Interactions between Sox10, Edn3 and Ednrb during enteric nervous system and melanocyte development.

The requirement for SOX10 and endothelin-3/EDNRB signalling pathway during enteric nervous system (ENS) and melanocyte development, as well as their alterations in Waardenburg-Hirschsprung disease (hypopigmentation, deafness and absence of enteric ganglia) are well established. Here, we analysed the genetic interactions between these genes during ENS and melanocyte development. Through phenotype analysis of Sox10;Ednrb and Sox10;Edn3 double mutants, we show that a coordinate and balanced interaction between these molecules is required for normal ENS and melanocyte development.

Human Connexin 32, a gap junction protein altered in the X-linked form of Charcot-Marie-Tooth disease, is directly regulated by the transcription factor SOX10.

Mutations in SOX10, a transcription modulator crucial in the development of the enteric nervous system (ENS), melanocytes and glial cells, are found in Shah-Waardenburg syndrome (WS4), a neurocristopathy that associates intestinal aganglionosis, pigmentation defects and sensorineural deafness. Expression of MITF and RET, two genes that play important roles during melanocyte and ENS development, respectively, are controlled by SOX10. The observation that some WS4 patients present with myelination defects of the central and peripheral nervous systems correlates with the recent finding that P(0), a major component of the peripheral myelin, is another transcriptional target of SOX10.

The SOX10 transcription factor: evaluation as a candidate gene for central and peripheral hereditary myelin disorders.

The SOX10 transcription factor is involved in development of neural crest derivatives and fate determination in glial cells. SOX10 mutations have been found in patients with intestinal aganglionosis and depigmentation with deafness (Waardenburg-Hirschsprung). Associated neurological signs have been reported in some cases, including a patient exhibiting a central and peripheral myelin deficiency.

Interaction among SOX10, PAX3 and MITF, three genes altered in Waardenburg syndrome.

Waardenburg syndrome (WS) is an autosomal dominant disorder with an incidence of 1 in 40 000 that manifests with sensorineural deafness and pigmentation defects. It is classified into four types depending on the presence or absence of additional symptoms. WS1 and WS3 are due to mutations in the PAX3 gene whereas some WS2 cases are associated with mutations in the microphthalmia-associated transcription factor (MITF) gene.

Plasma lipoprotein distribution and lipid transfer activities in patients with type IIb hyperlipidemia treated with simvastatin.

The aim of the present study was to search in type IIb hyperlipidemic patients for putative concomitant effects of simvastatin on the physicochemical characteristics of low density lipoproteins (LDL) and high density lipoproteins (HDL), as well as on the activities of the cholesteryl ester transfer protein (CETP) and the phospholipid transfer protein (PLTP) that were determined in both endogenous lipoprotein-dependent and endogenous lipoprotein-independent assays. In a double-blind, randomized trial, patients received either placebo (one tablet/day; n = 12) or simvastatin (20 mg/day; n = 12) for a period of 8 weeks after a 5-week run-in period. Simvastatin, unlike placebo, reduced the lipid and apolipoprotein B contents of the most abundant LDL-1, LDL-2, and LDL-3 subfractions without inducing significant changes in the overall size distribution of LDL and HDL.

Comparison between extra virgin olive oil and oleic acid rich sunflower oil: effects on postprandial lipemia and LDL susceptibility to oxidation.

The aim of our study was to determine whether the minor polar components of virgin olive oil could have favorable effects (1) on fasting and postprandial lipid profile and (2) on low-density lipoprotein (LDL) composition and susceptibility to oxidation in vitro. Ten normolipidic subjects were included in a crossover study (two diet periods of 3 weeks) and received either virgin olive oil (OO diet) or oleic acid rich sunflower oil. An oral fat load was performed at the end of each period.

Expression of the SOX10 gene during human development.

SOX10, a new member of the SOX gene family, is a transcription factor defective in the Dom (Dominant megacolon) mouse and in the human Shah-Waardenburg syndrome. To help unravel its physiological role during human development, we studied SOX10 gene expression in embryonic, fetal, and adult human tissues by Northern blot and in situ hybridization. As in mice, the human SOX10 gene was essentially expressed in the neural crest derivatives that contribute to the formation of the peripheral nervous system, and in the adult central nervous system.

Mutation of the Sry-related Sox10 gene in Dominant megacolon, a mouse model for human Hirschsprung disease.

The spontaneous mouse mutant Dominant megacolon (Dom) is a valuable model for the study of human congenital megacolon (Hirschsprung disease). Here we report that the defect in the Dom mouse is caused by mutation of the gene encoding the Sry-related transcription factor Sox10. This assignment is based on (i) colocalization of the Sox10 gene with the Dom mutation on chromosome 15; (ii) altered Sox10 expression in the gut and in neural-crest derived structures of cranial ganglia of Dom mice; (iii) presence of a frameshift in the Sox10 coding region, and (iv) functional inactivation of the resulting truncated protein.

Lp(a) levels and antiestrogen antibodies in women with and without thrombosis in the course of oral contraception.

Several reports have shown that lipoprotein(a) is associated with ischemic diseases. Two characteristics might explain this association. Firstly, Lp(a) is an LDL-like lipoprotein which may be implicated in the atherosclerotic process and secondly, Lp(a) possesses an additional apolipoprotein(a) whose structure is close to that of plasminogen and might confer to the molecule prothrombotic properties.

Hyperhomocyst(e)inemia, anti-estrogen antibodies and other risk factors for thrombosis in women on oral contraceptives.

Hyperhomocyst(e)inemia was shown to be associated with vascular occlusion in atherosclerotic patients. We have conducted a study to determine if hyperhomocyst(e)inemia was also related to the vascular events observed in women on oral contraceptives, presumably having little or no atherosclerosis. Two hundred women receiving oral contraceptives were included in the study: 100 were healthy controls and 100 had documented vascular occlusion.

Oral contraceptives, sex steroid-induced antibodies and vascular thrombosis: results from 1318 cases.

The role of antiethinyl estradiol antibodies (anti EE Ab) and associated risk factors was evaluated in 1318 cases of venous or arterial thrombosis in oral contraceptives (OC) users, and compared to 61 non-users and 124 healthy current users. Anti EE Ab were absent in non-users and present in 33% of healthy users and 72% of those with thrombosis, either arterial or venous. Age, duration of use, hyperlipidaemia and smoking were factors associated with thrombosis only in women with an arterial disease.

Residual vascular risk of discontinued oral contraception. Role of antibodies to synthetic sex hormones.

Recent epidemiological data indicate that the risk of thromboembolic disease associated with oral contraception (OC) may persist after discontinuation of the drug. It was demonstrated on the other hand that antibodies to sex steroid hormones which develop in OC users, were significantly correlated with the incidence of thrombosis. It is well known that antibodies may persist years after the antigenic stimulation.

[Vascular complications of oral contraception. In whom and how to prevent them?].

Oral contraception entails an increased risk of arterial and venous thrombosis which can only be prevented by detecting women at risk. The relative importance of various predisposing or precipitating factors was evaluated by comparing 3 groups of women: 50 oral contraceptive (OC) users with thrombosis; 50 healthy OC users and 30 controls who had never used OC's. The factors investigated were: duration of use and dose of oestrogens, age, blood pressure, serum lipid levels and tobacco smoking.

Evaluation of risk factors associated with vascular thrombosis in women on oral contraceptives. Possible role of anti-sex steroid hormone antibodies.

Women on oral contraceptives have an increased risk of thrombosis. The prevention of the vascular complications relies on the detection of women who are at risk. In order to find out which characteristics correlate with the occurrence of the vascular disease, 3 groups of women were compared; 50 oral contraceptive users with thrombosis, 50 healthy users, and 30 controls.

Blood changes in sex steroid hormone users. Circulating immune complexes induced by estrogens and progestogens and their relation to vascular thrombosis.

Oral contraceptives (OC) have been shown to induce in some women antiethinylestradiol antibodies which may be detected as circulating immune complexes by precipitation in ammonium sulphate at 25% saturation (CIC.AS). A reevaluation of the presence of CIC.

Oral contraception, circulating immune complexes, antiethinylestradiol antibodies, and thrombosis.

Circulating immune complexes were detected in women on oral contraceptives (OC) by a simple antigen nonspecific method using precipitation of serum in 25% saturated ammonium sulfate (CIC-AS). A significant correlation was found between the presence of CIC-AS and the OC vascular risk. A radioimmunoassay with tritiated ethinylestradiol indicated that CIC-AS contained antiethinylestradiol antibodies (anti-EE Ab) in a number of OC users, but indicated also that 1) anti-EE Ab may be found in cases with no detectable CIC-AS, 2) CIC-AS containing no anti-EE Ab are found in nonusers, and 3) even in OC users the CIC-AS may contain antibodies to other ligands than EE.

[Detection of pill-induced antiethinylestradiol antibodies (author's transl)].

The synthetic hormones contained in contraceptive pills were shown to induce antiethinylestradiol (EE) antibodies in some women. These antibodies can be detected by the presence of circulating immune complexes (CIC) which are precipitated from serum in 25 p. cent saturated ammonium sulphate.

Vascular thrombosis and oral contraceptives - a risk correlated study.

An immunological mechanism of the vascular complications related to oral contraceptives (O.C.) was suggested by the demonstration of circulating anti-ethinylestradiol antibodies in several cases.

Ethinylestradiol and diethylstilbestrol induced antibodies and vascular thrombosis.

Antiethinylestradiol antibodies were demonstrated in several oral contraceptive users. The antibodies could be precipitated from serum immune complexes by 25% saturated ammonium sulfate. This test of serum precipitation was applied to a comparative study of 116 women on O.

Antiethinyloestradiol antibody activities in oral contraceptive users.

Oral contraceptives (OC) can induce in some women, serum immune complexes precipitated in 25% saturated (NH)SO, especially in the case of a thrombotic complication. In this work, the presence of antiethinyloestradiol (anti-EE) antibodies in the complexes was investigated. Binding of ethinyloestradiol-H (EE-H), either by (NH)SO precipitate directly, or in equilibrium dialysis experiments with the anti-EE gamma-globulin isolated through a purification-activation method combining dilution chromatography and affinity chromatography, was measured.