| 1. |
- Blunden, Jessica, et al.
(author)
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State of the Climate in 2012
- 2013
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In: Bulletin of The American Meteorological Society - (BAMS). - 0003-0007 .- 1520-0477. ; 94:8, s. S1-S258
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Journal article (peer-reviewed)abstract
- For the first time in serveral years, the El Nino-Southern Oscillation did not dominate regional climate conditions around the globe. A weak La Ni a dissipated to ENSOneutral conditions by spring, and while El Nino appeared to be emerging during summer, this phase never fully developed as sea surface temperatures in the eastern conditions. Nevertheless, other large-scale climate patterns and extreme weather events impacted various regions during the year. A negative phase of the Arctic Oscillation from mid-January to early February contributed to frigid conditions in parts of northern Africa, eastern Europe, and western Asia. A lack of rain during the 2012 wet season led to the worst drought in at least the past three decades for northeastern Brazil. Central North America also experienced one of its most severe droughts on record. The Caribbean observed a very wet dry season and it was the Sahel's wettest rainy season in 50 years. Overall, the 2012 average temperature across global land and ocean surfaces ranked among the 10 warmest years on record. The global land surface temperature alone was also among the 10 warmest on record. In the upper atmosphere, the average stratospheric temperature was record or near-record cold, depending on the dataset. After a 30-year warming trend from 1970 to 1999 for global sea surface temperatures, the period 2000-12 had little further trend. This may be linked to the prevalence of La Ni a-like conditions during the 21st century. Heat content in the upper 700 m of the ocean remained near record high levels in 2012. Net increases from 2011 to 2012 were observed at 700-m to 2000-m depth and even in the abyssal ocean below. Following sharp decreases in to the effects of La Ni a, sea levels rebounded to reach records highs in 2012. The increased hydrological cycle seen in recent years continued, with more evaporation in drier locations and more precipitation in rainy areas. In a pattern that has held since 2004, salty areas of the ocean surfaces and subsurfaces were anomalously salty on average, while fresher areas were anomalously fresh. Global tropical cyclone activity during 2012 was near average, with a total of 84 storms compared with the 1981-2010 average of 89. Similar to 2010 and 2011, the North Atlantic was the only hurricane basin that experienced above-normal activity. In this basin, Sandy brought devastation to Cuba and parts of the eastern North American seaboard. All other basins experienced either near-or below-normal tropical cyclone activity. Only three tropical cyclones reached Category 5 intensity-all in Bopha became the only storm in the historical record to produce winds greater than 130 kt south of 7 N. It was also the costliest storm to affect the Philippines and killed more than 1000 residents. Minimum Arctic sea ice extent in September and Northern Hemisphere snow cover extent in June both reached new record lows. June snow cover extent is now declining at a faster rate (-17.6% per decade) than September sea ice extent (-13.0% per decade). Permafrost temperatures reached record high values in northernmost Alaska. A new melt extent record occurred on 11-12 July on the Greenland ice sheet; 97% of the ice sheet showed some form of melt, four times greater than the average melt for this time of year. The climate in Antarctica was relatively stable overall. The largest maximum sea ice extent since records begain in 1978 was observed in September 2012. In the stratosphere, warm air led to the second smallest ozone hole in the past two decades. Even so, the springtime ozone layer above Antarctica likely will not return to its early 1980s state until about 2060. Following a slight decline associated with the global 2 emissions from fossil fuel combustion and cement production reached a record 9.5 +/- 0.5 Pg C in 2011 and a new record of 9.7 +/- 0.5 Pg C is estimated for 2012. Atmospheric CO2 concentrations increased by 2.1 ppm in 2012, to 392.6 ppm. In spring 2012, 2 concentration exceeded 400 ppm at 7 of the 13 Arctic observation sites. Globally, other greenhouse gases including methane and nitrous oxide also continued to rise in concentration and the combined effect now represents a 32% increase in radiative forcing over a 1990 baseline. Concentrations of most ozone depleting substances continued to fall.
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| 2. |
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| 3. |
- Beecham, Ashley H, et al.
(author)
-
Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis.
- 2013
-
In: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 45:11, s. 1353-60
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Journal article (peer-reviewed)abstract
- Using the ImmunoChip custom genotyping array, we analyzed 14,498 subjects with multiple sclerosis and 24,091 healthy controls for 161,311 autosomal variants and identified 135 potentially associated regions (P < 1.0 × 10(-4)). In a replication phase, we combined these data with previous genome-wide association study (GWAS) data from an independent 14,802 subjects with multiple sclerosis and 26,703 healthy controls. In these 80,094 individuals of European ancestry, we identified 48 new susceptibility variants (P < 5.0 × 10(-8)), 3 of which we found after conditioning on previously identified variants. Thus, there are now 110 established multiple sclerosis risk variants at 103 discrete loci outside of the major histocompatibility complex. With high-resolution Bayesian fine mapping, we identified five regions where one variant accounted for more than 50% of the posterior probability of association. This study enhances the catalog of multiple sclerosis risk variants and illustrates the value of fine mapping in the resolution of GWAS signals.
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| 4. |
- Palmer, Nicholette D, et al.
(author)
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A genome-wide association search for type 2 diabetes genes in African Americans.
- 2012
-
In: PloS one. - San Francisco : Public Library of Science (PLoS). - 1932-6203. ; 7:1, s. e29202-
-
Journal article (peer-reviewed)abstract
- African Americans are disproportionately affected by type 2 diabetes (T2DM) yet few studies have examined T2DM using genome-wide association approaches in this ethnicity. The aim of this study was to identify genes associated with T2DM in the African American population. We performed a Genome Wide Association Study (GWAS) using the Affymetrix 6.0 array in 965 African-American cases with T2DM and end-stage renal disease (T2DM-ESRD) and 1029 population-based controls. The most significant SNPs (n = 550 independent loci) were genotyped in a replication cohort and 122 SNPs (n = 98 independent loci) were further tested through genotyping three additional validation cohorts followed by meta-analysis in all five cohorts totaling 3,132 cases and 3,317 controls. Twelve SNPs had evidence of association in the GWAS (P<0.0071), were directionally consistent in the Replication cohort and were associated with T2DM in subjects without nephropathy (P<0.05). Meta-analysis in all cases and controls revealed a single SNP reaching genome-wide significance (P<2.5×10(-8)). SNP rs7560163 (P = 7.0×10(-9), OR (95% CI) = 0.75 (0.67-0.84)) is located intergenically between RND3 and RBM43. Four additional loci (rs7542900, rs4659485, rs2722769 and rs7107217) were associated with T2DM (P<0.05) and reached more nominal levels of significance (P<2.5×10(-5)) in the overall analysis and may represent novel loci that contribute to T2DM. We have identified novel T2DM-susceptibility variants in the African-American population. Notably, T2DM risk was associated with the major allele and implies an interesting genetic architecture in this population. These results suggest that multiple loci underlie T2DM susceptibility in the African-American population and that these loci are distinct from those identified in other ethnic populations.
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| 5. |
- Richards, Stephen, et al.
(author)
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Genome Sequence of the Pea Aphid Acyrthosiphon pisum
- 2010
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In: PLoS biology. - : Public Library of Science (PLoS). - 1544-9173 .- 1545-7885. ; 8:2, s. e1000313-
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Journal article (peer-reviewed)abstract
- Aphids are important agricultural pests and also biological models for studies of insect-plant interactions, symbiosis, virus vectoring, and the developmental causes of extreme phenotypic plasticity. Here we present the 464 Mb draft genome assembly of the pea aphid Acyrthosiphon pisum. This first published whole genome sequence of a basal hemimetabolous insect provides an outgroup to the multiple published genomes of holometabolous insects. Pea aphids are host-plant specialists, they can reproduce both sexually and asexually, and they have coevolved with an obligate bacterial symbiont. Here we highlight findings from whole genome analysis that may be related to these unusual biological features. These findings include discovery of extensive gene duplication in more than 2000 gene families as well as loss of evolutionarily conserved genes. Gene family expansions relative to other published genomes include genes involved in chromatin modification, miRNA synthesis, and sugar transport. Gene losses include genes central to the IMD immune pathway, selenoprotein utilization, purine salvage, and the entire urea cycle. The pea aphid genome reveals that only a limited number of genes have been acquired from bacteria; thus the reduced gene count of Buchnera does not reflect gene transfer to the host genome. The inventory of metabolic genes in the pea aphid genome suggests that there is extensive metabolite exchange between the aphid and Buchnera, including sharing of amino acid biosynthesis between the aphid and Buchnera. The pea aphid genome provides a foundation for post-genomic studies of fundamental biological questions and applied agricultural problems.
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| 6. |
- Weinstein, John N., et al.
(author)
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The cancer genome atlas pan-cancer analysis project
- 2013
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 45:10, s. 1113-1120
-
Research review (peer-reviewed)abstract
- The Cancer Genome Atlas (TCGA) Research Network has profiled and analyzed large numbers of human tumors to discover molecular aberrations at the DNA, RNA, protein and epigenetic levels. The resulting rich data provide a major opportunity to develop an integrated picture of commonalities, differences and emergent themes across tumor lineages. The Pan-Cancer initiative compares the first 12 tumor types profiled by TCGA. Analysis of the molecular aberrations and their functional roles across tumor types will teach us how to extend therapies effective in one cancer type to others with a similar genomic profile. © 2013 Nature America, Inc. All rights reserved.
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| 7. |
- Bentley, Michael J., et al.
(author)
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A community-based geological reconstruction of Antarctic Ice Sheet deglaciation since the Last Glacial Maximum
- 2014
-
In: Quaternary Science Reviews. - : Elsevier BV. - 0277-3791 .- 1873-457X. ; 100, s. 1-9
-
Journal article (peer-reviewed)abstract
- A robust understanding of Antarctic Ice Sheet deglacial history since the Last Glacial Maximum is important in order to constrain ice sheet and glacial-isostatic adjustment models, and to explore the forcing mechanisms responsible for ice sheet retreat. Such understanding can be derived from a broad range of geological and glaciological datasets and recent decades have seen an upsurge in such data gathering around the continent and Sub-Antarctic islands. Here, we report a new synthesis of those datasets, based on an accompanying series of reviews of the geological data, organised by sector. We present a series of timeslice maps for 20 ka, 15 ka, 10 ka and 5 ka, including grounding line position and ice sheet thickness changes, along with a clear assessment of levels of confidence. The reconstruction shows that the Antarctic Ice sheet did not everywhere reach the continental shelf edge at its maximum, that initial retreat was asynchronous, and that the spatial pattern of deglaciation was highly variable, particularly on the inner shelf. The deglacial reconstruction is consistent with a moderate overall excess ice volume and with a relatively small Antarctic contribution to meltwater pulse la. We discuss key areas of uncertainty both around the continent and by time interval, and we highlight potential priorities for future work. The synthesis is intended to be a resource for the modelling and glacial geological community.
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| 8. |
- Ferrari, Raffaele, et al.
(author)
-
Frontotemporal dementia and its subtypes: a genome-wide association study.
- 2014
-
In: Lancet Neurology. - 1474-4465. ; 13:7, s. 686-699
-
Journal article (peer-reviewed)abstract
- Frontotemporal dementia (FTD) is a complex disorder characterised by a broad range of clinical manifestations, differential pathological signatures, and genetic variability. Mutations in three genes-MAPT, GRN, and C9orf72-have been associated with FTD. We sought to identify novel genetic risk loci associated with the disorder.
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| 9. |
- Helgadottir, Anna, et al.
(author)
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Apolipoprotein(a) Genetic Sequence Variants Associated With Systemic Atherosclerosis and Coronary Atherosclerotic Burden But Not With Venous Thromboembolism
- 2012
-
In: Journal of the American College of Cardiology. - : Elsevier BV. - 0735-1097 .- 1558-3597. ; 60:8, s. 722-729
-
Journal article (peer-reviewed)abstract
- Objectives The purpose of this study is investigate the effects of variants in the apolipoprotein(a) gene (LPA) on vascular diseases with different atherosclerotic and thrombotic components. Background It is unclear whether the LPA variants rs10455872 and rs3798220, which correlate with lipoprotein(a) levels and coronary artery disease (CAD), confer susceptibility predominantly via atherosclerosis or thrombosis. Methods The 2 LPA variants were combined and examined as LPA scores for the association with ischemic stroke (and TOAST [Trial of Org 10172 in Acute Stroke Treatment] subtypes) (effective sample size [n(e)] = 9,396); peripheral arterial disease (n(e) = 5,215); abdominal aortic aneurysm (ne = 4,572); venous thromboembolism (ne = 4,607); intracranial aneurysm (ne = 1,328); CAD (n(e) = 12,716), carotid intima-media thickness (n = 3,714), and angiographic CAD severity (n = 5,588). Results LPA score was associated with ischemic stroke subtype large artery atherosclerosis (odds ratio [OR]: 1.27; p = 6.7 X 10(-4)), peripheral artery disease (OR: 1.47; p = 2.9 x 10(-14)), and abdominal aortic aneurysm (OR: 1.23; p = 6.0 x 10(-5)), but not with the ischemic stroke subtypes cardioembolism (OR: 1.03; p = 0.69) or small vessel disease (OR: 1.06; p = 0.52). Although the LPA variants were not associated with carotid intima-media thickness, they were associated with the number of obstructed coronary vessels (p = 4.8 x 10(-12)). Furthermore, CAD cases carrying LPA risk variants had increased susceptibility to atherosclerotic manifestations outside of the coronary tree (OR: 1.26; p = 0.0010) and had earlier onset of CAD (-1.58 years/allele; p = 8.2 x 10(-8)) than CAD cases not carrying the risk variants. There was no association of LPA score with venous thromboembolism (OR: 0.97; p = 0.63) or intracranial aneurysm (OR: 0.85; p = 0.15). Conclusions LPA sequence variants were associated with atherosclerotic burden, but not with primarily thrombotic phenotypes. (J Am Coll Cardiol 2012; 60: 722-9) (C) 2012 by the American College of Cardiology Foundation
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| 10. |
- Rosenberg, Philip D., et al.
(author)
-
Quantifying particle size and turbulent scale dependence of dust flux in the Sahara using aircraft measurements
- 2014
-
In: Journal of Geophysical Research - Atmospheres. - 2169-897X .- 2169-8996. ; 119:12, s. 7577-7598
-
Journal article (peer-reviewed)abstract
- The first size-resolved airborne measurements of dust fluxes and the first dust flux measurements from the central Sahara are presented and compared with a parameterization by Kok (2011a). High-frequency measurements of dust size distribution were obtained from 0.16 to 300 mu m diameter, and eddy covariance fluxes were derived. This is more than an order of magnitude larger size range than previous flux estimates. Links to surface emission are provided by analysis of particle drift velocities. Number flux is described by a -2 power law between 1 and 144 mu m diameter, significantly larger than the 12 mu m upper limit suggested by Kok (2011a). For small particles, the deviation from a power law varies with terrain type and the large size cutoff is correlated with atmospheric vertical turbulent kinetic energy, suggesting control by vertical transport rather than emission processes. The measured mass flux mode is in the range 30-100 mu m. The turbulent scales important for dust flux are from 0.1 km to 1-10 km. The upper scale increases during the morning as boundary layer depth and eddy size increase. All locations where large dust fluxes were measured had large topographical variations. These features are often linked with highly erodible surface features, such as wadis or dunes. We also hypothesize that upslope flow and flow separation over such features enhance the dust flux by transporting large particles out of the saltation layer. The tendency to locate surface flux measurements in open, flat terrain means these favored dust sources have been neglected in previous studies.
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| 11. |
- Wang, Xiaofeng, et al.
(author)
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Evidence for type ia supernova diversity from ultraviolet observations with the hubble space telescope
- 2012
-
In: Astrophysical Journal. - 0004-637X .- 1538-4357. ; 749:2, s. 126-
-
Journal article (peer-reviewed)abstract
- We present ultraviolet (UV) spectroscopy and photometry of four Type Ia supernovae (SNe 2004dt, 2004ef, 2005M, and 2005cf) obtained with the UV prism of the Advanced Camera for Surveys on the Hubble Space Telescope. This data set provides unique spectral time series down to 2000 angstrom. Significant diversity is seen in the near-maximum-light spectra (similar to 2000-3500 angstrom) for this small sample. The corresponding photometric data, together with archival data from Swift Ultraviolet/Optical Telescope observations, provide further evidence of increased dispersion in the UV emission with respect to the optical. The peak luminositiesmeasured in the uvw1/F250W filter are found to correlate with the B-band light-curve shape parameter Delta m(15)(B), but with much larger scatter relative to the correlation in the broadband B band (e.g., similar to 0.4 mag versus similar to 0.2 mag for those with 0.8 mag < Delta m(15)(B) < 1.7 mag). SN 2004dt is found as an outlier of this correlation (at > 3 sigma), being brighter than normal SNe Ia such as SN 2005cf by similar to 0.9 mag and similar to 2.0 mag in the uvw1/F250W and uvm2/F220W filters, respectively. We show that different progenitor metallicity or line-expansion velocities alone cannot explain such a large discrepancy. Viewing-angle effects, such as due to an asymmetric explosion, may have a significant influence on the flux emitted in the UV region. Detailed modeling is needed to disentangle and quantify the above effects.
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| 12. |
- Aerts, Joel, et al.
(author)
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Guidance on current good radiopharmacy practice for the small-scale preparation of radiopharmaceuticals using automated modules : a European perspective
- 2014
-
In: Journal of labelled compounds & radiopharmaceuticals. - : Wiley-Blackwell. - 0362-4803 .- 1099-1344. ; 57:10, s. 615-620
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Journal article (peer-reviewed)abstract
- This document is meant to complement Part B of the EANM Guidelines on current good radiopharmacy practice (cGRPP) in the preparation of radiopharmaceuticals issued by the Radiopharmacy Committee of the European Association of Nuclear Medicine, covering small-scale in-house preparation of radiopharmaceuticals with automated modules. The aim is to provide more detailed and practice-oriented guidance to those who are involved in the small-scale preparation of radiopharmaceuticals, which are not intended for commercial purposes or distribution.
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| 13. |
- Bjelosevic, Haris, et al.
(author)
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Platinum(II) and gold(I) complexes based on 1,1 '-bis(diphenylphosphino)metallocene derivatives: Synthesis, characterization and biological activity of the gold complexes
- 2012
-
In: Journal of Organometallic Chemistry. - : Elsevier BV. - 0022-328X. ; 720, s. 52-59
-
Journal article (peer-reviewed)abstract
- The synthesis of series of 1,2,1' substituted bis(diphenylphosphino)- ruthenocenyl (1-4) and ferrocenyl cis-platinum(II) (5-7) and gold(I) (8-12) complexes are described. Crystal structures of 2 and 4, as well as 5, 6 and 10 confirm the molecular geometry of these ligands and their metal complexes. Preliminary investigation of four gold complexes as potential anticancer, antiHIV and antimalaria showed at least one gold compound that has excellent activity towards one of these diseases. The three gold(I) complexes, {1- [1-(dimethylamino)ethyl]-1 ,2-bis(diphenylphosphino)ruthenocene-kappa P-2,P'}bis[chlorogold(I)] (8) (IC50 = 1.40 mu M), {1-[1-(acetoxyethyl)-1',2-bis(diphenylphosphino)ferrocene-kappa P-2,P']bis[chlorogold(1)] (9) (IC50 = 0.51 mu M), {1-[1-(3-carboxypropanamido)ethyl]-1',2-bis(diphenylphosphino)-ruthenocene kappa P-2,P'} bis[chlorogold(I)] (12) (IC50 = 1.784 mu M), have the best activities against cancer, HIV and malaria respectively. (C) 2012 Elsevier B.V. All rights reserved.
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| 14. |
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| 15. |
- Brilakis, Emmanouil S., et al.
(author)
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Effect of ticagrelor on the outcomes of patients with prior coronary artery bypass graft surgery : Insights from the PLATelet inhibition and patient outcomes (PLATO) trial
- 2013
-
In: American Heart Journal. - : Elsevier BV. - 0002-8703 .- 1097-6744. ; 166:3, s. 474-480
-
Journal article (peer-reviewed)abstract
- Background Patients with prior coronary artery bypass graft surgery (CABG) who present with an acute coronary syndrome have a high risk for recurrent events. Whether intensive antiplatelet therapy with ticagrelor might be beneficial compared with clopidogrel is unknown. In this substudy of the PLATO trial, we studied the effects of randomized treatment dependent on history of CABG. Methods Patients participating in PLATO were classified according to whether they had undergone prior CABG. The trial's primary and secondary end points were compared using Cox proportional hazards regression. Results Of the 18,613 study patients, 1,133 (6.1%) had prior CABG. Prior-CABG patients had more high-risk characteristics at study entry and a 2-fold increase in clinical events during follow-up, but less major bleeding. The primary end point (composite of cardiovascular death, myocardial infarction, and stroke) was reduced to a similar extent by ticagrelor among patients with (19.6% vs 21.4%; adjusted hazard ratio [HR], 0.91 [0.67, 1.24]) and without (9.2% vs 11.0%; adjusted HR, 0.86 [0.77, 0.96]; P-interaction = .73) prior CABG. Major bleeding was similar with ticagrelor versus clopidogrel among patients with (8.1% vs 8.7%; adjusted HR, 0.89 [0.55, 1.47]) and without (11.8% vs 11.4%; HR, 1.08 [0.98, 1.20]; P-interaction =.46) prior CABG. Conclusions Prior-CABG patients presenting with acute coronary syndrome are a high-risk cohort for death and recurrent cardiovascular events but have a lower risk for major bleeding. Similar to the results in no-prior-CABG patients, ticagrelor was associated with a reduction in ischemic events without an increase in major bleeding.
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| 16. |
- Bruins, Harman M, et al.
(author)
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The impact of the extent of lymphadenectomy on oncologic outcomes in patients undergoing radical cystectomy for bladder cancer : a systematic review
- 2014
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In: European Urology. - : Elsevier. - 0302-2838 .- 1873-7560. ; 66:6, s. 1065-1077
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Journal article (peer-reviewed)abstract
- CONTEXT: Controversy exists regarding the therapeutic value of lymphadenectomy (LND) in patients undergoing radical cystectomy (RC) for muscle-invasive bladder cancer (MIBC). OBJECTIVE: To systematically review the relevant literature assessing the impact of LND on oncologic and perioperative outcomes in patients undergoing RC for MIBC. EVIDENCE ACQUISITION: Medline, Medline In-Process, Embase, the Cochrane Central Register of Controlled Trials, and the Latin American and Caribbean Center on Health Sciences Information (LILACS) were searched up to December 2013. Comparative studies reporting on no LND, limited LND (L-LND), standard LND (S-LND), extended LND (E-LND), superextended LND (SE-LND), and oncologic and perioperative outcomes were included. Risk-of-bias and confounding assessments were performed. EVIDENCE SYNTHESIS: Twenty-three studies reporting on 19 793 patients were included. All but one study were retrospective. Planned meta-analyses were not possible because of study heterogeneity; therefore, data were synthesized narratively. There were high risks of bias and confounding across most studies as well as extreme heterogeneity in the definition of the anatomic boundaries of LND templates. All seven studies comparing LND with no LND favored LND in terms of better oncologic outcomes. Seven of 14 studies comparing (super)extended LND with L-LND or S-LND reported a beneficial outcome for (super)extended LND in at least a subset of patients. No difference in outcome was reported in two studies comparing E-LND and S-LND. The comparative harms of different extents of LND remain unclear. CONCLUSIONS: Although the quality of the data was poor, the available evidence indicates that any kind of LND is advantageous over no LND. Similarly, E-LND appears to be superior to lesser degrees of dissection, while SE-LND offered no additional benefits. It is hoped that data from ongoing randomized clinical trials will clarify remaining uncertainties. PATIENT SUMMARY: The current literature suggests that removal of lymph nodes in bladder cancer surgery is beneficial and might result in better outcomes in terms of prolonging survival; however, the quality of the available studies is poor, and high-quality studies are needed.
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| 17. |
- Cerhan, James R., et al.
(author)
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A Pooled Analysis of Waist Circumference and Mortality in 650,000 Adults
- 2014
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In: Mayo Clinic proceedings. - : ELSEVIER SCIENCE INC. - 0025-6196 .- 1942-5546. ; 89:3, s. 335-345
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Journal article (peer-reviewed)abstract
- Objectives: To assess the independent effect of waist circumference on mortality across the entire body mass index (BMI) range and to estimate the loss in life expectancy related to a higher waist circumference. Patients and Methods: We pooled data from 11 prospective cohort studies with 650,386 white adults aged 20 to 83 years and enrolled from January 1, 1986, through December 31, 2000. We used proportional hazards regression to estimate hazard ratios (HRs) and 95% CIs for the association of waist circumference with mortality. Results: During a median follow-up of 9 years (maximum, 21 years), 78,268 participants died. After accounting for age, study, BMI, smoking status, alcohol consumption, and physical activity, a strong positive linear association of waist circumference with all-cause mortality was observed for men (HR, 1.52 for waist circumferences of >= 110 vs < 90 cm; 95% CI, 1.45-1.59; HR, 1.07 per 5-cm increment in waist circumference; 95% CI, 1.06-1.08) and women (HR, 1.80 for waist circumferences of >= 95 vs < 70 cm; 95% CI, 1.70-1.89; HR, 1.09 per 5-cm increment in waist circumference; 95% CI, 1.08-1.09). The estimated decrease in life expectancy for highest vs lowest waist circumference was approximately 3 years for men and approximately 5 years for women. The HR per 5-cm increment in waist circumference was similar for both sexes at all BMI levels from 20 to 50 kg/m(2), but it was higher at younger ages, higher for longer follow-up, and lower among male current smokers. The associations were stronger for heart and respiratory disease mortality than for cancer. Conclusions: In white adults, higher waist circumference was positively associated with higher mortality at all levels of BMI from 20 to 50 kg/m(2). Waist circumference should be assessed in combination with BMI, even for those in the normal BMI range, as part of risk assessment for obesity-related premature mortality. (C) 2014 Mayo Foundation for Medical Education and Research
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| 18. |
- Coelho, Teresa, et al.
(author)
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Safety and efficacy of RNAi therapy for transthyretin amyloidosis
- 2013
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In: The New England journal of medicine. - 1533-4406. ; 369:9, s. 819-29
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Journal article (peer-reviewed)abstract
- BACKGROUND: Transthyretin amyloidosis is caused by the deposition of hepatocyte-derived transthyretin amyloid in peripheral nerves and the heart. A therapeutic approach mediated by RNA interference (RNAi) could reduce the production of transthyretin. METHODS: We identified a potent antitransthyretin small interfering RNA, which was encapsulated in two distinct first- and second-generation formulations of lipid nanoparticles, generating ALN-TTR01 and ALN-TTR02, respectively. Each formulation was studied in a single-dose, placebo-controlled phase 1 trial to assess safety and effect on transthyretin levels. We first evaluated ALN-TTR01 (at doses of 0.01 to 1.0 mg per kilogram of body weight) in 32 patients with transthyretin amyloidosis and then evaluated ALN-TTR02 (at doses of 0.01 to 0.5 mg per kilogram) in 17 healthy volunteers. RESULTS: Rapid, dose-dependent, and durable lowering of transthyretin levels was observed in the two trials. At a dose of 1.0 mg per kilogram, ALN-TTR01 suppressed transthyretin, with a mean reduction at day 7 of 38%, as compared with placebo (P=0.01); levels of mutant and nonmutant forms of transthyretin were lowered to a similar extent. For ALN-TTR02, the mean reductions in transthyretin levels at doses of 0.15 to 0.3 mg per kilogram ranged from 82.3 to 86.8%, with reductions of 56.6 to 67.1% at 28 days (P<0.001 for all comparisons). These reductions were shown to be RNAi-mediated. Mild-to-moderate infusion-related reactions occurred in 20.8% and 7.7% of participants receiving ALN-TTR01 and ALN-TTR02, respectively. CONCLUSIONS: ALN-TTR01 and ALN-TTR02 suppressed the production of both mutant and nonmutant forms of transthyretin, establishing proof of concept for RNAi therapy targeting messenger RNA transcribed from a disease-causing gene. (Funded by Alnylam Pharmaceuticals; ClinicalTrials.gov numbers, NCT01148953 and NCT01559077.).
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| 19. |
- Commins, Scott P, et al.
(author)
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Galactose-α-1,3-galactose-specific IgE is associated with anaphylaxis but not asthma.
- 2012
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In: American journal of respiratory and critical care medicine. - 1535-4970 .- 1073-449X. ; 185:7, s. 723-30
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Journal article (peer-reviewed)abstract
- IgE antibodies to the mammalian oligosaccharide galactose-α-1,3-galactose (α-gal) are common in the southeastern United States. These antibodies, which are induced by ectoparasitic ticks, can give rise to positive skin tests or serum assays with cat extract.
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| 20. |
- Commins, Scott P., et al.
(author)
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The relevance of tick bites to the production of IgE antibodies to the mammalian oligosaccharide galactose-alpha-1,3-galactose
- 2011
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In: Journal of Allergy and Clinical Immunology. - : Elsevier BV. - 0091-6749 .- 1097-6825. ; 127:5, s. 1286-1293.e6
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Journal article (peer-reviewed)abstract
- Background: In 2009, we reported a novel form of delayed anaphylaxis to red meat that is related to serum IgE antibodies to the oligosaccharide galactose-alpha-1,3-galactose (alpha-gal). Most of these patients had tolerated meat for many years previously. The implication is that some exposure in adult life had stimulated the production of these IgE antibodies. Objectives: We sought to investigate possible causes of this IgE antibody response, focusing on evidence related to tick bites, which are common in the region where these reactions occur.Methods: Serum assays were carried out with biotinylated proteins and extracts bound to a streptavidin ImmunoCAP.Results: Prospective studies on IgE antibodies in 3 subjects after tick bites showed an increase in levels of IgE to alpha-gal of 20fold or greater. Other evidence included (1) a strong correlation between histories of tick bites and levels of IgE to alpha-gal (chi(2) = 26.8, P < .001), (2) evidence that these IgE antibodies are common in areas where the tick Amblyomma americanum is common, and (3) a significant correlation between IgE antibodies to alpha-gal and IgE antibodies to proteins derived from A americanum (r(s) = 0.75, P < .001).Conclusion: The results presented here provide evidence that tick bites are a cause, possibly the only cause, of IgE specific for alpha-gal in this area of the United States. Both the number of subjects becoming sensitized and the titer of IgE antibodies to alpha-gal are striking. Here we report the first example of a response to an ectoparasite giving rise to an important form of food allergy.
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| 21. |
- Craddock, Nick, et al.
(author)
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Genome-wide association study of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls
- 2010
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In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 464:7289, s. 713-720
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Journal article (peer-reviewed)abstract
- Copy number variants (CNVs) account for a major proportion of human genetic polymorphism and have been predicted to have an important role in genetic susceptibility to common disease. To address this we undertook a large, direct genome-wide study of association between CNVs and eight common human diseases. Using a purpose-designed array we typed,19,000 individuals into distinct copy-number classes at 3,432 polymorphic CNVs, including an estimated similar to 50% of all common CNVs larger than 500 base pairs. We identified several biological artefacts that lead to false-positive associations, including systematic CNV differences between DNAs derived from blood and cell lines. Association testing and follow-up replication analyses confirmed three loci where CNVs were associated with disease-IRGM for Crohn's disease, HLA for Crohn's disease, rheumatoid arthritis and type 1 diabetes, and TSPAN8 for type 2 diabetes-although in each case the locus had previously been identified in single nucleotide polymorphism (SNP)-based studies, reflecting our observation that most common CNVs that are well-typed on our array are well tagged by SNPs and so have been indirectly explored through SNP studies. We conclude that common CNVs that can be typed on existing platforms are unlikely to contribute greatly to the genetic basis of common human diseases.
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| 22. |
- Cruz-Ramírez, Alfredo, et al.
(author)
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A Bistable Circuit Involving SCARECROW-RETINOBLASTOMA Integrates Cues to Inform Asymmetric Stem Cell Division
- 2012
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In: Cell. - : Elsevier. - 0092-8674 .- 1097-4172. ; 150:5, s. 1002-1015
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Journal article (peer-reviewed)abstract
- In plants, where cells cannot migrate, asymmetric cell divisions (ACDs) must be confined to the appropriate spatial context. We investigate tissue-generating asymmetric divisions in a stem cell daughter within the Arabidopsis root. Spatial restriction of these divisions requires physical binding of the stem cell regulator SCARECROW (SCR) by the RETINOBLASTOM-RELATED (RBR) protein. In the stem cell niche, SCR activity is counteracted by phosphorylation of RBR through a cyclinD6;1-CDK complex. This cyclin is itself under transcriptional control of SCR and its partner SHORT ROOT (SHR), creating a robust bistable circuit with either high or low SHR-SCR complex activity. Auxin biases this circuit by promoting CYCD6;1 transcription. Mathematical modeling shows that ACDs are only switched on after integration of radial and longitudinal information, determined by SHR and auxin distribution, respectively. Coupling of cell-cycle progression to protein degradation resets the circuit, resulting in a "flip flop" that constrains asymmetric cell division to the stem cell region.
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| 23. |
- Ellinghaus, David, et al.
(author)
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Association between variants of PRDM1 and NDP52 and Crohn's disease, based on exome sequencing and functional studies
- 2013
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In: Gastroenterology. - : Elsevier BV. - 0016-5085 .- 1528-0012. ; 145:2, s. 339-347
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Journal article (peer-reviewed)abstract
- BACKGROUND & AIMS: Genome-wide association studies (GWAS) have identified 140 Crohn's disease (CD) susceptibility loci. For most loci, the variants that cause disease are not known and the genes affected by these variants have not been identified. We aimed to identify variants that cause CD through detailed sequencing, genetic association, expression, and functional studies.METHODS: We sequenced whole exomes of 42 unrelated subjects with CD and 5 healthy subjects (controls) and then filtered single nucleotide variants by incorporating association results from meta-analyses of CD GWAS and in silico mutation effect prediction algorithms. We then genotyped 9348 subjects with CD, 2868 subjects with ulcerative colitis, and 14,567 control subjects and associated variants analyzed in functional studies using materials from subjects and controls and in vitro model systems.RESULTS: We identified rare missense mutations in PR domain-containing 1 (PRDM1) and associated these with CD. These mutations increased proliferation of T cells and secretion of cytokines on activation and increased expression of the adhesion molecule L-selectin. A common CD risk allele, identified in GWAS, correlated with reduced expression of PRDM1 in ileal biopsy specimens and peripheral blood mononuclear cells (combined P = 1.6 x 10(-8)). We identified an association between CD and a common missense variant, Val248Ala, in nuclear domain 10 protein 52 (NDP52) (P = 4.83 x 10(-9)). We found that this variant impairs the regulatory functions of NDP52 to inhibit nuclear factor kappa B activation of genes that regulate inflammation and affect the stability of proteins in Toll-like receptor pathways.CONCLUSIONS: We have extended the results of GWAS and provide evidence that variants in PRDM1 and NDP52 determine susceptibility to CD. PRDM1 maps adjacent to a CD interval identified in GWAS and encodes a transcription factor expressed by T and B cells. NDP52 is an adaptor protein that functions in selective autophagy of intracellular bacteria and signaling molecules, supporting the role of autophagy in the pathogenesis of CD.
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| 24. |
- Estrada, Karol, et al.
(author)
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Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture.
- 2012
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In: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 44:5, s. 491-501
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Journal article (peer-reviewed)abstract
- Bone mineral density (BMD) is the most widely used predictor of fracture risk. We performed the largest meta-analysis to date on lumbar spine and femoral neck BMD, including 17 genome-wide association studies and 32,961 individuals of European and east Asian ancestry. We tested the top BMD-associated markers for replication in 50,933 independent subjects and for association with risk of low-trauma fracture in 31,016 individuals with a history of fracture (cases) and 102,444 controls. We identified 56 loci (32 new) associated with BMD at genome-wide significance (P < 5 × 10(-8)). Several of these factors cluster within the RANK-RANKL-OPG, mesenchymal stem cell differentiation, endochondral ossification and Wnt signaling pathways. However, we also discovered loci that were localized to genes not known to have a role in bone biology. Fourteen BMD-associated loci were also associated with fracture risk (P < 5 × 10(-4), Bonferroni corrected), of which six reached P < 5 × 10(-8), including at 18p11.21 (FAM210A), 7q21.3 (SLC25A13), 11q13.2 (LRP5), 4q22.1 (MEPE), 2p16.2 (SPTBN1) and 10q21.1 (DKK1). These findings shed light on the genetic architecture and pathophysiological mechanisms underlying BMD variation and fracture susceptibility.
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| 25. |
- Franke, Andre, et al.
(author)
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Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci
- 2010
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:12, s. 1118-1125
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Journal article (peer-reviewed)abstract
- We undertook a meta-analysis of six Crohn's disease genome-wide association studies (GWAS) comprising 6,333 affected individuals (cases) and 15,056 controls and followed up the top association signals in 15,694 cases, 14,026 controls and 414 parent-offspring trios. We identified 30 new susceptibility loci meeting genome-wide significance (P < 5 × 10⁻⁸). A series of in silico analyses highlighted particular genes within these loci and, together with manual curation, implicated functionally interesting candidate genes including SMAD3, ERAP2, IL10, IL2RA, TYK2, FUT2, DNMT3A, DENND1B, BACH2 and TAGAP. Combined with previously confirmed loci, these results identify 71 distinct loci with genome-wide significant evidence for association with Crohn's disease.
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