Pathophisiology of Sickle Cell Disease and New Drugs for the Treatment

A homozygous mutation in the gene for β globin, a subunit of adult hemoglobin A (HbA), is the proximate cause of sickle cell disease (SCD). Sickle hemoglobin (HbS) shows peculiar biochemical properties, which lead to polymerizing when deoxygenated. HbS polymerization is associated with a reduction in cell ion and water content (cell dehydration), increased red cell density which further accelerate HbS polymerization. Dense, dehydrated erythrocytes are likely to undergo instant polymerization in conditions of mild hypoxia due to their high HbS concentration, and HbS polymers may be formed under normal oxygen pressure. Pathophysiological studies have shown that the dense, dehydrated red cells may play a central role in acute and chronic clinical manifestations of sickle cell disease, in which intravascular sickling in capillaries and small vessels leads to vaso-occlusion and impaired blood flow in a variety of organs and tissue. The persistent membrane damage associated with HbS polymerization also favors the generation of distorted rigid cells and further contributes to vaso-occlusive crisis (VOCs) and cell destruction in the peripheral circulation. These damaged, dense sickle red cells also show a loss of phospholipid asymmetry with externalization of phosphatidylserine (PS), which is believed to play a significant role in promoting macrophage recognition with removal of erythrocytes (erythrophagocytosis). Vaso-occlusive events in the microcirculation result from a complex scenario involving the interactions between different cell types, including dense, dehydrated sickle cells, reticulocytes, abnormally activated endothelial cells, leukocytes, platelets and plasma factors such as cytokine and oxidized pro-inflammatory lipids. Hydroxycarbamide (hydroxyurea) is currently the only drug approved for chronic administration in adult patients with sickle cell disease to prevent acute painful crises and reduce the incidence of transfusion and acute chest crises. Here, we will focus on consolidated and experimental therapeutic strategies for the treatment of sickle cell disease, including: agents which reduce or prevent sickle cell dehydrationagents which reduce sickle cell-endothelial adhesive eventsnitric oxide (NO) or NO-related compoundsanti-oxidant agent

Adaptabilidade, estabilidade e efeito de variáveis meteorológicas sobre a qualidade tecnológica de cultivares de trigo no estado do Paraná

Wheat (Triticum aestivum L.) growing has great importance in the agricultural system of the southern region of Brazil, and is responsible for about 95% of the country’s wheat yield. Climatic variability is very expressive in the southern states. Wheat cultivars therefore respond differently in the various environments where they are grown, and this is often the cause of decreased production and productivity, affecting the technological quality of wheat during the period when the crop remains in the field. Consequently, for a wheat cultivar to be successful it must be stable, provide high productivity, and have superior quality, since technological aptitude represents an opportunity for added market value, especially in face of the international market and the industrial sector. Based on that, this study aimed to investigate, by means of a literature review, which preharvest factors affect the technological quality of wheat; compare different adaptability and stability methods (both parametric and non-parametric) in the selection of cultivars more stable and responsive to environmental conditions; and determine the influence of weather variables on wheat technological quality. It was concluded that genetic, weather, and management factors are crucial in obtaining the desired quality. In this respect, the selection of an adequate cultivar, knowledge about the climatic limitations of the wheat-growing region and soil fertility, and accomplishing the management practices recommended by research can substantially contribute toward obtaining the physical, chemical, and biological characteristics that lend quality to flour and flour-based products. In addition, the Lin and Binns (1988) and Eberhart and Russel (1966) methods were more informative in the identification of more productive, adapted and stable wheat cultivars, as compared to the ecovalence and Cruz et al. (1989) methods. As to the influence of weather variables on wheat technological quality, it was observed that precipitation, maximum temperature, minimum temperature, and solar radiation provided increases and, in some cases, limited the technological quality expression of wheat cultivars evaluated in the State of Paraná. The estimates of associations between technological quality parameters and weather variables were different among the localities evaluated, both in the meaning and the magnitude of the association. It is thus concluded that by adequately choosing a cultivar (adapted, stable, and with the desired genetic potential for quality), performing essential management practices (soil fertility, crop rotation, and control of weeds, pests, and diseases), and knowing the periods when weather conditions are more detrimental in the various cultivation localities, both the technological quality and the productivity of wheat can be maximized in the State of Paraná.O cultivo de trigo (Triticum aestivum L.) tem grande importância no sistema agrícola da região sul, sendo responsável por cerca de 95% da produção de trigo no Brasil. Nesses estados, a variabilidade climática é muito expressiva, fazendo com que os cultivares respondam de maneira diferenciada nos diversos ambientes de cultivo, ocasionando muitas vezes diminuição da produção, produtividade e afetando a qualidade tecnológica de trigo, durante a permanência da cultura na lavoura. Logo para que um cultivar tenha sucesso este deve apresentar estabilidade e elevada produtividade além de qualidade superior, uma vez que a aptidão tecnológica representa uma oportunidade de agregar valor de mercado ao trigo, principalmente em face do mercado internacional e do setor industrial. Baseado nisso, este trabalho teve por objetivos investigar, através de revisão de literatura, quais fatores pré-colheita afetam a qualidade tecnológica do trigo; comparar diferentes métodos (paramétricos e não paramétricos) de adaptabilidade e estabilidade, na seleção de cultivares mais estáveis e responsivos às condições de ambiente e; verificar a influência de variáveis metereológicas sobre a qualidade tecnológica. Conclui-se que os fatores genéticos, meteorológicos e de manejo são determinantes para a obtenção da qualidade desejada. Neste sentido, a adequada escolha do cultivar, o conhecimento das limitações climáticas da região de cultivo e da fertilidade do solo e a execução dos tratos culturais recomendados pela pesquisa, podem contribuir substancialmente para a obtenção das características físicas, químicas e biológicas que conferem qualidade à farinha de trigo e aos produtos que dela derivam. Também, foi possível observar que os métodos de Lin e Binns (1988) e de Eberhart e Russel (1966) foram mais informativos na identificação de cultivares de trigo mais produtivos, adaptados e estáveis, quando comparados aos métodos de ecovalência e de Cruz et al. (1989). Com relação à influência das variáveis meteorológicas sobre a qualidade tecnológica do trigo, observou-se que a precipitação pluvial, a temperatura máxima, a temperatura mínima e a radiação solar promoveram acréscimos e, também, em alguns casos, limitaram a expressão da qualidade tecnológica dos cultivares de trigo avaliados no estado do Paraná. As estimativas de associação entre os parâmetros de qualidade tecnológica e variáveis meteorológicas foram diferentes entre os locais avaliados, tanto no sentido, quanto na magnitude da associação. Desta forma, conclui-se que, através da escolha adequada do cultivar (adaptado, estável e com o potencial genético de qualidade desejado), da execução das práticas de manejo essenciais (fertilidade do solo, rotação de culturas e controle de plantas daninhas, pragas e doenças) e do conhecimento dos períodos em que as condições meteorológicas são mais prejudiciais, nos diferentes locais de cultivo, é possível maximizar tanto a qualidade tecnológica, quanto a produtividade, do trigo no estado do Paraná

Andreev reflection in Si-engineered Al/InGaAs hybrid junctions

Andreev-reflection dominated transport is demonstrated in Al/n-In0.38Ga0.62As superconductor-semiconductor junctions grown by molecular beam epitaxy on GaAs(001). High junction transparency was achieved in low-doped devices by exploiting Si interface bilayers to suppress the native Schottky barrier. It is argued that this technique is ideally suited for the fabrication of ballistic transport hybrid microstructures.Comment: 9 REVTEX pages + 3 postscript figures, to be published in APL 73, (28dec98

Emerging drugs in randomized controlled trials for sickle cell disease: are we on the brink of a new era in research and treatment?

ABSTRACT Introduction: Sickle cell disease (SCD) is caused by a mutation in the HBB gene which is key for making a component of hemoglobin. The mutation leads to the formation of an abnormal hemoglobin molecule called sickle hemoglobin (HbS). SCD is a chronic, complex disease with a multiplicity of pathophysiological targets; it has high morbidity and mortality. Hydroxyurea has for many years been the only approved drug for SCD; hence, the development of new therapeutics is critical. Areas covered: This article offers an overview of the key studies of new therapeutic options for SCD. We searched the PubMed database and Cochrane Database of Systemic Reviews for agents in early phase clinic trials and preclinical development. Expert opinion: Although knowledge of SCD has progressed, patient survival and quality of life must be improved. Phase II and phase III clinical trials investigating pathophysiology-based novel agents show promising results in the clinical management of SCD acute events. The design of longterm clinical studies is necessary to fully understand the clinical impact of these new therapeutics on the natural history of the disease. Furthermore, the building of global collaborations will enhance the clinical management of SCD and the design of primary outcomes of future clinical trials

The psychophysical impact that COVID-19 has on children must not be underestimated

Italy has been one of the European countries that has been most affected by the COVID\u201019 pandemic. By 16 April 2020, 159,107 Italian residents had tested positive for COVID\u201019 and these included 1,123 children, up to nine years of age (0.7%) and 1,804 adolescents, aged between 10 and 19 years old (1.1%) (1). These data were in line with the case studies reported for the Chinese population, where the respective percentage (proportion) was 0.9% and 1.2% respectively (2). A five\u2010year\u2010old Italian child, who had been affected by many previous and unspecified pathologies, died after testing positive for COVID\u201019 infection (1). The lower vulnerability of the paediatric population to COVID\u201019 seems eviden

Pharmacological Induction of Fetal Hemoglobin in β-Thalassemia and Sickle Cell Disease: An Updated Perspective

A significant amount of attention has recently been devoted to the mechanisms involved in hemoglobin (Hb) switching, as it has previously been established that the induction of fetal hemoglobin (HbF) production in significant amounts can reduce the severity of the clinical course in diseases such as beta-thalassemia and sickle cell disease (SCD). While the induction of HbF using lentiviral and genome-editing strategies has been made possible, they present limitations. Meanwhile, progress in the use of pharmacologic agents for HbF induction and the identification of novel HbF-inducing strategies has been made possible as a result of a better understanding of gamma-globin regulation. In this review, we will provide an update on all current pharmacological inducer agents of HbF in beta-thalassemia and SCD in addition to the ongoing research into other novel, and potentially therapeutic, HbF-inducing agents

Magnesium for treating sickle cell disease

Sickle cell disease is an autosomal recessive inherited haemoglobinopathy which causes painful vaso-occlusive crises due to sickle red blood cell dehydration. Vaso-occlusive crises are common painful events responsible for a variety of clinical complications; overall mortality is increased and life expectancy decreased compared to the general population. Experimental studies suggest that intravenous magnesium has proven to be well-tolerated in individuals hospitalised for the immediate relief of acute (sudden onset) painful crisis and has the potential to decrease the length of hospital stay. Some in vitro studies and open studies of long-term oral magnesium showed promising effect on pain relief but failed to show its efficacy. The studies show that oral magnesium therapy may prevent sickle red blood cell dehydration and prevent recurrent painful episodes. There is a need to access evidence for the impact of oral and intravenous magnesium effect on frequency of pain, length of hospital stay and quality of life

EHA Research Roadmap on Hemoglobinopathies and Thalassemia: An Update

The inherited disorders of hemoglobin, which include sickle cell disease and thalassemias, are the most common and widespread distributed monogenic disorders. Due to a selective advantage in malaria regions, these hemoglobin defects are particularly frequent in Africa, Asia, or in the Mediterranean areas, where malaria was endemic until the last century. In recent decades, the globalization of migration has contributed to generate multiethnic European societies. Due to migration from countries or regions with high hemoglobinopathy frequencies such as Africa, Middle East, or Asia, large numbers of patients with these disorders are living in almost every European country today. Furthermore, the numbers are increasing because of increasing refugee flows toward Europe. Additional requirements are the development of European recommendations and guidelines for diagnosis and effective therapeutic approaches. These, together with the advancement of clinical trials using new drugs and therapeutic procedures could ameliorate the quality of life of patients affectedwith these diseases and increase their life expectancy. Lastly, coordinated efforts should bemade todevelop diagnostic pathways for thalassemias and hemoglobinopathies, in order to plan interventions, including prenatal diagnosis and cure. For these reasons, the development of new tools to reliably diagnose anemias is urgently needed and fits well with the needs of personalized medicine. In the last 15 years, hematology research has made many big leaps forward. Our general aim will be to solve several hematologic problems using these new approaches. We expect that the development of such a diagnostic tool will improve timely diagnosis throughout Europe, especially in those countries where it is difficult to gain access to \u201cclassical\u201d diagnostic tests

Hemopexin Therapy Improves Cardiovascular Function by Preventing Heme-Induced Endothelial Toxicity in Mouse Models of Hemolytic Diseases

Background-Hemolytic diseases are characterized by enhanced intravascular hemolysis resulting in heme-catalyzed reactive oxygen species generation, which leads to endothelial dysfunction and oxidative damage. Hemopexin (Hx) is a plasma heme scavenger able to prevent endothelial damage and tissue congestion in a model of heme overload. Here, we tested whether Hx could be used as a therapeutic tool to counteract heme toxic effects on the cardiovascular system in hemolytic diseases. Methods and Results\u2014By using a model of heme overload in Hx-null mice, we demonstrated that heme excess in plasma, if not bound to Hx, promoted the production of reactive oxygen species and the induction of adhesion molecules and caused the reduction of nitric oxide availability. Then, we used \u3b2-thalassemia and sickle cell disease mice as models of hemolytic diseases to evaluate the efficacy of an Hx-based therapy in the treatment of vascular dysfunction related to heme overload. Our data demonstrated that Hx prevented heme-iron loading in the cardiovascular system, thus limiting the production of reactive oxygen species, the induction of adhesion molecules, and the oxidative inactivation of nitric oxide synthase/nitric oxide, and promoted heme recovery and detoxification by the liver mainly through the induction of heme oxygenase activity. Moreover, we showed that in sickle cell disease mice, endothelial activation and oxidation were associated with increased blood pressure and altered cardiac function, and the administration of exogenous Hx was found to almost completely normalize these parameters. Conclusions-Hemopexin treatment is a promising novel therapy to protect against heme-induced cardiovascular dysfunction in hemolytic disorders