Association of rs7719175, located in the IL13 gene promoter, with Schistosoma haematobium infection levels and identification of a susceptibility haplotype.

Urinary schistosomiasis is a parasitic disease caused by Schistosoma haematobium helminths. S. haematobium eggs may remain trapped within the bladder or the ureter walls, causing major pathological disorders in the urogenital system. The polymorphism rs1800925(C/T) of the IL13 gene promoter, which is functional, has previously been associated with susceptibility to S. haematobium infection. The aim of this study was to further our understanding and to determine whether, in the 5q31-q33 region, rs1800925 affects infection levels alone or in synergy with other polymorphisms. After sequencing the IL13 promoter and increasing the single-nucleotide polymorphism density, we performed a linkage disequilibrium analysis between rs1800925 and the other markers in a Malian population. Multivariate linear regression analysis and electrophoretic mobility shift assay (EMSA) were performed to characterized markers in linkage disequilibrium with rs1800925. An additional polymorphism, rs7719175, in the IL13 promoter was associated with controlling infection levels in multivariate analysis. The haplotype rs7719175T-rs1800925C was associated with high infection levels. EMSA indicated that rs7719175 affects the binding of transcriptional factors to the promoter region. Polymorphisms rs7719175 and rs1800925 have a synergistic role in the control of infection levels caused by S. haematobium and using them as a haplotype allows a better discrimination between infected subjects.

A STAT6 gene polymorphism is associated with high infection levels in urinary schistosomiasis.

Th2-mediated immunity is critical for human defence against schistosome, and susceptibility to infection is controlled by a major genetic locus, mapped on the 5q31-q33 region comprising the genes IL4, IL5 and IL13. We have reported an association between the rs1800925 polymorphism in the IL13 promoter and infection levels in a Dogon population (693 subjects in Ségué and 148 in Boul), where Schistosoma haematobium is endemic. In the same population, we investigated whether other polymorphisms in genes involved in type 2 cytokine immune response could affect susceptibility to schistosome infection. By logistic regression analysis, we found an association between a single-nucleotide polymorphism (SNP) in the STAT6 gene (rs324013) and infection levels (P=0.04). We confirmed this association in analyses restricted to subjects under 20 years age and living in Boul, the village with the highest levels of infection (P=0.005). We detected an additive effect of the rs324013 and rs1800925 polymorphisms (P=0.011). These SNPs were not strongly correlated with any other tested markers surrounding the two genes. Furthermore, electrophoretic mobility shift assay has shown that both polymorphisms affect transcription factor binding. These results are consistent with the Th2 cytokine pathway enhancing resistance to schistosome infection in humans.

Met31p and Met32p, two related zinc finger proteins, are involved in transcriptional regulation of yeast sulfur amino acid metabolism.

Sulfur amino acid metabolism in Saccharomyces cerevisiae is regulated by the level of intracellular S-adenosylmethionine (AdoMet). Two cis-acting elements have been previously identified within the 5' upstream regions of the structural genes of the sulfur network. The first contains the CACGTG motif and is the target of the transcription activation complex Cbflp-Met4p-Met28p. We report here the identification of two new factors, Met31p and Met32p, that recognize the second cis-acting element. Met31p was isolated through the use of the one-hybrid method, while Met32p was identified during the analysis of the yeast methionine transport system. Met31p and Met32p are highly related zinc finger-containing proteins. Both LexA-Met31p and LexA-Met32p fusion proteins activate the transcription of a LexAop-containing promoter in a Met4p-dependent manner. Northern blot analyses of cells that do not express either Met31p and/or Met32p suggest that the function of the two proteins during the transcriptional regulation of the sulfur network varies from one gene to the other. While the expression of both the MET3 and MET14 genes was shown to strictly depend upon the presence of either Met31p or Met32p, the transcription of the MET25 gene is constitutive in cells lacking both Met31p and Met32p. These results therefore emphasise the diversity of the mechanisms allowing regulation of the expression of the methionine biosynthetic genes.

[Non-palpable breast lesions and core needle biopsy with Mammotome 11G: is surgery required in patients with atypical ductal hyperplasia?]. / Lésions mammaires impalpables et macrobiopsies stéréotaxiques avec le Mammotome 11 G: faut-il opérer après diagnostic d'hyperplasie canalaire atypique?

Atypical ductal hyperplasia (ADH) of the breast is a difficult histologic diagnosis. It is usually found, but not always, on clusters of microcalcifications. The subsequent risk of breast carcinoma is 4 to 5 times more important and the carcinoma can arise in the same breast or in the contralateral breast. Diagnosis can be establish on core needle biopsy with Mammotome 11G. The risk of under-estimation (ductal carcinoma in situ or invasive carcinoma) is about 20%. This risk is drastically decreased if the target (the calcifications) is completely removed by the Mammotome. This study includes 62 cases of ADH found on 633 calcifications biopsied by Mammotome 11G. In 31 cases, surgery was performed and ADH was confirmed in 25 cases (6 cases was under-estimated). In the other 31 cases, all calcifications were removed, there was no other risk factor and follow-up was suggested. Like after surgery, yearly bilateral mammography during about 20 years is recommended. In this last group, there was no false-negative result, median follow-up: 35,5 months (22-62).

The study of methionine uptake in Saccharomyces cerevisiae reveals a new family of amino acid permeases.

The screening of mutants resistant to the oxidized analogues of methionine (methionine sulphoxide and ethionine sulphoxide) allowed the characterisation of a yeast mutant strain lacking the high affinity methionine permease and defining a new locus that was called MUP1. The study of MUP1 mutants showed that methionine is transported into yeast cells by three different permeases, a high affinity and two low affinity permeases. The MUP1 gene was cloned and was shown to encode an integral membrane protein with 13 putative membrane-spanning regions. Database comparisons revealed that the yeast genome contains an ORF whose product is highly similar to the MUP1 protein. This protein is shown here to encode very low affinity methionine permease and the corresponding gene was thus called MUP3. It has previously been suggested that the amino acid permeases from yeast all belong to a single family of highly similar proteins. The two methionine permeases encoded by genes MUP1 and MUP3 are only distantly related to this family and thus define a new family of amino acid transporters.

Localization of transforming growth factors, TGFbeta1 and TGFbeta3, in hypothalamic magnocellular neurones and the neurohypophysis.

The distribution of transforming growth factor beta (TGFbeta) in the rat and human hypothalamus and neurohypophysis was investigated by immunocytochemical techniques using rabbit polyclonal antisera against TGFbeta(1) and TGFbeta(3). Colocalization of TGFbeta(1) or TGFbeta(3) and arginine vasopressin (AVP) in the rat hypothalamus was studied by double immunolabelling in light microscopy, while their subcellular localization in the rat neurohypophysis was investigated by immunoelectron microscopy. TGFbeta(1) and TGFbeta(3) immunoreactivity was demonstrated in the cell bodies and processes of neurones in the supraoptic nucleus (SON) and paraventricular nucleus (PVN). The TGFbeta-immunoreactive cells were more numerous in the SON compared to the PVN. TGFbeta/AVP double-labelled cells were seen in both nuclei, but some neurones in the SON were labelled for TGFbeta(1) or TGFbeta(3), although not for AVP. In the rat and human neurohypophysis, TGFbeta(3) immunolabelling was more diffuse and stronger than TGFbeta(1) immunolabelling. TGFbeta(1) expression was seen in axonal vesicles and in neurosecretory granules of the axonal endings, while TGFbeta(3) was observed in axonal fibres. Colocalization of TGFbeta(3) or TGFbeta(1) and AVP was observed in some neurosecretory granules, but many were either single-labelled for TGFbeta or AVP or unlabelled. Our results demonstrate, for the first time, the colocalization of TGFbeta and neurohypophysial hormones in magnocellular neurones. We suggest that TGFbeta secreted by the neurohypophysis regulates the proliferation and secretion of certain anterior pituitary cells.

[Impalpable breast abnormalities. Contribution of cytologic puncture under stereotaxic guidance. Apropos of 159 cases]. / Anomalies mammaires impalpables. Apport de la ponction cytologique par repérage stéréotaxique. A propos de 159 cas.

The authors report the results of a cooperative study of X ray guided fine needle aspiration for the cytologic diagnosis of non palpable breast lesions. They discuss the limits of this method. In 60% of 159 cases cytologic examination was diagnosis. In their series, no false positive was reported but in 64 cases no sufficient material was obtained.

[Malignancy in ACR 3 category mammographic lesions, masses and calcifications]. / Les opacités et les microcalcifications de la classification ACR 3 liées à un cancer.

At screening mammography, lesions must be assigned to BI-RADS classification. Category 3 is used for nonpalpable probably benign lesions. This category is defined either by a subset of lesions that are so likely to be benign that follow-up is a reasonable alternative to immediate biopsy, or by a less than 2% malignancy rate for American BI-RADS, or than 5% for French ANAES. The initial work-up to analyze the lesion must be complete, not only with four screening standard views but with magnification views and sonography if necessary. The risk of malignancy is very low and the pronostic factors are the same as in screening detected carcinomas.

[Stereotactic 11-gauge directional vacuum-assisted breast biopsy: experience with 249 patients]. / Macrobiopsies stéréotaxiques par système à aspiration 11-G: à propos de 249 patientes.

PURPOSE: To assess the value of percutaneous vacuum-assisted core biopsy to improve the diagnosis of non palpable mammographic abnormalities. MATERIALS AND METHODS: A total of 252 core biopsies using an 11G Mammotome((R))were performed in 249 patients. Stereotactic localization was performed in the prone position on a dedicated digital Fischer table. RESULTS: Fifty-one, or 25%, of 200 clusters of microcalcifications corresponded to carcinomas: 126 benign lesions, 23 atypical hyperplasia and LCIS, 31 DCIS, 15 invasive ductal carcinomas, and 4 false negative biopsies. In these 4 last cases, surgery was performed because radiographs of the core biopsy showed no microcalcifications; carcinoma was confirmed at histology of the surgical specimen. Using the BI-RADS system, 7 lesions were category 3, 175 lesions were category 4, and 18 lesions were category 5. From a total of 52 masses, 31 were benign lesions, 2 were borderline lesions, and 19 were invasive carcinomas. From these, 5 lesions were category 3, 31 were category 4, and 16 were category 5. Diagnostic surgical biopsy was avoided in 161 cases (63%), in 152 cases for benign lesions including 151 lesions classified as category 4 lesions and in 9 cases for multifocal or recurrent malignant lesions. CONCLUSION: When technical pitfalls are avoided and when presence of microcalcifications in the core biopsy sample is verified, vacuum assisted core biopsy with Mammotome((R)) 11G provides accurate diagnosis of non-palpable mammographic abnormalities.

H2O2 sensing through oxidation of the Yap1 transcription factor.

The yeast transcription factor Yap1 activates expression of antioxidant genes in response to oxidative stress. Yap1 regulation involves nuclear accumulation, but the mechanism sensing the oxidative stress signal remains unknown. We provide biochemical and genetic evidence that upon H2O2 treatment, Yap1 is activated by oxidation and deactivated by enzymatic reduction with Yap1-controlled thioredoxins, thus providing a mechanism for autoregulation. Two cysteines essential for Yap1 oxidation are also essential for its activation by H2O2. The data are consistent with a model in which oxidation of Yap1 leads to disulfide bond formation with the resulting change of conformation masking recognition of the nuclear export signal by Crm1/Xpo1, thereby promoting nuclear accumulation of the protein. In sharp contrast to H2O2, diamide does not lead to the same Yap1 oxidized form and still activates mutants lacking cysteines essential for H2O2 activation, providing a molecular basis for differential activation of Yap1 by these oxidants. This is the first example of an H2O2-sensing mechanism in a eukaryote that exploits the oxidation of cysteines in order to respond rapidly to stress conditions.