Angiogenesis-Related Genes in Endothelial Progenitor Cells May Be Involved in Sickle Cell Stroke.

Background The clinical aspects of sickle cell anemia (SCA) are heterogeneous, and different patients may present significantly different clinical evolutions. Almost all organs can be affected, particularly the central nervous system. Transient ischemic events, infarcts, and cerebral hemorrhage can be observed and affect ≈25% of the patients with SCA. Differences in the expression of molecules produced by endothelial cells may be associated with the clinical heterogeneity of patients affected by vascular diseases. In this study, we investigated the differential expression of genes involved in endothelial cell biology in SCA patients with and without stroke. Methods and Results Endothelial progenitor cells from 4 SCA patients with stroke and 6 SCA patients without stroke were evaluated through the polymerase chain reaction array technique. The analysis of gene expression profiling identified 29 differentially expressed genes. Eleven of these genes were upregulated, and most were associated with angiogenesis (55%), inflammatory response (18%), and coagulation (18%) pathways. Downregulated expression was observed in 18 genes, with the majority associated with angiogenesis (28%), apoptosis (28%), and cell adhesion (22%) pathways. Remarkable overexpression of the MMP1 (matrix metalloproteinase 1) gene in the endothelial progenitor cells of all SCA patients with stroke (fold change: 204.64; P=0.0004) was observed. Conclusions Our results strongly suggest that angiogenesis is an important process in sickle cell stroke, and differences in the gene expression profile of endothelial cell biology, especially MMP1, may be related to stroke in SCA patients.

Predictors of early mortality after rabbit antithymocyte globulin as first-line treatment in severe aplastic anemia.

Despite being recommended as first-line immunosuppressive therapy in severe aplastic anemia (SAA), horse antithymocyte globulin (ATG) is still unavailable in many countries outside the USA. Rabbit ATG is more lymphocytoxic than horse ATG, and this might result in a higher incidence of severe infections and early mortality. This study was designed to identify the risk factors for early mortality and overall survival (OS) after rabbit ATG in patients with SAA. We retrospectively reviewed 185 patients with SAA who underwent rabbit ATG and cyclosporine. The incidence of death in 3 months following rabbit ATG therapy was 15.1% (28/185). Early mortality was mainly related to infectious complications, despite adequate antibiotic and/or antifungal treatment. Age > 35 years (odds ratio [OR] 5.06, P = 0.001) and baseline absolute neutrophil count (ANC) ≤ 0.1 × 109/L (OR 7.64, P < 0.001) were independent risk factors for early mortality after immunosuppressive therapy with this agent. Hematological response at 6 months was observed in only 29.7% of all patients. OS at 1 year after rabbit ATG was 75.3%; and age > 35 years (OR 1.88, P = 0.03), baseline ANC ≤ 0.1 × 109/L (OR 2.65, P < 0.001), and lack of response to rabbit ATG (OR 11.40, P < 0.001) were independently associated with mortality. Alternative strategies are needed for the treatment of SAA patients in countries were horse ATG is unavailable, particularly for those at high risk for early mortality after rabbit ATG due to a higher age and very low pre-treatment neutrophil count.

Causas genéticas de deficiência de ferro: [revisão] / Genetic causes for iron deficiency: [review]

As causas genéticas de deficiência de ferro, real ou funcional, ocorrem por defeitos em muitas proteínas envolvidas na absorção e metabolismo de ferro. Neste capítulo descreveremos sucintamente causas genéticas de carência de ferro para a síntese de hemoglobina, que cursa então com anemia microcítica e hipocrômica. Ressalto que estas são alterações raras, com poucas descrições na literatura. Em alguns casos, o ferro funcional não está disponível para os eritroblastos sintetizarem hemoglobina, ou o eritroblasto é incapaz de captar ferro da circulação, mas o ferro está acumulado em tecidos ou nas mitocôndrias. Nos últimos anos, várias descobertas, principalmente oriundas de descrições em humanos ou de modelos animais, ajudaram a elucidar a implicação dos componentes do metabolismo do ferro na deficiência de ferro hereditária, que afetam desde a absorção intestinal até sua inclusão final no heme.

The genetic causes of iron deficiency, real or functional, occur due to defects in many proteins involved in the absorption and metabolism of iron. In this chapter we briefly describe the genetic causes of iron deficiency in the synthesis of hemoglobin, resulting in hypochromic or microcytic anemia. These alterations are rare with few descriptions in the literature. In some cases, functional iron is not available for erythroblasts to synthesis hemoglobin, or erythroblasts may be incapable of capturing iron from the circulation although iron is accumulated in tissues and mitochondrias. Many discoveries have been made over the last few years, mainly resulting from the description of human or animal models, which have elucidated the implications of the components in iron metabolism in hereditary iron deficiency involving all processes from intestinal absorption to the final inclusion into heme.

Toll-like receptor 4 and inducible nitric oxide synthase gene polymorphisms are associated with Type 2 diabetes.

BACKGROUND: The toll-like receptor 4 (TLR4) and inducible nitric oxide synthase are proteins from the innate immune system that, when activated, can induce insulin resistance. Polymorphisms in these genes, TLR4 and NOS2, respectively, could affect the immune response, as well as the prevalence of Type 2 diabetes (T2DM). OBJECTIVE: The aim of the present study was to investigate the contribution of four polymorphisms (two from TLR4 and two from NOS2) to susceptibility to T2DM in a southeast Brazilian population. DESIGN: A total of 211 patients with T2DM and 200 unrelated controls were genotyped for the Asp299Gly and Thr399Ile polymorphisms of the TLR4 gene and for the insertion (I)/deletion (D) AAAT and (CCTTT)n polymorphisms of the NOS2 promoter gene. RESULTS: With regard to the NOS2 promoter region, the data showed that the I allele of the I/D AAAT polymorphism was more prevalent in the T2DM group and that the L/L genotype of the (CCTTT)n polymorphism was also more frequent in the same group. In contrast, the 299Gly allele and the 399Ile allele from the Asp299Gly and Thr399Ile TLR4 gene polymorphisms, respectively, were associated with protection of T2DM. It is believed that the persistence of these genetic variations in human populations may be indicative of a selective advantage in the face of different environmental pressures. CONCLUSIONS: Genetic variations in the NOS2 gene promoter and TLR4 coding sequence may lead to deleterious and protective effects, respectively, arising from altered function of the innate immune system in patients with T2DM.