Genetics update: monogenetics, polygene disorders and the quest for modifying genes

The genetic channelopathies are a broad collection of diseases. Many ion channel genes demonstrate wide phenotypic pleiotropy, but nonetheless concerted efforts have been made to characterise genotype-phenotype relationships. In this review we give an overview of the factors that influence genotype-phenotype relationships across this group of diseases as a whole, using specific individual channelopathies as examples. We suggest reasons for the limitations observed in these relationships. We discuss the role of ion channel variation in polygenic disease and highlight research that has contributed to unravelling the complex aetiological nature of these conditions. We focus specifically on the quest for modifying genes in inherited channelopathies, using the voltage-gated sodium channels as an example. Epilepsy related to genetic channelopathy is one area in which precision medicine is showing promise. We will discuss the successes and limitations of precision medicine in these conditions

The story of Oh: the aesthetics and rhetoric of a common vowel sound

Studies in Musical Theatre is the only peer-reviewed journal dedicated to musical theatre. It was launched in 2007 and is now in its seventh volume. It has an extensive international readership and is edited by Dominic Symonds and George Burrows. This article investigates the use of the ‘word’ ‘Oh’ in a variety of different performance idioms. Despite its lack of ‘meaning’, the sound is used in both conversation and poetic discourse, and I discuss how it operates communicatively and expressively through contextual resonances, aesthetic manipulation and rhetorical signification. The article first considers the aesthetically modernist work of Cathy Berberian in Bussotti’s La Passion Selon Sade; then it considers the rhetorically inflected use of ‘Oh’ to construct social resonance in popular song;finally, it discusses two important uses of the sound ‘Oh’ which bookend the Broadway musical Oklahoma!, serving to consolidate the allegorical and musico-dramatic narrative of the show

Automorphisms of Harbater-Katz-Gabber curves

Let k be a perfect field of characteristic p > 0, and let G be a finite group. We consider the pointed G-curves over k associated by Harbater, Katz, and Gabber to faithful actions of G on k[[t]] over k. We use such "HKG G-curves" to classify the automorphisms of k[[t]] of p-power order that can be expressed by particularly explicit formulas, namely those mapping t to a power series lying in a Z/pZ Artin-Schreier extension of k(t). In addition, we give necessary and sufficient criteria to decide when an HKG G-curve with an action of a larger finite group J is also an HKG J-curve.Comment: 25 pages. The introduction was rewritten. The final publication is available at Springer via http://dx.doi.org/10.1007/s00208-016-1490-

Estimation of a preference based single index from the sexual quality of life questionnaire (SQOL) using ordinal data

There is increasing interest in using ordinal methods to estimate cardinal values for health states to calculate quality adjusted life years. This paper reports the estimation of models of rank data and discrete choice experiment (DCE) data to derive a preference-based index from a condition specific measure relating to sexual health and to compare the results to values generated from time trade-off valuation (TTO). The DCE data were analysed using a random effects probit model and the DCE predicted values were rescaled according to the highest and lowest predicted TTO values corresponding to the best and worst SQOL health states respectively. The rank data were analysed using a rank ordered logit model and re-scaled using two alternative methods. Firstly, re-scaling the rank predicted values using identical methods to those employed for DCE and secondly, re-scaling the rank model coefficients by dividing each level coefficient by the coefficient relating to death. The study raises some important issues about the use of ordinal data to produce cardinal health state valuations

Does measurement technique explain the mismatch between European head size and WHO charts?

Objective To test whether different measuring techniques produce systematic differences in head size that could explain the large head circumferences found in Northern European children compared with the WHO standard. Design: Cross-sectional observational study. Setting: Scotland, UK. Patients: Study 1: 68 healthy children aged 0.4–18 months from mother and baby groups and a medical students teaching session. Study 2: 81 children aged 0.4 to 25 months from hospital wards and neonatal follow-up clinics. Interventions: Study 1: heads measured with plastic tape using both the WHO tight and UK loose technique. Study 2: heads measured using WHO research technique and a metal measuring tape and compared with routinely acquired measurements. Main outcome measures: Mean difference in head z-scores using WHO standard between the two methods. Results: The tight technique resulted in a mean (95% CI) z-score difference of 0.41 (0.27 to 0.54, p<0.001) in study 1 and 0.44 (0.36 to 0.53, p<0.001) in study 2. However, the mean WHO measurements in the healthy infants still produced a mean z-score that was two-third of a centile space (0.54 SD (0.28 to 0.79) p<0.001) above the 50th centile. Conclusion: The WHO measurement techniques produced significantly lower measures of head size, but average healthy Scottish children still had larger heads than the WHO standard using this method

Volcano remote sensing with ground-based spectroscopy

The chemical compositions and emission rates of volcanic gases carry important information about underground magmatic and hydrothermal conditions, with application in eruption forecasting. Volcanic plumes are also studied because of their impacts upon the atmosphere, climate and human health. Remote sensing techniques are being increasingly used in this field because they provide real-time data and can be applied at safe distances from the target, even throughout violent eruptive episodes. However, notwithstanding the many scientific insights into volcanic behaviour already achieved with these approaches, technological limitations have placed firm restrictions upon the utility of the acquired data. For instance, volcanic SO2 emission rate measurements are typically inaccurate (errors can be greater than 100%) and have poor time resolution (ca once per week). Volcanic gas geochemistry is currently being revolutionized by the recent implementation of a new generation of remote sensing tools, which are overcoming the above limitations and are providing degassing data of unprecedented quality. In this article, I review this field at this exciting point of transition, covering the techniques used and the insights thereby obtained, and I speculate upon the breakthroughs that are now tantalizingly close

Estimation of a preference based single index from the sexual quality of life questionnaire (SQOL) using ordinal data

There is increasing interest in using ordinal methods to estimate cardinal values for health states to calculate quality adjusted life years. This paper reports the estimation of models of rank data and discrete choice experiment (DCE) data to derive a preference-based index from a condition specific measure relating to sexual health and to compare the results to values generated from time trade-off valuation (TTO). The DCE data were analysed using a random effects probit model and the DCE predicted values were rescaled according to the highest and lowest predicted TTO values corresponding to the best and worst SQOL health states respectively. The rank data were analysed using a rank ordered logit model and re-scaled using two alternative methods. Firstly, re-scaling the rank predicted values using identical methods to those employed for DCE and secondly, re-scaling the rank model coefficients by dividing each level coefficient by the coefficient relating to death. The study raises some important issues about the use of ordinal data to produce cardinal health state valuations.sexual health, quality of life, preference-based measures

Estimation of a preference based single index from the sexual quality of life questionnaire (SQOL) using ordinal data

There is increasing interest in using ordinal methods to estimate cardinal values for health states to calculate quality adjusted life years. This paper reports the estimation of models of rank data and discrete choice experiment (DCE) data to derive a preference-based index from a condition specific measure relating to sexual health and to compare the results to values generated from time trade-off valuation (TTO). The DCE data were analysed using a random effects probit model and the DCE predicted values were rescaled according to the highest and lowest predicted TTO values corresponding to the best and worst SQOL health states respectively. The rank data were analysed using a rank ordered logit model and re-scaled using two alternative methods. Firstly, re-scaling the rank predicted values using identical methods to those employed for DCE and secondly, re-scaling the rank model coefficients by dividing each level coefficient by the coefficient relating to death. The study raises some important issues about the use of ordinal data to produce cardinal health state valuations

The transcription factors Egr2 and Egr3 are essential for the control of inflammation and antigen-induced proliferation of B and T cells

This article is available open access under a Creative Commons license (http://creativecommons.org/licenses/by-nc-nd/3.0/). Copyright @ 2012 Elsevier Inc.Lymphocytes provide optimal responses against pathogens with minimal inflammatory pathology. However, the intrinsic mechanisms regulating these responses are unknown. Here, we report that deletion of both transcription factors Egr2 and Egr3 in lymphocytes resulted in a lethal autoimmune syndrome with excessive serum proinflammatory cytokines but also impaired antigen receptor-induced proliferation of B and T cells. Egr2- and Egr3-defective B and T cells had hyperactive signal transducer and activator of transcription-1 (STAT1) and STAT3 while antigen receptor-induced activation of transcription factor AP-1 was severely impaired. We discovered that Egr2 and/or Egr3 directly induced expression of suppressor of cytokine signaling-1 (SOCS1) and SOCS3, inhibitors of STAT1 and STAT3, and also blocked the function of Batf, an AP-1 inhibitor, in B and T cells. Thus, Egr2 and Egr3 regulate B and T cell function in adaptive immune responses and homeostasis by promoting antigen receptor signaling and controlling inflammation.Arthritis Research U