Plasma HDL cholesterol and risk of myocardial infarction: A mendelian randomisation study

Background: High plasma HDL cholesterol is associated with reduced risk of myocardial infarction, but whether this association is causal is unclear. Exploiting the fact that genotypes are randomly assigned at meiosis, are independent of non-genetic confounding, and are unmodified by disease processes, mendelian random isation can be used to test the hypothesis that the association of a plasma biomarker with disease is causal.
Methods: We performed two mendelian randomisation analyses. First, we used as an instrument a single nucleotide polymorphism (SNP) in the endothelial lipase gene (LIPG Asn396Ser) and tested this SNP in 20 studies (20 913 myocardial infarction cases, 95 407 controls). Second, we used as an instrument a genetic score consisting of 14 common SNPs that exclusively associate with HDL cholesterol and tested this score in up to 12 482 cases of myocardial infarction and 41 331 controls. As a positive control, we also tested a genetic score of 13 common SNPs exclusively associated with LDL cholesterol.
Findings: Carriers of the LIPG 396Ser allele (2·6% frequency) had higher HDL cholesterol (0·14 mmol/L higher p=8×10-13) but similar levels of other lipid and non-lipid risk factors for myocardial infarction compared with noncarriers. This difference in HDL cholesterol is expected to decrease risk of myocardial infarction by 13% (odds ratio [OR] 0·87, 95% CI 0·84-0·91). However, we noted that the 396Ser allele was not associated with risk of myocardial infarction (OR 0·99, 95% CI 0·88-1·11, p=0·85). From observational epidemiology, an increase of 1 SD in HDL cholesterol was associated with reduced risk of myocardial infarction (OR 0·62, 95% CI 0·58-0·66). However, a 1 SD increase in HDL cholesterol due to genetic score was not associated with risk of myocardial infarction (OR 0·93 95% CI 0·68-1·26, p=0·63). For LDL cholesterol, the estimate from observational epidemiology (a 1 SD increase in LDL cholesterol associated with OR 1·54, 95% CI 1·45-1·63) was concordant with that from genetic score (OR 2·13 95% CI 1·69-2·69, p=2×10 -10).
Interpretation: Some genetic mechanisms that raise plasma HDL cholesterol do not seem to lower risk of myocardial infarction. These data challenge the concept that raising of plasma HDL cholesterol will uniformly translate into reductions in risk of myocardial infarction.

Red-shifts and red herrings in geographical ecology

I draw attention to the need for ecologists to take spatial structure into account more seriously in hypothesis testing. If spatial autocorrelation is ignored, as it usually is, then analyses of ecological patterns in terms of environmental factors can produce very misleading results. This is demonstrated using synthetic but realistic spatial patterns with known spatial properties which are subjected to classical correlation and multiple regression analyses. Correlation between an autocorrelated response variable and each of a set of explanatory variables is strongly biased in favour of those explanatory variables that are highly autocorrelated - the expected magnitude of the correlation coefficient increases with autocorrelation even if the spatial patterns are completely independent. Similarly, multiple regression analysis finds highly autocorrelated explanatory variables "significant" much more frequently than it should. The chances of mistakenly identifying a "significant" slope across an autocorrelated pattern is very high if classical regression is used. Consequently, under these circumstances strongly autocorrelated environmental factors reported in the literature as associated with ecological patterns may not actually be significant. It is likely that these factors wrongly described as important constitute a red-shifted subset of the set of potential explanations, and that more spatially discontinuous factors (those with bluer spectra) are actually relatively more important than their present status suggests. There is much that ecologists can do to improve on this situation. I discuss various approaches to the problem of spatial autocorrelation from the literature and present a randomisation test for the association of two spatial patterns which has advantages over currently available methods.

The impact of a rice based diet on urinary arsenic

Rice is elevated in arsenic (As) compared to other staple grains. The Bangladeshi community living in the United Kingdom (UK) has a ca. 30-fold higher consumption of rice than white Caucasians. In order to assess the impact of this difference in rice consumption, urinary arsenicals of 49 volunteers in the UK (Bangladeshi n = 37; white Caucasians n = 12) were monitored along with dietary habits. Total urinary arsenic (As(t)) and speciation analysis for dimethylarsinic acid (DMA), monomethylarsonic acid (MA) and inorganic arsenic (iAs) was conducted. Although no significant difference was found for As(t) (median: Bangladeshis 28.4 µg L(-1)) and white Caucasians (20.6 µg L(-1)), the sum of medians of DMA, MA and iAs for the Bangladeshi group was found to be over 3-fold higher (17.9 µg L(-1)) than for the Caucasians (3.50 µg L(-1)). Urinary DMA was significantly higher (p <0.001) in the UK Bangladeshis (median: 16.9 µg DMA L(-1)) than in the white Caucasians (3.16 µg DMA L(-1)) as well as iAs (p <0.001) with a median of 0.630 µg iAs L(-1) for Bangladeshi and 0.250 µg iAs L(-1) for Caucasians. Cationic compounds were significantly lower in the Bangladeshis (2.93 µg L(-1)) than in Caucasians (14.9 µg L(-1)). The higher DMA and iAs levels in the Bangladeshis are mainly the result of higher rice consumption: arsenic is speciated in rice as both iAs and DMA, and iAs can be metabolized, through MA, to DMA by humans. This study shows that a higher dietary intake of DMA alters the DMA/MA ratio in urine. Consequently, DMA/MA ratio as an indication of methylation capacity in populations consuming large quantities of rice should be applied with caution since variation in the quantity and type of rice eaten may alter this ratio.

Accumulation or production of arsenobetaine in humans?

Arsenobetaine has always been referred to as a non-toxic but readily bioavailable compound and the available data would suggest that it is neither metabolised by nor accumulated in humans. Here this study investigates the urine of five volunteers on an arsenobetaine exclusive diet for twelve days and shows that arsenobetaine was consistently excreted by three of the five volunteers. From the expected elimination pattern of arsenobetaine in rodents, no significant amount of arsenobetaine should have been detectable after 5 days of the trial period. The arsenobetaine concentration found in the urine was constant after 5 days and varied between 0.2 and 12.2 microg As per L for three of the volunteers. Contrary to the established belief that arsenobetaine is neither accumulated nor generated by humans, the presented results would suggest that either accumulated arsenobetaine in the tissues is slowly released over time or that arsenobetaine is a human metabolite of dimethylarsinic acid or inorganic arsenic from the trial food, or both. Either possibility is intriguing and raises fundamental questions about human arsenic metabolism and the toxicological and environmental inertness of arsenobetaine.

Arsenic speciation in Japanese rice drinks and condiments

Rice has been demonstrated to be one of the major contributors to inorganic arsenic (i-As) intake in humans. However, little is known about rice products as additional source of i-As exposure. In this study, misos, syrups and amazake (a fermented sweet rice drink) produced from rice, barley and millet were analysed for total arsenic (t-As) and a subset of samples were also analyzed for As speciation. Rice based products displayed a higher i-As content than those derived from barley and millet. Most of the t-As in the rice products studied was inorganic (63-83%), the remainder being dimethylarsinic acid. Those who regularly consume rice drinks and condiments, such as the Japanese population and those who follow health conscious diets based on the Japanese cuisine, could reach up to 23% of the World Health Organization's Provisional Tolerable Daily Intake of i-As, by only consuming these kinds of products. This study provides a wide appreciation of how i-As derived from rice based products enters the human diet and how this may be of concern to populations who are already exposed to high levels of i-As through consumption of foods such as rice and seaweed.

Paraquat-Induced Retinal Degeneration Is Exaggerated in CX3CR1-Deficient Mice and Is Associated with Increased Retinal Inflammation

PURPOSE:
To investigate the role of the Fractalkine receptor CX3CR1 pathway in oxidative insults-mediated retinal degeneration and immune activation.
METHODS:
A prooxidant, paraquat (0.75 µM) was injected into the vitreous of C57BL/6J, CX3CR1(gpf/+), and CX3CR1(gfp/gfp) mice. Retinal lesions were investigated clinically by topic endoscopic fundus imaging and fluorescence angiography, and pathologically by light- and electron microscopy. Retinal immune gene expression was determined by real-time RT-PCR. Microglial activation and immune cell infiltration were examined by confocal microscopy of retinal flatmounts.
RESULTS:
Intravitreal injection of paraquat (0.75 µM) resulted in acute retinal capillary nonperfusion within 2 days, which improved from 4 days to 4 weeks postinjection (p.i.). Panretinal degeneration was observed at 4 days p.i. and progressed further at 4 weeks p.i. In the absence of CX3CR1, retinal degeneration was exaggerated and was accompanied by increased TNF-a, iNOS, IL-1ß, Ccl2, and Casp-1 gene expression. Confocal microscopy of retinal flatmounts revealed microglial activation and CD44(+)MHC-II(+) monocyte and GR1(+) neutrophil infiltration in paraquat-injected eyes. The number of activated microglia and infiltrating leukocytes was significantly higher in CX3CR1(gfp/gfp) mice than in CX3CR1(gfp/+) mice.
CONCLUSIONS:
Our results suggest that the CX3CR1 signaling pathway may play an important role in controlling retinal inflammation under oxidative and ischemia/reperfusion conditions. In the absence of CX3CR1, uncontrolled retinal inflammation results in exaggerated retinal degeneration.

Arsenic Bioaccessibility in Cooked Rice as Affected by Arsenic in Cooking Water

Rice can easily accumulate arsenic (As) into its grain and is known to be the highest As-containing cereal. In addition, the As burden in rice may increase during its processing (such as when cooking using As-polluted water). The health risk posed by the presence of As in cooked rice depends on its release from the matrix along the digestive system (bioaccessibility). Two types of white polished long-grain rice, namely, nonparboiled and parboiled (total As: 202 and 190 mu g As kg(-1), respectively), were cooked in excess of water with different levels of As (0, 10, 47, 222, and 450 mu g As L-1). The bioaccessibility of As from these cooked rice batches was evaluated with an in vitro dynamic digestion process. Rice cooked with water containing 0 and 10 mu g As L-1 showed lower As concentrations than the raw (uncooked) rice. However, cooking water with relatively high As content (>= 47 mu g As L-1) significantly increased the As concentration in the cooked rice up to 8- and 9-fold for the nonparboiled and parboiled rice, respectively. Parboiled rice, which is most widely consumed in South Asia, showed a higher percentage of As bioaccessibility (59% to 99%) than nonparboiled rice (36% to 69%) and most of the As bioaccessible in the cooked rice (80% to 99%) was released easily during the first 2 h of digestion. The estimation of the As intake through cooked rice based on the As bioaccessibility highlights that a few grams of cooked rice (less than 25 g dry weight per day) cooked with highly As contaminated water is equivalent to the amount of As from 2 L water containing the maximum permissible limit (10 mu g As L-1).

Arsenic Contents in Spanish Infant Rice, Pureed Infant Foods, and Rice

It seems there is a positive correlation between rice content and arsenic level in foods. This is of extraordinary importance for infants below 1 y of age because their diet is very limited and in some cases is highly dependent on rice-based products; this is particularly true for infants with the celiac disease because they have no other option than consume gluten-free products, such as rice or corn. Arsenic contents were significantly higher (P <0.001) in gluten-free infant rice (0.057 mg kg-1) than in products with gluten, based on a mixture of cereals (0.024 mg kg-1). Besides, especial precaution must be taken when preparing rice-based products at home, because arsenic content in Spanish rice was high, with levels being above 0.3 mg kg-1 in some cases.

Relative Biological Effectiveness Variation Along Monoenergetic and Modulated Bragg Peaks of a 62-MeV Therapeutic Proton Beam: A Preclinical Assessment

iological optimization of proton therapy critically depends on detailed evaluation of relative biological effectiveness (RBE) variations along the Bragg curve. The clinically accepted RBE value of 1.1 is an oversimplification, which disregards the steep rise of linear energy transfer (LET) at the distal end of the spread-out Bragg peak. We observed significant cell killing RBE variations dependent on beam modulation, intrinsic radiosensitivity, and LET in agreement with the LEM predicted values, indicating dose-averaged LET as a suitable parameter for biological effectiveness. Data have also been used to validate a RBE parameterized model.

Experimental Autoimmune Uveoretinitis (EAU)-Related Tissue Damage and Angiogenesis Is Reduced in CCL2−/−CX3CR1gfp/gfp Mice

Purpose: To investigate the roles of the CCL2-CCR2 and CX3CL1-CX3CR1 pathways in experimental autoimmune uveoretinitis (EAU)-mediated retinal tissue damage and angiogenesis.

Methods: The C57BL/6J wild-type (WT) and CCL2−/−CX3CR1gfp/gfp (double knockout [DKO]) mice were immunized with IRBP1-20. Retinal inflammation and tissue damage were evaluated clinically and histologically at different days postimmunization (p.i.). Retinal neovascular membranes were evaluated by confocal microscopy of retinal flat mounts, and immune cell infiltration by flow cytometry.

Results: At day 25 p.i., DKO mice had lower clinical and histological scores and fewer CD45highCD11b+ infiltrating cells compared with WT mice. The F4/80+macrophages constitute 40% and 21% and CD11b+Gr-1+Ly6G+ neutrophils constitute 10% and 22% of retinal infiltrating cells in WT and DKO mice, respectively. At the late stages of EAU (day 60–90 p.i.), DKO and WT mice had similar levels of inflammatory score. However, less structural damage and reduced angiogenesis were detected in DKO mice. Neutrophils were rarely detected in the inflamed retina in both WT and DKO mice. Macrophages and myeloid-derived suppressor cells (MDSCs) accounted for 8% and 3% in DKO EAU retina, and 19% and 10% in WT EAU retina; 71% of infiltrating cells were T/B-lymphocytes in DKO EAU retina and 50% in WT EAU retina.

Conclusions: Experimental autoimmune uveoretinitis–mediated retinal tissue damage and angiogenesis is reduced in CCL2−/−CX3CR1gfp/gfp mice. Retinal inflammation is dominated by neutrophils at the acute stage and lymphocytes at the chronic stage in these mice. Our results suggest that CCR2+ and CX3CR1+monocytes are both involved in tissue damage and angiogenesis in EAU.

Defining the role of common variation in the genomic and biological architecture of adult human height

Using genome-wide data from 253,288 individuals, we identified 697 variants at genome-wide significance that together explained one-fifth of the heritability for adult height. By testing different numbers of variants in independent studies, we show that the most strongly associated 1/42,000, 1/43,700 and 1/49,500 SNPs explained 1/421%, 1/424% and 1/429% of phenotypic variance. Furthermore, all common variants together captured 60% of heritability. The 697 variants clustered in 423 loci were enriched for genes, pathways and tissue types known to be involved in growth and together implicated genes and pathways not highlighted in earlier efforts, such as signaling by fibroblast growth factors, WNT/I 2-catenin and chondroitin sulfate-related genes. We identified several genes and pathways not previously connected with human skeletal growth, including mTOR, osteoglycin and binding of hyaluronic acid. Our results indicate a genetic architecture for human height that is characterized by a very large but finite number (thousands) of causal variants.

Genetic studies of body mass index yield new insights for obesity biology

Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10(-8)), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ∼2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.

Cytokine and C-reactive protein profiles induced by porcine circovirus type 2 experimental infection in 3-week-old piglets

The purpose of this study was to determine serum profiles of cytokines at a protein level and Creactive protein (CRP) during the development of postweaning multisystemic wasting syndrome (PMWS) in experimentally inoculated pigs. Levels of serum IFN-alpha, IL-6, IL-10, and CRP were examined for a 35-day period in 10 piglets experimentally infected with PCV2 at 3 weeks of age. Four of the infected piglets developed severe PMWS at 14 to 21 days post-infection (d.p.i.) and died prior to termination of the experiment. The remaining six PCV2-infected piglets experienced transient fever, but did not display overt clinical signs of PMWS and were considered as subclinically infected. A bioassay was used to detect IL-6 and ELISAs were used to detect IFN-alpha, IL-10, and CRP. There were no significant differences in cytokine or CRP expression from 0 to 7 d.p.i. between the PMWS-affected and the subclinically infected piglets. Levels of IL-10 and CRP were elevated from 10 and 14 d.p.i. respectively in the PMWS-affected piglets compared to the subclinically infected piglets. There were no significant differences in IFN-alpha and IL-6 expression between the PMWS-affected piglets and the subclinically infected piglets. The present study shows that elevated levels of serum CRP and IL-10 were associated with PCV2-infected piglets that subsequently developed severe PMWS. This may help to provide further insight into the immunoaetiogenesis of this syndrome.

Potentially Voting across the Divide in Deeply Divided Places: Ethnic Catch-All Voting in Consociational Northern Ireland

I elaborate a model of cross-bloc party support in deeply divided places. The model expects that the variation in the level of electoral support that citizens in Community A have for parties in Community B is a function of citizens' evaluations of the relative ability of parties in Community B to represent the interests of all communities. This 'ethnic catch-all' model of cross-bloc party support is tested in the context of consociational Northern Ireland, using data from a representative survey conducted directly after the 2010 Westminster general election. The findings are asymmetric: the model explains Protestant support for nationalist parties but not Catholic support for unionist parties. The findings, and their implications, are discussed.

Pressure anisotropy effects on nonlinear electrostatic excitations in magnetized electron-positron-ion plasmas

The propagation of linear and nonlinear electrostatic waves is investigated in a magnetized anisotropic electron-positron-ion (e-p-i) plasma with superthermal electrons and positrons. A two-dimensional plasma geometry is assumed. The ions are assumed to be warm and anisotropic due to an external magnetic field. The anisotropic ion pressure is defined using the double adiabatic Chew-Golberger-Low (CGL) theory. In the linear regime, two normal modes are predicted, whose characteristics are investigated parametrically, focusing on the effect of superthermality of electrons and positrons, ion pressure anisotropy, positron concentration and magnetic field strength. A Zakharov-Kuznetsov (ZK) type equation is derived for the electrostatic potential (disturbance) via a reductive perturbation method. The parametric role of superthermality, positron content, ion pressure anisotropy and magnetic field strength on the characteristics of solitary wave structures is investigated. Following Allen and Rowlands [J. Plasma Phys. 53, 63 (1995)], we have shown that the pulse soliton solution of the ZK equation is unstable to oblique perturbations, and have analytically traced the dependence of the instability growth rate on superthermality and ion pressure anisotropy.