Estrogen plays an essential role in the growth and maturation of the mammalian oocyte, and recent studies suggest that it also influences follicle formation in the neonatal ovary. In the course of studies designed to assess the effect of the estrogenic chemical bisphenol A (BPA) on mammalian oogenesis, we uncovered an estrogenic effect at an even earlier stage of oocyte development—at the onset of meiosis in the fetal ovary. Pregnant mice were treated with low, environmentally relevant doses of BPA during mid-gestation to assess the effect of BPA on the developing ovary. Oocytes from exposed female fetuses displayed gross aberrations in meiotic prophase, including synaptic defects and increased levels of recombination. In the mature female, these aberrations were translated into an increase in aneuploid eggs and embryos. Surprisingly, we observed the same constellation of meiotic defects in fetal ovaries of mice homozygous for a targeted disruption of ERβ, one of the two known estrogen receptors. This, coupled with the finding that BPA exposure elicited no additional effects in ERβ null females, suggests that BPA exerts its effect on the early oocyte by interfering with the actions of ERβ. Together, our results show that BPA can influence early meiotic events and, importantly, indicate that the oocyte itself may be directly responsive to estrogen during early oogenesis. This raises concern that brief exposures during fetal development to substances that mimic or antagonize the effects of estrogen may adversely influence oocyte development in the exposed female fetus.

The requirement for oxidative metabolism of pyruvate during oogenesis in vivo was evaluated by inactivating Pdha1, a gene encoding an enzymatic subunit of pyruvate dehydrogenase complex, in murine oocytes at the beginning of the follicular growth phase. Immunohistochemical analysis revealed that Pdha1(-) oocytes have dramatically reduced amounts of pyruvate dehydrogenase enzyme by the secondary follicle stage. Despite this reduction, these oocytes grow to normal size, are ovulated, and can be fertilized. Pdha1(-) oocytes are, however, impaired in their ability to support embryonic development, as demonstrated by the failure of fertilized oocytes to develop beyond the one-cell zygote stage in vivo. Immunocytochemical evaluation showed that almost all (98.4%) ovulated Pdha1(-) oocytes have not completed meiotic maturation and/or have gross abnormalities of the meiotic spindle and chromatin. Meiotic maturation is even more compromised when these oocytes are matured in vitro in the absence of cumulus cells or in the presence of the gap junction inhibitor 18-alpha glycyrrhetinic acid, indicating that cumulus cells can partially compensate for this enzymatic deficiency through a gap junction-mediated mechanism. Ovulated Pdha1(-) oocytes were also shown to have reduced levels of total ATP content and NAD(P)H autofluorescence relative to oocytes without this enzymatic deficiency. These studies demonstrate that oxidative metabolism of pyruvate is essential for proper completion of oogenesis, serving as a vital source of energy during meiotic maturation. At earlier stages of oogenesis this metabolic pathway may not be necessary due to metabolic compensation by the granulosa cells.

Combined homicide-suicides have been classified based on the psychopathology of the perpetrator and the nature of the relationship between perpetrator and victim(s). To further understand the nature of this tragic phenomenon and to test the validity and practicality of a previously suggested classification system, investigators systematically collected data on all combined homicide-suicide events that occurred in Galveston County, Texas over a continuous 18-year period (n = 20). The most common psychopathological finding for perpetrators was high serum alcohol levels that suggested intoxication. Most combined homicide-suicides fell into one of the relational categories and most of these, as predicted, were of the consortial type, possessive subtype. As expected, due to the small sample size, the less common types of combined homicide-suicide were not represented in this sample.

The two children who form the subject of this paper were shown at the Section for the Study of Disease in Children of the Royal Society of Medicine on March 25, 1938, when it was considered that they were examples of a previously undescribed condition (Freeman and Sheldon, 1938). Both cases exemplify a number of similar features, and as there can be little doubt that these go together to form one disease entity, a full account is offered in view of the fact that this appears to be its first description. Clinical Records Case 1. A male aged two years nine months, with no relevant family history or consanguinity of parents, was an elder child, the second baby being normal. The patient was a seven-and-one-half-months baby, born by normal labour without instruments. The weight at birth was 34 lb. including clothes. His appearance at birth caused such consternation 'that he was taken downstairs and shown to the grandmother, and then put out to die.' The legs were born fully flexed on the trunk in a ' Buddha ' position, and at the back of the head was a lump described as 'jelly-blood' which disappeared naturally in some three or four days. The nature of this is uncertain. Its description is not that of a cephalhaematoma, and neither by x-rays nor clinically is there now any evidence of abnormality in the posterior part of the head. The face was abnormal. The lower forehead and eyebrows were occupied by a soft but prominent transverse swelling and the eyes were buried so deeply that they were hardly visible. The nose could barely be recognized and the mouth was small. In addition to these features, the hands showed ulnar deviation and the feet a severe degree of talipes equino-varus. In spite of the immediate reaction to his appearance in the world, efforts were made to rear him, which were all the more difficult in that for some days he was unable to suckle owing to difficulty in swallowing. He was fed with drops of fluid from an eyedropper, since more than one drop at a time ' stuck in his throat.' Eventually swallowing became normal, and he was reared on a dried milk. On account of the deformity in the feet he was sent to the Orthopaedic Department of the Royal Hospital, Wolverhampton, when a fortnight old. He continued to receive treatment for the feet until May, 1937 (age twenty-three months), when he was admitted under Mr. R. Milnes Walker, F.R.C.S., Hon. Surgeon to the 277 copyright.