RESUMEN
ABSTRACT: Pyruvate kinase (PK) is a key enzyme in glycolysis, the sole source of adenosine triphosphate, which is essential for all energy-dependent activities of red blood cells. Activating PK shows great potential for treating a broad range of hemolytic anemias beyond PK deficiency, because they also enhance activity of wild-type PK. Motivated by observations of sickle-cell complications in sickle-trait individuals with concomitant PK deficiency, activating endogenous PK offers a novel and promising approach for treating patients with sickle-cell disease.
Asunto(s)
Anemia Hemolítica Congénita no Esferocítica , Anemia de Células Falciformes , Piruvato Quinasa/deficiencia , Errores Innatos del Metabolismo del Piruvato , Humanos , Anemia Hemolítica Congénita no Esferocítica/tratamiento farmacológico , Anemia Hemolítica Congénita no Esferocítica/etiología , Eritrocitos , Anemia de Células Falciformes/tratamiento farmacológico , Anemia de Células Falciformes/complicacionesRESUMEN
Stem cell transplantation and genetic therapies offer potential cures for patients with sickle cell disease (SCD), but these options require advanced medical facilities and are expensive. Consequently, these treatments will not be available for many years to the majority of patients suffering from this disease. What is urgently needed now is an inexpensive oral drug in addition to hydroxyurea, the only drug approved by the FDA that inhibits sickle-hemoglobin polymerization. Here, we report the results of the first phase of our phenotypic screen of the 12,657 compounds of the Scripps ReFRAME drug repurposing library using a recently developed high-throughput assay to measure sickling times following deoxygenation to 0% oxygen of red cells from sickle trait individuals. The ReFRAME library is a very important collection because the compounds are either FDA-approved drugs or have been tested in clinical trials. From dose-response measurements, 106 of the 12,657 compounds exhibit statistically significant antisickling at concentrations ranging from 31 nM to 10 µM. Compounds that inhibit sickling of trait cells are also effective with SCD cells. As many as 21 of the 106 antisickling compounds emerge as potential drugs. This estimate is based on a comparison of inhibitory concentrations with free concentrations of oral drugs in human serum. Moreover, the expected therapeutic potential for each level of inhibition can be predicted from measurements of sickling times for cells from individuals with sickle syndromes of varying severity. Our results should motivate others to develop one or more of these 106 compounds into drugs for treating SCD.
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Anemia de Células Falciformes , Antidrepanocíticos , Antidrepanocíticos/farmacología , Antidrepanocíticos/uso terapéutico , Reposicionamiento de Medicamentos , Hemoglobina Falciforme , Humanos , Hidroxiurea/farmacología , Oxígeno/uso terapéuticoRESUMEN
The root cause of sickle cell disease (SCD) has been known for nearly a century, however, few therapies to treat the disease are available. Over several decades of work, with advances in gene editing technology and after several iterations of mice with differing genotype/phenotype relationships, researchers have developed humanized SCD mouse models. However, while a large body of preclinical studies has led to huge gains in basic science knowledge about SCD in mice, this knowledge has not led to the development of effective therapies to treat SCD-related complications in humans, thus leading to frustration with the paucity of translational progress in the SCD field. The use of mouse models to study human diseases is based on the genetic and phenotypic similarities between mouse and humans (face validity). The Berkeley and Townes SCD mice express only human globin chains and no mouse hemoglobin. With this genetic composition, these models present many phenotypic similarities, but also significant discrepancies that should be considered when interpreting preclinical studies results. Reviewing genetic and phenotypic similarities and discrepancies and examining studies that have translated to humans and those that have not, offer a better perspective of construct, face, and predictive validities of humanized SCD mouse models.
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Anemia de Células Falciformes , Ratones , Humanos , Animales , Anemia de Células Falciformes/genética , Anemia de Células Falciformes/terapia , Anemia de Células Falciformes/complicaciones , Modelos Animales de Enfermedad , HemoglobinasRESUMEN
Chronic hemolytic anemia and intermittent acute pain episodes are the 2 hallmark characteristics of sickle cell disease (SCD). Anemia in SCD not only signals a reduction of red cell mass and oxygen delivery, but also ongoing red cell breakdown and release of cell-free hemoglobin, which together contribute to a number of pathophysiological responses and play a key role in the pathogenesis of cumulative multiorgan damage. However, although anemia is clearly associated with many detrimental outcomes, it may also have an advantage in SCD in lowering risks of potential viscosity-related complications. Until recently, clinical drug development for SCD has predominantly targeted a reduction in the frequency of vaso-occlusive crises as an endpoint, but increasingly, more attention is being directed toward addressing the contribution of chronic anemia to poor outcomes in SCD. This article aims to explore the complex pathophysiology and mechanisms of anemia in SCD, as well as the need to balance the benefits of raising hemoglobin levels with the potential risks of increasing blood viscosity, in the context of the current therapeutic landscape for anemia in SCD.
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Dolor Agudo , Anemia de Células Falciformes , Anemia de Células Falciformes/complicaciones , Anemia de Células Falciformes/terapia , Viscosidad Sanguínea , Eritrocitos/metabolismo , HumanosRESUMEN
Mitapivat, a pyruvate kinase activator, shows great potential as a sickle cell disease (SCD)-modifying therapy. The safety and efficacy of mitapivat as a long-term maintenance therapy are currently being evaluated in two open-label studies. Here we applied a comprehensive multi-omics approach to investigate the impact of activating pyruvate kinase on red blood cells (RBC) from 15 SCD patients. HbSS patients were enrolled in one of the open-label, extended studies (NCT04610866). Leukodepleted RBC obtained from fresh whole blood at baseline, prior to drug initiation, and at longitudinal timepoints over the course of the study were processed for multi-omics through a stepwise extraction of metabolites, lipids and proteins. Mitapivat therapy had significant effects on the metabolome, lipidome and proteome of SCD RBC. Mitapivat decreased 2,3-diphosphoglycerate levels, increased adenosine triphosphate levels, and improved hematologic and sickling parameters in patients with SCD. Agreement between omics measurements and clinical measurements confirmed the specificity of mitapivat on targeting late glycolysis, with glycolytic metabolites ranking as the top correlates to parameters of hemoglobin S oxygen affinity (p50) and sickling kinetics (t50) during treatment. Mitapivat markedly reduced levels of proteins of mitochondrial origin within 2 weeks of initiation of treatment, with minimal changes in reticulocyte counts. In the first 6 months of treatment there were also transient elevations of lysophosphatidylcholines and oxylipins with depletion of free fatty acids, suggestive of an effect on membrane lipid remodeling. Multi-omics analysis of RBC identified benefits for glycolysis, as well as activation of the Lands cycle.
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Anemia de Células Falciformes , Eritrocitos , Piruvato Quinasa , Humanos , Anemia de Células Falciformes/tratamiento farmacológico , Anemia de Células Falciformes/sangre , Eritrocitos/metabolismo , Piruvato Quinasa/metabolismo , Masculino , Femenino , Adulto , Metaboloma , Metabolómica/métodos , Proteoma , Proteómica/métodos , Adolescente , Adulto Joven , Activación Enzimática , Glucólisis/efectos de los fármacos , Activadores de Enzimas/uso terapéutico , Activadores de Enzimas/farmacología , Resultado del Tratamiento , MultiómicaRESUMEN
Burkitt lymphoma (BL) is an aggressive B-cell lymphoma that significantly contributes to childhood cancer burden in sub-Saharan Africa. Plasmodium falciparum, which causes malaria, is geographically associated with BL, but the evidence remains insufficient for causal inference. Inference could be strengthened by demonstrating that mendelian genes known to protect against malaria-such as the sickle cell trait variant, HBB-rs334(T)-also protect against BL. We investigated this hypothesis among 800 BL cases and 3845 controls in four East African countries using genome-scan data to detect polymorphisms in 22 genes known to affect malaria risk. We fit generalized linear mixed models to estimate odds ratios (OR) and 95% confidence intervals (95% CI), controlling for age, sex, country, and ancestry. The ORs of the loci with BL and P. falciparum infection among controls were correlated (Spearman's ρ = 0.37, p = .039). HBB-rs334(T) was associated with lower P. falciparum infection risk among controls (OR = 0.752, 95% CI 0.628-0.9; p = .00189) and BL risk (OR = 0.687, 95% CI 0.533-0.885; p = .0037). ABO-rs8176703(T) was associated with decreased risk of BL (OR = 0.591, 95% CI 0.379-0.992; p = .00271), but not of P. falciparum infection. Our results increase support for the etiological correlation between P. falciparum and BL risk.
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Linfoma de Burkitt , Malaria Falciparum , Malaria , Rasgo Drepanocítico , Humanos , África Oriental , Alelos , Linfoma de Burkitt/epidemiología , Linfoma de Burkitt/genética , Malaria Falciparum/epidemiología , Malaria Falciparum/genética , Malaria Falciparum/complicaciones , Rasgo Drepanocítico/epidemiología , Rasgo Drepanocítico/genética , Rasgo Drepanocítico/complicaciones , Nectinas/metabolismoRESUMEN
The issue of treating sickle cell disease with drugs that increase hemoglobin oxygen affinity has come to the fore with the US Food and Drug Administration approval in 2019 of voxelotor, the only antisickling drug approved since hydroxyurea in 1998. Voxelotor reduces sickling by increasing the concentration of the nonpolymerizing, high oxygen affinity R (oxy) conformation of hemoglobin S (HbS). Treatment of sickle cell patients with voxelotor increases Hb levels and decreases indicators of hemolysis, but with no indication as yet that it reduces the frequency of pain episodes. In this study, we used the allosteric model of Monod, Wyman, and Changeux to simulate whole-blood oxygen dissociation curves and red cell sickling in the absence and presence of voxelotor under the in vivo conditions of rapid oxygen pressure decreases. Our modeling agrees with results of experiments using a new robust assay, which shows the large, expected decrease in sickling from the drug. The modeling indicates, however, that the increase in oxygen delivery from reduced sickling is largely offset by the increase in oxygen affinity. The net result is that the drug increases overall oxygen delivery only at the very lowest oxygen pressures. However, reduction of sickling mitigates red cell damage and explains the observed decrease in hemolysis. More importantly, our modeling of in vivo oxygen dissociation, sickling, and oxygen delivery suggests that drugs that increase fetal Hb or decrease mean corpuscular hemoglobin concentration (MCHC) should be more therapeutically effective than drugs that increase oxygen affinity.
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Anemia de Células Falciformes/tratamiento farmacológico , Antidrepanocíticos/uso terapéutico , Benzaldehídos/uso terapéutico , Hemoglobina Falciforme/metabolismo , Oxígeno/metabolismo , Pirazinas/uso terapéutico , Pirazoles/uso terapéutico , Anemia de Células Falciformes/sangre , Anemia de Células Falciformes/metabolismo , Antidrepanocíticos/farmacología , Benzaldehídos/farmacología , Eritrocitos/efectos de los fármacos , Eritrocitos/metabolismo , Hemoglobina Falciforme/química , Humanos , Modelos Moleculares , Oxígeno/sangre , Pirazinas/farmacología , Pirazoles/farmacologíaRESUMEN
The pathophysiology of sickle cell disease (SCD) is driven by chronic inflammation fueled by damage associated molecular patterns (DAMPs). We show that elevated cell-free DNA (cfDNA) in patients with SCD is not just a prognostic biomarker, it also contributes to the pathological inflammation. Within the elevated cfDNA, patients with SCD had a significantly higher ratio of cell-free mitochondrial DNA (cf-mtDNA)/cell-free nuclear DNA compared with healthy controls. Additionally, mitochondrial DNA in patient samples showed significantly disproportionately increased hypomethylation compared with healthy controls, and it was increased further in crises compared with steady-state. Using flow cytometry, structured illumination microscopy, and electron microscopy, we showed that circulating SCD red blood cells abnormally retained their mitochondria and, thus, are likely to be the source of the elevated cf-mtDNA in patients with SCD. Patient plasma containing high levels of cf-mtDNA triggered the formation of neutrophil extracellular traps (NETs) that was substantially reduced by inhibition of TANK-binding kinase 1, implicating activation of the cGAS-STING pathway. cf-mtDNA is an erythrocytic DAMP, highlighting an underappreciated role for mitochondria in sickle pathology. These trials were registered at www.clinicaltrials.gov as #NCT00081523, #NCT03049475, and #NCT00047996.
Asunto(s)
Anemia de Células Falciformes/sangre , Ácidos Nucleicos Libres de Células/sangre , Metilación de ADN , ADN Mitocondrial/sangre , Adulto , Anciano , Biomarcadores/sangre , Trampas Extracelulares/metabolismo , Femenino , Humanos , Inflamación/sangre , Masculino , Proteínas de la Membrana/metabolismo , Persona de Mediana Edad , Nucleotidiltransferasas/metabolismo , Transducción de SeñalRESUMEN
The pathology of sickle cell disease is caused by polymerization of the abnormal hemoglobin S upon deoxygenation in the tissues to form fibers in red cells, causing them to deform and occlude the circulation. Drugs that allosterically shift the quaternary equilibrium from the polymerizing T quaternary structure to the nonpolymerizing R quaternary structure are now being developed. Here we update our understanding on the allosteric control of fiber formation at equilibrium by showing how the simplest extension of the classic quaternary two-state allosteric model of Monod, Wyman, and Changeux to include tertiary conformational changes provides a better quantitative description. We also show that if fiber formation is at equilibrium in vivo, the vast majority of cells in most tissues would contain fibers, indicating that it is unlikely that the disease would be survivable once the nonpolymerizing fetal hemoglobin has been replaced by adult hemoglobin S at about 1 y after birth. Calculations of sickling times, based on a recently discovered universal relation between the delay time prior to fiber formation and supersaturation, show that in vivo fiber formation is very far from equilibrium. Our analysis indicates that patients survive because the delay period allows the majority of cells to escape the small vessels of the tissues before fibers form. The enormous sensitivity of the duration of the delay period to intracellular hemoglobin composition also explains why sickle trait, the heterozygous condition, and the compound heterozygous condition of hemoglobin S with pancellular hereditary persistence of fetal hemoglobin are both relatively benign conditions.
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Anemia de Células Falciformes/metabolismo , Hemoglobina Falciforme/química , Oxígeno/metabolismo , Regulación Alostérica , Eritrocitos/química , Eritrocitos/metabolismo , Hemoglobina Fetal/química , Hemoglobina Fetal/metabolismo , Hemoglobina Falciforme/metabolismo , Humanos , Cinética , Oxígeno/químicaRESUMEN
Polymerization of deoxygenated sickle hemoglobin (HbS) leads to erythrocyte sickling. Enhancing activity of the erythrocyte glycolytic pathway has anti-sickling potential as this reduces 2,3-diphosphoglycerate (2,3-DPG) and increases ATP, factors that decrease HbS polymerization and improve erythrocyte membrane integrity. These factors can be modulated by mitapivat, which activates erythrocyte pyruvate kinase (PKR) and improves sickling kinetics in SCD patients. We investigated mechanisms by which mitapivat may impact SCD by examining its effects in the Townes SCD mouse model. Control (HbAA) and sickle (HbSS) mice were treated with mitapivat or vehicle. Surprisingly, HbSS had higher PKR protein, higher ATP, and lower 2,3-DPG levels, compared to HbAA mice, in contrast with humans with SCD, in whom 2,3-DPG is elevated compared to healthy subjects. Despite our inability to investigate 2,3-DPG-mediated sickling and hemoglobin effects, mitapivat yielded potential benefits in HbSS mice. Mitapivat further increased ATP without significantly changing 2,3-DPG or hemoglobin levels, and decreased levels of leukocytosis, erythrocyte oxidative stress, and the percentage of erythrocytes that retained mitochondria in HbSS mice. These data suggest that, even though Townes HbSS mice have increased PKR activity, further activation of PKR with mitapivat yields potentially beneficial effects that are independent of changes in sickling or hemoglobin levels.
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Anemia de Células Falciformes , 2,3-Difosfoglicerato/metabolismo , Adenosina Trifosfato/metabolismo , Animales , Modelos Animales de Enfermedad , Eritrocitos/metabolismo , Hemoglobina Falciforme/metabolismo , Hemoglobinas/análisis , Humanos , Ratones , Mitocondrias/metabolismo , Estrés Oxidativo , Piperazinas , QuinolinasRESUMEN
BACKGROUND: MRI T2* and R2* mapping have gained clinical acceptance for noninvasive assessment of iron overload. Lower field MRI may offer increased measurement dynamic range in patients with high iron concentration and may potentially increase MRI accessibility, but it is compromised by lower signal-to-noise ratio that reduces measurement precision. PURPOSE: To characterize a high-performance 0.55 T MRI system for evaluating patients with liver iron overload. STUDY TYPE: Prospective. POPULATION: Forty patients with known or suspected iron overload (sickle cell anemia [n = 5], ß-thalassemia [n = 3], and hereditary spherocytosis [n = 2]) and a liver iron phantom. FIELD STRENGTH/SEQUENCE: A breath-held multiecho gradient echo sequence at 0.55 T and 1.5 T. ASSESSMENT: Patients were imaged with T2*/R2* mapping 0.55 T and 1.5 T within 24 hours, and 16 patients returned for follow-up exams within 6-16 months, resulting in 56 paired studies. Liver T2* and R2* measurements and standard deviations were compared between 0.55 T and 1.5 T and used to validate a predictive model between field strengths. The model was then used to classify iron overload at 0.55 T. STATISTICAL TESTS: Linear regression and Bland-Altman analysis were used for comparisons, and measurement precision was assessed using the coefficient of variation. A P-value < 0.05 was considered statistically significant. RESULTS: R2* was significantly lower at 0.55 T in our cohort (488 ± 449 s-1 at 1.5 T vs. 178 ± 155 s-1 at 0.55 T, n = 56 studies) and in the patients with severe iron overload (937 ± 369 s-1 at 1.5 T vs. 339 ± 127 s-1 at 0.55 T, n = 23 studies). The coefficient of variation indicated reduced precision at 0.55 T (3.5 ± 2.2% at 1.5 T vs 6.9 ± 3.9% at 0.55 T). The predictive model accurately predicted 1.5 T R2* from 0.55 T R2* (Bland Altman bias = -6.6 ± 20.5%). Using this model, iron overload at 0.55 T was classified as: severe R2* > 185 s-1 , moderate 81 s-1 < R2* < 185 s-1 , and mild 45 s-1 < R2* < 91 s-1 . DATA CONCLUSION: We demonstrated that 0.55 T provides T2* and R2* maps that can be used for the assessment of liver iron overload in patients. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 2.
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Sobrecarga de Hierro , Humanos , Hierro/análisis , Sobrecarga de Hierro/diagnóstico por imagen , Hígado/diagnóstico por imagen , Imagen por Resonancia Magnética/métodos , Estudios ProspectivosRESUMEN
In the 100 years since sickle cell anemia (SCA) was first described in the medical literature, studies of its molecular and pathophysiological basis have been at the vanguard of scientific discovery. By contrast, the translation of such knowledge into treatments that improve the lives of those affected has been much too slow. Recent years, however, have seen major advances on several fronts. A more detailed understanding of the switch from fetal to adult hemoglobin and the identification of regulators such as BCL11A provide hope that these findings will be translated into genomic-based approaches to the therapeutic reactivation of hemoglobin F production in patients with SCA. Meanwhile, an unprecedented number of new drugs aimed at both the treatment and prevention of end-organ damage are now in the pipeline, outcomes from potentially curative treatments such as allogeneic hematopoietic stem cell transplantation are improving, and great strides are being made in gene therapy, where methods employing both antisickling ß-globin lentiviral vectors and gene editing are now entering clinical trials. Encouragingly, after a century of neglect, the profile of the vast majority of those with SCA in Africa and India is also finally improving.
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Anemia de Células Falciformes/genética , Anemia de Células Falciformes/fisiopatología , Fenotipo , Anemia de Células Falciformes/diagnóstico , Anemia de Células Falciformes/terapia , Proteínas Portadoras/genética , Terapia Genética , Hemoglobinas/metabolismo , Humanos , Proteínas Nucleares/genética , Proteínas Represoras , Resultado del TratamientoRESUMEN
Risk assessment for patients with sickle cell disease (SCD) remains challenging as it depends on an individual physician's experience and ability to integrate a variety of test results. We aimed to provide a new risk score that combines clinical, laboratory, and imaging data. In a prospective cohort of 600 adult patients with SCD, we assessed the relationship of 70 baseline covariates to all-cause mortality. Random survival forest and regularised Cox regression machine learning (ML) methods were used to select top predictors. Multivariable models and a risk score were developed and internally validated. Over a median follow-up of 4·3 years, 131 deaths were recorded. Multivariable models were developed using nine independent predictors of mortality: tricuspid regurgitant velocity, estimated right atrial pressure, mitral E velocity, left ventricular septal thickness, body mass index, blood urea nitrogen, alkaline phosphatase, heart rate and age. Our prognostic risk score had superior performance with a bias-corrected C-statistic of 0·763. Our model stratified patients into four groups with significantly different 4-year mortality rates (3%, 11%, 35% and 75% respectively). Using readily available variables from patients with SCD, we applied ML techniques to develop and validate a mortality risk scoring method that reflects the summation of cardiopulmonary, renal and liver end-organ damage. Trial Registration: ClinicalTrials.gov Identifier: NCT#00011648.
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Anemia de Células Falciformes/mortalidad , Fenotipo , Medición de Riesgo , Adolescente , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Fosfatasa Alcalina/sangre , Anemia de Células Falciformes/sangre , Nitrógeno de la Urea Sanguínea , Índice de Masa Corporal , Estudios de Casos y Controles , Análisis por Conglomerados , Femenino , Estudios de Seguimiento , Frecuencia Cardíaca , Válvulas Cardíacas/fisiopatología , Humanos , Aprendizaje Automático , Masculino , Persona de Mediana Edad , Modelos Biológicos , Pronóstico , Modelos de Riesgos Proporcionales , Estudios Prospectivos , Adulto JovenRESUMEN
The nucleotide-binding domain leucine-rich repeat containing protein 3 (NLRP3) inflammasome is a critical inflammatory mechanism identified in platelets, which controls platelet activation and aggregation. We have recently shown that the platelet NLRP3 inflammasome is upregulated in sickle cell disease (SCD), which is mediated by Bruton tyrosine kinase (BTK). Here, we investigated the effect of pharmacological inhibition of NLRP3 and BTK on platelet aggregation and the formation of in vitro thrombi in Townes SCD mice. Mice were injected for 4 weeks with the NLRP3 inhibitor MCC950, the BTK inhibitor ibrutinib or vehicle control. NLRP3 activity, as monitored by caspase-1 activation, was upregulated in platelets from SCD mice, which was dependent on BTK. Large areas of platelet aggregates detected in the liver of SCD mice were decreased when mice were treated with MCC950 or ibrutinib. Moreover, platelet aggregation and in vitro thrombus formation were upregulated in SCD mice and were inhibited when mice were subjected to pharmacological inhibition of NLRP3 and BTK. Targeting the NLRP3 inflammasome might be a novel approach for antiplatelet therapy in SCD.
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Agammaglobulinemia Tirosina Quinasa/antagonistas & inhibidores , Anemia de Células Falciformes/fisiopatología , Proteína con Dominio Pirina 3 de la Familia NLR/antagonistas & inhibidores , Agregación Plaquetaria/efectos de los fármacos , Inhibidores de Proteínas Quinasas/farmacología , Adenina/análogos & derivados , Adenina/farmacología , Agammaglobulinemia Tirosina Quinasa/metabolismo , Animales , Plaquetas/efectos de los fármacos , Plaquetas/patología , Modelos Animales de Enfermedad , Femenino , Furanos , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Indenos , Inflamasomas , Hígado/efectos de los fármacos , Hígado/patología , Masculino , Ratones Transgénicos , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Piperidinas/farmacología , Agregación Plaquetaria/fisiología , Sulfonamidas , Sulfonas/farmacología , Trombosis/tratamiento farmacológico , Trombosis/etiologíaRESUMEN
Not available.
Asunto(s)
Anemia de Células Falciformes , Enfermedad de la Hemoglobina SC , Anemia de Células Falciformes/complicaciones , Anemia de Células Falciformes/genética , Infarto Cerebral/genética , Estudio de Asociación del Genoma Completo , Hemoglobina Falciforme/genética , HumanosRESUMEN
OBJECTIVES: Sickle cell disease-related pulmonary hypertension (SCD-PH) is a complex disorder with multifactorial contributory mechanisms. Previous trials have evaluated the efficacy of pulmonary arterial hypertension (PAH) therapies in SCD-PH with mixed results. We hypothesized that a subset of patients with right heart catheterization (RHC) confirmed disease may benefit from PAH therapy. METHODS: We performed a retrospective chart review of patients with SCD-PH diagnosed by RHC who were treated with phosphodiesterase 5 inhibitor (PDE5-I) therapy for ≥4 months between 2008 and 2019 at two institutions. RESULTS: Thirty-six patients were included in the analysis. The median age (IQR) upon PDE5-I initiation was 47.5 years (35-51.5 years); 58% were female and twenty-nine (81%) had HbSS disease. Of these, 53% of patients had a history of acute chest syndrome, 42% had a history of venous thromboembolism, and 38% had imaging consistent with chronic thromboembolic PH. Patients were treated for a median duration of 25 months (IQR 13-60 months). Use of PDE5-I was associated with a significant improvement in symptoms as assessed by NYHA Class (P = .002). CONCLUSIONS: In SCD patients with PH defined by RHC, PDE5-I therapy was tolerated long-term and may improve physical activity.
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Anemia de Células Falciformes/tratamiento farmacológico , Hipertensión Pulmonar/tratamiento farmacológico , Inhibidores de Fosfodiesterasa 5/farmacología , Adulto , Femenino , Hemodinámica , Hemoglobinas/análisis , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Resultado del Tratamiento , Tromboembolia VenosaRESUMEN
BACKGROUND: Mutations of HBB give rise to two prevalent haemoglobin disorders-sickle cell disease (SCD) and ß-thalassaemia. While SCD is caused by a single base substitution, nearly 300 mutations that downregulate expression of HBB have been described. The vast majority of ß-thalassaemia alleles are point mutations or small insertion/deletions within the HBB gene; deletions causing ß-thalassaemia are very rare. We have identified three individuals with haemoglobin Sß0-thalassaemia in which the ß0-thalassaemia mutation is caused by a large deletion. OBJECTIVE: To use whole genome sequence data to determine whether these deletions arose from a single origin. METHODS: We used two approaches to confirm unrelatedness: pairwise comparison of SNPs and identity by descent analysis. Eagle, V.2.4, was used to generate phased haplotypes for the 683 individuals. The Neighbor-Net method implemented in SplitsTree V.4.13.1 was used to construct the network of haplotypes. RESULTS: All three deletions involved 1393 bp, encompassing the ß-promoter, exons 1 and 2, and part of intron 2, with identical breakpoints. The cases were confirmed to be unrelated. Haplotypes based on 29 SNPs in the HBB cluster showed that the three individuals harboured different ßS haplotypes. In contrast, the haplotype harbouring the 1393 bp deletion was the same in all three individuals. CONCLUSION: We suggest that all the reported cases of the 1393 bp HBB deletion, including the three cases here, are likely to be of the same ancestral origin.
Asunto(s)
Anemia de Células Falciformes/genética , Eliminación de Gen , Hemoglobina Falciforme/genética , Hemoglobinas/genética , Talasemia beta/genética , Adulto , Alelos , Anemia de Células Falciformes/epidemiología , Anemia de Células Falciformes/patología , Haplotipos , Hemoglobinas Anormales/genética , Humanos , Intrones , Masculino , Mutación Puntual/genética , Polimorfismo de Nucleótido Simple/genética , Adulto Joven , Talasemia beta/epidemiología , Talasemia beta/patologíaRESUMEN
With increasing survival, cumulative complications of sickle cell disease (SCD), which develop insidiously over time, are becoming more apparent and common in older patients, particularly those in their fifth decade and beyond. The older patient is also more likely to develop other age-related nonsickle conditions that interact and add to the disease morbidity. A common misconception is that any symptom in a SCD patient is attributable to their SCD and this may lead to delays in diagnosis and appropriate intervention. We recommend regular comprehensive reviews and monitoring for early signs of organ damage and a low threshold for the use of hydroxyurea and blood transfusions as preventative measures for end-organ disease. Treatable comorbidities and acute deterioration should be managed aggressively. Although the primary goal in management of the older adult with SCD is improving anemia and minimizing organ damage, the time has come for us to be more proactive in considering curative therapies previously offered to the younger patient. Curative or experimental interventions should be discussed early, before complications render the patients ineligible for these treatments.
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Anemia de Células Falciformes/complicaciones , Anemia de Células Falciformes/terapia , Adulto , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Recurring episodes of acute pain, also referred to as vaso-occlusive crises (VOC), are characteristic of sickle cell disease (SCD), during which pro-inflammatory cytokines, chemokines, adhesion markers and white cell count, some already elevated at steady state, increase further. Hydroxyurea (HU) is licensed by the FDA for reducing frequency of VOCs in SCD; increased fetal hemoglobin (HbF) together with reduction of the neutrophil count and circulating inflammatory markers, contribute to its clinical efficacy. Here, using paired plasma samples from HbSS patients (in steady-state and VOC) we determined that despite HU treatment, the SCD environment remained highly inflammatory and particularly at VOC, triggered neutrophil activity. While neutrophil extracellular traps (NETs) induction by the steady state plasmas were comparable to that of plasma from healthy donors, the NETs response triggered by crisis plasmas was significantly increased over that of the steady state (P = 0.0124*). Levels of IL-6 and IL-1α, IL-1ra/IL1F3 and adhesion molecule P-selectin were significantly increased in the VOC plasma when compared with steady state plasma. Higher levels of IL-6 and IL-1ra were also found in the crises samples that yielded an increased NETs response suggesting that increased NETs production associated with increased levels of the inflammatory products of the IL-6 family and regulators of IL-1 family of cytokines during sickle VOCs.
Asunto(s)
Anemia de Células Falciformes/sangre , Citocinas/sangre , Mediadores de Inflamación/sangre , Neutrófilos/metabolismo , Enfermedades Vasculares/sangre , Adulto , Anemia de Células Falciformes/complicaciones , Anemia de Células Falciformes/tratamiento farmacológico , Estudios de Cohortes , Trampas Extracelulares/metabolismo , Femenino , Humanos , Hidroxiurea/uso terapéutico , Masculino , Microscopía Fluorescente , Persona de Mediana Edad , Adulto JovenRESUMEN
BACKGROUND: There is a renewed interest in lower field magnetic resonance imaging (MRI) systems for cardiovascular magnetic resonance (CMR), due to their favorable physical properties, reduced costs, and increased accessibility to patients with implants. We sought to assess the diagnostic capabilities of high-performance low-field (0.55 T) CMR imaging for quantification of right and left ventricular volumes and systolic function in both healthy subjects and patients referred for clinical CMR. METHODS: Sixty-five subjects underwent paired exams at 1.5 T using a clinical CMR scanner and using an identical CMR system modified to operate at 0.55 T. Volumetric coverage of the right ventricle (RV) and left ventricles (LV) was obtained using either a breath-held cine balanced steady-state free-precession acquisition or a motion-corrected free-breathing re-binned cine acquisition. Bland-Altman analysis was used to compare LV and RV end-systolic volume (ESV), end-diastolic volume (EDV), ejection fraction (EF), and LV mass. Diagnostic confidence was scored on a Likert-type ordinal scale by blinded readers. RESULTS: There were no significant differences in LV and RV EDV between the two scanners (e.g., LVEDV: p = 0.77, bias = 0.40 mL, correlation coefficient = 0.99; RVEDV: p = 0.17, bias = - 1.6 mL, correlation coefficient = 0.98), and regional wall motion abnormality scoring was similar (kappa 0.99). Blood-myocardium contrast-to-noise ratio (CNR) at 0.55 T was 48 ± 7% of the 1.5 T CNR, and contrast was sufficient for endocardial segmentation in all cases. Diagnostic confidence of images was scored as "good" to "excellent" for the two field strengths in the majority of studies. CONCLUSION: A high-performance 0.55 T system offers good bSSFP CMR image quality, and quantification of biventricular volumes and systolic function that is comparable to 1.5 T in patients. TRIAL REGISTRATION: Clinicaltrials.gov NCT03331380, NCT03581318.