| 221. |
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| 222. |
- Ferwerda, Bart, et al.
(författare)
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Functional and genetic evidence that the Mal/TIRAP allele variant 180L has been selected by providing protection against septic shock.
- 2009
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 106:25, s. 10272-10277
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Tidskriftsartikel (refereegranskat)abstract
- Adequate responses by our innate immune system toward invading pathogens were of vital importance for surviving infections, especially before the antibiotic era. Recently, a polymorphism in Mal (Ser180Leu, TIRAP rs8177374), an important adaptor protein downstream of the Toll-like receptor (TLR) 2 and 4 pathways, has been described to provide protection against a broad range of infectious pathogens. We assessed the functional effects of this polymorphism in human experimental endotoxemia, and we demonstrate that individuals bearing the TIRAP 180L allele display an increased, innate immune response to TLR4 and TLR2 ligands, but not to TLR9 stimulation. This phenotype has been related to an increased resistance to infection. However, an overshoot in the release of proinflammatory cytokines by TIRAP 180L homozygous individuals suggests a scenario of balanced evolution. We have also investigated the worldwide distribution of the Ser180Leu polymorphism in 14 populations around the globe to correlate the genetic makeup of TIRAP with the local infectious pressures. Based on the immunological, clinical, and genetic data, we propose that this mutation might have been selected in West Eurasia during the early settlement of this region after the out-of-Africa migration of modern Homo sapiens. This combination of functional and genetic data provides unique insights to our understanding of the pathogenesis of sepsis.
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| 223. |
- Freer, J., et al.
(författare)
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Flood risk and uncertainty
- 2013
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Ingår i: Risk and Uncertainty Assessment for Natural Hazards. - : Cambridge University Press. - 9781139047562 - 9781107006195 ; , s. 190-233
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Bokkapitel (övrigt vetenskapligt/konstnärligt)abstract
- IntroductionExtreme floods are among the most destructive forces of nature. Flooding accounts for a significant proportion of the total number of reported natural disasters occurring in the world (Figure 7.1a) and over the last 30 years this proportion has been increasing (Figure 7.1b). Reasons for this trend may not be clear; for each hazard there is a need to quantify whether this is an increase in the hazard itself, an increase in exposure to the hazard internationally or a change in the reporting of what constitutes a natural disaster. Internationally, the costs and scale of flooding are enormous but differ depending on the types of impact that are analysed and the databases used. Globally in 2007 it was estimated that annually 520 million people are affected by floods and that the death toll is approximately 25 000 people in any one year. Jonkman (2005) found for a study using data from 1974 to 2003 (from data maintained by the Centre for Research on the Epidemiology of Disasters in Brussels) that floods are the most significant natural disaster type in terms of the number of people affected – some 51% of the total of that period of approximately five billion people affected by natural disaster (droughts are second with 36%, and earthquakes third at 2%). However, in terms of overall estimated deaths flooding accounts for 10% of the approximately two million reported deaths associated with natural disasters over the 1974–2003 period (droughts 44% and earthquakes 27%). In monetary terms an assessment by Munich RE for the period 1980–2010 determined that at 2010 prices the losses totalled US$3000 billion from ~19 400 events with 2.275 million fatalities. Of these, hydrological catastrophes (flooding and mass movement, i.e. landslips and debris flow in this case) accounted for 24% of these monetary losses, from 35% of the total events, and 11% of the fatalities. Other categories of natural disasters included in these totals were geophysical, meteorological and climatological (NatCatSERVICE, 2011).
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| 224. |
- Greiser, K. H., et al.
(författare)
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Association of neighbourhood socioeconomic status and individual socioeconomic status with cardiovascular risk factors in an Eastern German population : the CARLA Study 2002–2006
- 2011
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Ingår i: IEA World Congress of Epidemiology, 7–11 August 2011, Edinburgh International Conference Centre, Edinburgh, Scotland Programme and abstracts. - : BMJ. ; , s. A249-
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Konferensbidrag (refereegranskat)abstract
- Introduction/objectives: Individual socioeconomic status (SES) is a determinant of cardiovascular risk factors (RF). Recent studies suggest an independent association of neighbourhood SES with cardiovascular RF, but the mechanisms have not fully been understood. Our aim was to assess the association of neighbourhood and individual SES with cardiovascular RF in an Eastern German population. Methods: We used cross-sectional data of 1779 participants aged 45–83 years of the population-based CARLA study. We calculated linear mixed models to assess the age-adjusted influence of neighbourhood-specific unemployment rates and individual SES on smoking, systolic blood pressure (SBP), and body mass index (BMI). Spatial dependencies within and between neighbourhoods were adjusted for by using ICAR models. Results: Neighbourhood-specific unemployment rates varied between 6.3 and 35.3%. Per 1% increase in the neighbourhood's unemployment rate, the number of cigarettes smoked/day increased by 0.11 in men (95% CI 0.09 to 0.12) and 0.05, (CI 0.04 to 0.07) in women. In women, SBP increased by 0.04 mm Hg with unemployment rate (CI 0.03 to 0.06), while there was no statistically significant association of SBP with SES in men. BMI was only in women significantly associated with unemployment (increase in BMI per 1% increase in unemployment rate 0.04 (CI 0.02 to 0.05)). Associations of RF with individual SES were stronger than with neighbourhood SES in multiple models. Conclusions: Our findings confirm the previously described association of neighbourhood SES with smoking independent of individual SES, while we found inconsistent associations with SBP and BMI. The neighbourhood environment may be more relevant for behavioural than for biomedical risk factors.
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| 225. |
- Haghikia, A., et al.
(författare)
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Propionate attenuates atherosclerosis by immune-dependent regulation of intestinal cholesterol metabolism
- 2022
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Ingår i: European Heart Journal. - : Oxford University Press (OUP). - 0195-668X .- 1522-9645. ; 43:6, s. 518-533
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Tidskriftsartikel (refereegranskat)abstract
- Aims Atherosclerotic cardiovascular disease (ACVD) is a major cause of mortality and morbidity worldwide, and increased low-density lipoproteins (LDLs) play a critical role in development and progression of atherosclerosis. Here, we examined for the first time gut immunomodulatory effects of the microbiota-derived metabolite propionic acid (PA) on intestinal cholesterol metabolism. Methods and results Using both human and animal model studies, we demonstrate that treatment with PA reduces blood total and LDL cholesterol levels. In apolipoprotein E-/- (Apoe(-/-)) mice fed a high-fat diet (HFD), PA reduced intestinal cholesterol absorption and aortic atherosclerotic lesion area. Further, PA increased regulatory T-cell numbers and interleukin (IL)-10 levels in the intestinal microenvironment, which in turn suppressed the expression of Niemann-Pick C1-like 1 (Npc1l1), a major intestinal cholesterol transporter. Blockade of IL-10 receptor signalling attenuated the PA-related reduction in total and LDL cholesterol and augmented atherosclerotic lesion severity in the HFD-fed Apoe(-/-) mice. To translate these preclinical findings to humans, we conducted a randomized, double-blinded, placebo-controlled human study (clinical trial no. NCT03590496). Oral supplementation with 500 mg of PA twice daily over the course of 8 weeks significantly reduced LDL [-15.9 mg/dL (-8.1%) vs. -1.6 mg/dL (-0.5%), P = 0.016], total [-19.6 mg/dL (-7.3%) vs. -5.3 mg/dL (-1.7%), P = 0.014] and non-high-density lipoprotein cholesterol levels [PA vs. placebo: -18.9 mg/dL (-9.1%) vs. -0.6 mg/dL (-0.5%), P = 0.002] in subjects with elevated baseline LDL cholesterol levels. Conclusion Our findings reveal a novel immune-mediated pathway linking the gut microbiota-derived metabolite PA with intestinal Npc1l1 expression and cholesterol homeostasis. The results highlight the gut immune system as a potential therapeutic target to control dyslipidaemia that may introduce a new avenue for prevention of ACVDs.
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| 226. |
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| 227. |
- Isacsson, G., et al.
(författare)
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Bibloc and Monobloc Oral appliances in the Treatment of Obstructive Sleep apnoea : a Multicenter, Randomized, Blinded, Parallel-Group Trial
- 2017
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Ingår i: Sleep Medicine. - : Elsevier. - 1389-9457 .- 1878-5506. ; 40:Suppl 1, s. E142-E143
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Introduction: The clinical benefit of bibloc over monobloc appliances has not been established in randomized trials treating obstructive sleep apnoea (OSA). We hypothesized that the two types of appliances are equally effective in treating moderate to severe OSA. Materials and methods: We performed a blinded, multicenter, randomized, controlled, prospective, parallel-group trial including patients aged 18 years or older who had moderate-to-severe OSA. Patients were randomly assigned to receive either a bibloc or a monobloc appliance with the intention to protrude the mandible 75% of the individual maximal protrusion capacity. At baseline a one-night respiratory polygraphy was done without any respiratory support. The polygraphy was iterated with the appliance in place at a 6-week follow-up. The primary outcome was the absolute change in the apnoea-hypopnea-index (AHI) from baseline to the 6-week follow-up, analysed in the per-protocol population. All patients who received an appliance were included in the safety analysis. This trial is registered with ClinicalTrials.gov, number NCT02148510, and approved by Uppsala Regional Ethical Review Board, Sweden (#2014/021). Results: We recruited patients from three dental specialist clinics in Sweden; enrolment of 302 patients was done between March 2014 and April 2016; 146 randomized to bibloc and 156 to monobloc appliance. Twenty-three patients in the bibloc group and 17 in the monobloc group were withdrawn due to reasons like appliance could not be fitted, lack of compliance, adverse events or non-valid follow-up polygraphy i.e. a per-protocol group of 123 bibloc and 139 monobloc treated patients. The mean change of AHI from baseline to 6 weeks of treatment was -13.8 (95% CI -16.1 to -11.5; p < 0.001) in the bibloc group and -12.5 (95% CI -14.8 to -10.3; p < 0.001) in the monobloc group. The mean difference was not significant between the groups (-1.3 (95% CI -4.5 to 1.9). The most common adverse event in the orofacial region was upper airway infection followed by complains from various parts of the mouth, jaws and teeth. Conclusions: Bibloc and monobloc appliance treatment was equal in their effects in treating OSA as measured by at home polygraphic respiratory measures and the appliances were associated with a similar degree of adverse events. Acknowledgements: Funding from Uppsala-Örebro Regional Research Council and Vastmanland County Council, Sweden.
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| 228. |
- Isacsson, G., et al.
(författare)
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Pain relief following a single-dose intra-articular injection of methylprednisolone in the temporomandibular joint arthralgia-A multicentre randomised controlled trial
- 2019
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Ingår i: J Oral Rehabil. - : Wiley. - 0305-182X .- 1365-2842. ; 46:1, s. 5-13
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Tidskriftsartikel (refereegranskat)abstract
- Background Temporomandibular joint (TMJ) arthralgia is a painful condition assumed to be associated with local inflammation. Objective The objective of the present study was to determine the efficacy for reducing pain of a single-dose intra-articular (IA) injection of methylprednisolone to the TMJ. The hypothesis was that methylprednisolone would effectively reduce TMJ pain. Methods This randomised, double-blind, parallel-group, multicentre, controlled study included visits for enrolment, treatment and 4-week follow-up. The study included patients 18 years and older who had been diagnosed with unilateral TMJ arthralgia. All participants were randomly assigned to receive 1 mL IA injections of methylprednisolone or saline. The primary outcome was change in recorded pain intensity on a visual analogue scale (VAS) at maximum jaw opening, analysed in the per protocol population. Results In total, 54 patients were randomly assigned to single-dose IA injections with methylprednisolone (n = 27) or saline (n = 27). Between baseline and the 4-week follow-up, VAS-rated pain intensity at maximum jaw opening decreased from a mean of 61.0 (95% confidence interval [CI]: 50.1; 70.7) to 33.9 (95% CI: 21.6; 46.2) in the methylprednisolone group and from 59.6 (95% CI: 50.7; 65.9) to 33.9 (95% CI: 23.8; 43.9) in the saline group. The between-group difference was not significant (P = 0.812). Treatment-related adverse events were doubled in the methylprednisolone group. Conclusion Methylprednisolone provided no additional benefit for reducing pain, but caused more harm compared with saline following a single-dose IA injection in patients with TMJ arthralgia.
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| 229. |
- Jia, TY, et al.
(författare)
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Epigenome-wide meta-analysis of blood DNA methylation and its association with subcortical volumes: findings from the ENIGMA Epigenetics Working Group
- 2021
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Ingår i: Molecular psychiatry. - : Springer Science and Business Media LLC. - 1476-5578 .- 1359-4184. ; 26:8, s. 3884-3895
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Tidskriftsartikel (refereegranskat)abstract
- DNA methylation, which is modulated by both genetic factors and environmental exposures, may offer a unique opportunity to discover novel biomarkers of disease-related brain phenotypes, even when measured in other tissues than brain, such as blood. A few studies of small sample sizes have revealed associations between blood DNA methylation and neuropsychopathology, however, large-scale epigenome-wide association studies (EWAS) are needed to investigate the utility of DNA methylation profiling as a peripheral marker for the brain. Here, in an analysis of eleven international cohorts, totalling 3337 individuals, we report epigenome-wide meta-analyses of blood DNA methylation with volumes of the hippocampus, thalamus and nucleus accumbens (NAcc)—three subcortical regions selected for their associations with disease and heritability and volumetric variability. Analyses of individual CpGs revealed genome-wide significant associations with hippocampal volume at two loci. No significant associations were found for analyses of thalamus and nucleus accumbens volumes. Cluster-based analyses revealed additional differentially methylated regions (DMRs) associated with hippocampal volume. DNA methylation at these loci affected expression of proximal genes involved in learning and memory, stem cell maintenance and differentiation, fatty acid metabolism and type-2 diabetes. These DNA methylation marks, their interaction with genetic variants and their impact on gene expression offer new insights into the relationship between epigenetic variation and brain structure and may provide the basis for biomarker discovery in neurodegeneration and neuropsychiatric conditions.
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| 230. |
- Judd, N., et al.
(författare)
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Cognitive and brain development is independently influenced by socioeconomic status and polygenic scores for educational attainment
- 2020
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 117:22, s. 12411-12418
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Tidskriftsartikel (refereegranskat)abstract
- Genetic factors and socioeconomic status (SES) inequalities play a large role in educational attainment, and both have been associated with variations in brain structure and cognition. However, genetics and SES are correlated, and no prior study has assessed their neural associations independently. Here we used a polygenic score for educational attainment (EduYears-PGS), as well as SES, in a longitudinal study of 551 adolescents to tease apart genetic and environmental associations with brain development and cognition. Subjects received a structural MRI scan at ages 14 and 19. At both time points, they performed three working memory (WM) tasks. SES and EduYears-PGS were correlated (r = 0.27) and had both common and independent associations with brain structure and cognition. Specifically, lower SES was related to less total cortical surface area and lower WM. EduYears-PGS was also related to total cortical surface area, but in addition had a regional association with surface area in the right parietal lobe, a region related to nonverbal cognitive functions, including mathematics, spatial cognition, and WM. SES, but not EduYears-PGS, was related to a change in total cortical surface area from age 14 to 19. This study demonstrates a regional association of EduYears-PGS and the independent prediction of SES with cognitive function and brain development. It suggests that the SES inequalities, in particular parental education, are related to global aspects of cortical development, and exert a persistent influence on brain development during adolescence.
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