Social inequalities in alcohol-related adult mortality by National Statistics Socio-economic Classification, England and Wales, 2001-03.

BACKGROUND: This article is the first analysis of the social inequalities in adult alcohol-related mortality in England and Wales at the start of the 21st century, using the National Statistics Socio-economic Classification (NS-SEC). It presents the socio-economic patterns of alcohol-related mortality by gender, age and region, for England and Wales as a whole, Wales and the regions of England. METHODS: Death registrations provided the number of deaths for working age adults, using the National Statistics definition of alcohol-related mortality. Population estimates for England and Wales in 2001-03 were used to estimate alcohol-related mortality rates by sex, five-year age group, NS-SEC and region. Inequalities were measured using ratios of alcohol-related mortality rates between the least and most advantaged classes. RESULTS: There were substantial socio-economic variations in adult alcohol-related mortality, with the inequalities being greater for women than for men. The mortality rate of men in the Routine class was 3.5 times those of men in Higher and Managerial occupations, while for women the corresponding figure was 5.7 times. Greater socio-economic inequalities in mortality were observed for men aged 25-49 than for men aged 50-64; however the highest mortality rate of men occurred for Routine workers aged 50-54. Women in the Routine class experienced mortality rates markedly higher than other classes. The highest mortality rate of women also occurred for Routine workers, but at a younger age than for men (45-49). Within England, the North-West showed the largest inequalities, with particularly high rates in the Routine class for both sexes. In general, there was no association between levels of mortality and socio-economic gradients in mortality across the English regions and Wales. CONCLUSIONS: Rates of alcohol-related mortality in England and Wales increased significantly for people between the early 1990s and early 21st century, and were substantially greater for those in more disadvantaged socio-economic classes. There is also evidence that these socio-economic differences were greater at younger ages, especially for men at ages 25-49.

Shape of tropoelastin, the highly extensible protein that controls human tissue elasticity.

Elastin enables the reversible deformation of elastic tissues and can withstand decades of repetitive forces. Tropoelastin is the soluble precursor to elastin, the main elastic protein found in mammals. Little is known of the shape and mechanism of assembly of tropoelastin as its unique composition and propensity to self-associate has hampered structural studies. In this study, we solve the nanostructure of full-length and corresponding overlapping fragments of tropoelastin using small angle X-ray and neutron scattering, allowing us to identify discrete regions of the molecule. Tropoelastin is an asymmetric coil, with a protruding foot that encompasses the C-terminal cell interaction motif. We show that individual tropoelastin molecules are highly extensible yet elastic without hysteresis to perform as highly efficient molecular nanosprings. Our findings shed light on how biology uses this single protein to build durable elastic structures that allow for cell attachment to an appended foot. We present a unique model for head-to-tail assembly which allows for the propagation of the molecule's asymmetric coil through a stacked spring design.

Social inequalities in fatal childhood accidents and assaults: England and Wales, 2001-03.

BACKGROUND: This article presents age-specific mortality rates of children for selected causes of accidents and assault using the National Statistics Socio-economic Classification (NS-SEC). The study is an analysis of the social inequalities in fatal childhood accidents and assault at the start of the 21st century. It aims to identify the causes and age groups for which these inequalities are the widest. METHODS: In order to classify children by NS-SEC, the most advantaged class of the biological or adoptive parents was used. Death registrations provided the number of deaths from accidents and assault for children aged from 28 days to 15 years, in England and Wales, between 2001 and 2003. The population of children by NS-SEC and age group was obtained from the 2001 Census. Age-specific mortality rates were estimated. Inequalities were measured using socio-economic gradients in mortality. RESULTS: There were wide social inequalities in fatal accidents and assaults for children aged between 28 days and 15 years. The overall mortality rate in the routine class was 64 per million children aged up to 15, 4.5 times the rate of children with parents in the higher managerial and professional class. The greatest inequalities in accidental mortality for children in that age group were observed for fire and pedestrian accidents, followed by accidental suffocation. Infants at least 28 days but less than one year were subject to the widest inequalities of all age groups in fatal accidents and assault. The highest mortality rate in this study resulted from assault on babies whose parents could not be classified by occupation. Pedestrian and other transport accidents were the greatest causes of death for children between 5 and 15 years old. Inequalities were much larger for pedestrian than for other transport accidents for children aged 14 years and under. The leading cause of death for children aged less than five years was suffocation, followed by drowning and exposure to fire/hot substances. In that age group, the risk of death from exposure to fire was significantly higher for children whose parents could not be classified by occupation. CONCLUSIONS: Substantial social inequalities in childhood mortality from accidents and assault existed in 2001-03. Reducing the large inequalities between the most advantaged class and the most disadvantaged group in the non-occupied category, would make a substantial impact on childhood deaths from accidents and assaults. If the mortality rates in the latter group were the same as in the most advantaged managerial and professional class, deaths of infants of at least 28 days but less than one year, from assault would be reduced by 62 per cent. Deaths from fire, accidental suffocation and pedestrian accidents in the under fives would be reduced by 50 per cent, 25 per cent and 28 per cent respectively. Deaths in pedestrian and transport accidents for children aged 5-15 would be reduced by 25 per cent and 16 per cent respectively.

Regional differences in male mortality inequalities using the National Statistics Socio-Economic Classification, England and Wales, 2001-03.

This article represents the first use by the Office for National Statistics of the National Statistics Socio-economic Classification (NS-SEC) to analyse regional variations in inequalities in male mortality. It is part of a serie of articles on social inequalities in mortality by NS-SEC. Deaths in th years 2001-03 among men aged 25-64, from all causes and selected major cause groups, are examined in each of the Government Office Regions of England and in Wales. The results provide insights into both social gradients in mortality within regions, and regional differences in mortality for each NS-SEC class. The socioeconomic differences in mortality were more marked for men in Wales, the North East and the North West. The regional differences in mortality were small for the most advantaged classes and greatest for the least advantaged classes.

Social inequalities in male mortality for selected causes of death by the National Statistics Socio-economic Classification, England and Wales, 2001-03.

This article reports social inequalities in mortality in selected causes of death for men aged 25-64 years in England and Wales in 2001-03. It is the first compilation of mortali statistics in causes of death by the final version of the National Statistics Socio-economic Classification, which was introduced into deat registrations in 2001. These results follow-up the all cause analyses reported previously using similar methods, and provide insights into the impacts of different social and occupational circumstances on selected causes of death.

Marfan syndrome-causing mutations in fibrillin-1 result in gross morphological alterations and highlight the structural importance of the second hybrid domain.

Mutations in fibrillin-1 result in Marfan syndrome, which affects the cardiovascular, skeletal and ocular systems. The multiorgan involvement and wide spectrum of associated phenotypes highlights the complex pathogenesis underlying Marfan syndrome. To elucidate the genotype to phenotype correlations, we engineered four Marfan syndrome causing mutations into a fibrillin-1 fragment encoded by exons 18-25, a region known to interact with tropoelastin. Biophysical and biochemical approaches, including small angle x-ray scattering, analytical ultracentrifugation, and circular dichroism, were used to study the impact of these mutations upon the structure and function of the protein. Mutations G880S, C862R, and C908R, situated within the second hybrid domain, disrupted the ratio of alpha-helix to beta-sheet leading to a more compact conformation. These data clearly demonstrate the importance of the previously uncharacterized hybrid domain in fibrillin-1 structure. In contrast, mutation K1023N situated within the linker region between the third eight cysteine motif and cbEGF 11 markedly extended the length of the fragment. However, none of the mutations affected tropoelastin binding. The profound effects of all four mutations on fragment conformation suggest that they contribute to the pathogenesis of Marfan syndrome by disrupting protein folding and its assembly into fibrillin-rich microfibrils.

Nanostructure of fibrillin-1 reveals compact conformation of EGF arrays and mechanism for extensibility.

Fibrillin-1 is a 330-kDa multidomain extracellular matrix protein that polymerizes to form 57-nm periodic microfibrils, which are essential for all tissue elasticity. Fibrillin-1 is a member of the calcium-binding EGF repeat family and has served as a prototype for structural analyses. Nevertheless, both the detailed structure of fibrillin-1 and its organization within microfibrils are poorly understood because of the complexity of the molecule and the resistance of EGF arrays to crystallization. Here, we have used small-angle x-ray scattering and light scattering to analyze the solution structure of human fibrillin-1 and to produce ab initio structures of overlapping fragments covering 90% of the molecule. Rather than exhibiting a uniform rod shape as current models predict, the scattering data revealed a nonlinear conformation of calcium-binding EGF arrays in solution. This finding has major implications for the structures of the many other EGF-containing extracellular matrix and membrane proteins. The scattering data also highlighted a very compact, globular region of the fibrillin-1 molecule, which contains the integrin and heparan sulfate-binding sites. This finding was confirmed by calculating a 3D reconstruction of this region using electron microscopy and single-particle image analysis. Together, these data have enabled the generation of an improved model for microfibril organization and a previously undescribed mechanism for microfibril extensibility.

Proteoglycan alterations and collagen reorganisation in the secondary avian cornea during development.

PURPOSE: It is thought that proteoglycan (PG) alterations, collagen matrix reorganisation and the onset of corneal transparency in the developing avian cornea might be related events. The current histochemical study was designed to establish the character and distribution of corneal PG filaments in relation to collagen organisation during tissue morphogenesis. METHODS: Corneas from days 13-18 developing chicken embryos were treated with cuprolinic blue (CuB) to examine sulphated PGs by transmission electron microscopy and quantitative image analysis. RESULTS: On developmental day 13, corneas contained poorly defined lamellae and a large number of both small and large CuB-stained PG filaments, randomly distributed and often in collagen-free regions. By day 14 and after, the large CuB-stained PG filaments were much less abundant. At this time, too, collagen fibrils displayed an axial alignment and an occasional periodic arrangement of small CuB-stained PG filaments along their axes. By developmental day 15, lamellae were well formed and continued to increase in number and size thereafter. Between developmental days 16 and 17, there was a significant increase (p < 0.001) in the number of small, collagen-associated PG filaments. This increase persisted into day 18. CONCLUSIONS: The size, number and distribution of sulphated, CuB-stained PG filaments in the developing avian cornea change over time. This is particularly true between developmental days 13 and 14 and between days 16 and 17, concurrent with previously documented structural changes.

Collagen organization in the secondary chick cornea during development.

PURPOSE: The latter stages of morphogenesis in the embryonic chick cornea are instrumental in the establishment of a properly formed corneal stroma. This study was designed to provide better appreciation of collagen reorganization in the avian corneal stroma during the latter stages of embryogenesis. METHODS: High-angle synchrotron x-ray diffraction patterns were obtained from 47 developing chick corneas daily at developmental days 13 through 18 (n = 7 or 8 at each time point) and analyzed to establish collagen molecular spacing and fibril orientation. RESULTS: Collagen intermolecular x-ray reflections were of approximately constant intensity between days 13 and 15 of development, but thereafter became progressively more intense, suggesting that extra collagen is deposited in embryonic chick corneas after day 16 of development. At all times, the mean collagen intermolecular spacing measured approximately 1.43 nm. X-ray intensity was not uniform around the intermolecular x-ray reflections at earlier time points. Rather, a fourfold symmetry was evident, indicative of an orthogonal array of collagen fibrils. An index of this symmetry was essentially unchanged between developmental days 13 and 15, but thereafter diminished considerably. CONCLUSIONS: The lateral spacing of fibril-forming collagen molecules does not change as the chick cornea develops between days 13 and 18. An orthogonal array of collagen fibrils is present in the corneas of developmental day-13 to -18 chicks, but starting at developmental day 16, additional collagen is deposited in a less well-oriented manner and thus acts to obscure the overall orthogonality, with implications for the biomechanical strength and shape of the cornea.