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Histamine as a Potential Initiator of Sickle Pain crisis by Mediation of Sickle Erythrocyte Adherence in a Shear-Dependent MannerWagner, Matthew Christian 11 April 2006 (has links)
The genetic disorder sickle cell anemia causes hemolytic anemia and sickle pain crisis, episodes of microvascular occlusion resulting in painful ischemic tissue damage. Pain crisis is thought to occur when sickle erythrocytes adhere in the post-capillary venule, partially occluding the vessel. The resulting slowed blood flow causes more extensive cell adherence and entrapment of rigid, deoxygenated erythrocytes until the vessel is entirely occluded. It was hypothesized that the inflammatory mediators histamine and tumor necrosis factor-, factors known to cause endothelial expression of adhesive ligands, might significantly increase sickle erythrocyte adhesion, and thus be capable of initiating sickle pain crisis. It was also hypothesized that the perfusion shear stress environment of the endothelium, known to be oscillatory and reduced in sickle cell patients, was a significant mediating factor of sickle cell adhesion. An in-vitro flow chamber using cultured endothelial cells and erythrocytes from blood samples of sickle cell anemic patients was used to quantify sickle erythrocyte adherence to stimulated and unstimulated endothelial cells under shear stresses from 1.0 to 0.1 dyne/cm2. Results showed that both endothelial stimulation and reduction of the perfusion shear stress increased sickle erythrocyte adherence. In combination, the use of inflammatory stimulation with reduced shear stress resulted in further increased adhesion, but only when above the range of 0.1 V 0.2 or 0.4 dyne/cm2, depending on the inflammatory mediator. Adhesion below this level of shear is not significantly increased by endothelial stimulation. The mechanism by which histamine mediates adhesion was investigated, and found to involve the endothelial H2 and H4 receptors and expression of the P-selectin ligand. These data suggest that irregular flow, typical of sickle microvasculature, may act in conjunction with the pro-inflammatory state of sickle vasculature and the histaminergic nature of some pain treatments to initiate or propagate sickle vaso-occlusion. Findings concerning histamine, tumor necrosis factor-alpha, and shear stress effects on adherence are discussed in relation to their possible applicability to patient health, future studies are outlined to confirm the relation of in vitro data to in vivo patient condition, and proposals are made for applying these methodologies to other potential mediators of sickle erythrocyte adhesion.
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Avaliação de biomarcadores de risco em pacientes com anemia falciforme em crise vaso-oclusiva.[manuscrito] / João Henrique de Oliveira Reis.- 2013.Reis, João Henrique de Oliveira January 2013 (has links)
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Previous issue date: 2013 / Universidade Federal da Bahia. Faculdade de Medicina da Bahia. Salvador, BA, Brasil / Fundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, Brasil. / Os indivíduos com anemia falciforme (HbSS) possuem quadro clínico heterogêneo, com alterações múltiplas em órgãos ou tecidos, que são secundárias a hemólise contínua e aos fenômenos de vaso-oclusão, sendo estes últimos decorrentes da falcização dos eritrócitos e da ativação de moléculas na superfície de leucócitos, plaquetas e células endoteliais, além do aumento de proteínas plasmáticas inflamatórias. O presente estudo teve como objetivo avaliar biomarcadores relacionados ao prognóstico em pacientes HbSS hospitalizados em crise e no estado estável, de maneira a identificar marcadores de risco para cada uma dessas fases da doença. A casuística foi composta por 31 pacientes HbSS em crise e 45 em estado estável provenientes do hospital pediátrico das Obras Sociais irmã Dulce (HPOSID) e da Fundação de Hematologia e Hemoterapia do estado da Bahia (HEMOBA), respectivamente. O estudo foi aprovado pelo CEP do CPqGM da FIOCRUZ e os dados clínicos foram obtidos a partir da consulta aos prontuários médicos. A dosagem sorológica de citocinas, quimiocinas e moléculas de adesão (ICAM-1s e VCAM-1s) solúveis foram realizadas pela reação de ELISA. A análise de moléculas na superfície dos leucócitos foi investigada por citometria de fluxo. A citocina IL-1β teve correlação negativa significativa com a fração de LDL-c (r=0,450, p=0,011) nos pacientes HbSS em crise. Correlações positivas significativas foram observadas para a análise entre VCAM-1s e ácido úrico (r=0,547, p=0,002), triglicérides e IL6 (r=0,547, p=0,00). Em relação ao parâmetro HDL-c foi verificado que os pacientes que apresentaram níveis menores do que a média (percentil <50) tiveram risco de 11,6 vezes maior de desenvolver vaso-oclusão. Os pacientes HbSS que apresentaram níveis ≥ a média (percentil ≥50) das citocinas IL-12 e IL-8 tiveram risco maior para o desenvolvimento de crise álgica. Os pacientes HbSS em crise apresentaram níveis mais elevados para a AST e LDH quando comparados aos pacientes HbSS no estado estável; e os níveis de colesterol total, HDL-c e LDL-c foram menores nos pacientes HbSS em crise que nos pacientes no estado estável. Os níveis da citocina TNF-α estiveram associados aos níveis elevados de VCAM-1s, IL-1 e IL-10 nos pacientes em crise, quando comparados aos pacientes no estado estável. Com base nos resultados, pode-se concluir que a citocina TNF-α está associada a elevação sérica de VCAM-1s nos pacientes HbSS em crise; o nível de triglicerídeos foi considerado fator protetor para o desenvolvimento de infecção nos pacientes HbSS em crise. Os pacientes que apresentaram níveis menores do que a média de HDL-c tiveram risco maior para o desenvolvimento de vaso-oclusão. Os pacientes HbSS que apresentaram níveis superiores a média de VCAM-1s apresentaram risco elevado para vaso-oclusão, tanto no estado estável quanto em crise. Verificou-se que existe correlação positiva significativa entre ácido úrico e VCAM-1s. Em conjunto, os nossos resultados indicam que moléculas distintas estão associadas ao período estável e de crise nas duas fases da HbSS investigadas, de forma a constituirem elementos importantes para estratégias voltadas ao desenho de fármacos e ao monitoramento clínico destes pacientes / Sickle cell anemia (HbSS) individuals have heterogeneous clinical picture, with multiple changes in organs or tissues, which are secondary to ongoing hemolysis and vaso-occlusive phenomena, the latter are due to sickling of erythrocytes and molecules activation on the leukocytes, platelets and endothelial cells surface, as well as an increase of inflammatory plasma proteins. The aim of this study was evaluate biomarkers related to prognosis in HbSS patients hospitalized in crisis and in steady-state in order to identify markers of risk for each of these disease stages. A total of 31 HbSS patients in crisis and 45 in steady-state from the pediatric hospital of Obras Sociais irmã Dulce (HPOSID) and the Fundação de Hematologia e Hemoterapia Bahia state (HEMOBA) were studied respectively. The study was approved by the Research Board of CPqGM/FIOCRUZ and clinical data were obtained from medical records. Serum levels of cytokines, chemokines and solubles adhesion molecules (ICAM-1s and VCAM-1s) were investigated by ELISA. The analysis of leukocyte surface molecules was investigated by flow cytometry. The cytokine IL-1β had a significant negative correlation with the fraction of LDL-C (r = 0.450, p = 0.011) in HbSS patients in crisis-state. Significant positive correlations were observed for the analysis of VCAM-1s and uric acid (r = 0.547, p = 0.002), triglycerides and IL6 (r = 0.547, p = 0.00). Regarding the parameter HDL-C was found that patients who had lower than average (percentile <50) had 11.6 fold greater risk of developing vascular occlusion. HbSS patients who had levels ≥ average (percentile ≥ 50) cytokine IL8 and IL12 had a greater risk for the development of painful crises. Patients HbSS in crisis-state had higher levels for AST and LDH compared to HbSS steady-state patients and the levels of total cholesterol, HDL-c and LDL-c were lower in HbSS patients in crisis-state than in patients in steady-state. Levels of the cytokine TNF-α were associated with elevated levels of VCAM-1s, IL-1 and IL-10 in patients in crisis-state when compared with patients in steady-state. Based on the results, we can conclude that the cytokine TNF-α is associated with an increase of serum VCAM-1s in HbSS patients in crisis-state, the triglyceride level was considered a protective factor against the development of infection in patients in crisis-state. HbSS patients with HDL-C levels lower than average had an increased risk for the vaso-occlusion development. HbSS patients who had higher than average levels of VCAM-1s showed elevated risk for vaso-occlusion in both steady-state and in crisis-state. It has been found that there is positive correlation between uric acid and VCAM-1s. Based on the results, it is concluded that different molecules are associated with the steady and crisis-state, the two stages studied in HbSS, which can constitute an important element in the design of drugs strategies of and clinical monitoring of these patients
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Increasing Hydroxyurea Adherence for Pediatric Patients With Sickle Cell AnemiaReed, Caroline 01 January 2016 (has links)
Sickle cell disease is a disabling chronic autosomal recessive blood disease characterized by abnormal hemoglobin, pain crises, and frequent emergency department visits. Adherence to hydroxyurea therapy has been shown to improve these patient outcomes. Guided by the theory of comfort, the purpose of this project was to determine if an educational intervention would increase adherence to hydroxyurea therapy in pediatric patients between 2 and 17 years of age recruited from an urban university hospital hematology clinic. The RE-AIM model was used to support the translation of evidence and the change process. An educational video produced by AFLAC was viewed by patients' parents 4 weeks after enrollment into this pretest/posttest design project. A total of 22 African-American parent participants completed the 8-item Morisky Medication Adherence Scale at baseline and again at 8 weeks to assess hydroxyurea adherence. The Short Test of Functional Health Literacy in Adults tool was used to assess parents' health learning needs; all parents met the adequate literacy level at baseline. Using t test statistics, no statistically significant differences were found pretest to posttest on the Morisky Medication Adherence Scale scores, mean corpuscular hemoglobin, and fetal hemoglobin percentages. Wilcoxon Signed Rank tests showed no significant differences in emergency room visits nor number of pain crisis. Although no significant changes emerged in short-term hematologic findings, emergency room visits, and pain crises, social change in the health care setting was promoted by confirming parents were able to understand education and a high level of hydroxyurea adherence was maintained; literature indicated that long-term adherence to hydroxyurea limits severe attacks.
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Implication du stress oxydant dans la physiopathologie de la drépanocytose : crises vaso-occlusives, taux d'anticorps anti-bande 3 et oxydation du globule rouge / Implication of oxidative stress in the pathophysiology of sickle cell disease : vaso-occlusive crisis, antiband 3 antibodies levels and red blood cell oxidationHierso, Régine 08 July 2015 (has links)
A partir du défaut premier de la drépanocytose, la polymérisation de l’hémoglobine S (HbS), se développe toute une série de processus anormaux qui contribuent au développement d’une réponse inflammatoire et d’un stress oxydant dus à une hypoxie-reperfusion traumatisante et à l’auto-oxydation de l’HbS. L’exacerbation du stress oxydatif semble participer de manière active aux mécanismes physiopathologiques de la maladie et jouer un rôle dans la survenue des crises vaso-occlusives (CVO). Les travaux menés dans le cadre de cette thèse avaient pour objectif de mieux documenter les effets délétères du stress oxydant sur le globule rouge et son impact dans le développement des CVO. Nous avons, en premier lieu, évalué in vitro l’impact du stress oxydant sur la rhéologie sanguine des patients drépanocytaires SS et SC à l’aide d’un agent à fort potentiel oxydant, le t-butyl hydroperoxide (TBHP). Nous avons montré que les globules rouges des patients drépanocytaires (GR SS) produisent en présence du TBHP davantage de radicaux libres que les GR provenant de sujets contrôles (GR AA) et que ces GR SS présentent un système de défense anti-oxydant diminué. L’induction d’un stress oxydant accentue les altérations rhéologiques déjà présentes chez les patients drépanocytaires (i.e, déformabilité diminuée, diminution de l’indice d’agrégation, augmentation du seuil de désagrégation) tandis qu’il induit chez les sujets contrôles un profil hémorhéologique altéré proche de celui déjà préexistant chez les patients drépanocytaires. Ces résultats suggèrent que le stress oxydant, en participant aux anomalies hémorhéologiques associées à la drépanocytose, pourrait être l’un des facteurs favorisant la survenue des complications drépanocytaires. Nous nous sommes de plus attachés à documenter directement l’impact du stress oxydant dans le développement des CVO en analysant des prélèvements sanguins provenant de patients drépanocytaires SS en crise et à l’état de base. Il s’agissait : 1) de tester l’hypothèse selon laquelle la protéine bande 3, protéine de la membrane du GR, est une cible majeure des espèces réactives de l’oxygène qui provoquent au niveau de cette protéine l’apparition d’épitopes de senescence reconnus par des auto anticorps anti-bande 3 ; 2) d’évaluer l’évolution de marqueurs moléculaires et cellulaires pro- et anti-oxydants ; 3) d’étudier l’évolution des paramètres hémorhéologiques ; 4) d’explorer l’activité du système nerveux autonome, considéré comme un marqueur potentiel de sévérité. Nous avons mis en évidence au cours des CVO : 1) une exacerbation du stress oxydant ; 2) une diminution du taux d’anticorps anti-bande 3 et une augmentation de la concentration plasmatique de microparticules érythrocytaires, suggérant que ces deux processus sont liés au phénomène de clusterisation de la protéine bande 3 déclenché par le stress oxydant ; 3) une exacerbation des anomalies hémorhéologiques se traduisant par une réduction de la déformabilité érythrocytaire, une augmentation de l’agrégation érythrocytaire et du seuil de désagrégation ; 4) une altération du système nerveux autonome marqué par un retrait de l’activité parasympathique, ce déséquilibre étant accentué au cours des CVO. Les travaux de cette thèse se traduisent par à une meilleure compréhension de la physiopathologie extrêmement complexe de la drépanocytose en précisant l’impact du stress oxydant dans le déclenchement des CVO, première cause d’hospitalisation des sujets drépanocytaires. Les données obtenues, qui mettent en évidence des marqueurs pertinents de ce stress oxydant au cours de la CVO du sujet drépanocytaire, pourront favoriser la mise en œuvre de nouvelles pistes thérapeutiques anti-oxydantes et une amélioration in fine de la prise en charge des patients. / Besides the primary defect of sickle cell disease, hemoglobin S (HbS) polymerization, other abnormal processes may contribute to the development of an inflammatory response and to an oxidative stress caused by traumatic hypoxia-reperfusion and autoxidation of HbS. The exacerbation of oxidative stress seems to participate actively in the pathophysiology of the disease and play a role in vaso-occlusive crisis (VOC). The aim of this thesis was to document the deleterious effects of oxidative stress on the red blood cell and its impact in the development of VOC. First, we have evaluated the impact of tert-butyl hydroperoxide-induced oxidative stress on blood rheology of SS and SC sickle cell patients. We have shown that sickle red blood cells (SS RBC) produce more free radicals in the presence of tert-butyl hydroperoxide (TBHP) than control subject red blood cells (AA RBC). Furthermore, SS RBC have a decreased anti-oxidant defense system. Induction of oxidative stress increases the rheological alterations already present in sickle cell patients (ie, decreased deformability, reduced aggregation, increased disaggregation threshold). In control subjects, oxidative stress induces an altered hemorheological profile close to that already present in sickle cell patients. These results suggest that oxidative stress by modulating the hemorheological abnormalities associated with sickle cell disease, could be one of the factors promoting the occurrence of sickle cell complications. Then, we have studied the impact of oxidative stress in the development of VOC, analyzing blood samples from SS patients in crisis and at steady state. 1) We have tested the hypothesis that the protein band 3 of RBC, is a major target of reactive oxygen species, which cause the appearance of senescence epitopes of this protein recognized by auto anti-band 3 antibodies; 2) We have evaluated pro- and anti-oxidants molecular and cellular markers; 3) We have studied the evolution of hemorheological parameters; 4) We have explored the activity of the autonomic nervous system, seen as a potential marker of severity. Our results show during VOC: 1) an exacerbation of the oxidative stress; 2) a decrease in anti-band 3 antibodies levels and an increase in the plasma concentration of erythrocyte microparticles, suggesting that these two processes are linked to the clustering phenomenon of band 3 protein triggered by oxidative stress; 3) an exacerbation of hemorheological abnormalities resulting in a reduction of SS RBC deformability, increased aggregation and disaggregation threshold; 4) an impairment of the autonomic nervous system marked by a withdrawal of parasympathetic activity and this imbalance is accentuated during VOC. This work allows a better understanding of the complex pathophysiology of sickle cell disease, highlighting the impact of oxidative stress in the development of VOC, the leading cause of hospitalization of sickle cell subjects. The data obtained, which reveal relevant markers of oxidative stress during VOC, could promote the implementation of new antioxidant therapeutic approaches and help improving sickle cell patients care.
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