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Congenital tufting enteropathy (CTE) is a life-threatening hereditary disease that is characterized by enteric mucosa tufting degeneration and early onset, severe diarrhea. Loss-of-function mutations of the human EPCAM gene (TROP1, TACSTD1) have been indicated as the cause of CTE. However, loss of mTrop1/Epcam in mice appeared to lead to death in utero, due to placental malformation. This and indications of residual Trop-1/EpCAM expression in cases of CTE cast doubt on the role of mTrop1/Epcam in this disease. The aim of this study was to determine the role of TROP1/EPCAM in CTE and to generate an animal model of this disease for molecular investigation and therapy development. Using a rigorous gene-trapping approach, we obtained mTrop1/Epcam -null (knockout) mice. These were born alive, but failed to thrive, and died soon after birth because of hemorrhagic diarrhea. The intestine from the mTrop1/Epcam knockout mice showed intestinal tufts, villous atrophy and colon crypt hyperplasia, as in human CTE. No structural defects were detected in other organs. These results are consistent with TROP1/EPCAM loss being the cause of CTE, thus providing a viable animal model for this disease, and a benchmark for its pathogenetic course. In the affected enteric mucosa, E-cadherin and β-catenin were shown to be dysregulated, leading to disorganized transition from crypts to villi, with progressive loss of membrane localization and increasing intracellular accumulation, thus unraveling an essential role for Trop-1/EpCAM in the maintenance of intestinal architecture and functionality.Supporting information is available for this article.

Partners of infertile couples requiring IVF or ICSI treatment appear to be affected by higher frequency of chromosomal rearrangements than the general population. Categories with greater risk were represented by men with sperm cell count <20 x 10(6) sperm/ml, and women with history of pregnancy loss.

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The effects of ATP (5-500 microM) were evaluated on the proliferation rate of cultured astrocytes by measuring 3H-thymidine incorporation and by flow cytometric analysis of the cell cycle. Determinations after 16 hours showed that ATP present in the culture medium for the whole period caused a dose-dependent reduction of cell proliferation, while if the exposure to ATP was limited to the first 8 hours, the proliferation was increased (always in a dose-dependent manner). A time course study of 3H-thymidine incorporation showed that, in the presence of ATP, 3H-thymidine was incorporated at a slower rate than in controls; the replacement of the culture medium with an ATP-free fresh medium, at the 8th hour, was followed by a 3H-thymidine incorporation occurring at such a fast rate to overshoot the control values. High performance liquid chromatography (HPLC) analysis, carried out to identify purine compounds present in the culture medium during cell exposure to ATP, indicated that more than 95% of the added ATP was metabolized within 1 hr. Conversely, an increase of purine metabolites was measured, this accumulation being greater at the highest concentrations of added ATP. The presence of high levels of extracellular ATP catabolites suggested that these compounds may act on the regulation of cell replication via the different purine receptors. This hypothesis was tested and confirmed by using agonists and antagonists selective for the P1 and the P2 sites. One hundred microM 2methylthio-ATP (2MeSATP), a P2Y agonist metabolized as fast as ATP, reproduced effects very similar to the ATP-induced ones. On the other hand, the nonhydrolisable ATP analogue, adenosine 5'-(beta, gamma-imido)-triphosphate (AMP-PNP) at 100 microM, induced a mitogenic effect as well as the A2 site stimulation. On the contrary, the activation of A1 receptors by 5 microM R-phenyl-isopropyladenosine (R-PIA) inhibited astrocyte proliferation; moreover, 100 nM 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), an A1 site antagonist, reversed the ATP-induced inhibition of cell proliferation. These results indicate that exogenous ATP, as a consequence of its rapid extracellular breakdown, exerts a dual influence on astrocyte proliferation by the involvement of both P1 and P2Y receptors. These findings might be relevant to such pathological conditions of the central nervous system (CNS), as seizures, hypoxia or ischemia, in which great amounts of purines released in the brain can influence a reactive astrocyte proliferative response to injury.

This study raises the issue of celiac disease screening in ART programmes. Given the available evidence in the literature combined with our observations from this study, the value of serological testing for celiac disease in infertile women remains uncertain. Further studies to address this issue are required.

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