Performing Puberty: Fertile Complexions in Shakespeare's Plays

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Discussion required for correct interpretation

Thank you for the opportunity to comment on the editorial by Romero and colleagues [1], which raises a number of important and interesting questions. Such discussion is mandatory if results of scientific techniques such as gene array are to be correctly interpreted and used as the basis for future improvements in patient care

Labor-associated gene expression in the human uterine fundus, lower segment, and cervix

Background Preterm labor, failure to progress, and postpartum hemorrhage are the common causes of maternal and neonatal mortality or morbidity. All result from defects in the complex mechanisms controlling labor, which coordinate changes in the uterine fundus, lower segment, and cervix. We aimed to assess labor-associated gene expression profiles in these functionally distinct areas of the human uterus by using microarrays. Methods and Findings Samples of uterine fundus, lower segment, and cervix were obtained from patients at term (mean +/- 6 SD = 39.1 +/- 0.5 wk) prior to the onset of labor (n = 6), or in active phase of labor with spontaneous onset (n = 7). Expression of 12,626 genes was evaluated using microarrays ( Human Genome U95A; Affymetrix) and compared between labor and non-labor samples. Genes with the largest labor-associated change and the lowest variability in expression are likely to be fundamental for parturition, so gene expression was ranked accordingly. From 500 genes with the highest rank we identified genes with similar expression profiles using two independent clustering techniques. Sets of genes with a probability of chance grouping by both techniques less than 0.01 represented 71.2%, 81.8%, and 79.8% of the 500 genes in the fundus, lower segment, and cervix, respectively. We identified 14, 14, and 12 those sets of genes in the fundus, lower segment, and cervix, respectively. This enabled networks of coregulated and co-expressed genes to be discovered. Many genes within the same cluster shared similar functions or had functions pertinent to the process of labor. Conclusions Our results provide support for many of the established processes of parturition and also describe novel-to-labor genes not previously associated with this process. The elucidation of these mechanisms likely to be fundamental for controlling labor is an important prerequisite to the development of effective treatments for major obstetric problems - including prematurity, with its long-term consequences to the health of mother and offspring

Cyclic AMP increases COX-2 expression via mitogen-activated kinase in human myometrial cells

Cyclic AMP (cAMP) is the archetypal smooth muscle relaxant, mediating the effects of many hormones and drugs. However, recently PGI2, acting via cAMP/PKA, was found to increase contraction-associated protein expression in myometrial cells and to promote oxytocin-driven myometrial contractility. Cyclo-oxygenase-2 (COX-2) is the rate-limiting enzyme in prostaglandin synthesis, which is critical to the onset and progression of human labour. We have investigated the impact of cAMP on myometrial COX-2 expression, synthesis and activity. Three cAMP agonists (8-bromo-cAMP, forskolin and rolipram) increased COX-2 mRNA expression and further studies confirmed that this was associated with COX-2 protein synthesis and activity (increased PGE2 and PGI2 in culture supernatant) in primary cultures of human myometrial cells. These effects were neither reproduced by specific agonists nor inhibited by specific inhibitors of known cAMP-effectors (PKA, EPAC and AMPK). We then used shRNA to knockdown the same effectors and another recently described cAMP-effector PDZ-GEF1-2, without changing the response to cAMP. We found that MAPK activation mediated the cAMP effects on COX-2 expression and that PGE2 acts through EP-2 to activate MAPK and increase COX-2. These data provide further evidence in support of a dual role for cAMP in the regulation of myometrial function

Asymmetric synthesis using sulfimides

Asymmetric synthesis, the synthesis of chiral molecules, has developed into one of the most important areas of chemistry. Numerous methods are used to prepare chiral compounds, one of which involves using chiral acyl anion equivalents. The potential of imides of cyclic sulfimides 148 as chiral acyl anion equivalents was found to be limited to simple alkylations using sodium hydride and an alkyl iodide in DMF. Alkylated adducts 154,158 and 159 were prepared with good diastereoselectivity, with the anti and anti-anti geometries being preferred for 154 and 158, and 159, respectively. The conformations of the parent sulfimides 148 were investigated. We found that cyclic sulfimides (1,3,4-oxathiazines) 132 were inaccessible, which precluded our investigation into the potential of this new class of compound as chiral acyl anion equivalents. In the course of this work, the BPTM group was developed as a replacement for the troublesome PTM group as a protecting group for primary, secondary and benzylic alcohols. Vinyl sulfimides 186 were prepared using a modified Wadsworth-Emmons reaction, with good E selectivity. Additions of alcohols to give adducts 185 proceeded with good diastereoselectivity. The attempted deprotection of adduct 185b using hydrogenolysis resulted in reduction of the sulfimide group to yield protected ß-hydroxy sulfide 192. Radical additions to vinyl sulfimides 186 resulted in 2-vinyl oxa-heterocycles 202 and 210, with THE and THP as solvent, respectively. A radical addition mechanism has been proposed, but uncertainty still exists as this mechanism can not explain both triethylborane and benzoyl peroxide mediated reactions as the E/Z selectivities are different. At this stage, an ionic mechanism can not be ruled out. 2-Vinyl oxa-heterocycles 202 and 210 have been converted, using Taylor's variant of the Malherbe-Bellus reaction, into 9- and 10-membered lactones 220 and 221, respectively, which are closely related to a number of important natural products. Considerable progress has been made in developing a new asymmetric sulfimidation procedure. Promising enantioselectivites have been observed using a copper-catalysed decompsition of tosyl azide or PhI=NTs 224 into nitrenes. Interception of the nitrenes by sulfide within the chiral influence of C-2 symmetric chiral ligands 225 or 231 yielded sulfimide 65. A discrete copper-nitrene species is thought to be an intermediate in the catalytic cycle

Black, White and Blue: Pregnancy and Unsettled Binaries in The Masque of Blackness (1605)

This article examines the construction of national and racial identities within Ben Jonson’s and Inigo Jones’s Masque of Blackness against the backdrop of King James’ investment in creating a ‘British’ union at the start of his reign. The article re-examines the blackface performance of the Queen and her ladies in the contexts of the Queen’s and Inigo Jones’ European connections, the Queen’s reputation as ‘wilful’, and her pregnant body’s ability to evoke widespread cultural beliefs about the maternal imagination’s power to determine a child’s racial make-up. We argue that the masque’s striking use of blue-face along with black and white-face reveals a deep investment in Britain’s ancient customs which stands in tension with Blackness’ showcasing of foreign bodies, technologies, and cultural reference points. By demonstrating the significance of understanding Queen Anna’s pregnancy and her ‘wilful’ personality within the context of early modern humoral theory, moreover, we develop existing discussions of the humoral theory that underpins the masque’s representation of racial identities. We suggest that the Queen’s pregnant performance in blackface, by reminding the viewer that her maternal mind could ‘will’ the racial identity of royal progeny into being, had the power to unsettle King James I’s white male nationalist supremacy in the very act of celebrating it before their new English court and its foreign guests

Is rat an appropriate animal model to study the involvement of d-serine catabolism in schizophrenia? insights from characterization of d-amino acid oxidase.

d-Amino acid oxidase (DAAO; EC1.4.3.3) has been proposed to play a main role in the degradation of d-serine, an allosteric activator of the N-methyl-d-aspartate-type glutamate receptor in the human brain, and to be associated with the onset of schizophrenia. To prevent excessive d-serine degradation, novel drugs for schizophrenia treatment based on DAAO inhibition were designed and tested on rats. However, the properties of rat DAAO are unknown and various in\u2003vivo trials have demonstrated the effects of DAAO inhibitors on d-serine concentration in rats. In the present study, rat DAAO was efficiently expressed in Escherichia\u2003coli. The recombinant enzyme was purified as an active, 40\u2003kDa monomeric flavoenzyme showing the basic properties of the dehydrogenase-oxidase class of flavoproteins. Rat DAAO differs significantly from the human counterpart because: (a) it possesses a different substrate specificity; (b) it shows a lower kinetic efficiency, mainly as a result of a low substrate affinity; (c) it differs in affinity for the binding of classical inhibitors; (d) it is a stable monomer in the absence of an active site ligand; and (e) it interacts with the mammalian protein modulator pLG72 yielding a 3c\u2003100\u2003kDa complex in addition to the 3c\u2003200\u2003kDa one, as formed by the human DAAO. Furthermore, the concentration of endogenous d-serine in U87 glioblastoma cells was not affected by transfection with rat DAAO, whereas it was significantly decreased when expressing the human homologue. These results raise doubt on the use of the rat as a model system for testing new drugs against schizophrenia and indicate a different physiological function of DAAO in rodents and humans. Structured digital abstract \u2022 \u2002pLG72\ua0binds\u2003rDAAO\u2003by\u2003molecular sieving\u2003(View interaction)

A Qualitative Study of an Integrated Maternity, Drugs and Social Care Service for Drug-using Women

Background: The care of drug-using pregnant women is a growing health and social care concern in many countries. A specialist clinic was established offering multidisciplinary care and advice to pregnant drug users in and around Aberdeen (UK) in 1997. The majority of women stabilise and reduce their drug use. By determining the needs and views of the women more appropriate services and prevention strategies may be developed. There has been little research conducted in this area and none in Scotland. Methods: This is a qualitative study that aimed to gain an understanding of the experiences of women drug users, seeking and receiving prenatal care and drug services from a specialist clinic. Twelve women participated in semi-structured one-to-one interviews. Results: The women preferred the multidisciplinary clinic (one-stop shop) to traditional prenatal care centred within General Practice. The relationships of the clients to the range of Clinic professionals and in hospital were explored as well as attitudes to Clinic care. The study participants attributed success in reducing their drug use to the combination of different aspects of care of the multi-agency clinic, especially the high level prenatal support. It is this arrangement of all aspects of care together that seem to produce better outcomes for mother and child than single care elements delivered separately. Some women reported that their pregnancy encouraged them to rapidly detoxify due to the guilt experienced. The most important aspects of the Clinic care were found to be non-judgemental attitude of staff, consistent staff, high level of support, reliable information and multi-agency integrated care. Conclusion: There is an impetus for women drug users to change lifestyle during pregnancy. The study highlighted a need for women to have access to reliable information on the effects of drugs on the baby. Further research is required to determine whether positive outcomes related to clinic attendance in the prenatal period are sustained in the postnatal period. Early referral to a specialist clinic is of benefit to the women, as they reported to receive more appropriate care, especially in relation to their drug use. A greater awareness of needs of the pregnant drug user could help the design of more effective prevention strategies

Poundbury Camp in context – a new perspective on the lives of children from urban and rural Roman England

Objectives The current understanding of child morbidity in Roman England is dominated by studies of single sites/regions. Much of the data are derived from third to fifth century AD Poundbury Camp, Dorchester, Dorset, considered an unusual site due to high levels of non-adult morbidity. There is little understanding of children in rural areas, and whether Poundbury Camp was representative of Romano-British childhood. Materials and methods The study provides the first large scale analysis of child health in urban and rural Roman England, adding to the previously published intra-site analysis of non-adult paleopathology at Poundbury Camp. Age-at-death and pathology prevalence rates were reassessed for 953 non-adults (0–17 years) from five major urban, six minor urban, and four rural sites (first to fifth century AD). The data were compared to the results from 364 non-adults from Poundbury Camp. Results Rural sites demonstrated higher levels of infant burials, and greater prevalence of cribra orbitalia in the 1.1–2.5 year (TPR 64.3%), and 6.6–10.5 year cohorts (TPR 66.7%). Endocranial lesions were more frequent in the minor urban sample (TPR 15.9%). Three new cases of tuberculosis were identified in urban contexts. Vitamin D deficiency was most prevalent at Poundbury Camp (CPR 18.8%), vitamin C deficiency was identified more frequently in rural settlements (CPR 5.9%). Discussion The Poundbury Camp data on morbidity and mortality are not representative of patterns in Roman England and other major urban sites. Rural children suffered from a distinct set of pathologies described as diseases of deprivation, prompting reconsideration of how Romano-British land management affected those at the bottom of the social hierarchy