uma hemoglobina anormal denominada HbS. Apesar de sua importância para a saúde pública mundial e seu grande impacto social, a doença falciforme ainda apresenta muitas questões fisiopatológicas não esclarecidas e desafios terapêuticos. Paralelamente, existe a necessidade da descoberta de novos biomarcadores fisiopatológicos da doença falciforme e de biomarcadores de resposta terapêutica. O objetivo desse trabalho foi quantificar, em amostras de soro de indivíduos sadios (N=19) e de pacientes com doença falciforme sem tratamento (N=14) ou tratados com hidroxiuréia (N=15), transfusão crônica (N=15) ou transplante alogênico de células-tronco hematopoéticas (N=21), biomarcadores de ativação endotelial (VCAM-1, ICAM-1, E-selectina, P-selectina, HGF, FGF, VEGF-A, endothelina-1, CXCL4/PF4, TGF-? e óxido nítrico), biomarcadores de ativação plaquetária (von Willebrand e trombomodulina), biomarcadores de inflamação (IL-1?, pentraxina-3, IL-18, IL-6, IL-8, IL-2, IL-17A, TNF-?, INF-?, CCL2/MCP-1, CCL4/MIP-1?, IL-12p70, IL-33, IL-27, GM-CSF, CD163, osteopontina, BAFF, APRIL e heme) e biomarcadores relacionados à imunomodulação (arginase-1 e IL-10). De acordo com os resultados obtidos e as análises de correlação, os pacientes com doença falciforme sem tratamento, tratados com transfusão crônica ou transplante apresentaram perfis mais inflamatórios que os pacientes tratados com hidroxiuréia. Os tratamentos com transfusão crônica e transplante não foram capazes de diminuir os níveis séricos dos biomarcadores de inflamação, de ativação endotelial e plaquetária para níveis similares aos dos indivíduos sadios. Os pacientes tratados com transfusão crônica apresentaram o perfil mais inflamatório de todos os grupos analisados. Apesar dos pacientes tratados com hidroxiuréia apresentarem os menores níveis séricos de biomarcadores de inflamação e de ativação endotelial e plaquetária, estes continuaram apresentando níveis séricos elevados de heme e da citocina pró-inflamatória IL-18. Os pacientes transplantados apresentaram perfil inflamatório intenso, com níveis elevados de P-selectina, trombomodulina e IL-8 (relacionados à ativação endotelial, ativação plaquetária e inflamação, respectivamente) em comparação com todos os grupos analisados. Porém, os pacientes transplantados apresentaram níveis séricos de IL-18 significativamente menores que os pacientes com doença falciforme sem tratamento. Os pacientes transplantados apresentaram níveis séricos da citocina anti-inflamatória IL-10 similares aos de indivíduos sadios, porém, significativamente maiores que os pacientes tratados com hidroxiuréia. Os resultados obtidos nesse trabalho podem direcionar estudos futuros para o monitoramento laboratorial de respostas terapêuticas aos diferentes tratamentos atualmente utilizados para doença falciforme e para o desenvolvimento de novos tratamentos ou de terapias complementares às que estão atualmente disponíveis. / Sickle cell disease is a group of hereditary hemoglobinopathies characterized by a point mutation in the ? globin chain, which results in an abnormal hemoglobin named HbS. Despite its importance for global public health and its great social impact, sickle cell disease still presents many unclarified pathophysiological issues and therapeutic challenges. In parallel, there is a need for the discovery of new pathophysiological biomarkers of sickle diseases and biomarkers of therapeutic response. The aim of this study was to quantify serum samples from healthy subjects (N = 19) and patients with sickle cell disease (N = 14) or treated with hydroxyurea (N = 15), chronic transfusion (N = 15) or allogeneic hematopoietic stem cell transplantation (N = 21) endothelial activation biomarkers (VCAM-1, ICAM-1, E-selectin, P-selectin, HGF, FGF, VEGF-A, endothelin-1, CXCL4 / PF4, TGF-? and nitric oxide), platelet activation biomarkers (von Willebrand and thrombomodulin), inflammatory biomarkers (IL-1?, pentraxin-3, IL-18, IL-6, IL-8, IL-2, IL-17A, TNF-?, INF-?, CCL2/MCP-1, CCL4/MIP-1?, IL-12p70, IL-33, IL-27, GM-CSF, CD163, osteopontin, BAFF, APRIL and heme) and immunomodulatory biomarkers (arginase-1 and IL-10). According to the obtained results and correlation analyzes, patients with sickle disease without treatment, treated with chronic transfusion or transplantation presented more high inflammatory profiles than patients treated with hydroxyurea. Patients treated with chronic transfusion and transplantation were not able to decrease the elevated serum biomarkers of inflammation and endothelial and platelet activation similar to healthy subjects levels. Patients treated with chronic transfusion presented the most inflammatory profile of all groups analyzed. Although patients treated with hydroxyurea had the lowest serum levels of inflammatory and endothelial/platelet activation biomarkers, they continued to have high serum levels of heme and proinflammatory cytokine IL-18. Transplanted patients presented a high inflammatory profile, with elevated levels of P-selectin, thrombomodulin and IL-8 (related to endothelial activation, platelet activation and inflammation, respectively) compared to all groups analyzed. However, transplant patients had significantly lower serum IL-18 levels than patients with untreated sickle cell disease. Notably, transplanted patients had levels of the anti-inflammatory cytokine IL-10 similar to those of healthy subjects, but significantly higher than patients treated with hydroxyurea. The results obtained in this study may pave the way for future studies for the laboratory monitoring of therapeutic responses to different sickle cell disease treatments and for the development of new or complementary treatments to the currently available therapies.

Submitted by Ricardo Cedraz Duque Moliterno (ricardo.moliterno@uefs.br) on 2017-08-08T21:31:24Z No. of bitstreams: 1 TESE_Odailson Paz - com ficha.pdf: 4071411 bytes, checksum: 033f0c18eb721e7010e1ddd7ec27e10c (MD5) / Made available in DSpace on 2017-08-08T21:31:24Z (GMT). No. of bitstreams: 1 TESE_Odailson Paz - com ficha.pdf: 4071411 bytes, checksum: 033f0c18eb721e7010e1ddd7ec27e10c (MD5) Previous issue date: 2017-05-25 / Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior - CAPES / Adenosine receptors are considered as potential targets for the development of drugs against different pathologies because they are involved in several physiological pathways. Due to the role of adenosine receptors of subtype 2B (RA2B) in the process of sickling cell, antagonists capable of blocking RA2B may be lead compounds for the development of new therapeutic alternatives to treatment of patients with sickle cell anemia. Then, the objective of this work was to identify anti-sickle cell agents capable of blocking RA2B activity. To achieve this goal, was built a pharmacophore model (model 04) capable of differentiating true ligands false-positive (area under the ROC curve = 0.94) and to classify RA2B antagonists, not used in the calibration of the model, regarding their Biological activities pKi = 7.5-9.3 (high potency), 5.5-7.4 (intermediate potency) and 5.4-4.0 (low potency). This pharmacophore model allowed the selection of 33 lead-like compounds from the ZINC database, between them12 compounds presented anti-sickle cell activity. In vitro cell assay with an agonist (NECA) and a RA2B antagonist (MRS1754), suggest that the anti-sickle cell activity is related to modulation of RA2B. Compounds Z1139491704 (pEC50= 7,77?0,17), Z168278894 (pEC50= 7,64?0,09) e Z847449186 (pEC50= 7,66?0,21) have anti-sickling activity Higher than MRS1754 (pEC50= 7,63?0,12) and do not present cytotoxic activity at micromolar range. In sum, it can be concluded that the in silico strategy used succeeded in identifying compounds with probable action antagonists of RA2B that can be considered as prototypes for the development of drugs useful in the treatment of patients with sickle cell anemia. / Os receptores de adenosina s?o considerados como alvos potenciais para o desenvolvimento de f?rmacos contra diferentes patologias por estarem envolvidos em diversas vias fisiol?gicas. Devido ao papel dos receptores de adenosina do subtipo 2B (RA2B) no processo de falciza??o de hem?cias, antagonistas capazes de bloquear RA2B podem ser compostos prot?tipos para o desenvolvimento de novas alternativas terap?uticas para o tratamento de pacientes com anemia falciforme.Diante desse cen?rio, o objetivo desse trabalho foi identificar agentes antifalcizantes capazes de antagonizar a atividade do RA2B. Para alcan?ar esse objetivo foi constru?do um modelo farmacof?rico (modelo 04 - 3 caracter?sticas aceptor e 1 doador de liga??o de hidrog?nio e 3 centros hidrof?bicos) que ? capaz de diferenciar ligantes verdadeiros de falso-positivos (?rea sob a curva ROC= 0,94)e classificar antagonistas de RA2B,n?o utilizados na calibra??o do modelo, quanto as suas atividades biol?gicas(pKi= 7,5-9,3 (alta pot?ncia), 5,5-7,4 (pot?ncia intermedi?ria) e 5,4-4,0 (baixa pot?ncia)). Esse modelo farmacof?rico permitiu a sele??o de 33 compostos lead like do banco de dados ZINC database para avalia??o biol?gica, dos quais 12 apresentaram atividade antifalcizante.Testes in vitro com um agonista (NECA) e um antagonista de RA2B (MRS1754), sugerem que a atividade antifalcizante est? relacionada a modula??o de RA2B.Os compostosZ1139491704(pEC50= 7,77?0,17),Z168278894 (pEC50= 7,64?0,09) e Z847449186 (pEC50= 7,66?0,21)possuem atividade antifalcizante superior ao MRS1754 (pEC50=7,63?0,12)e n?o apresentam atividade citot?xica em concentra??es micromolares. Dessa forma, pode-se concluir que a estrat?gia in silico utilizada logrou sucesso em identificar compostos com prov?vel a??o antagonistas de RA2B que podem ser considerados como prot?tipos para o desenvolvimento de f?rmacos ?teis no tratamento de pacientes com anemia falciforme.