Vaginal progesterone prophylaxis for preterm birth (the OPPTIMUM study) : a multicentre, randomised, double-blind trial

Acknowledgments We thank the members of the Trial Steering and Data Monitoring Committee and all the people who helped in the conduct of the study (including the OPPTIMUM collaborative group and other clinicians listed in the appendix). We are grateful to Paul Piette (Besins Healthcare Corporate, Brussels, Belgium) and Besins Healthcare for their kind donation of active and placebo drug for use in the study, and to staff of the pharmacy and research and development departments of the participating hospitals. We are also grateful to the many people who helped in this study but who we have been unable to name, and in particular all the women (and their babies) who participated in OPPTIMUM. OPPTIMUM was funded by the Efficacy and Mechanism Evaluation (EME) Programme, a Medical Research Council (MRC) and National Institute of Health Research (NIHR) partnership, award number G0700452, revised to 09/800/27. The EME Programme is funded by the MRC and NIHR, with contributions from the Chief Scientist Office in Scotland and National Institute for Social Care and Research in Wales. The views expressed in this publication are those of the author(s) and not necessarily those of the MRC, National Health Service, NIHR, or the Department of Health. The funder had no involvement in data collection, analysis or interpretation, and no role in the writing of this manuscript or the decision to submit for publication.

Purifying selection and birth-and-death evolution in the ubiquitin gene family

Ubiquitin is a highly conserved protein that is encoded by a multigene family. It is generally believed that this gene family is subject to concerted evolution, which homogenizes the member genes of the family. However, protein homogeneity can be attained also by strong purifying selection. We therefore studied the proportion (pS) of synonymous nucleotide differences between members of the ubiquitin gene family from 28 species of fungi, plants, and animals. The results have shown that pS is generally very high and is often close to the saturation level, although the protein sequence is virtually identical for all ubiquitins from fungi, plants, and animals. A small proportion of species showed a low level of pS values, but these values appeared to be caused by recent gene duplication. It was also found that the number of repeat copies of the gene family varies considerably with species, and some species harbor pseudogenes. These observations suggest that the members of this gene family evolve almost independently by silent nucleotide substitution and are subjected to birth-and-death evolution at the DNA level.

Backtracking leukemia to birth: Identification of clonotypic gene fusion sequences in neonatal blood spots

Epidemiological evidence has suggested that some pediatric leukemias may be initiated in utero and, for some pairs of identical twins with concordant leukemia, this possibility has been strongly endorsed by molecular studies of clonality. Direct evidence for a prenatal origin can only be derived by prospective or retrospective detection of leukemia-specific molecular abnormalities in fetal or newborn samples. We report a PCR-based method that has been developed to scrutinize neonatal blood spots (Guthrie cards) for the presence of numerically infrequent leukemic cells at birth in individuals who subsequently developed leukemia. We demonstrate that unique or clonotypic MLL-AF4 genomic fusion sequences are present and detectable in neonatal blood spots from individuals who were diagnosed with acute lymphoblastic leukemia at ages 5 months to 2 years and, therefore, have arisen during fetal hematopoiesis in utero. This result provides unequivocal evidence for a prenatal initiation of acute leukemia in young patients. The method should be applicable to other fusion genes in children with common subtypes of leukemia and will be of value in attempts to unravel the natural history and etiology of this major subtype of pediatric cancer.

Numbers of deaths related to intrapartum asphyxia and timing of birth in all Wales perinatal survey, 1993-5

Objectives: To investigate the relation between the timing of birth and the occurrence of death related to an intrapartum event.