Aneuploidy: the impact of chromosome imbalance on nuclear organization and overall genome expression.

The organization and dynamics of chromatin within the interphase nucleus as chromosome territories (CTs) and the relationship with transcriptional regulation are not fully understood. We studied a natural example of chromosomal disorganization: aneuploidy due to trisomies 13, 18 and 21. We hypothesized that the presence of an extra copy of one chromosome alters the CT distribution, which perturbs transcriptional activity. We used 3D-FISH to study the position of the chromosomes of interest (18 and 21) in cultured amniocytes and chorionic villus cells from pregnancies with a normal or aneuploid karyotype. We studied the volumes of nuclei and CTs in both conditions and performed a compared transcriptome analysis. We did not observe any differences between euploid and aneuploid cells in terms of the radial and relative CT positions, suggesting that the same rules govern nuclear organization in cases of trisomy. We observed lower volumes for CTs 18 and 21. Overall genome expression profiles highlighted changes in the expression of a subset of genes in trisomic chromosomes, while the majority of transcriptional changes concerned genes located on euploid chromosomes. Our results suggest that a dosage imbalance of the genes on trisomic chromosomes is associated with a disturbance of overall genomic expression.

Genetic variation in TGFB1 gene and risk of idiopathic recurrent pregnancy loss.

Transforming growth factor ß1 plays a significant role in pregnancy outcome. We investigated the association of TGFB1 exon 1 (rs1800471, rs1800470) and promoter region (rs1800469, rs1800468) polymorphisms with recurrent pregnancy loss (RPL) in 675 Tunisian women: 304 women with a history of three consecutive pregnancy losses of unknown etiology with the same partner and 371 age-matched multiparous control women. TGFB1 genotyping was done by TaqMan assays. Higher minor allele frequency for rs1800471 (P< 0.001), but not for rs1800470, rs1800469 or rs1800468 was found in RPL cases compared with controls. A significant difference in the distribution of rs1800471 genotypes was seen between the RPL cases and control women, irrespective of the genetic model used. Increased RPL risk was seen with rs1800471 allele C in the heterozygous state and to a greater degree in the homozygous state, thus establishing a dose-dependent effect. Haploview analysis revealed differential linkage disequilibrium between the TGFB1 single-nucleotide polymorphisms analyzed. TGFB1 haplotype analysis identified eight common haplotypes (rs1800471/rs1800470/rs1800469/rs1800468) with three (GTTG, Pc = 0.02; CCTG, Pc = 0.02 and CTCG, Pc = 0.02) positively associated with RPL and one (GCCG, Pc = 0.009) negatively associated with RPL. This study provides the first evidence that the TGFB1 genotype may influence RPL.

Identification of specific vascular endothelial growth factor susceptible and protective haplotypes associated with recurrent spontaneous miscarriages.

BACKGROUND: We investigated the association of vascular endothelial growth factor (VEGF) gene polymorphism with recurrent spontaneous miscarriage (RSM). METHODS: VEGF -2578C/A, -1154G/A, -634G/C, +936C/T single nucleotide polymorphisms (SNPs) were assessed in 304 RSM patients, and 371 age-and body mass index-matched control subjects using real-time PCR. RESULTS: Higher minor allele frequency of -1154G/A (P < 0.001) and +936C/T (P < 0.001), but not -2578C/A (P = 0.55) or -634G/C (P = 0.87) SNPs, were seen in patients. Significant differences in the distribution of -1154G/A (P = 0.006) and +936C/T (P = 0.015), but not -2578C/A (P = 0.473) or -634G/C (P = 1.000) genotypes, were seen in cases compared with control women. Of the possible 16 VEGF haplotypes, 9 were found to be common, and were included. A significantly lower frequency of C G C C (P = 0.008), and A G G C (P < 0.001) haplotypes, and a higher frequency C G C T (P = 0.020), and C G T (P = 0.004) haplotypes were seen in patients. CONCLUSIONS: These results strongly support that VEGF polymorphisms, in particular-1154G/A and +936C/T, are significantly associated with RSM. Our results confirm, in the largest sample to date, previous works in other populations on VEGF polymorphism in RSM.

Identification of the translocation t(15;17) in acute myeloid leukemia (AML) initially classified as FAB M1: case report and review of the literature.

We report a case of a patient aged about 53 years, who initially presented with hematological disorders (WBC: 44000/mm3, Hb: 11g/dl, Pit: 127000/mm3) without tumoral syndrome. The Wright-Giemsa stained bone marrow and peripheral blood smears showed a population of blast cells characterized by cells with high N/C and strongly basophilic cytoplasm without granules. The nuclei were predominantly round. Nuclear chromatin was fine and contained small nucleoli. Cytochemisty was positive for peroxidase activity. Immunophenotyping showed myeloid typical markers of granulocytic lineage (MP0+, CD13+, CD33+, CD117+, CD34-). The karyotype revealed the expression of t(15;17) chromosomal translocation. The diagnosis of acute myeloid leukaemia (AML) was then evoked initially. The cytological features corresponded closely to the M1 subtype as defined in the FAB classification. The patient was treated with induction therapy according to the 7/3 protocol. One month later, he was discharged from hospital on hematological and cytogenetic remission. He died at home because of a heart attack. From the biological findings the patient was retrospectively diagnosed as having promyelocytic leukemia (hyperbasophilic form).

[Hematologic abnormalities in infantile visceral leishmaniasis]. / Anomalies hématologiques au cours de la leishmaniose viscérale infantile.

The clinical and biological manifestations of visceral leishmaniasis are often confusing, most particularly because it can mimic and lead to a variety of hematological disorders. The aim of this study was to investigate the hematologic abnormalities observed in infantile visceral leishmaniasis from January 2000 and December 2013. The study included 35 children with a mean age of 3.5 years. Clinical manifestations were dominated by splenomegaly, fever, and paleness, defining the classic triad in 16% of our patients. Anemia was present in all patients. Leukopenia was found in 51% of the cases. Thrombocytopenia was observed in 48% of our patients and 36% had pancytopenia. All cases were confirmed by the presence of Leishman bodies (amastigotes) in the bone marrow smears. Quantitative and qualitative megakaryocyte abnormalities were found. Similarly, dysgranulopoiesis was observed in 31% of the cases, eosinophilia was present in 6%, erythroid hypoplasia in 3%, and erythroid hyperplasia in 34%. Different features of dyserythropoiesis were revealed in 71% of the patients with images of hemophagocytosis in 6% and multiple dysplasias in 9%. The knowledge of these hematological abnormalities associated with infantile visceral leishmaniasis can assist us in searching for Leishman bodies in the bone marrow smears to provide a diagnosis more quickly without necessarily resorting to more sophisticated tests.