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- Sweeney, M. D., et al.
(författare)
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Vascular dysfunction-The disregarded partner of Alzheimer's disease
- 2019
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Ingår i: Alzheimers & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 15:1, s. 158-167
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Tidskriftsartikel (refereegranskat)abstract
- Increasing evidence recognizes Alzheimer's disease (AD) as a multifactorial and heterogeneous disease with multiple contributors to its pathophysiology, including vascular dysfunction. The recently updated AD Research Framework put forth by the National Institute on Aging-Alzheimer's Association describes a biomarker-based pathologic definition of AD focused on amyloid, tau, and neuronal injury. In response to this article, here we first discussed evidence that vascular dysfunction is an important early event in AD pathophysiology. Next, we examined various imaging sequences that could be easily implemented to evaluate different types of vascular dysfunction associated with, and/or contributing to, AD pathophysiology, including changes in blood-brain barrier integrity and cerebral blood flow. Vascular imaging biomarkers of small vessel disease of the brain, which is responsible for >50% of dementia worldwide, including AD, are already established, well characterized, and easy to recognize. We suggest that these vascular biomarkers should be incorporated into the AD Research Framework to gain a better understanding of AD pathophysiology and aid in treatment efforts. (C) 2018 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.
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- Zewinger, Stephen, et al.
(författare)
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Relations between lipoprotein(a) concentrations, LPA genetic variants, and the risk of mortality in patients with established coronary heart disease : a molecular and genetic association study
- 2017
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Ingår i: The Lancet Diabetes and Endocrinology. - : ELSEVIER SCIENCE INC. - 2213-8587 .- 2213-8595. ; 5:7, s. 534-543
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Tidskriftsartikel (refereegranskat)abstract
- Background: Lipoprotein(a) concentrations in plasma are associated with cardiovascular risk in the general population. Whether lipoprotein(a) concentrations or LPA genetic variants predict long-term mortality in patients with established coronary heart disease remains less clear.Methods: We obtained data from 3313 patients with established coronary heart disease in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study. We tested associations of tertiles of lipoprotein(a) concentration in plasma and two LPA single-nucleotide polymorphisms ([SNPs] rs10455872 and rs3798220) with all-cause mortality and cardiovascular mortality by Cox regression analysis and with severity of disease by generalised linear modelling, with and without adjustment for age, sex, diabetes diagnosis, systolic blood pressure, BMI, smoking status, estimated glomerular filtration rate, LDL-cholesterol concentration, and use of lipid-lowering therapy. Results for plasma lipoprotein(a) concentrations were validated in five independent studies involving 10 195 patients with established coronary heart disease. Results for genetic associations were replicated through large-scale collaborative analysis in the GENIUS-CHD consortium, comprising 106 353 patients with established coronary heart disease and 19 332 deaths in 22 studies or cohorts.Findings: The median follow-up was 9.9 years. Increased severity of coronary heart disease was associated with lipoprotein(a) concentrations in plasma in the highest tertile (adjusted hazard radio [HR] 1.44, 95% CI 1.14-1.83) and the presence of either LPA SNP (1.88, 1.40-2.53). No associations were found in LURIC with all-cause mortality (highest tertile of lipoprotein(a) concentration in plasma 0.95, 0.81-1.11 and either LPA SNP 1.10, 0.92-1.31) or cardiovascular mortality (0.99, 0.81-1.2 and 1.13, 0.90-1.40, respectively) or in the validation studies.Interpretation: In patients with prevalent coronary heart disease, lipoprotein(a) concentrations and genetic variants showed no associations with mortality. We conclude that these variables are not useful risk factors to measure to predict progression to death after coronary heart disease is established.
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- Lissek, T, et al.
(författare)
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Building Bridges through Science
- 2017
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Ingår i: Neuron. - : Elsevier BV. - 1097-4199 .- 0896-6273. ; 96:4, s. 730-735
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Tidskriftsartikel (refereegranskat)
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| 7. |
- McKay, James D., et al.
(författare)
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Large-scale association analysis identifies new lung cancer susceptibility loci and heterogeneity in genetic susceptibility across histological subtypes
- 2017
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 49:7, s. 1126-1132
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Tidskriftsartikel (refereegranskat)abstract
- Although several lung cancer susceptibility loci have been identified, much of the heritability for lung cancer remains unexplained. Here 14,803 cases and 12,262 controls of European descent were genotyped on the OncoArray and combined with existing data for an aggregated genomewide association study (GWAS) analysis of lung cancer in 29,266 cases and 56,450 controls. We identified 18 susceptibility loci achieving genome-wide significance, including 10 new loci. The new loci highlight the striking heterogeneity in genetic susceptibility across the histological subtypes of lung cancer, with four loci associated with lung cancer overall and six loci associated with lung adenocarcinoma. Gene expression quantitative trait locus (eQTL) analysis in 1,425 normal lung tissue samples highlights RNASET2, SECISBP2L and NRG1 as candidate genes. Other loci include genes such as a cholinergic nicotinic receptor, CHRNA2, and the telomere-related genes OFBC1 and RTEL1. Further exploration of the target genes will continue to provide new insights into the etiology of lung cancer.
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| 8. |
- Nijkamp, P., et al.
(författare)
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Towards a regional science academy : A manifesto
- 2016
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Ingår i: Region. - : European Regional Science Association. - 2409-5370. ; 3:1, s. R1-R16
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Tidskriftsartikel (refereegranskat)abstract
- This Manifesto provides a joint proposal to create a Regional Science Academy as a think-tank support platform for a strategic development of the spatial sciences. The Regional Science Academy is a strategic spatial knowledge catalyst: it acts as a global intellectual powerhouse for new knowledge network initiatives and scholarly views on regions and cities as vital centrepieces of interconnected spatial systems. This contribution highlights its role and presents various activity plans.
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| 9. |
- Burda, P, et al.
(författare)
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Characterization and review of MTHFD1 deficiency: four new patients, cellular delineation and response to folic and folinic acid treatment.
- 2015
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Ingår i: Journal of Inherited Metabolic Disease. - : Wiley. - 0141-8955 .- 1573-2665. ; 38:5, s. 863-872
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Tidskriftsartikel (refereegranskat)abstract
- In the folate cycle MTHFD1, encoded by MTHFD1, is a trifunctional enzyme containing 5,10-methylenetetrahydrofolate dehydrogenase, 5,10-methenyltetrahydrofolate cyclohydrolase and 10-formyltetrahydrofolate synthetase activity. To date, only one patient with MTHFD1 deficiency, presenting with hyperhomocysteinemia, megaloblastic anaemia, hemolytic uremic syndrome (HUS) and severe combined immunodeficiency, has been identified (Watkins et al J Med Genet 48:590-2, 2011). We now describe four additional patients from two different families. The second patient presented with hyperhomocysteinemia, megaloblastic anaemia, HUS, microangiopathy and retinopathy; all except the retinopathy resolved after treatment with hydroxocobalamin, betaine and folinic acid. The third patient developed megaloblastic anaemia, infection, autoimmune disease and moderate liver fibrosis but not hyperhomocysteinemia, and was successfully treated with a regime that included and was eventually reduced to folic acid. The other two, elder siblings of the third patient, died at 9weeks of age with megaloblastic anaemia, infection and severe acidosis and had MTFHD1 deficiency diagnosed retrospectively. We identified a missense mutation (c.806C>T, p.Thr296Ile) and a splice site mutation (c.1674G>A) leading to exon skipping in the second patient, while the other three harboured a missense mutation (c.146C>T, p.Ser49Phe) and a premature stop mutation (c.673G>T, p.Glu225*), all of which were novel. Patient fibroblast studies revealed severely reduced methionine formation from [(14)C]-formate, which did not increase in cobalamin supplemented culture medium but was responsive to folic and folinic acid. These additional cases increase the clinical spectrum of this intriguing defect, provide in vitro evidence of disturbed methionine synthesis and substantiate the effectiveness of folic or folinic acid treatment.
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- Gonzalez-Alfonso, E., et al.
(författare)
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HIGH-LYING OH ABSORPTION, [C II] DEFICITS, AND EXTREME LFIR/MH2 RATIOS IN GALAXIES
- 2015
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Ingår i: Astrophysical Journal. - 1538-4357 .- 0004-637X. ; 800:1, s. 1-10
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Tidskriftsartikel (refereegranskat)abstract
- Herschel/PACS observations of 29 local (ultra) luminous infrared galaxies, including both starburst and active galactic nucleus (AGN) dominated sources as diagnosed in the mid-infrared/optical, show that the equivalent width of the absorbing OH 65 mu m.3/2 J = 9/2-7/2 line (Weq(OH65)) with lower level energy Elow 300 K, is anticorrelated with the [Cii] 158 mu m line to far-infrared luminosity ratio, and correlated with the far-infrared luminosity per unit gas mass and with the 60-to-100 mu m far-infrared color. While all sources are in the active LIR/MH2 > 50L /M mode as derived from previous CO line studies, the OH65 absorption shows a bimodal distribution with a discontinuity at LFIR/MH2 100L /M . In the most buried sources, OH65 probes material partially responsible for the silicate 9.7 mu m absorption. Combined with observations of the OH 71 mu m.1/2 J = 7/2-5/2 doublet (Elow 415 K), radiative transfer models characterized by the equivalent dust temperature, Tdust, and the continuum optical depth at 100 mu m, t100, indicate that strong [C ii] 158 mu m deficits are associated with far-IR thick (t100 0.7, NH 1024 cm-2), warm (Tdust 60 K) structures where the OH 65 mu m absorption is produced, most likely in circumnuclear disks/tori/cocoons. With their high LFIR/MH2 ratios and columns, the presence of these structures is expected to give rise to strong [C ii] deficits. Weq(OH65) probes the fraction of infrared luminosity arising from these compact/warm environments, which is 30%-50% in sources with high Weq(OH65). Sources with high Weq(OH65) have surface densities of both LIR and MH2 higher than inferred from the half-light (CO or UV/optical) radius, tracing coherent structures that represent the most buried/active stage of (circum) nuclear starburst-AGN co-evolution.
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