Regional variations in the economic burden attributable to excess weight, physical inactivity and tobacco smoking across British Columbia.

INTRODUCTION: Prevalence rates of excess weight, tobacco smoking and physical inactivity vary substantially by geographical region within British Columbia (B.C.). The purpose of this study is to determine the potential reduction in economic burden in B.C. if all regions in the province achieved prevalence rates of these three risk factors equivalent to those of the region with the lowest rates. METHODS: We used a previously developed approach based on population-attributable fractions to estimate the economic burden associated with the various risk factors. Sex-specific relative risk and age/sex-specific prevalence data was used in the modelling. RESULTS: The annual economic burden attributable to the three risk factors in B.C. was about $5.6 billion in 2013, with a higher proportion of this total attributable to excess weight ($2.6 billion) than to tobacco smoking ($2.0 billion). While B.C. has lower prevalence rates of the risk factors than any other Canadian province, there is significant variation within the province. If each region in the province were to achieve the best prevalence rates for the three risk factors, then $1.4 billion (24% of the $5.6 billion) in economic burden could be avoided annually. CONCLUSION: There are notable disparities in the prevalence of each risk factor across health regions within B.C., which were mirrored in each region's attributable economic burden. A variety of social, environmental and economic factors likely drive some of this geographical variation and these underlying factors should be considered when developing prevention programs.

TITRE: Écarts régionaux dans le fardeau économique attribuable au surplus de poids, à la sédentarité et à l'usage du tabac en Colombie-Britannique. INTRODUCTION: Les taux de prévalence du surplus de poids, de l'usage du tabac et de la sédentarité varient sensiblement d'une région à l'autre en Colombie-Britannique (C.-B.). La présente étude vise à déterminer la portée d'une éventuelle réduction du fardeau économique en C.-B. si toutes les régions de la province atteignaient des taux de prévalence équivalents à ceux de la région dont les taux sont les plus bas pour ces trois facteurs de risque. MÉTHODOLOGIE: Nous avons utilisé une approche élaborée précédemment fondée sur la fraction étiologique du risque pour estimer le fardeau économique associé aux divers facteurs de risque. Le risque relatif selon le sexe et les données de prévalence selon l'âge et le sexe ont été utilisés dans la modélisation. RÉSULTATS: Le fardeau économique annuel attribuable à ces trois facteurs de risque en C.-B. s'élevait à environ 5,6 milliards de dollars en 2013, la proportion la plus élevée de ce total étant attribuable au surplus de poids (2,6 milliards), suivie de celle de l'usage du tabac (2 milliards). Même si la C.-B. possède des taux de prévalence de ces facteurs de risque plus bas que toute autre province canadienne, il existe d'importants écarts en son sein. Si chaque région de la province devait atteindre les taux de prévalence les plus bas pour les trois facteurs de risque, un fardeau économique de 1,4 milliard (24 % du total de 5,6 milliards) pourrait être supprimé annuellement. CONCLUSION : Il existe des disparités notables dans la prévalence de chacun des facteurs de risque au sein des régions sanitaires de la C.-B., qui se reflètent dans le fardeau économique attribuable à chaque région. Un éventail de facteurs sociaux, environnementaux et économiques expliquent probablement une partie de ces écarts géographiques, et ces facteurs sous-jacents devraient être pris en compte lors de la mise en place de programmes de prévention.

Redd1 is a novel marker of testis development but is not required for normal male reproduction.

In an effort to identify novel candidate genes involved in testis determination, we previously used suppression subtraction hybridisation PCR on male and female whole embryonic (12.0-12.5 days post coitum) mouse gonads. One gene to emerge from our screen was Redd1. In the current study, we demonstrate by whole-mount in situ hybridisation that Redd1 is differentially expressed in the developing mouse gonad at the time of sex determination, with higher expression in testis than ovary. Furthermore, Redd1 expression was first detected as Sry expression peaks, immediately prior to morphological sex determination, suggesting a potential role for Redd1 during testis development. To determine the functional importance of this gene during testis development, we generated Redd1-deficient mice. Morphologically, Redd1-deficient mice were indistinguishable from control littermates and showed normal fertility. Our results show that Redd1 alone is not required for testis development or fertility in mice. The lack of a male reproductive phenotype in Redd1 mice may be due to functional compensation by the related gene Redd2.

Expression, crystallization and derivatization of the complete extracellular domain of the beta(c) subunit of the human IL-5, IL-3 and GM-CSF receptors.

The major signalling entity of the receptors for the haemopoietic cytokines granulocyte-macrophage colony stimulating factor (GM-CSF), interleukin-3 (IL-3) and interleukin-5 (IL-5) is the shared beta(c) receptor, which is activated by ligand-specific alpha receptors. The beta(c) subunit is a stable homodimer whose extracellular region consists of four fibronectin domains and appears to be a duplication of the cytokine receptor homology module. No four domain structure has been determined for this receptor family and the structure of the beta(c) subunit remains unknown. We have expressed the extracellular domain in insect cells using the baculovirus system, purified it to homogeneity and determined its N-terminal sequence. N-glycosylation at two sites was demonstrated. Crystals of the complete domain have been obtained that are suitable for X-ray crystallographic studies, following mutagenesis to remove one of the N-glycosylation sites. The rhombohedral crystals of space group R3, with unit cell dimensions 186.1 A and 103.5 A, diffracted to a resolution of 2.9 A using synchrotron radiation. Mutagenesis was also used to engineer cysteine substitution mutants which formed isomorphous Hg derivatives in order to solve the crystallographic phase problem. The crystal structure will help to elucidate how the beta(c) receptor is activated by heterodimerization with the respective alpha/ligand complexes.

Structure of the complete extracellular domain of the common beta subunit of the human GM-CSF, IL-3, and IL-5 receptors reveals a novel dimer configuration.

The receptor systems for the hemopoietic cytokines GM-CSF, IL-3, and IL-5 consist of ligand-specific alpha receptor subunits that play an essential role in the activation of the shared betac subunit, the major signaling entity. Here, we report the structure of the complete betac extracellular domain. It has a structure unlike any class I cytokine receptor described thus far, forming a stable interlocking dimer in the absence of ligand in which the G strand of domain 1 hydrogen bonds into the corresponding beta sheet of domain 3 of the dimer-related molecule. The G strand of domain 3 similarly partners with the dimer-related domain 1. The structure provides new insights into receptor activation by the respective alpha receptor:ligand complexes.

The cytokine interleukin-5 (IL-5) effects cotransport of its receptor subunits to the nucleus in vitro.

Interleukin (IL)-5 is central in regulating eosinophilia in allergic disease and parasitic infections. We have recently shown that human (h) IL-5 both possesses a functional nuclear localization signal capable of targeting a heterologous protein to the nucleus and localises to the nucleus of intact receptor-expressing cells. In this study, the extracellular domains of the hIL-5 alpha- and beta-receptor subunits were expressed in baculovirus, fluorescently labelled and assayed for nuclear targeting in vitro in the absence and presence of IL-5. The beta-subunit, which lacks IL-5 binding activity, only accumulated in the nucleus in the presence of both the hIL-5 binding alpha-subunit and hIL-5. The IL-5-binding alpha-subunit showed similar results. IL-5 thus effected nuclear transport of its alpha- and beta-receptor subunits apparently through a 'piggy back' mechanism, raising the possibility that IL-5's nuclear signalling role may be to cotarget its receptor subunits to the nucleus. This is the first demonstration of nuclear protein piggy back transport in vitro.

A functional bipartite nuclear localisation signal in the cytokine interleukin-5.

Interleukin (IL)-5 is central in regulating eosinophilia in allergic disease and parasitic infections. We have identified a bipartite nuclear localisation signal (NLS) within amino acids 95-111 of human IL-5 (hIL-5), also present in mouse IL-5 (mIL-5). hIL-5 and mIL-5 were labelled fluorescently, and nuclear uptake subsequent to membrane binding and internalisation by intact receptor expressing cells visualised and quantified using confocal laser scanning microscopy. hIL-5 and mIL-5 were shown to be transported to the nucleus in in vivo and in vitro nuclear protein import assays. The hIL-5 NLS was able to target a heterologous protein to the nucleus both in vivo and in vitro. Mutations within the proximal arm of the NLS abrogated nuclear targeting activity, confirming its bipartite nature. The results imply a nuclear signalling role for IL-5 additional to pathways linked to the membrane receptor system.