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Biomedical subjects

S T Saad

Publications and source records attributed to S T Saad.

At least 19 recordsLinked to original sources
PubMed2006

Third-trimester erythrocytapheresis in pregnant patients with sickle cell disease.

OBJECTIVE: To evaluate the effects of prophylactic transfusion by means of erythrocytapheresis at the beginning of the third trimester of pregnancy in women with sickle cell disease (SCD). METHODS: A cohort of 14 pregnant women with SCD who received prophylactic erythrocytapheresis transfusions at the beginning of the third trimester was retrospectively compared with a cohort of 17 pregnant women who received simple prophylactic transfusions for no indication other than SCD severity. RESULTS: Prophylactic erythrocytapheresis transfusions were associated with a lower risk of intrauterine growth restriction (OR, 0.11; 95% confidence interval, 0.01-1.00) and oligohydramnios (OR, 0.65; 95% confidence interval, 0.45-0.92) in pregnant women with SCD. CONCLUSION: These results suggest that erythrocytapheresis transfusions are beneficial in women with SCD who are in the third trimester of pregnancy. Given the decrease in transfusion risks, this therapy deserves further evaluation in future trials.

Adult↗
PubMed2001

p53, Mdm2, and c-Myc overexpression is associated with a poor prognosis in aggressive non-Hodgkin's lymphomas.

The expression of p53, p21/WAF-1, Mdm2, c-Myc, and proliferating cell nuclear antigen (PCNA) proteins was examined by the immunohistochemistry of paraffin-embedded tissues of 62 patients with aggressive non-Hodgkin's lymphomas (NHL) and correlated to clinical data. Expression of p53, p21/WAF-1, Mdm2, and c-Myc protein was observed in 17 out of 62 cases (30%), 25 out of 60 (42%), 13 out of 44 (30%), and 39 out of 51 (76.5%), respectively. The p53+/p21WAF-1 phenotype, which is more frequently found in p53 mutations, was associated with a worse overall survival (P = 0.04) and with a lower rate of complete response (CR) (PF = 0.01). p53 and c-Myc negative expression was related to a better response to chemotherapy (PF = 0.005 and 0.035, respectively). The expression of p53, c-Myc, and Mdm2 was related to a shortened overall survival (P < 0.001, 0.05, and 0.037, respectively), suggesting that the expression of these proteins could be associated with a poor outcome in these patients.

Actuarial Analysis↗
PubMed2001

Increased risk for acute myeloid leukaemia in individuals with glutathione S-transferase mu 1 (GSTM1) and theta 1 (GSTT1) gene defects.

OBJECTIVES: Glutathione S-transferases (GST) modulate the effects of exposure to various cytotoxic and genotoxic agents, including those associated with increased risks of the myelodysplastic syndrome (MDS), acute myeloid leukaemia (AML) and aplastic anemia (AA). Both the GST mu 1 (GSTM1) and GST theta 1 (GSTT1) genes have a null variant allele in which the entire gene is absent. In this study, we tested whether null genotypes for the GSTM1 and GSTT1 genes altered the risks for MDS, AML and AA. METHODS: Genomic DNA from 49 MDS, 38 AML and 37 AA patients and 276 controls was analysed using the polymerase chain reaction (PCR). RESULTS: The frequencies of GSTM1 (73.6%) and GSTT1 (34.2%) null genotypes were significantly higher in AML patients than in the controls (36.9 and 18.1%, respectively). A higher frequency of the combined null genotype for both genes was also observed in patients with AML (26.3% compared with 5.0% in the controls). In contrast, no differences in the frequencies of the null genotypes were found among MDS patients, AA patients and the controls. CONCLUSION: Our observation of a 4.7-fold (95% CI: 2.1-11.0) and 2.3-fold (95% CI: 1.0-5.2) increased risk associated with the GSTM1 and GSTT1 null genotypes, respectively, and a 6.6-fold (95% CI: 2.4-7.9) increased risk associated with the combined null genotype presents preliminary evidence that the inherited absence of this carcinogen detoxification pathway may be an important determinant of AML.

Acute Disease↗
PubMed2001

beta-Spectrin S(ta) Bárbara: a novel frameshift mutation in hereditary spherocytosis associated with detectable levels of mRNA and a germ cell line mosaicism.

Hereditary spherocytosis (HS) is a common inherited anaemia characterized by the presence of spherocytic red cells and by a heterogeneous nature in terms of its clinical presentation, molecular basis and inheritance. Defects in several membrane protein genes have been involved in the pathogenesis of HS, including defects in the beta-spectrin gene. We detected a novel frameshift mutation in the beta-spectrin gene, a C deletion at codon 638, in a patient presenting with HS and spectrin deficiency. The mutant protein was not detected in the membrane or in other cellular compartments, but detectable levels of mutant mRNA were found in the patient. Interestingly, this mutation was not present in the patient's parents, suggesting a genetic mosaicism, especially as the patient has an affected brother with the same molecular defect. We analysed DNA from different tissues of the parents and the mutation was absent from all tissues analysed. This mutation seems to be confined to the germ cell lineage of the patient's mother and must present a mosaic pattern in these cells as the patient also has unaffected siblings.

Adult↗
PubMed2001

Hydroxyurea promotes the reduction of spontaneous BFU-e to normal levels in SS and S/beta thalassemic patients.

We have studied the effects of hydroxyurea on growth and differentiation of early erythroid progenitor cells (BFU-e) from peripheral blood of sickle cell disease patients (five SS and two Hb S/beta-thalassemia) in the presence or absence of exogenous stimulating factors. When the mononuclear cells from the sickle cell disease patients were cultured at diagnosis (before hydroxyurea treatment), there was an increased number of BFU-e in relation to controls (p < 0.05, Wilcoxon test) when cells were grown in the presence or absence of 5637 conditioned medium and erythropoietin. Colonies that developed in the absence of added growth factors were considered "spontaneous". A significant difference was observed after hydroxyurea treatment in the number of BFU-e obtained in the presence and absence of stimulus, with a higher reduction in the spontaneous BFU-e number. As expected, there was an increased Hb F level in these patients when compared with their pretreatment levels. There was no correlation between spontaneous BFU-e and hemoglobin levels in all patients studied.

Anemia, Sickle Cell↗
PubMed2001

Expression of inducible nitric oxide synthase is increased in acute myeloid leukaemia.

Significant activity of inducible nitric oxide synthase (iNOS) has been reported in tumour cells, including chronic lymphoid leukaemic cells. In this study, we analysed the expression of iNOS in 15 untreated patients with acute myeloid leukaemia (AML) and in 7 normal controls. Using flow cytometry and immunocytochemistry, we demonstrated that patients with AML had a high expression of iNOS when compared to controls. There was no correlation between the expression of iNOS and the expression of p53 and K, H, and N-ras mutation and expression, suggesting that the high expression of iNOS is independent of these proteins and could be the result of transcription factors expressed in AML.

Acute Disease↗
PubMed2001

The Agamma-195 (C-->G) mutation in hereditary persistence of fetal hemoglobin is not associated with activation of a reporter gene in vitro.

Hereditary persistence of fetal hemoglobin is an uncommon, benign disorder in which the expression of gamma-globin genes persists into adult life. Several point mutations have been associated with the increased gamma-globin gene promoter activity. We evaluated the -195 (C-->G) mutation by a functional in vitro assay based on the luciferase reporter gene system. The results indicated that the increased promoter activity observed in vivo could not be reproduced in vitro under the conditions employed, suggesting that other factors may be involved in the overexpression of the gamma-globin gene containing the -195 (C-->G) mutation. Furthermore, this is the first time that the -195 (C-->G) mutation of the Agamma-globin gene has been evaluated by in vitro gene expression.

Adult↗
PubMed2001

Detection of somatic mutations of the PIG-A gene in Brazilian patients with paroxysmal nocturnal hemoglobinuria.

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired clonal syndrome characterized by intravascular hemolysis mediated by complement, thrombotic events and alterations in hematopoiesis. Basically, the molecular events which underlie the complexity of the syndrome consist of the absence of the glycosylphosphatidylinositol (GPI) anchor as a consequence of somatic mutations in the PIG-A gene, located on the X chromosome. The GPI group is responsible for the attachment of many proteins to the cytoplasmic membrane. Two of them, CD55 and CD59, have a major role in the inhibition of the action of complement on the cellular membrane of blood cells. The absence of GPI biosynthesis can lead to PNH. Since mutations in the PIG-A gene are always present in patients with PNH, the aim of this study was to characterize the mutations in the PIG-A gene in Brazilian patients. The analysis of the PIG-A gene was performed using DNA samples derived from bone marrow and peripheral blood. Conformation-sensitive gel electrophoresis was used for screening the mutation and sequencing methods were used to identify the mutations. Molecular analysis permitted the identification of three point mutations in three patients: one G-->A transition in the 5' portion of the second intron, one T-->A substitution in the second base of codon 430 (Leu430-->stop), and one deletion DeltaA in the third base of codon 63. This study represents the first description of mutations in the PIG-A gene in a Brazilian population.

Adolescent↗
PubMed2001

Lack of association between N-ras gene mutations and clinical prognosis in Brazilian children with acute lymphoblastic leukemia.

Point mutations in codons 12, 13 and 61 of the N-ras proto-oncogene have been detected in several human malignancies. We studied 170 patients with acute lymphoblastic leukemia (ALL), treated from 1988 to 1994 according to a protocol derived from BFM-83 studies, in order to evaluate the incidence and prognostic significance of mutations in this gene in childhood ALL. DNA was extracted from bone marrow smears at diagnosis and amplified by polymerase chain reaction (PCR). After screening with SSCP, PCR products were hybridized with allele specific probes and, in some cases, cloned in a pMOS Blue T vector and sequenced. Exon 2 was also studied in 101 children. Our results showed 4% of mutations in codons 12 and 13 and 2% in exon 2. Similar to a previous report, we identified 7% of mutations among children who were studied for both exons. A new mutation in codon 64 of the N-ras gene was detected in one patient. No significant clinical differences between patients with and without mutations were detected (sex, age, leukocyte counts at diagnosis, nutritional status, and risk factor according to the BFM protocol). Children with mutations in codons 12 and 13 showed significantly higher reactivity to PAS staining on blast cells than children with a wild type N-ras gene configuration. Comparison of overall- and recurrence-free survival did not show significant difference between groups with and without mutations. Our results suggest that mutations in the ras gene are infrequent in children with ALL at diagnosis and seem to be of low prognostic value.

Amino Acid Substitution↗
PubMed2000

Low frequency of ankyrin mutations in hereditary spherocytosis: identification of three novel mutations.

Hereditary spherocytosis (HS) is a common hemolytic anemia caused by defects in the erythrocyte membrane proteins. The screening of mutations in the ankyrin-1 (ANK1) gene of 28 Brazilian HS patients showed two new missense mutations (His276Arg and Ile1054Thr) and one novel promoter mutation (-153 G-->A). The His276Arg mutation affected the invariable TPLH sequence on repeat 9. The -153 mutation was linked in cis to the known -108 T-->C mutation. In contrast to other populations, we were able to detect mutations in the ankyrin-1 gene in only 10% of our patients. It is also interesting to point out that, from 15 informative subjects for the 3' Acn repeats, only one presented a loss of heterozigosity at the cDNA level. Taken together, these results suggest that mutations in the ankyrin-1 gene might not be as common in Brazil as described for other populations.

Adolescent↗
PubMed2000

Association of the alpha-spectrin R28H mutation with allele alphaLELY and with alphaI/alphaII domain haplotypes in three Brazilian families.

We have studied three Brazilian kindreds presenting spectrin alpha/74 hereditary elliptocytosis (HE) due to a G-->A substitution, responsible for the R28H mutation. The mutant allele was associated with alphaI domain haplotype 1 (XbaI-/MspI-/PvuII+) in all three families and with two different alphaII domain haplotypes (1/RIT, 4/RVR). This result may reflect that this mutation occurs in a "hot spot" and may have arisen more than once or that a crossing over event may have occurred between the two domains studied. We detected one new haplotype in the alphaI domain (haplotype 3 -XbaI(+)/MspI(-)/PvuII(+)). The mutant allele was associated with the lack of the alphaII domain Alu insertion in all three cases. Allele alphaLELY, detected by PCR and restriction enzyme digestion, was present in the heterozygous form in patient 1 (alphaHE/alphaLELY) and in the homozygous form in patients 2 and 3(alphaHE-LEL/alphaLELY). It was found to be associated with domain haplotypes I (RIT) and 4 (RVR) and with the presence and absence of the Alu insertion. This may have arisen through recombination events, since this polymorphism is located in the alphaIV-alphaV domain junction, which is far distant from the alphaII domain.

Amino Acid Substitution↗
PubMed2000

A recurrent frameshift mutation of the ankyrin gene associated with severe hereditary spherocytosis.

During a survey of typical, dominant hereditary spherocytosis (HS) patients, we identified a frameshift mutation of the ankyrin gene in three unrelated probands. All three probands, who were from different ethnic backgrounds, suffered from severe HS requiring splenectomy. Analysis of both intragenic and flanking polymorphisms revealed that these probands did not share a common ankyrin allele, providing evidence that these mutations arose independently on separate chromosomal backgrounds. This frameshift mutation associated with severe HS, Ankyrin Florianópolis, is the first description of a recurrent mutation in the ankyrin gene.

Ankyrins↗
PubMed2000

Molecular heterogeneity of the A3 subgroup.

The molecular characterization of the subgroup A3 remains unclear. Four unrelated A3 blood donors were studied. Family studies were possible in three of them. The A3 subgroup was defined by immunohaematological evaluation with four different commercially available serums. Exons VI and VII of the ABO gene, responsible for 91% of the catalytic active part of the glycosyltransferase, were amplified and subjected to direct sequencing. The results in all samples showed heterozygosity for the G261 deletion. In the A3 allele, the following associations were found: C467T mutation and 1060C deletion in one A3 blood donor and in another G829A and 1060C. In one case, only the 1060C deletion was demonstrated in the A3 allele. One blood donor presented the T646A and the G829A mutations in homozygosity. It was concluded that the A3 blood group is very heterogeneous at the molecular level.

ABO Blood-Group System↗
PubMed2000

Decreased GATA3 mRNA expression in human T-cell lymphotropic virus type 1 (HTLV-1) infection.

GATA3 is a specific T-cell transcription factor involved in the expression of T-cell receptor (TCR). In order to characterize the relationship between HTLV-1 infection, which has been reported to be associated with down-regulation of genes belonging to the TCR/CD3 complex, and the transcription factor GATA3, we evaluated, by semi-quantitative RT-PCR, the expression of GATA3 gene in HTLV-1 carriers and individuals with related diseases. The study included 4 asymptomatic carriers, 2 patients with adult T-cell leukaemia/lymphoma (ATLL), 1 patient with HTLV-1 associated myelopathy (HAM)/tropical spastic paraparesis (TSP) and 7 healthy blood donors. A considerable decrease in the expression of the GATA3 mRNA was observed in all subjects infected by HTLV-1 and no expression of GATA3 mRNA was observed in 1 subject with ATLL and in 1 with HAM/TSP.

Blood Donors↗
PubMed2000

C282Y mutation in the HLA-H gene is not a risk factor for patients with myocardial infarction.

BACKGROUND: Iron is suspected to play a role in the development of atherosclerosis and in the progression of the disease, and consequently in myocardial infarction. Authors of a recent study identified a mutation in HLA-H gene, C282Y, that is an excellent marker for hemochromatosis, which is the most common cause of iron overload. There is a high prevalence of carriers of heterozygous hemochromatosis, most of whom are asymptomatic even with abnormalities of iron metabolism. OBJECTIVE: To study C282Y mutation in the HLA-H gene of 173 survivors of myocardial infarction matched with 172 controls by age, race, and sex, and 119 patients upon diagnosis of acute myocardial infarction. METHODS: Identification of the mutation was performed by PCR amplification of the DNA fragment followed by Rsal digestion. RESULTS: The prevalence of heterozygotes for the mutated allele both among patients and among controls was 1.74%. None of the 119 patients studied upon diagnosis was a carrier of the mutation. CONCLUSION: Our data suggested that the most common cause of iron overload is not associated with myocardial infarction.

Adult↗