No abstract

Neural tube defects (NTDs), such as spina bifida and anencephaly, are severe birth defects which result from failure of closure of the neural tube (the precursor of the brain and the spinal cord). In humans, NTDs affect 1 per 1000 pregnancies, with multifactorial aetiology suggestive of a combination of one or more genetic factors with contribution from environmental risk factors. The curly tail (ct/ct) mouse represents an established model for NTDs; affected embryos develop spina bifida which closely resembles the corresponding birth defects in humans both in terms of pathology and multifactorial etiology. The major genetic defect in curly tail is a regulatory mutation that results in reduced expression of grainyhead-like-3 (Grhl3). We identified a putative regulatory mutation in the Grhl3 gene, and showed by transgenic BAC rescue that increased expression of Grhl3 prevents NTDs in ct/ct embryos. However, the penetrance is strongly influenced by, as yet unidentified modifier genes. In the course of proteomic analysis of curly tail we identified differences in the migration of lamin B1 on 2D gels, between samples from ct/ct embryos and a closely matched wild-type strain. Migration differences have been found to result from a genomic polymorphism that results in variation in protein sequence. Analysis of sub-strains of mice carrying different combinations of the laminB1 polymorphism and the Grhl3 mutation suggest that Lmnb1 could potentially act as a modifier of NTD risk in curly tail mice.Rspo2 is a secreted agonist of the canonical Wnt signaling pathway that signals through Lrp6 invitro and invivo. Rspo2 deficient murine fetuses die at birth and exhibit a variety of malformations including tracheal and laryngeal cartilage defects, cleft palate, reduced lung size, and limb reduction defects. Further invivo studies have revealed that Rspo2 signaling is also mediated through the Lrp5 receptor. The combined absence of Rspo2 and Lrp5 or Lrp6 results in an impairment in lung branching morphogenesis resulting in a lung that is normally patterned along the proximal distal axis but possesses hyper-dilated proximal airways. Rspo2 / Lrp5 / Lrp6 +/ individuals fail to form any tracheal cartilage rings, form only rudiments of the cricoid and arytenoid cartilages, are athymic, and have micromandibles frequently accompanied by a cleft upper lip. More than 50% of the fetuses also possessed complete tracheal esophageal fistulas originating cranially at the level of the arytenoid cartilages. These findings indicate that Rspo2 signaling plays a role not only in lung branching morphogenesis but also separation of the trachea and esophagus.Background: It is estimated that 1/3 of the epilepsy patients are in fertile age, and that 1 out of 250 pregnant women are exposed to antiepileptic, which requires experimental models of teratogenicity. Objective: To compare the teratogenic effect of valproic acid (VPA), carbamazepine (CARB) and lamotrigine (LAMO) in rat fetuses. Methods: Wistar rats were treated with AV, CARB and LAMO (200 or 400...

Background: The influence of PAD4 concentration and its polymorphisms in SAKI development are poorly evaluated. Thus, the aim of this study is to evaluate the PAD 4 concentration and PADI4 polymorphisms, as predictors of AKI development, need for renal replacement therapy (RRT), and mortality in patients with septic shock. Methods: We included all individuals aged ≥ 18 years, with the diagnosis of septic shock at ICU admission. Blood samples were taken within the first 24 hours of the patient’s admission to determine serum PAD4 concentration and its polymorphism PADI4 (rs11203367) and (rs874881). Patients were followed during their ICU stay and the development of SAKI was evaluated. Among the patients in whom SAKI developed, mortality and need for RRT were also evaluated. Results: 99 patients were included in the analysis. SAKI developed in approximately 51.5% of patients during the ICU stay; of these, 21.5% required RRT and 80% died. There was no difference between PAD4 concentration (p = 0.116) and its polymorphisms rs11203367 (p = 0.910) and rs874881 (p = 0.769) in patients in whom SAKI did or did not develop. However, PAD4 had a positive correlation with plasma urea concentration (r = 0.269 and p = 0.007) and creatinine (r = 0.284 and p = 0.004). The PAD4 concentration and PADI4 polymorphisms were also not associated with RRT and with mortality in patients with SAKI. Conclusion: PAD4 concentration and its polymorphisms were not associated with SAKI development, the need for RRT, or mortality in patients with septic shock. However, PAD4 concentrations were associated with creatinine and urea levels in these patients.