RESUMO
KEY CONTENT: Following the diagnosis of absolute uterine factor infertility (AUFI), women may experience considerable psychological harm as a result of a loss of reproductive function and the realisation of permanent and irreversible infertility.Adoption enables women with AUFI, and their partners, to experience social and legal parenthood, also often providing benefits for the adopted child.Surrogacy offers the opportunity to have genetically related offspring. Outcomes are generally positive in both surrogates and the children born as a result.Uterine transplantation is the only option to restore reproductive anatomy and functionality. While associated with considerable risk, it allows the experience of gestation and the achievement of biological, social and legal parenthood. LEARNING OBJECTIVES: To gain an understanding of the routes to parenthood available for women with AUFI experiencing involuntary childlessness, such as adoption, surrogacy and, most recently, uterine transplantationTo consider a suggested management plan to facilitate counselling in women with AUFI who experience involuntary childlessness. ETHICAL ISSUES: In the UK, while the number of children requiring adoption continues to increase, the number being adopted from care is decreasing.Some cultures may hold ethical or religious beliefs that surrogacy is unacceptable, and its legal position in many jurisdictions is problematic.Restrictive selection criteria and high costs may limit future availability of uterine transplantation.
RESUMO
Variants of human paraoxonase 1 (PON1) are being developed as catalytic bioscavengers for the organophosphorus chemical warfare agents (OP). It is preferable that the new PON1 variants have broad spectrum hydrolase activities to hydrolyze both G- and V-class OPs. H115W PON1 has shown improvements over wild type PON1 in its capacity to hydrolyze some OP compounds. We improved upon these activities either by substituting a tryptophan (F347W) near the putative active site residues for enhanced substrate binding or by reducing a bulky group (Y71A) at the periphery of the putative enzyme active site. When compared to H115W alone, we found that H115W/Y71A and H115W/F347W maintained VX catalytic efficiency but showed mixed results for the capacity to hydrolyze paraoxon. Testing our double mutants against racemic sarin, we observed reduced values of K(M) for H115W/F347W that modestly improved catalytic efficiency over wild type and H115W. Contrary to previous reports, we show that H115W can hydrolyze soman, and the double mutant H115W/Y71A is nearly 4-fold more efficient than H115W for paraoxon hydrolysis. We also observed modest stereoselectivity for hydrolysis of the P(-) stereoisomer of tabun by H115W/F347W. These data demonstrate enhancements made in PON1 for the purpose of developing an improved catalytic bioscavenger to protect cholinesterase against chemical warfare agents.
