SLC26A4 variations among Graves' hyper-functioning thyroid gland

Deleterious mutations of SLC26A4 cause Pendred syndrome (PS), an autosomal recessive disorder comprising goitre and deafness with enlarged vestibular aqueducts (EVA), and nonsyndromic hearing loss (NSHL). However, the SLC26A4 hyperactivity was recently associated with the emergence of autoimmune thyroid diseases (AITD) and asthma among human and mouse model. Here, by direct sequencing, we investigate the sequences of the 20 coding exons (2 to 21) of SLC26A4 and their flanking intron-exon junctions among patients affected with Graves' disease (GD) hyperthyroidism. Ten mono-allelic variants were identified, seven of which are intronic and previously unreported. Two, c.898A>C (p.I300L) and c.1061T>C (p.F354S), of the three exonic variants are non synonymous. The p.F354S variant is already described to be involved in PS or NSHL inheritances. The exploration by PCR-RFLP of p.I300L and p.F354S variants among 132 GD patients, 105 Hashimoto thyroiditis (HT), 206 Healthy subjects and 102 families with NSHL have shown the presence of both variants. The p.F354S variation was identified both among patients (1~HT and 3 GD) and healthy subjects (n=5). Whereas, the p.I300L variant was identified only in GD patients (n=3). Our studies provide evidence of the importance of systematic analysis of SLC26A4 gene sequences on models other than deafness. This approach allows the identification of new variants and the review of the pathogenic effects of certain mono-allelic variants reported responsible for PS and NSHL development.     

Genome-Wide Association Studies (GWAS) breast cancer susceptibility loci in Arabs: susceptibility and prognostic implications in Tunisians

Genome-wide Association Studies (GWAS) revealed novel genetic markers for breast cancer susceptibility. But little is known about the risk factors and molecular events associated with breast cancer in Arab Population. Therefore, we designed a broad study to investigate the susceptibility and prognostic implications of the GWAS breast cancer loci in the Tunisian population. In a cohort of 640 unrelated patients with breast cancer and 371 healthy control subjects, we characterized the variation of 9 single nucleotide polymorphisms (SNPs), namely rs1219648, rs2981582; rs8051542, rs12443621, and rs3803662; rs889312; rs3817198; rs13387042 and rs13281615. Only 5 out of 9 GWAS breast cancer loci were found to be significantly associated with breast cancer in Tunisians: The rs1219648 (G vs. A allele: OR?=?1.36, P?=?1?×?10(-3)) and rs2981582 (A vs. G allele: OR?=?1.55, P?=?3?×?10(-6)) of FGFR2 gene; the rs8051542 of the TNRC9 gene (T vs. C allele: OR?=?1.40, P?=?4?×?10(-4)); the rs889312 of the MAP3K1 gene (C vs. A allele: OR?=?1.33, P?=?3?×?10(-3)) and the rs13281615 located on 8q24 (G vs. A allele: OR?=?1.21, P?=?0.03). Homozygous variant genotypes of rs2981582 were strongly related to lymph node negative breast cancer (OR?=?3.33, P?=?6?×?10(-7)) and the minor allele of rs2981582 was associated with increased risk of ER+ tumors (OR?=?1.57, P?=?0.02; OR?=?2.15, P?=?0.001, for heterozygous and homozygous variant genotypes, respectively) and increased risk of distant metastasis development (OR?=?2.30, P?=?4?×?10(-3); OR?=?3.57, P?=?6?×?10(-5), for heterozygous and homozygous variant genotypes, respectively) in a dose dependent manner. The association for rs8051542 was stronger for high-grade SBR tumors (OR?=?2.54, P?=?2?×?10(-4)). GG genotype of rs13387042 on 2q35 showed a significant association with the risk of developing distant metastasis (OR?=?1.94, P?=?0.02). The G allele of rs1219648 in FGFR2 and the A allele of rs13387042 on 2q35 indicated a better prognosis by showing a significantly higher overall survival rates (P?=?0.013 and P?=?0.005, respectively). In conclusion, GWAS breast cancer FGFR2, TNRC9, MAP3K1, and 8q24 loci are associated with an increased risk of breast cancer and genetic variation in FGFR2 gene may predict the aggressiveness of breast cancer in Tunisians.     

Bcl-2 expression and triple negative profile in breast carcinoma

Appearance of non-Hodgkin’s lymphomas (NHL) and renal cell carcinoma (RCC) in same person has been reported in the literature. There is a higher-than-expected incidence of co-occurrence of these neoplastic disorders. The cause for this association remains speculative. Two epidemiological studies have shown that the observed-to-expected ratio for occurrence of RCC in NHL patients were 1.86 to 2.67. We herein describe five patients with both RCC and lymphoid malignancies, and reviewed possible explanations for the association. In three of the five patients, RCC was diagnosed during lymphoproliferative disease work-up, and remaining two cases had been diagnosed with chronic lymphocytic leukemia 1 and 5 years prior to RCC. All RCC cases were detected during staging of the primary tumor, usually by CT scan and/or ultrasound. Our data are in correlation with the literature that there is an increased association of RCC and NHL more often among male patients, and that the lymphoproliferative disease often presents with extranodal involvement. The specialists should be alerted for this possibility when evaluating patients at diagnosis or during follow-up.     

Isolated tricuspid valve infective endocarditis. A report of 6 cases

Six cases of isolated tricuspid valve endocarditis in young women are described. Preceding genital sepsis was a predisposing factor in 4 patients. Cardiac signs are unusual at presentation, rendering the diagnosis difficult. Pleuropulmonary manifestations are the predominant findings, while overt signs of tricuspid insufficiency and right heart failure occur late in the disease. Staphylococcus aureus is the pathogen most commonly found and requires energetic treatment for a minimum of 4 weeks. The value of echocardiography in establishing an early diagnosis is stressed. Persistent sepsis constitutes a major indication for surgery.     

Evaluation of parenchymal and nonparenchymal cell injury after different conditions of storage and reperfusion

We used the isolated perfused rat liver model (IPRL) to assess parenchymal and nonparenchymal cell integrity after different conditions of storage and reperfusion. Two studies were performed. In study 1, the IPRL was applied to evaluate the effects of 30 min of normothermic reperfusion with Elohes solution, enriched William's medium (Wif), or Carolina rinse solution (CRS) following 24 h of cold preservation in high-K⁺ or high-Na⁺ UW solution. As indicated by creatine kinase-BB (CK-BB) release, reperfusion with CRS provided greater protection of endothelial cells after storage in high-K⁺ UW solution than after storage in high-Na⁺ UW solution. In study 2, livers were cold-preserved (24 h, 4 °C) in either high-K⁺ or high-Na⁺ UW solution, then flushed with either CRS or Wif solution at room temperature before reperfusion (120 min, 37 °C) with 5 % albumin-William's medium E. There was no statistical difference between the rinse solutions for bile flow and transaminases release. However, CRS improved bile indocyanine green excretion, which is known to be a marker of parenchymal and nonparenchymal cell integrity. Therefore, we can assume that this rinse solution protects rat liver grafts from reperfusion-induced microvascular damage. Received: 29 December 1997 Received after revision: 31 March 1998 Accepted: 15 April 1998     

Effect of UDP-glucuronyltransferase induction on zearalenone metabolism

Experiments were conducted to determine the UDP-glucuronyltransferase (UDP-GT) isoenzyme which catalyzes zearalenone (Z) conjugation, and the effect of increased enzyme activity on Z metabolism. In competitive enzyme assays, the activity of rat liver UDP-GT towards Z was inhibited by 1-naphthol (NA), a GT1 substrate, and 4-hydroxybiphenyl (HB), a GT2 substrate. When enzyme activity was induced with either 3-methylcholanthrene (MC), a GT1 inducer, or phenobarbital (PB), a GT2 inducer, increased UDP-GT activity towards Z, NA and HB was observed. UDP-GT induction by PB increased urinary excretion of conjugated alpha-zearalenol. These results indicate that UDP-GT isoenzymes have overlapping substrate specificities, and that Z detoxification may be enhanced by UDP-GT enzyme induction, resulting in increased urinary excretion of conjugated alpha-zearalenol.