The nuclear factor of activated T cells (NFAT) family of transcription factors plays important roles in many biologic processes, including the development and function of the immune and vascular systems. Cells usually express more than one NFAT member, raising the question of whether NFATs play overlapping roles or if each member has selective functions. Using mRNA knock-down, we show that NFATc3 is specifically required for IL2 and cyclooxygenase-2 (COX2) gene expression in transformed and primary T cells and for T-cell proliferation. We also show that NFATc3 regulates COX2 in endothelial cells, where it is required for COX2, dependent migration and angiogenesis in vivo. These results indicate that individual NFAT members mediate specific functions through the differential regulation of the transcription of target genes. These effects, observed on shortterm suppression by mRNA knock-down, are likely to have been masked by compensatory effects in gene-knockout studies. (Blood. 2011;118(3):795-803) IntroductionThe nuclear factor of activated T cells (NFAT) family of transcription factors consists of 4 members regulated by the Ca 2ϩ -calmodulin-dependent phosphatase calcineurin (CN). NFAT proteins were initially identified in T cells, and their functions in the immune system have been analyzed extensively. 1 In resting T cells, NFATs are present in the cytoplasm in a hyperphosphorylated and inactive form. Increases in the levels of intracellular Ca 2ϩ activate CN, which dephosphorylates NFAT. This promotes the translocation of NFATs to the nucleus, where they generally cooperate with other transcription factors to regulate an array of genes involved in the functions of the immune system, 2-5 including IL2 6 and cyclooxygenase 2 (COX2). 7 Expression of NFATc1, NFATc2, and NFATc3 (but not NFATc4) has been detected in normal and transformed T cells. 8 The co-occurrence of different NFAT members in the same cells raises the question of whether there is a degree of functional redundancy or if the immunoregulatory functions of each member are unique. The NFAT DNA-binding domain is highly conserved among members, 2,3 and the immune phenotypes of mice deficient in a single NFAT member are relatively mild, 1 which supports the existence of functional redundancy in T-cell activation. The use of Nfatc1 knockout (KO) cells in complementation experiments in Rag 2 Ϫ/Ϫ mice indicated that NFATc1 plays a role in the expansion of mature peripheral B and T lymphocytes and in Th2 cytokine production, but is not required for earlier differentiation and activation events. 9,10 Similarly, Nfatc2 Ϫ/Ϫ mice have mild defects in the immune response 11 and impaired Th2 differentiation due to overproduction of IL4. 12,13 Nfatc3-deficient mice show impaired thymic development, characterized by a loss of CD4 ϩ /CD8 ϩ double-positive cells through programmed cell death. 14 More recently, the use of conditional NFATc3 KO mice has revealed a role in both positive selection and double-negative development, but these mice showed no detectable alter...

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Objective To determine whether differences exist in the rate of levator ani muscle (LAM) avulsion between women who had undergone either Malmström vacuum delivery (MVD) or Kielland forceps delivery (KFD), allowing for potential confounding factors. Methods This was a prospective observational study of nulliparous women undergoing instrumental delivery using Malmström vacuum extractor or Kielland forceps, at two hospital centers in Spain. Fetal head position (anterior, posterior or transverse) and fetal head station (low or mid) were assessed by ultrasound and digital examination, respectively. Avulsion was defined on tomographic ultrasound imaging as an abnormal insertion of the LAM in the three central slices from the plane of minimal hiatal dimensions. Results In total, 414 patients were included in the study (212 MVD and 202 KFD). We observed a higher rate of LAM avulsion in the KFD group (KFD 49.5% vs MVD 32.5%; P = 0.001). When the results were evaluated according to fetal head position and station, we observed no differences in LAM avulsion. The crude odds ratio (OR) for the difference in avulsion between women in the KFD and MVD groups was 2.03 (95% CI, 1.36–3.03). However, when adjusted for duration of second stage of labor, fetal head circumference and fetal head station, the OR was no longer statistically significant (OR, 2.14 (95% CI, 0.95–4.85); P = 0.068). Conclusion When potential confounding factors are taken into account, the rate of LAM avulsion does not differ between women according to whether they have undergone KFD or MVD. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Alpha-1 antitrypsin deficiency (AATD) is under-recognized by clinicians, with long diagnostic delays between patients' first symptom and initial diagnosis. Recent recommendations by official societies encourage testing for AATD in all symptomatic adults with spirometric evidence of COPD, though compliance with this recommendation has been variable. For 6 months, the following physician alert was added to PFT reports of patients with airflow obstruction of GOLD Stage II or higher: "The American Thoracic Society recommends testing for AATD in all patients with FEV1 < 80% predicted and FEV1/FVC less than 0.70, if clinically indicated. Appropriate counseling suggested." During the "Pre-alert Period," 821 spirometry tests were performed; 178 of these 821 unique patients (22%) satisfied spirometric criteria of > GOLD Stage II and 11 (6%) were tested for AATD. In contrast, during the "Physician Alert" intervention period, 689 spirometry tests were performed on 689 unique patients, of whom 140 (20%) satisfied criteria for > GOLD II airflow obstruction; AAT testing was done more frequently (18 [13%], p = 0.04). The overall rate of misclassifying patients' reports for testing by the respiratory therapists was very low (3.3%). An analysis of "number needed to test" suggests that 98-290 patients must be tested to have 95% certainty to identify a single patient with severe AATD. In conclusion, implementing a physician alert on PFT reports of patients with COPD can increase physicians' testing for AATD. The incomplete rate of testing suggests the need for additional strategies to enhance clinicians' detection of individuals with AATD.