Regulation of female reproduction by p53 and its family members.

Tumor suppressor p53 is crucial for embryonic implantation through transcriptional up-regulation of uterine leukemia inhibitory factor (LIF). This article reports that p53 and estrogen receptor α were activated in endometrial tissues during implantation to coordinately regulate LIF production. By using human p53 knockin (Hupki) mice carrying a single nucleotide polymorphism (SNP) at codon 72 (arginine/proline), the arginine allele was demonstrated to produce higher uterine LIF levels during implantation than the proline allele. In humans, the diversity of haplotypes of the p53 gene has decreased during evolution, because the arginine allele, existing in only a subset of haplotypes, is under positive selection. This observation is consistent with previous results showing that the proline allele is enriched in patients undergoing in vitro fertilization (IVF). Studies with p63- and p73-knockout mice have demonstrated the involvement of p63 and p73 in female reproduction and their roles in egg formation and apoptosis (p63) and spindle checkpoint (p73) in female mice. Here, the role of p63 and p73 in human reproduction was investigated. Selected alleles of SNPs in p63 and p73 genes were enriched in IVF patients. These findings demonstrate that the p53 family members are involved in several steps to regulate female reproduction in mice and humans.

Effect of Picture Archiving and Communication System Image Manipulation on the Agreement of Chest Radiograph Interpretation in the Neonatal Intensive Care Unit.

OBJECTIVE: Variability in image interpretation has been attributed to differences in the interpreters' knowledge base, experience level, and access to the clinical scenario. Picture archiving and communication system (PACS) has allowed the user to manipulate the images while developing their impression of the radiograph. The aim of this study was to determine the agreement of chest radiograph (CXR) impressions among radiologists and neonatologists and help determine the effect of image manipulation with PACS on report impression. MATERIALS AND METHODS: Prospective cohort study included 60 patients from the Neonatal Intensive Care Unit undergoing CXRs. Three radiologists and three neonatologists reviewed two consecutive frontal CXRs of each patient. Each physician was allowed manipulation of images as needed to provide a decision of "improved," "unchanged," or "disease progression" lung disease for each patient. Each physician repeated the process once more; this time, they were not allowed to individually manipulate the images, but an independent radiologist presets the image brightness and contrast to best optimize the CXR appearance. Percent agreement and opposing reporting views were calculated between all six physicians for each of the two methods (allowing and not allowing image manipulation). RESULTS: One hundred percent agreement in image impression between all six observers was only seen in 5% of cases when allowing image manipulation; 100% agreement was seen in 13% of the cases when there was no manipulation of the images. CONCLUSION: Agreement in CXR interpretation is poor; the ability to manipulate the images on PACS results in a decrease in agreement in the interpretation of these studies. New methods to standardize image appearance and allow improved comparison with previous studies should be sought to improve clinician agreement in interpretation consistency and advance patient care.

Novel Method to Improve Radiologist Agreement in Interpretation of Serial Chest Radiographs in the ICU.

OBJECTIVES: To determine whether a novel method and device, called a variable attenuation plate (VAP), which equalizes chest radiographic appearance and allows for synchronization of manual image windowing with comparison studies, would improve consistency in interpretation. MATERIALS AND METHODS: Research ethics board approved the prospective cohort pilot study, which included 50 patients in the intensive care unit (ICU) undergoing two serial chest radiographs with a VAP placed on each one of them. The VAP allowed for equalization of density and contrast between the patients' serial chest radiographs. Three radiologists interpreted all the studies with and without the use of VAP. Kappa and percent agreement was used to calculate agreement between radiologists' interpretations with and without the plate. RESULTS: Radiologist agreement was substantially higher with the VAP method, as compared to that with the non-VAP method. Kappa values between Radiologists A and B, A and C, and B and C were 46%, 55%, and 51%, respectively, which improved to 73%, 81%, and 66%, respectively, with the use of VAP. Discrepant report impressions (i.e., one radiologist's impression of unchanged versus one or both of the other radiologists stating improved or worsened in their impression) ranged from 24 to 28.6% without the use of VAP and from 10 to 16% with the use of VAP (χ (2) = 7.454, P < 0.01). Opposing views (i.e., one radiologist's impression of improved and one of the others stating disease progression or vice versa) were reported in 7 (12%) cases in the non-VAP group and 4 (7%) cases in the VAP group (χ (2) = 0.85, P = 0.54). CONCLUSION: Numerous factors play a role in image acquisition and image quality, which can contribute to poor consistency and reliability of portable chest radiographic interpretations. Radiologists' agreement of image interpretation can be improved by use of a novel method consisting of a VAP and associated software and has the potential to improve patient care.

Lactase persistence and lipid pathway selection in the Maasai.

The Maasai are a pastoral people in Kenya and Tanzania, whose traditional diet of milk, blood and meat is rich in lactose, fat and cholesterol. In spite of this, they have low levels of blood cholesterol, and seldom suffer from gallstones or cardiac diseases. Field studies in the 1970s suggested that the Maasai have a genetic adaptation for cholesterol homeostasis. Analysis of HapMap 3 data using Fixation Index (Fst) and two metrics of haplotype diversity: the integrated Haplotype Score (iHS) and the Cross Population Extended Haplotype Homozygosity (XP-EHH), identified genomic regions and single nucleotide polymorphisms (SNPs) as strong candidates for recent selection for lactase persistence and cholesterol regulation in 143-156 founder individuals from the Maasai population in Kinyawa, Kenya (MKK). The non-synonmous SNP with the highest genome-wide Fst was the TC polymorphism at rs2241883 in Fatty Acid Binding Protein 1(FABP1), known to reduce low density lipoprotein and tri-glyceride levels in Europeans. The strongest signal identified by all three metrics was a 1.7 Mb region on Chr2q21. This region contains the genes LCT (Lactase) and MCM6 (Minichromosome Maintenance Complex Component) involved in lactase persistence, and the gene Rab3GAP1 (Rab3 GTPase-activating Protein Catalytic Subunit), which contains polymorphisms associated with total cholesterol levels in a genome-wide association study of >100,000 individuals of European ancestry. Sanger sequencing of DNA from six MKK samples showed that the GC-14010 polymorphism in the MCM6 gene, known to be associated with lactase persistence in Africans, is segregating in MKK at high frequency (∼58%). The Cytochrome P450 Family 3 Subfamily A (CYP3A) cluster of genes, involved in cholesterol metabolism, was identified by Fst and iHS as candidate loci under selection. Overall, our study identified several specific genomic regions under selection in the Maasai which contain polymorphisms in genes associated with lactase persistence and cholesterol regulation.