Milena Magalhães Aleluia

Sickle Cell Anemia Patients in Use of Hydroxyurea: Association between Polymorphisms in Genes Encoding Metabolizing Drug Enzymes and Laboratory Parameters

This study investigated associations between SNPs in genes encoding metabolizing drug enzymes and laboratory parameters in sickle cell anemia patients under hydroxyurea (SCA-HU+). We evaluated hematologic and biochemical parameters by electronic methods and SNPs by PCR-RFLP and multiplex PCR in 35 SCA-HU+ patients and 67 SCA-HU− patients. The HbS, total cholesterol, lactate dehydrogenase, aspartate aminotransferase, total bilirubin and fractions levels, and leukocyte, eosinophil, monocyte, and erythroblast counts were reduced in SCA-HU+ patients (p < 0.05). Moreover, they presented higher HbF, C-reactive protein, and ferritin levels and elevated MCH and MCV values (p < 0.05). Genotype frequencies of variants GA + AA of MPO −463G>A and c1c2 + c2c2 of CYP2E1 −1293G>C/−1053C>T were higher in SCA-HU+ patients (p < 0.05). Independent associations were found between the variant A allele and lower total cholesterol, between c2 allele and low alpha-1 antitrypsin and between the null GSTT1 variant and high indirect and total bilirubin in SCA-HU+ patients. In SCA-HU− patients, independent associations were found between the variant A allele and high uric acid and between c2 allele and high urea. Our results suggest that SNPs MPO −463G>A, CYP2E1 −1293G>C/−1053C>T, and GSTT1 can be associated with alterations in lipid, inflammatory, renal, hemolytic, and hepatic profiles. However, further studies are needed to elucidate these associations.

Laboratory and Genetic Biomarkers Associated with Cerebral Blood Flow Velocity in Hemoglobin SC Disease

Reference values for cerebral blood flow velocity (CBFV) in hemoglobin SC disease (HbSC) have not been established. We aimed to investigate associations between laboratory and genetic biomarkers associated with CBFV in HbSC children. Sixty-eight HbSC children were included; CBFV was analyzed by transcranial Doppler, and the time-averaged maximum mean velocity (TAMMV) was estimated. Hematological, biochemical, immunological, and genetic analyses were performed. TAMMV was negatively correlated with red blood cell count (RBC) count, hemoglobin, hematocrit, and direct bilirubin (DB), yet positively correlated with monocytes and ferritin. We found that children with TAMMV ≥ 128 cm/s had decreased red blood cell distribution width (RDW) and nitric oxide metabolite (NOx) concentration. Children with TAMMV ≥ 143.50 cm/s had decreased hemoglobin and hematocrit, as well as increased ferritin levels. Decreased hemoglobin, hematocrit, RDW, and NOx and increased ferritin were detected in children with TAMMV ≥ 125.75 cm/s. The CAR haplotype was associated with higher TAMMV. In association analyses, RBC, hemoglobin, hematocrit, RDW, monocyte, DB, NOx, and ferritin, as well as the CAR haplotype, were found to be associated with higher TAMMV in HbSC children. Multivariate analysis suggested that high TAMMV was independently associated with hematocrit, RDW, and NOx. Additional studies are warranted to validate the establishment of a cutoff value of 125.75 cm/s associated with elevated TAMMV in HbSC children.

The origin of HTLV-1 in the South Bahia by phylogenetic, mitochondrial DNA and β-globin analysis

In order to clarify the HTLV introduction and dispersion in the south of Bahia, we analyzed 29 samples from HTLV-1 seropositive women. Before the blood collection, all of them answered a standardized questionnaire. The DNA was extracted by QIAgen Kit. It was performed a nested-PCR to the LTR region of the HTLV. The sequences were submitted to the LASP HTLV-1 Automated Subtyping Tool. The phylogenetic analyses were generated using the neighbor-joining e maxima-verossimilhanca methods. The evolutionary model of Tamura-Nei with gamma distribution was selected as the best adaptive model by software Modeltest 3.7. The likelihood ratio was used to calculate the statistical support for the branches in trees. Bayesian tree were constructed to verify the posterior probability statistical parameter. To evaluate genetic ancestry of the population, it was analyzed mtDNA ancestry markers and β-globina haplotypes. From the total, 21 samples were successfully amplified and sequenced and they were classified as HTLV-1 aA (bootstrap support of 100%). The phylogeny analysis showed multiple introductions of the virus in Brazil. In addition, for the first time, Mozambique sequences were grouped with Brazilian and South Africa sequences, supporting the hypothesis that Africans infected with the virus have been brought from the southern regions of Africa. In relation to the genetic ancestry, the African ethnicity was predominantly found by mtDNA markers. In addition, the type benin was detected by β-globin analyses. These data corroborate to clarify the introduction and dispersion of this virus in Brazil, especially in the Bahia.

Evaluation of Cardiometabolic Parameters among Obese Women Using Oral Contraceptives

Background Combined oral contraceptive (COC) use has been associated with an unfavorable impact on carbohydrate and lipid metabolism in diverse populations of normal weight and obese women. The present study aimed to evaluate the cardiometabolic and inflammatory profiles of women in northeastern Brazil with respect to COC use and obesity. Methods We performed a cross-sectional study to verify cardiovascular parameters, including blood pressure (BP), fasting serum glucose, lipid, and inflammatory profile, in a population of women aged 15–45 years, considering obesity and COC use. Our sample consisted of 591 women, 481 women who were COC users, and 110 age-matched women who were COC non-users, classified as obese and non-obese according to BMI. Results COC use and obesity were associated with increased systolic (p ≤ 0.001) and diastolic BP (p = 0.001), blood glucose (p ≤ 0.001), total cholesterol (p = 0.008), low-density lipoprotein cholesterol (p ≤ 0.001), very low-density lipoprotein cholesterol (p ≤ 0.001), triglycerides (p ≤ 0.001), ferritin (p = 0.006), C-reactive protein (CRP) (p ≤ 0.001), and nitric oxide metabolites (p ≤ 0.001), as well as decreased high-density lipoprotein cholesterol (HDL-c) (p ≤ 0.001) in comparison to controls. CRP and HDL-c levels in obese COC users were determined to be outside reference range values. The odds of having lower levels of HDL-c and elevated CRP increased among obese COC users. COC use was independently associated with low levels of HDL-c, especially second-generation progestins (p < 0.001; OR = 8.976; 95% CI 2.786–28.914). Conclusion Obesity and COC use were associated with alterations in lipid and inflammatory cardiometabolic parameters, particularly increased CRP levels and decreased HDL-c, which are considered markers of cardiovascular disease (CVD) risk. Given the need to prevent unintended pregnancy among obese women, together with weight loss counseling, it is important to evaluate the most effective and safest contraceptive methods to avoid the potential risk of developing CVD.

Comparative study of sickle cell anemia and hemoglobin SC disease: clinical characterization, laboratory biomarkers and genetic profiles

BackgroundIn this study, we evaluate the association of different clinical profiles, laboratory and genetic biomarkers in patients with sickle cell anemia (SCA) and hemoglobin SC disease (HbSC) in attempt to characterize the sickle cell disease (SCD) genotypes.MethodsWe conducted a cross-sectional study from 2013 to 2014 in 200 SCD individuals (141 with SCA; 59 with HbSC) and analyzed demographic data to characterize the study population. In addition, we determined the association of hematological, biochemical and genetic markers including the βS-globin gene haplotypes and the 3.7 Kb deletion of α-thalassemia (−α3.7Kb-thal), as well as the occurrence of clinical events in both SCD genotypes.ResultsLaboratory parameters showed a hemolytic profile associated with endothelial dysfunction in SCA individuals; however, the HbSC genotype was more associated with increased blood viscosity and inflammatory conditions. The BEN haplotype was the most frequently observed and was associated with elevated fetal hemoglobin (HbF) and low S hemoglobin (HbS). The -α3.7Kb-thal prevalence was 0.09 (9%), and it was associated with elevated hemoglobin and hematocrit concentrations. Clinical events were more frequent in SCA patients.ConclusionsOur data emphasize the differences between SCA and HbSC patients based on laboratory parameters and the clinical and genetic profile of both genotypes.

Genetic modulation of fetal hemoglobin in hydroxyurea-treated sickle cell anemia

viruses, Hydroxyurea, and bone marrow stress due to chronic anemia. Interestingly, patients with sickle cell disease share these risk factors and have been also noted to exhibit an increased risk of malignancies, mostly of the hematologic type. Aside from blood donor screening to decrease the risk of transmission of viruses such as HTLV-1, CMV, and Hepatitis C, optimization of iron chelation practices, and leukoreduction of the transfused blood, there are currently no specific recommendations as far as risk factor modification is concerned. There are no screening guidelines for hematologic malignancies in patients with thalassemia. While the association between thalassemia and hematologic malignancies remains in its early stages, it will be important to continue to explore the field and conduct more large scale studies with long-term follow-up. It is also paramount to remain very attentive to new signs and symptoms patients with thalassemia exhibit that may indicate a hematologic malignancy, with the understanding that some of these findings may overlap with those of thalassemia, such as worsening anemia, fatigue, and splenomegaly.

Interfamilial transmission of HTLV-1 in the South of Bahia, Brazil

The objective of this study was to investigate the prevalence of HTLV in the south of Bahia and to verify the interfamilial transmission of this virus. Initially, blood was collected from pregnant women in hospitals in southern Bahia.The HTLV-1 status was analyzed by ELISA and confirmed by Western Blot and PCR. The HTLV positive women were contacted and visited. In this opportunity, it was explained the results and collected samples from family members. They signed a consent informed and it was applied questionnaire. A total of 2766 pregnant women were analyzed. The prevalence was 1.05% (n=29) (CI95%:0,70-1,50). Besides, it was possible to follow 18 mothers (16 positives and 2 indeterminates) for 2 years. During the following, it was collected samples from 34 family members, including: partners (n=8), mothers (n=7), father (n=1), sisters (n=2), brothers (n=4), sons (n=5), daughters (n=4), others (n=3). Specific reactivity was observed in 11/34 (32,35%) individuals, of which two samples were from children (1 son and 1 daughter - 2,3 and 8 years old, respectively). The others members were: 3 mothers, 1 father, 3 partners, 2 sisters. In one case, we had three generation HTLV-1 positive: grandmother, mother and daughter. These results are very relevant because: (1) so far no studies of HTLV-1 seroprevalence in pregnant/puerperal women from the South region of Bahia had been described, (2) previous studies in areas endemic for the HTLV in Brazil found: 0.84% - Salvador, Bahia and 1.1% in Belo Horizonte, Minas Gerais, (3) evidence of important interfamilial transmission in this area.

Hydroxyurea in the management of sickle cell disease: pharmacogenomics and enzymatic metabolism

Hydroxyurea (HU) was approved to be used in the treatment of sickle cell disease (SCD) because of its anti-sickling potential. However, there is variability in HU response among SCD patients and this can be due to physiological, socioeconomic, environmental, metabolic and/or genetic factors. The present review focuses on the latter two. Three quantitative trait loci, HBG2, BCL11A and HMIP, have been suggested as important markers for HU response. Other genes (ASS1, KLF10, HAO2, MAP3K5, PDE7B, TOX, NOS1, NOS2A, FLT1, ARG1, ARG2, UGT1A1, OR51B5/6, SIN3A, SALL2, SAR1A, UTB, OCTN1, CYP2C9, AQP9, MPO, CYP2E1, and GSTT1) have also been considered. Studies implicate catalase, urease, horseradish peroxidase and enzymes of CYP450 family in HU metabolism. However, little is known about these enzymes. Therefore, further studies are needed to elucidate the metabolic pathway of HU, which will facilitate pharmacogenomic studies and help in identification of candidate genes for predicting HU response.

Genetic Polymorphisms Associated with Environmental Exposure to Polycyclic Derivatives in African Children

Background The nonracial leukopenia may be a result of exposure to polycyclic derivatives (benzene-toluene-xylene (BTX)) and may arise from a possible change in the bone marrow microenvironment. The present study sought to evaluate the association of genetic polymorphisms in xenobiotic-metabolizing enzymes with hematological and biochemical profiles. Methods We evaluated 89 African descendant children, exposed indirectly to benzene derivatives. Laboratory parameters were investigated by automated methods and genetic polymorphisms by PCR-RFLP and PCR multiplex. Results Children with leukopenia had significantly decreased white blood cells (WBCs) and platelet counts, which is not consistent with benign leukopenia. In the same group, we have found that carriers of the CYP2E1 variant allele had decreased WBC and lymphocytes. Those with NQO1 variant allele had decreased WBC, neutrophil, eosinophil, monocyte, and lymphocyte counts. Carriers of the MPO variant allele had decreased WBC, neutrophil, eosinophil, basophil, monocyte, lymphocyte, and platelet counts and an elevated free iron level. Children with GSTT and GSTM null exhibited decreased WBC, neutrophil, basophil, and lymphocyte counts. Our multivariate analysis model reveals that females were independently associated with leukopenia. Conclusion Our results suggest that the polymorphisms investigated were associated with hematological changes in the studied population. These alterations could be heightened by exposure to benzene derivatives.

Heme-mediated cell activation: the inflammatory puzzle of sickle cell anemia

ABSTRACT Introduction: Hemolysis triggers the onset of several clinical manifestations of sickle cell anemia (SCA). During hemolysis, heme, which is derived from hemoglobin (Hb), accumulates due to the inability of detoxification systems to scavenge sufficiently. Heme exerts multiple harmful effects, including leukocyte activation and migration, enhanced adhesion molecule expression by endothelial cells and the production of pro-oxidant molecules. Area covered: In this review, we describe the effects of heme on leukocytes and endothelial cells, as well as the features of vascular endothelial cells related to vaso-occlusion in SCA. Expert commentary: Free Hb, heme and iron, potent cytotoxic intravascular molecules released during hemolysis, can exacerbate, modulate and maintain the inflammatory response, a main feature of SCA. Endothelial cells in the vascular environment, as well as leukocytes, can become activated via the molecular signaling effects of heme. Due to the hemolytic nature of SCA, hemolysis represents an interesting therapeutic target for heme-scavenging purposes.