A molecular staging model for accurately dating the endometrial biopsy.

Natural variability in menstrual cycle length, coupled with rapid changes in endometrial gene expression, makes it difficult to accurately define and compare different stages of the endometrial cycle. Here we develop and validate a method for precisely determining endometrial cycle stage based on global gene expression. Our 'molecular staging model' reveals significant and remarkably synchronised daily changes in expression for over 3400 endometrial genes throughout the cycle, with the most dramatic changes occurring during the secretory phase. Our study significantly extends existing data on the endometrial transcriptome, and for the first time enables identification of differentially expressed endometrial genes with increasing age and different ethnicities. It also allows reinterpretation of all endometrial RNA-seq and array data that has been published to date. Our molecular staging model will significantly advance understanding of endometrial-related disorders that affect nearly all women at some stage of their lives, such as heavy menstrual bleeding, endometriosis, adenomyosis, and recurrent implantation failure.

Pestilence, Plague and Pandemics: A Troubled History.

Humankind has lived with the danger of endemic, epidemic and pandemic disease for thousands of years. The effects of these outbreaks have often devastated human populations. Sixteen pandemic events causing an estimated 147 million deaths have occurred since the eighth century, The Black Death and the influenza pandemic of 1918-1920 probably having the greatest impact. Animal populations, both wild and domestic, have similarly suffered devastating outbreaks of disease which, on occasions, have translated into serious effects on human health. The deliberate or accidental introduction of animals into virgin areas has given rise to unforeseen disease events occasionally leading to extinction. Similarly, human intent or negligence and the vagaries of nature itself has resulted in ill health and loss of life. This paper describes the history of pandemics, epidemics and disasters, and the attempts to bring them under control.

A SHORT HISTORY OF OCCUPATIONAL DISEASE: 2. ASBESTOS, CHEMICALS, RADIUM AND BEYOND.

Historically, the weighing out and manipulation of dangerous chemicals frequently occurred without adequate protection from inhalation or accidental ingestion. The use of gloves, eye protection using goggles, masks or visors was scant. From Canary Girls and chimney sweeps to miners, stone cutters and silo fillers, these are classic exemplars of the subtle (and in some cases not so subtle) effects that substances, environments and practices can have on individual health.

A SHORT HISTORY OF OCCUPATIONAL DISEASE: 1. LABORATORY-ACQUIRED INFECTIONS.

Laboratory-acquired infections are as old as laboratories themselves. As soon as the culture of microorganisms was introduced, so too was their transfer to laboratory workers. It is only in relatively recent history that such infections have been fully understood, and methods of spread and their prevention or avoidance developed. This paper endeavours to provide an overview of the history of laboratory-acquired infection and the steps taken, particularly in the UK, for its prevention.

A SHORT HISTORY OF OCCUPATIONAL DISEASE: 3. LEISURE CAN MAKE YOU SICK.

The risk of infection associated with occupations can, and does, extend to certain leisure and sports activities. Generally, such pastimes are regarded as important for human health and mental wellbeing. However, infections may, rarely, be acquired during leisure activities that include water sports and water-related relaxation, and certain sports.

Genetic risk factors for endometriosis near estrogen receptor 1 and coexpression of genes in this region in endometrium.

The etiology and pathogenesis of endometriosis are complex with both genetic and environmental factors contributing to disease risk. Genome-wide association studies (GWAS) have identified multiple signals in the estrogen receptor 1 (ESR1) region associated with endometriosis and other reproductive traits and diseases. In addition, candidate gene association studies identified signals in the ESR1 region associated with endometriosis risk suggesting genetic regulation of genes in this region may be important for reproductive health. This study aimed to investigate hormonal and genetic regulation of genes in the ESR1 region in human endometrium. Changes in serum oestradiol and progesterone concentrations and expression of hormone receptors ESR1 and progesterone receptor (PGR) were assessed in endometrial samples from 135 women collected at various stages of the menstrual cycle. Correlation between hormone concentrations, receptor expression and expression of genes in the ESR1 locus was investigated. The effect of endometriosis risk variants on expression of genes in the region was analyzed to identify gene targets. Hormone concentrations and receptor expression varied significantly across the menstrual cycle. Expression of genes in the ESR1 region correlated with progesterone concentration; however, they were more strongly correlated with expression of ESR1 and PGR suggesting coregulation of genes. There was no evidence that endometriosis risk variants directly regulated expression of genes in the region. Limited sample size and cellular heterogeneity in endometrial tissue may impact the ability to detect significant genetic effects on gene expression. Effects of these variants should be validated in a larger dataset and in relevant individual cell types.

Genome-wide association and epidemiological analyses reveal common genetic origins between uterine leiomyomata and endometriosis.

Uterine leiomyomata (UL) are the most common neoplasms of the female reproductive tract and primary cause for hysterectomy, leading to considerable morbidity and high economic burden. Here we conduct a GWAS meta-analysis in 35,474 cases and 267,505 female controls of European ancestry, identifying eight novel genome-wide significant (P < 5 × 10-8) loci, in addition to confirming 21 previously reported loci, including multiple independent signals at 10 loci. Phenotypic stratification of UL by heavy menstrual bleeding in 3409 cases and 199,171 female controls reveals genome-wide significant associations at three of the 29 UL loci: 5p15.33 (TERT), 5q35.2 (FGFR4) and 11q22.3 (ATM). Four loci identified in the meta-analysis are also associated with endometriosis risk; an epidemiological meta-analysis across 402,868 women suggests at least a doubling of risk for UL diagnosis among those with a history of endometriosis. These findings increase our understanding of genetic contribution and biology underlying UL development, and suggest overlapping genetic origins with endometriosis.

Generation of immortalized human endometrial stromal cell lines with different endometriosis risk genotypes.

Endometriotic lesions are composed in part of endometrial-like stromal cells, however, there is a shortage of immortalized human endometrial stromal cultures available for research. As genetic factors play a role in endometriosis risk, it is important that genotype is also incorporated into analysis of pathological mechanisms. Human telomerase reverse transcriptase (hTERT) immortalization (using Lenti-hTERT-green fluorescent protein virus) took place following genotype selection; 13 patients homozygous for either the risk or non-risk 'other' allele for one or more important endometriosis risk single nucleotide polymorphism on chromosome 1p36.12 (rs3820282, rs56318008, rs55938609, rs12037376, rs7521902 or rs12061255). Short tandem repeat DNA profiling validated that donor tissue matched that of the immortalized cell lines and confirmed that cultures were genetically novel. Expression of morphological markers (vimentin and cytokeratin) and key genes of interest (telomerase, estrogen and progesterone receptors and LINC00339) were examined and functional assays for cell proliferation, steroid hormone and inflammatory responses were performed for 7/13 cultures. All endometrial stromal cell lines maintained their fibroblast-like morphology (vimentin-positive) and homozygous endometriosis-risk genotype following introduction of hTERT. Furthermore, the new stromal cultures demonstrated positive and diverse responses to hormones (proliferation and decidualisation changes) and inflammation (dose-dependent response), while maintaining hormone receptor expression. In conclusion, we successfully developed a range of human endometrial stromal cell lines that carry important endometriosis-risk alleles. The wider implications of this approach go beyond advancing endometriosis research; these cell lines will be valuable tools for multiple endometrial pathologies offering a level of genetic and phenotypic diversity not previously available.

Copy number variation and variant discovery in Bullmastiff dogs.

Identification of genomic variants within dogs is important for understanding genetic factors contributing to breed diversity and phenotypic traits. This study aimed to identify sources of variation in the Bullmastiff using high-density signal intensity and whole-genome sequence data. Close to 3000 copy number variants (CNVs) were identified in Bullmastiff dogs using Canine HD BeadChip data. When CNVs were collated, 82 CNV regions (CNVRs) were detected, 50% in transcribed regions encompassing 432 genes. Fifty of the CNVRs detected have not been reported in other breeds and represent potential breed-specific variants. A proportion of the CNVR variants with predicted modifying effects on gene pathways may contribute to breed traits. Approximately 5 million putative variants per dog, inclusive of single nucleotide polymorphisms (SNPs), multi-nucleotide polymorphisms (MNPs) and insertion and deletions (INDELs), were identified from DNA sequence data on a small number of animals. Identification of genetic variants in the Bullmastiff highlights sources of variation in the breed and molecular markers that will assist in future trait and disease investigations in dogs.

Rubella antibody status of patients attending a south-west London antenatal clinic, 2007-2012.

Mass vaccination with the measles-mumps-rubella (MMR) vaccine for children aged 12-15 months was introduced in 1988; schoolgirl vaccination was discontinued in 1996 and replaced by a second dose of MMR for preschool children and post-partum vaccination of susceptible women identified through antenatal testing. In the UK, declining uptake rates due to concerns about the MMR vaccine, and increasing numbers of cases in some European countries where rubella surveillance and preconceptional vaccination are inadequate, coupled with poor uptake rates, has started to show in the number of rubella-susceptible patients presenting at antenatal clinics (ANCs). In this study, samples were collected in serum separator tubes at the West Middlesex University Hospital (WMUH) ANC and sent to the laboratory. Rubella status was determined using a third-generation rubella IgG enzyme immunoassay. Any negative results were retested and confirmed using an alternative method. The concentrations were expressed as iu/mL (World Health Organization [WHO] standard). Over a five-year period, the number of rubella-susceptible patients increased from 4.1% to 6.8% of the total number of specimens tested. The current population susceptibility levels seem to be influenced by a number of factors: the target population, age at vaccination and the level of coverage, and exposure to wild virus.