The clinical implementation of non-invasive prenatal diagnosis for single-gene disorders: challenges and progress made

Recently, we have witnessed the rapid translation into clinical practice of non-invasive prenatal testing for the common aneuploidies, most notably within the United States and China. This represents a lucrative market with testing being driven by companies developing and offering their services. These tests are currently aimed at women with high/medium-risk pregnancies identified by serum screening and/or ultrasound scanning. Uptake has been impressive, albeit limited to the commercial sector. However, non-invasive prenatal diagnosis (NIPD) for single-gene disorders has attracted less interest, no doubt because this represents a much smaller market opportunity and in the majority of cases has to be provided on a bespoke, patient or disease-specific basis. The methods and workflows are labour-intensive and not readily scalable. Nonetheless, there exists a significant need for NIPD of single-gene disorders, and the continuing advances in technology and data analysis should facilitate the expansion of the NIPD test repertoire. Here, we review the progress that has been made to date, the different methods and platform technologies, the technical challenges, and assess how new developments may be applied to extend testing to a wider range of genetic disorders. © 2013 John Wiley & Sons, Ltd.     

Age- and Sex-Specific Thorax Finite Element Model Development and Simulation

Objective: The shape, size, bone density, and cortical thickness of the thoracic skeleton vary significantly with age and sex, which can affect the injury tolerance, especially in at-risk populations such as the elderly. Computational modeling has emerged as a powerful and versatile tool to assess injury risk. However, current computational models only represent certain ages and sexes in the population. The purpose of this study was to morph an existing finite element (FE) model of the thorax to depict thorax morphology for males and females of ages 30 and 70 years old (YO) and to investigate the effect on injury risk.

Methods: Age- and sex-specific FE models were developed using thin-plate spline interpolation. In order to execute the thin-plate spline interpolation, homologous landmarks on the reference, target, and FE model are required. An image segmentation and registration algorithm was used to collect homologous rib and sternum landmark data from males and females aged 0–100 years. The Generalized Procrustes Analysis was applied to the homologous landmark data to quantify age- and sex-specific isolated shape changes in the thorax. The Global Human Body Models Consortium (GHBMC) 50th percentile male occupant model was morphed to create age- and sex-specific thoracic shape change models (scaled to a 50th percentile male size). To evaluate the thoracic response, 2 loading cases (frontal hub impact and lateral impact) were simulated to assess the importance of geometric and material property changes with age and sex.

Results: Due to the geometric and material property changes with age and sex, there were observed differences in the response of the thorax in both the frontal and lateral impacts. Material property changes alone had little to no effect on the maximum thoracic force or the maximum percent compression. With age, the thorax becomes stiffer due to superior rotation of the ribs, which can result in increased bone strain that can increase the risk of fracture. For the 70-YO models, the simulations predicted a higher number of rib fractures in comparison to the 30-YO models. The male models experienced more superior rotation of the ribs in comparison to the female models, which resulted in a higher number of rib fractures for the males.

Conclusion: In this study, age- and sex-specific thoracic models were developed and the biomechanical response was studied using frontal and lateral impact simulations. The development of these age- and sex-specific FE models of the thorax will lead to an improved understanding of the complex relationship between thoracic geometry, age, sex, and injury risk.     

Development of the vertebrate central nervous system: formation of the neural tube

The developmental process of neurulation involves a series of coordinated morphological events, which result in conversion of the flat neural plate into the neural tube, the primordium of the entire central nervous system (CNS). Failure of neurulation results in neural tube defects (NTDs), severe abnormalities of the CNS, which are among the commonest of congenital malformations in humans. In order to gain insight into the embryological basis of NTDs, such as spina bifida and anencephaly, it is necessary to understand the morphogenetic processes and molecular mechanisms underlying neural tube closure. The mouse is the most extensively studied mammalian experimental model for studies of neurulation, while considerable insight into underlying developmental mechanisms has also arisen from studies in other model systems, particularly birds and amphibians. We describe the process of neural tube formation, discuss the cellular mechanisms involved and highlight recent findings that provide links between molecular signaling pathways and morphogenetic tissue movements. Copyright © 2009 John Wiley & Sons, Ltd.     

Fishery Stability, Local Extinctions, and Shifts in Community Structure in Skates

Abstract: Skates are arguably the most vulnerable of exploited marine fishes. Their vulnerability is often assessed by examining fisheries catch trends, but these data are not generally recorded on a species basis except in France. Aggregated skate catch statistics tend to exhibit more stable trends than those of other elasmobranch fisheries. We tested whether such apparent stability in aggregated catch trends could mask population declines of individual species. We examined two time series of species-specific surveys of a relatively stable skate fishery in the northeast Atlantic. These surveys revealed the disappearance of two skate species, long-nose skate (   Dipturus oxyrhinchus ) and white skate (   Rostroraja alba ) and confirmed a previously documented decline of the common skate (   D. batis ). Of the remaining five skate species, the three larger ones have declined, whereas two smaller species have increased in abundance. The increase in abundance and biomass of the smaller species has resulted in the stability of the aggregated catch trends. Because there is significant dietary overlap among species, we suggest the increase in abundance of the smaller species may be due to competitive release as the larger species declined. A consequence of this kind of stability is that declining species cannot be detected without species-specific data, especially in taxa exhibiting competitive interactions. This may explain why previously documented disappearances of two species of skates went unnoticed for so long. The conservation of skates and other elasmobranchs requires species-specific monitoring and special attention to larger species.     

Arsenic stability and mobilization in soil at an amenity grassland overlying chemical waste (St. Helens, UK)

A 6.6 ha grassland, established on a former chemical waste site adjacent to a residential area, contains arsenic (As) in surface soil at concentrations 200 times higher than UK Soil Guideline Values. The site is not recognized as statutory contaminated land, partly on the assumption that mobility of the metalloid presents a negligible threat to human health, groundwater and ecological receptors. Evidence for this is evaluated, based on studies of the effect of organic (green waste compost) and inorganic (iron oxides, lime and phosphate) amendments on As fractionation, mobility, plant uptake and earthworm communities. Arsenic mobility in soil was low but significantly related to dissolved organic matter and phosphate, with immobilization associated with iron oxides. Plant uptake was low and there was little apparent impact on earthworms. The existing vegetation cover reduces re-entrainment of dust-blown particulates and pathways of As exposure via this route. Minimizing risks to receptors requires avoidance of soil exposure, and no compost or phosphate application.