Gene therapy for obstetric conditions

The first clinical trials of gene therapy in the 1990s offered the promise of a new paradigm for the treatment of genetic diseases. Over the decades that followed the challenges and setbacks which gene therapy faced often overshadowed any successes. Despite this, recent years have seen cause for renewed optimism. In 2012 Glybera™, an adeno-associated viral vector expressing lipoprotein lipase, became the first gene therapy product to receive marketing authorisation in Europe, with a licence to treat familial lipoprotein lipase deficiency. This followed the earlier licensing in China of two gene therapies: Gendicine™ for head and neck squamous cell carcinoma and Oncorine™ for late-stage nasopharyngeal cancer. By this stage over 1800 clinical trials had been, or were being, conducted worldwide, and the therapeutic targets had expanded far beyond purely genetic disorders. So far no trials of gene therapy have been carried out in pregnancy, but an increasing understanding of the molecular mechanisms underlying obstetric diseases means that it is likely to have a role to play in the future. This review will discuss how gene therapy works, its potential application in obstetric conditions and the risks and limitations associated with its use in this setting. It will also address the ethical and regulatory issues that will be faced by any potential clinical trial of gene therapy during pregnancy

Recent Advances in Cytogenetic Technology for Antenatal Genetic Testing

The examination of human chromosomes has been a part of the physician’s laboratory armamentarium since the correct diploid number of human chromosomes was established and a method was developed for the in vitro growth of peripheral blood leukocytes to yield metaphase chromosomes. The discovery that on ultraviolet microscopy (UV), metaphase chromosomes stained with fluorochrome dyes displayed a characteristic pattern of bright and dull bands unique for a given pair of homologous chromosomes, was a major technological breakthrough in human cytogenetics; for the first time, every chromosome in the karyotype could be unequivocally identified. Although the short storage life of fluorochrome-stained chromosomes and the costs of UV microscopy have limited the usability of fluorescence banding, the introduction of one discriminating procedure quickly led to the development of an array of similar banding techniques for conventional microscopy that yield comparable information. Some of these technical procedures depend on enzyme and/or heat denaturation of the chromosomes, resulting in the characteristic banding patterns seen by the trypsin-Giemsa method, the 5M urea method, and the acid-saline-Giemsa technique. A typical human karyotype prepared from metaphase chromosomes treated with trypsin, stained with Giemsa, and photographed with brightfield photomicrographic techniques is shown in Figure 1. Careful examination of this karyotype reveals that each chromosome in the homologous pair has an array of dark and light bands identical with those of its homolog and that each homologous pair, autosomes number 1 to number 22, has a characteristic, easily identifiable banding pattern

The Histone Deacetylase Complex (HDC) 1 protein of Arabidopsis thaliana has the capacity to interact with multiple proteins including histone 3-binding proteins and histone 1 variants

Intrinsically disordered proteins can adopt multiple conformations thereby enabling interaction with a wide variety of partners. They often serve as hubs in protein interaction networks. We have previously shown that the Histone Deacetylase Complex (HDC) 1 protein from Arabidopsis thaliana interacts with histone deacetylases and quantitatively determines histone acetylation levels, transcriptional activity and several phenotypes, including ABA-sensitivity during germination, vegetative growth rate and flowering time. HDC1-type proteins are ubiquitous in plants but they contain no known structural or functional domains. Here we explored the protein interaction spectrum of HDC1. In addition to binding histone deacetylases, HDC1 directly interacted with core histone H3-binding proteins and co-repressor associated proteins, but not with H3 or the co-repressors themselves. Surprisingly, HDC1 was also able to interact with variants of the linker histone H1. Truncation of HDC1 to the ancestral core sequence narrowed the spectrum of interactions and of phenotypic outputs but maintained binding to a H3-binding protein and to H1. The results indicate a potential link between H1 and histone modifying complexes

Development and evaluation of an interactive multimedia clinical skills teaching program designed for the pediatric clerkship.

Background and Purpose: The physical examination section of a multimedia program developed to teach infant history and physical examination skills was evaluated. Methods: 71 students participated: one group viewed only the physical examination section (PX), one the history section (HX), one none of the program (CX). Physical examination skills were assessed by direct observation of medical students performing an abdominal exam and scored using a checklist at baseline, immediately after intervention and at the end of the pediatric clerkship. Results were analyzed using ANOVA with repeated measures. Results: Baseline scores were: PX 2.5; HX 2.8. The PX group scored significantly higher immediately post intervention at 6.8 compared to the HX group 3.1. At the end of the clerkship significant differences between the groups remained. Final group mean scores were: PX 5.5, HX 4.4 and CX 2.7. Conclusion: The program improved examination skills with attenuation over 6 weeks

The Beginning of the End of the Anthropic Principle

We argue that if string theory as an approach to the fundamental laws of physics is correct, then there is almost no room for anthropic arguments in cosmology. The quark and lepton masses and interaction strengths are determined.Comment: 12 page

Identity, enlightenment and political dissent in late colonial Spanish America

During the long crisis of the Spanish empire between 1810 and 1825, the Creole leaders of Spanish American independence asserted a new identity for the citizens of the states which they sought to establish, calling them 'Americanos'. This general title was paralleled and often supplanted by other political neologisms, as movements for independence and new polities took shape in the various territories of Spanish America. In New Spain, the insurgents who fought against royalist government during the decade after 181 o tried to rally fellow 'Mexicans' to a common cause; at independence in 1821, die Creole political leadership created a 'Mexican empire', the title of which, with its reference to the Aztec empire which had preceded Spain's conquest, was designed to evoke a 'national' history shared by all members of Mexican society. In South America, die leaders of the new republics also sought to promote patriotic feelings for territories which had been converted from administrative units of Spanish government into independent states. Thus, San Martin and O'Higgins convoked 'Chileans' to the cause of independence in the old Captaincy-General of Chile; shortly afterwards and with notably less success, San Martin called upon 'Peruvians' to throw off Spanish rule. Bolivar was, likewise, to call 'Colombians' to his banner in die erstwhile Viceroyalty of New Granada, before advancing south to liberate Peru in die name of 'Peruvians', and Upper Peru in die name of 'Bolivians', where die Republic which his military feats and political vision made possible was named after him

Standing wave instabilities in a chain of nonlinear coupled oscillators

We consider existence and stability properties of nonlinear spatially periodic or quasiperiodic standing waves (SWs) in one-dimensional lattices of coupled anharmonic oscillators. Specifically, we consider Klein-Gordon (KG) chains with either soft (e.g., Morse) or hard (e.g., quartic) on-site potentials, as well as discrete nonlinear Schroedinger (DNLS) chains approximating the small-amplitude dynamics of KG chains with weak inter-site coupling. The SWs are constructed as exact time-periodic multibreather solutions from the anticontinuous limit of uncoupled oscillators. In the validity regime of the DNLS approximation these solutions can be continued into the linear phonon band, where they merge into standard harmonic SWs. For SWs with incommensurate wave vectors, this continuation is associated with an inverse transition by breaking of analyticity. When the DNLS approximation is not valid, the continuation may be interrupted by bifurcations associated with resonances with higher harmonics of the SW. Concerning the stability, we identify one class of SWs which are always linearly stable close to the anticontinuous limit. However, approaching the linear limit all SWs with nontrivial wave vectors become unstable through oscillatory instabilities, persisting for arbitrarily small amplitudes in infinite lattices. Investigating the dynamics resulting from these instabilities, we find two qualitatively different regimes for wave vectors smaller than or larger than pi/2, respectively. In one regime persisting breathers are found, while in the other regime the system rapidly thermalizes.Comment: 57 pages, 21 figures, to be published in Physica D. Revised version: Figs. 5 and 12 (f) replaced, some new results added to Sec. 5, Sec.7 (Conclusions) extended, 3 references adde

The eventization of leisure and the strange death of alternative Leeds

The communicative potential of city spaces as leisure spaces is a central assumption of political activism and the creation of alternative, counter-cultural and subcultural scenes. However, such potential for city spaces is limited by the gentrification, privatization and eventization of city centres in the wake of wider societal and cultural struggles over leisure, work and identity formation. In this paper, we present research on alternative scenes in the city of Leeds to argue that the eventization of the city centre has led to a marginalization and of alternative scenes on the fringes of the city. Such marginalization has not caused the death of alternative Leeds or political activism associated with those scenes—but it has changed the leisure spaces (physical, political and social) in which alternative scenes contest the mainstream

Aoraki/Mt Cook and the Mackenzie Basin’s transition from wilderness to tourist place

The natural landscapes of New Zealand are a key attraction for domestic and international visitors for a variety of recreation and leisure purposes. This paper explores the interactions between heritage and recreational values for a region in New Zealand known for its sublime landscape (Bell and Lyall 2002). The paper discusses the transient movements and activities of visitors encountering this sociocultural landscape, often seeking to view the iconic landmark - Aoraki/Mt Cook – part of the Te Wahipounamu South West New Zealand World Heritage area – which is accessed via the Mackenzie Basin. Aoraki/Mt Cook National Park is a wilderness region that has significance not only for local inhabitants but also for travellers sightseeing and recreating in the area. Early inhabitants of the region – Māori from the Kai Tahu iwi (tribe) - visited the Mackenzie Basin‟s numerous waterways and lakes to gather mahika kai (traditional foods) and continue to have strong associations with the area. Since European settlement in the mid 19th century the Mackenzie landscape has been shaped by human activities, particularly farming, tourism and recreation

Increase in the surface energy of metal and polymeric surfaces using the one atmosphere uniform glow discharge plasma (OAUGDP).

Plasma processed materials are used in our daily lives. Increasing the surface energy of metal and polymeric materials can make possible better coating, printing, bonding, and dyeing of their surfaces. With the patented technology of a One Atmosphere Uniform Glow Discharge Plasma (OAUGDP) reactor developed at the UTK Plasma Sciences Laboratory, one can obtain up to 70 dynes/cm, or erg/cm2, in a few seconds of exposure for most materials. The surface energy is measured with a series of mixtures of reagent-grade formamide (HCONH) and reagent-grade ethyl cellosolve (CH CH O-CH OH), which span the range from 30 dynes/cm to 70 dynes/cm. Several polymeric films, including samples made from linear low density polyethylene (LLDPE), low density polyethylene (LDPE), and polyethylene terephathalate (PET) films, as well as metalized paper have been exposed at an RF frequency of 5 kHz and at 6 kV(RMS) for various exposure durations, including 1, 2, 5, 10, 15, 30 and 60 seconds. These samples were exposed in open air to check the aging effect at various times after exposure. The behavior of surface energy with time after exposure shows a wide range of behavior, depending on the specific material under test. Photomicrographs of the surfaces were taken after selected exposure durations, and the morphological characteristics of the surface compared to the surface energy measurements