Selective progesterone receptor modulators (SPRMs): Progesterone receptor action, mode of action on the endometrium and treatment options in gynaecological therapies.

Introduction: The progesterone receptor plays an essential role in uterine physiology and reproduction. Selective progesterone receptor modulators (SPRMs) have emerged as a valuable treatment option for hormone dependent conditions like uterine fibroids, which have a major impact on women’s quality of life. SPRMs offer potential for longer term medical treatment and thereby patients may avoid surgical intervention. Areas covered: The authors have reviewed the functional role of the progesterone receptor and its isoforms and their molecular mechanisms of action via genomic and non-genomic pathways. The current knowledge of the interaction of the PR and different SPRMs tested in clinical trials has been reviewed. The authors focused on pharmacological effects of selected SPRMs on the endometrium, their anti-proliferative action, and their suppression of bleeding. Potential underlying molecular mechanisms and the specific histological changes in the endometrium induced by SPRMs (PAEC; Progesterone receptor modulator Associated Endometrial Changes) have been discussed. The clinical potential of this compound class including its impact on quality of life has been covered. Expert Opinion: Clinical studies indicate SPRMs hold promise for treatment of benign gynecological complaints (fibroids, heavy menstrual bleeding; HMB). There however remains a knowledge gap concerning mechanism of action

Subregional statistical shape modelling identifies lesser trochanter size as a possible risk factor for radiographic hip osteoarthritis, a cross-sectional analysis from the Osteoporotic Fractures in Men Study

BGF was a National Institute of Health Research academic clinical fellow whilst undertaking part of this research and is now a Medical Research Council clinical research fellow supported by grant MR/S021280/1. FRS was supported by a Medical Research Council UK grant MR/L010399/1 at the time of this study. This study used the SSM cohort funded by Versus Arthritis UK project grant ref 20244. The Osteoporotic Fractures in Men (MrOS) Study is supported by National Institutes of Health funding. The following institutes provide support: the National Institute on Aging (NIA), the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), the National Center for Advancing Translational Sciences (NCATS), and NIH Roadmap for Medical Research under the following grant numbers: R01 AR052000, K24 AR048841, U01 AG027810, U01 AG042124, U01 AG042139, U01 AG042140, U01 AG042143, U01 AG042145, U01 AG042168, U01 AR066160, and UL1 TR000128. Partial support for this work was provided by the Southwest Research Institute internal research project R9541 and NIAMS research grant AR052013. All authors have made significant contributions to the conception and design of this study, the acquisition of data, its analysis and interpretation. All authors helped draft the article before approving the final version of this manuscript. Dr B Faber ([email protected]) takes responsibility for the integrity of the work in its entirety.Peer reviewedPublisher PD

The intestinal expulsion of the roundworm Ascaris suum is associated with eosinophils, intra-epithelial T cells and decreased intestinal transit time

Ascaris lumbricoides remains the most common endoparasite in humans, yet there is still very little information available about the immunological principles of protection, especially those directed against larval stages. Due to the natural host-parasite relationship, pigs infected with A. suum make an excellent model to study the mechanisms of protection against this nematode. In pigs, a self-cure reaction eliminates most larvae from the small intestine between 14 and 21 days post infection. In this study, we investigated the mucosal immune response leading to the expulsion of A. suum and the contribution of the hepato-tracheal migration. Self-cure was independent of previous passage through the liver or lungs, as infection with lung stage larvae did not impair self-cure. When animals were infected with 14-day-old intestinal larvae, the larvae were being driven distally in the small intestine around 7 days post infection but by 18 days post infection they re-inhabited the proximal part of the small intestine, indicating that more developed larvae can counter the expulsion mechanism. Self-cure was consistently associated with eosinophilia and intra-epithelial T cells in the jejunum. Furthermore, we identified increased gut movement as a possible mechanism of self-cure as the small intestinal transit time was markedly decreased at the time of expulsion of the worms. Taken together, these results shed new light on the mechanisms of self-cure that occur during A. suum infections

SNPs Occur in Regions with Less Genomic Sequence Conservation

Rates of SNPs (single nucleotide polymorphisms) and cross-species genomic sequence conservation reflect intra- and inter-species variation, respectively. Here, I report SNP rates and genomic sequence conservation adjacent to mRNA processing regions and show that, as expected, more SNPs occur in less conserved regions and that functional regions have fewer SNPs. Results are confirmed using both mouse and human data. Regions include protein start codons, 3′ splice sites, 5′ splice sites, protein stop codons, predicted miRNA binding sites, and polyadenylation sites. Throughout, SNP rates are lower and conservation is higher at regulatory sites. Within coding regions, SNP rates are highest and conservation is lowest at codon position three and the fewest SNPs are found at codon position two, reflecting codon degeneracy for amino acid encoding. Exon splice sites show high conservation and very low SNP rates, reflecting both splicing signals and protein coding. Relaxed constraint on the codon third position is dramatically seen when separating exonic SNP rates based on intron phase. At polyadenylation sites, a peak of conservation and low SNP rate occurs from 30 to 17 nt preceding the site. This region is highly enriched for the sequence AAUAAA, reflecting the location of the conserved polyA signal. miRNA 3′ UTR target sites are predicted incorporating interspecies genomic sequence conservation; SNP rates are low in these sites, again showing fewer SNPs in conserved regions. Together, these results confirm that SNPs, reflecting recent genetic variation, occur more frequently in regions with less evolutionarily conservation