| 1. |
- Gaulton, Kyle J, et al.
(författare)
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Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci.
- 2015
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 47:12, s. 1415-1415
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Tidskriftsartikel (refereegranskat)abstract
- We performed fine mapping of 39 established type 2 diabetes (T2D) loci in 27,206 cases and 57,574 controls of European ancestry. We identified 49 distinct association signals at these loci, including five mapping in or near KCNQ1. 'Credible sets' of the variants most likely to drive each distinct signal mapped predominantly to noncoding sequence, implying that association with T2D is mediated through gene regulation. Credible set variants were enriched for overlap with FOXA2 chromatin immunoprecipitation binding sites in human islet and liver cells, including at MTNR1B, where fine mapping implicated rs10830963 as driving T2D association. We confirmed that the T2D risk allele for this SNP increases FOXA2-bound enhancer activity in islet- and liver-derived cells. We observed allele-specific differences in NEUROD1 binding in islet-derived cells, consistent with evidence that the T2D risk allele increases islet MTNR1B expression. Our study demonstrates how integration of genetic and genomic information can define molecular mechanisms through which variants underlying association signals exert their effects on disease.
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| 2. |
- Locke, Adam E, et al.
(författare)
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Genetic studies of body mass index yield new insights for obesity biology.
- 2015
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 518:7538, s. 197-401
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 3. |
- Shungin, Dmitry, et al.
(författare)
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New genetic loci link adipose and insulin biology to body fat distribution.
- 2015
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 518:7538, s. 187-378
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Tidskriftsartikel (refereegranskat)abstract
- Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.
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| 4. |
- Lahrouchi, Najim, et al.
(författare)
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Transethnic Genome-Wide Association Study Provides Insights in the Genetic Architecture and Heritability of Long QT Syndrome
- 2020
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Ingår i: Circulation. - : Lippincott Williams & Wilkins. - 0009-7322 .- 1524-4539. ; 142:4, s. 324-338
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Tidskriftsartikel (refereegranskat)abstract
- Background: Long QT syndrome (LQTS) is a rare genetic disorder and a major preventable cause of sudden cardiac death in the young. A causal rare genetic variant with large effect size is identified in up to 80% of probands (genotype positive) and cascade family screening shows incomplete penetrance of genetic variants. Furthermore, a proportion of cases meeting diagnostic criteria for LQTS remain genetically elusive despite genetic testing of established genes (genotype negative). These observations raise the possibility that common genetic variants with small effect size contribute to the clinical picture of LQTS. This study aimed to characterize and quantify the contribution of common genetic variation to LQTS disease susceptibility. Methods: We conducted genome-wide association studies followed by transethnic meta-analysis in 1656 unrelated patients with LQTS of European or Japanese ancestry and 9890 controls to identify susceptibility single nucleotide polymorphisms. We estimated the common variant heritability of LQTS and tested the genetic correlation between LQTS susceptibility and other cardiac traits. Furthermore, we tested the aggregate effect of the 68 single nucleotide polymorphisms previously associated with the QT-interval in the general population using a polygenic risk score. Results: Genome-wide association analysis identified 3 loci associated with LQTS at genome-wide statistical significance (P<5x10(-8)) nearNOS1AP,KCNQ1, andKLF12, and 1 missense variant inKCNE1(p.Asp85Asn) at the suggestive threshold (P<10(-6)). Heritability analyses showed that approximate to 15% of variance in overall LQTS susceptibility was attributable to common genetic variation (h2SNP0.148; standard error 0.019). LQTS susceptibility showed a strong genome-wide genetic correlation with the QT-interval in the general population (r(g)=0.40;P=3.2x10(-3)). The polygenic risk score comprising common variants previously associated with the QT-interval in the general population was greater in LQTS cases compared with controls (P<10-13), and it is notable that, among patients with LQTS, this polygenic risk score was greater in patients who were genotype negative compared with those who were genotype positive (P<0.005). Conclusions: This work establishes an important role for common genetic variation in susceptibility to LQTS. We demonstrate overlap between genetic control of the QT-interval in the general population and genetic factors contributing to LQTS susceptibility. Using polygenic risk score analyses aggregating common genetic variants that modulate the QT-interval in the general population, we provide evidence for a polygenic architecture in genotype negative LQTS.
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| 5. |
- Scott, Robert A., et al.
(författare)
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An Expanded Genome-Wide Association Study of Type 2 Diabetes in Europeans
- 2017
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 66:11, s. 2888-2902
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Tidskriftsartikel (refereegranskat)abstract
- To characterize type 2 diabetes (T2D)-associated variation across the allele frequency spectrum, we conducted a meta-analysis of genome-wide association data from 26,676 T2D case and 132,532 control subjects of European ancestry after imputation using the 1000 Genomes multiethnic reference panel. Promising association signals were followed up in additional data sets (of 14,545 or 7,397 T2D case and 38,994 or 71,604 control subjects). We identified 13 novel T2D-associated loci (P < 5 x 10(-8)), including variants near the GLP2R, GIP, and HLA-DQA1 genes. Our analysis brought the total number of independent T2D associations to 128 distinct signals at 113 loci. Despite substantially increased sample size and more complete coverage of low-frequency variation, all novel associations were driven by common single nucleotide variants. Credible sets of potentially causal variants were generally larger than those based on imputation with earlier reference panels, consistent with resolution of causal signals to common risk haplotypes. Stratification of T2D-associated loci based on T2D-related quantitative trait associations revealed tissue-specific enrichment of regulatory annotations in pancreatic islet enhancers for loci influencing insulin secretion and in adipocytes, monocytes, and hepatocytes for insulin action-associated loci. These findings highlight the predominant role played by common variants of modest effect and the diversity of biological mechanisms influencing T2D pathophysiology.
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| 6. |
- Patel, Riyaz S., et al.
(författare)
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Subsequent Event Risk in Individuals With Established Coronary Heart Disease : Design and Rationale of the GENIUS-CHD Consortium
- 2019
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Ingår i: Circulation. - 2574-8300. ; 12:4
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The Genetics of Subsequent Coronary Heart Disease (GENIUS-CHD) consortium was established to facilitate discovery and validation of genetic variants and biomarkers for risk of subsequent CHD events, in individuals with established CHD.METHODS: The consortium currently includes 57 studies from 18 countries, recruiting 185 614 participants with either acute coronary syndrome, stable CHD, or a mixture of both at baseline. All studies collected biological samples and followed-up study participants prospectively for subsequent events.RESULTS: Enrollment into the individual studies took place between 1985 to present day with a duration of follow-up ranging from 9 months to 15 years. Within each study, participants with CHD are predominantly of self-reported European descent (38%-100%), mostly male (44%-91%) with mean ages at recruitment ranging from 40 to 75 years. Initial feasibility analyses, using a federated analysis approach, yielded expected associations between age (hazard ratio, 1.15; 95% CI, 1.14-1.16) per 5-year increase, male sex (hazard ratio, 1.17; 95% CI, 1.13-1.21) and smoking (hazard ratio, 1.43; 95% CI, 1.35-1.51) with risk of subsequent CHD death or myocardial infarction and differing associations with other individual and composite cardiovascular endpoints.CONCLUSIONS: GENIUS-CHD is a global collaboration seeking to elucidate genetic and nongenetic determinants of subsequent event risk in individuals with established CHD, to improve residual risk prediction and identify novel drug targets for secondary prevention. Initial analyses demonstrate the feasibility and reliability of a federated analysis approach. The consortium now plans to initiate and test novel hypotheses as well as supporting replication and validation analyses for other investigators.
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| 7. |
- Feitosa, Mary F., et al.
(författare)
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Novel genetic associations for blood pressure identified via gene-alcohol interaction in up to 570K individuals across multiple ancestries
- 2018
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Ingår i: PLOS ONE. - : Public library science. - 1932-6203. ; 13:6
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Tidskriftsartikel (refereegranskat)abstract
- Heavy alcohol consumption is an established risk factor for hypertension; the mechanism by which alcohol consumption impact blood pressure (BP) regulation remains unknown. We hypothesized that a genome-wide association study accounting for gene-alcohol consumption interaction for BP might identify additional BP loci and contribute to the understanding of alcohol-related BP regulation. We conducted a large two-stage investigation incorporating joint testing of main genetic effects and single nucleotide variant (SNV)-alcohol consumption interactions. In Stage 1, genome-wide discovery meta-analyses in approximate to 131 K individuals across several ancestry groups yielded 3,514 SNVs (245 loci) with suggestive evidence of association (P <1.0 x 10(-5)). In Stage 2, these SNVs were tested for independent external replication in individuals across multiple ancestries. We identified and replicated (at Bonferroni correction threshold) five novel BP loci (380 SNVs in 21 genes) and 49 previously reported BP loci (2,159 SNVs in 109 genes) in European ancestry, and in multi-ancestry meta-analyses (P < 5.0 x 10(-8)). For African ancestry samples, we detected 18 potentially novel BP loci (P< 5.0 x 10(-8)) in Stage 1 that warrant further replication. Additionally, correlated meta-analysis identified eight novel BP loci (11 genes). Several genes in these loci (e.g., PINX1, GATA4, BLK, FTO and GABBR2 have been previously reported to be associated with alcohol consumption. These findings provide insights into the role of alcohol consumption in the genetic architecture of hypertension.
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| 8. |
- Patel, Riyaz S., et al.
(författare)
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Association of Chromosome 9p21 With Subsequent Coronary Heart Disease Events : A GENIUS-CHD Study of Individual Participant Data
- 2019
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Ingår i: Circulation. - 2574-8300. ; 12:4
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Genetic variation at chromosome 9p21 is a recognized risk factor for coronary heart disease (CHD). However, its effect on disease progression and subsequent events is unclear, raising questions about its value for stratification of residual risk.METHODS: A variant at chromosome 9p21 (rs1333049) was tested for association with subsequent events during follow-up in 103 357 Europeans with established CHD at baseline from the GENIUS-CHD (Genetics of Subsequent Coronary Heart Disease) Consortium (73.1% male, mean age 62.9 years). The primary outcome, subsequent CHD death or myocardial infarction (CHD death/myocardial infarction), occurred in 13 040 of the 93 115 participants with available outcome data. Effect estimates were compared with case/control risk obtained from the CARDIoGRAMplusC4D consortium (Coronary Artery Disease Genome-wide Replication and Meta-analysis [CARDIoGRAM] plus The Coronary Artery Disease [C4D] Genetics) including 47 222 CHD cases and 122 264 controls free of CHD.RESULTS: Meta-analyses revealed no significant association between chromosome 9p21 and the primary outcome of CHD death/myocardial infarction among those with established CHD at baseline (GENIUSCHD odds ratio, 1.02; 95% CI, 0.99-1.05). This contrasted with a strong association in CARDIoGRAMPlusC4D odds ratio 1.20; 95% CI, 1.18-1.22; P for interaction < 0.001 compared with the GENIUS-CHD estimate. Similarly, no clear associations were identified for additional subsequent outcomes, including all-cause death, although we found a modest positive association between chromosome 9p21 and subsequent revascularization (odds ratio, 1.07; 95% CI, 1.04-1.09).CONCLUSIONS: In contrast to studies comparing individuals with CHD to disease-free controls, we found no clear association between genetic variation at chromosome 9p21 and risk of subsequent acute CHD events when all individuals had CHD at baseline. However, the association with subsequent revascularization may support the postulated mechanism of chromosome 9p21 for promoting atheroma development.
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| 9. |
- Sung, Yun Ju, et al.
(författare)
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A multi-ancestry genome-wide study incorporating gene-smoking interactions identifies multiple new loci for pulse pressure and mean arterial pressure
- 2019
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Ingår i: Human Molecular Genetics. - : Oxford University Press. - 0964-6906 .- 1460-2083. ; 28:15, s. 2615-2633
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Tidskriftsartikel (refereegranskat)abstract
- Elevated blood pressure (BP), a leading cause of global morbidity and mortality, is influenced by both genetic and lifestyle factors. Cigarette smoking is one such lifestyle factor. Across five ancestries, we performed a genome-wide gene–smoking interaction study of mean arterial pressure (MAP) and pulse pressure (PP) in 129 913 individuals in stage 1 and follow-up analysis in 480 178 additional individuals in stage 2. We report here 136 loci significantly associated with MAP and/or PP. Of these, 61 were previously published through main-effect analysis of BP traits, 37 were recently reported by us for systolic BP and/or diastolic BP through gene–smoking interaction analysis and 38 were newly identified (P < 5 × 10−8, false discovery rate < 0.05). We also identified nine new signals near known loci. Of the 136 loci, 8 showed significant interaction with smoking status. They include CSMD1 previously reported for insulin resistance and BP in the spontaneously hypertensive rats. Many of the 38 new loci show biologic plausibility for a role in BP regulation. SLC26A7 encodes a chloride/bicarbonate exchanger expressed in the renal outer medullary collecting duct. AVPR1A is widely expressed, including in vascular smooth muscle cells, kidney, myocardium and brain. FHAD1 is a long non-coding RNA overexpressed in heart failure. TMEM51 was associated with contractile function in cardiomyocytes. CASP9 plays a central role in cardiomyocyte apoptosis. Identified only in African ancestry were 30 novel loci. Our findings highlight the value of multi-ancestry investigations, particularly in studies of interaction with lifestyle factors, where genomic and lifestyle differences may contribute to novel findings.
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| 10. |
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| 11. |
- Cronberg, Carin, et al.
(författare)
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Peripheral arterial disease.
- 2003
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Ingår i: Acta Radiologica. - : SAGE Publications. - 1600-0455 .- 0284-1851. ; 44:1, s. 59-66
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Tidskriftsartikel (refereegranskat)
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| 12. |
- de Vries, Paul S., et al.
(författare)
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Multiancestry Genome-Wide Association Study of Lipid Levels Incorporating Gene-Alcohol Interactions
- 2019
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Ingår i: American Journal of Epidemiology. - : Oxford University Press. - 0002-9262 .- 1476-6256. ; 188:6, s. 1033-1054
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Tidskriftsartikel (refereegranskat)abstract
- A person's lipid profile is influenced by genetic variants and alcohol consumption, but the contribution of interactions between these exposures has not been studied. We therefore incorporated gene-alcohol interactions into a multiancestry genome-wide association study of levels of high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides. We included 45 studies in stage 1 (genome-wide discovery) and 66 studies in stage 2 (focused follow-up), for a total of 394,584 individuals from 5 ancestry groups. Analyses covered the period July 2014-November 2017. Genetic main effects and interaction effects were jointly assessed by means of a 2-degrees-of-freedom (df) test, and a 1-df test was used to assess the interaction effects alone. Variants at 495 loci were at least suggestively associated (P < 1 x 10(-6)) with lipid levels in stage 1 and were evaluated in stage 2, followed by combined analyses of stage 1 and stage 2. In the combined analysis of stages 1 and 2, a total of 147 independent loci were associated with lipid levels at P < 5 x 10(-8) using 2-df tests, of which 18 were novel. No genome-wide-significant associations were found testing the interaction effect alone. The novel loci included several genes (proprotein convertase subtilisin/kexin type 5 (PCSK5), vascular endothelial growth factor B (VEGFB), and apolipoprotein B mRNA editing enzyme, catalytic polypeptide 1 (APOBEC1) complementation factor (A1CF)) that have a putative role in lipid metabolism on the basis of existing evidence from cellular and experimental models.
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| 13. |
- Diaz, Sandra, et al.
(författare)
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Hyperpolarized (3)He apparent diffusion coefficient MRI of the lung: Reproducibility and volume dependency in healthy volunteers and patients with emphysema.
- 2008
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Ingår i: Journal of Magnetic Resonance Imaging. - : Wiley. - 1522-2586 .- 1053-1807. ; 27, s. 763-770
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: To measure the apparent diffusion coefficient (ADC) of hyperpolarized (HP) (3)He gas using diffusion weighted MRI in healthy volunteers and patients with emphysema and examine the reproducibility and volume dependency. MATERIALS AND METHODS: A total of eight healthy volunteers and 16 patients with emphysema were examined after inhalation of HP (3)He gas mixed with nitrogen (N(2)) during breathhold starting from functional residual capacity (FRC) in supine position. Coronal diffusion-sensitized MR images were acquired. Each subject was imaged on three separate days over a seven-day period and received two different volumes (6% and 15% of total lung capacity [TLC]) of HP (3)He each day. ADC maps and histograms were calculated. The mean and standard deviation (SD) of the ADC at different days and volumes were compared. RESULTS: The reproducibility of the mean ADC and SD over several days was good in both healthy volunteers and patients (SD range of 0.003-0.013 cm(2)/second and 0.001-0.009 cm(2)/second at 6% and 15% of TLC for healthy volunteers, and a SD range of 0.001-0.041 cm(2)/second and 0.001-0.011 cm(2)/second, respectively, for patients). A minor but significant increase in mean ADC with increased inhaled gas volume was observed in both groups. CONCLUSION: Mean ADC and SD of HP (3)He MRI is reproducible and discriminates well between healthy controls and patients with emphysema at the higher gas volume. This method is robust and may be useful to gain new insights into the pathophysiology and course of emphysema. J. Magn. Reson. Imaging 2008. (c) 2008 Wiley-Liss, Inc.
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| 14. |
- Diaz, Sandra, et al.
(författare)
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Validity of apparent diffusion coefficient hyperpolarized He-3-MRI using MSCT and pulmonary function tests as references
- 2009
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Ingår i: European Journal of Radiology. - : Elsevier BV. - 1872-7727 .- 0720-048X. ; 71:2, s. 257-263
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: To compare apparent diffusion coefficient (ADC) measurements from hyperpolarized (HP) helium (He-3)-magnetic resonance imaging (MRI) with quantitative data from multislice Computed Tomography (CT) (MSCT) of the whole lungs and pulmonary function tests (PFT). Materials and methods: Twenty-seven subjects, 22 with established emphysema and 5 with preclinical emphysema defined by PFT criteria, were examined with Hp He-3-MRI and MSCT. Mean age was 55 (+/- 12) years, 18 female and 9 male. Mean ADC from He-3-MRI was compared with emphysema index (EI), 15th percentile and mean lung density (MLD) values from MSCT. Both mean ADC and MSCT data were compared to PFT, especially percent of predicted diffusing capacity of carbon monoxide (%predicted DLCO), using Pearson's correlation test. Results: Mean ADC and standard deviation values were 0.392 +/- 0.119 cm(2)/s for the established emphysema group and 0.216 +/- 0.046 for the pre-clinical emphysema group. MSCT values for the established emphysema group and pre-clinical emphysema group were: EI (%) 11 +/- 12 and 0.4 +/- 0.6, respectively; 15th percentile (Hounsfield Units (HU)), -956 +/- 25 and -933 +/- 13, respectively and MLD (HU) -877 +/- 20 and -863 +/- 15, respectively. Correlations between mean ADC and El and 15th percentile were both r=0.90 and for MLD r=0.59. There was higher correlation between mean ADC and %predicted DLCO (r=0.90) than between El and %predicted DLCO (r=0.76). Conclusion: Hp He-3-MRI correlates well with density measurements from MSCT and agrees better than MSCT with %predicted DLCO which is the PFT most related to emphysema. (C) 2008 Elsevier Ireland Ltd. All rights reserved.
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| 15. |
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| 16. |
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| 17. |
- Leander, Peter, et al.
(författare)
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A new liposomal liver-specific contrast agent for CT: first human phase-I clinical trial assessing efficacy and safety
- 2001
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Ingår i: European Radiology. - : Springer Science and Business Media LLC. - 0938-7994 .- 1432-1084. ; 11:4, s. 698-704
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Tidskriftsartikel (refereegranskat)abstract
- In this first clinical trial liposome-encapsulated iodixanol, CT particles (CTP) were studied. The aims of the present trial were to assess the efficacy of CTP in CT and to determine the safety of different doses of CTP. A total of 47 healthy volunteers were enrolled in the present study. The CTP was administered at doses 10, 30, 70 and 100 mg encapsulated I/kg bw. Efficacy was assessed using single-slice CT of the abdomen and evaluated by dose-response attenuation curves over time in liver, spleen, and abdominal vessels. Safety was assessed by blood tests, clinical examinations and recording of subjective adverse events (AE). The attenuations in liver tissue increased with the dose and maximal values above baseline were 20, 39 and 45 HU at the doses 30, 70 and 100 mg encapsulated I/kg bw, respectively. Maximal increases were seen 12.5 min after contrast administration. As for liver, the attenuations in spleen increased with the dose, but higher attenuations were obtained. In early images clinically significant enhancement was seen in abdominal vessels. Mild and moderate subjective AE were encountered at the doses 70 and 100 mg encapsulated I/kg bw. The CTP is efficacious in enhancing hepatic and splenic tissues and in early imaging of abdominal vessels. Adverse event precludes a clinical use of CTP in the current formulation.
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| 18. |
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| 19. |
- Leander, Peter, et al.
(författare)
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Orally Administered Manganese With and Without Ascorbic Acid as a Liver-Specific Contrast Agent and Bowel Marker for Magnetic Resonance Imaging: Phase I Clinical Trial Assessing Efficacy and Safety.
- 2010
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Ingår i: Investigative Radiology. - 0020-9996. ; 45:9, s. 559-564
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES:: The objectives of this clinical trial of orally administered manganese in magnetic resonance imaging (MRI) of the liver were to assess signal enhancements in the liver with and without the addition of an uptake promoter, ascorbic acid, and to evaluate acute safety. MATERIALS AND METHODS:: A total of 18 healthy adult males were enrolled in the present trial. Contrast medium: MnCl2, doses: 25, 50, and 100 mumoL/kg bw, respectively, and promoting agent: Ascorbic acid, doses: 50, 100, and 200 mumoL/kg bw, respectively, were used. All imaging was performed on a 1.5 T clinical MRI system. Three pulse-sequences in the abdomen were used: (1) T1-weighted axial gradient-echo (GRE), (2) T1-weighted coronal gradient-echo, and (3) T1-weighted axial spin-echo (SE). Time-points for imaging were precontrast, 1 hour, 2.5, 4, 6, 9, and 24 hours after MnCl2 intake. Safety parameters assessed were clinical examinations and vital signs, including heart rate and blood pressure. Hematology and clinical chemistry were assessed with standard laboratory procedures. RESULTS:: All pulse-sequences showed a clear dose-response in liver-enhancement. Temporally, high enhancements in the liver were seen between 2.5 and 6 hours after MnCl2 intake. At the manganese dose 50-mumoL/kg bw, with ascorbic acid and at the dose 100-mumoL/kg bw, both with and without ascorbic acid, the hepatic enhancements were higher than 100% with the GRE pulse-sequence. The promoting effect of ascorbic acid was significant at a manganese-dose of 100-mumoL/kg bw. The contrast media distributed well in the small intestine, delineating intra-abdominal organs well. No serious or unexpected adverse events were encountered. The drug was generally well tolerated, except for minor gastrointestinal adverse events. No significant alteration in hematology or clinical chemistry was seen. CONCLUSIONS:: Oral manganese is easy to use, and has few side effects. Besides the liver-specific effect, an additional benefit is the delineation of the intestine.
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| 20. |
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| 21. |
- Norén, Bengt, 1955-
(författare)
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Non-Invasive Assessment of Liver Fibrosis with 31P-Magnetic Resonance Spectroscopy and Dynamic Contrast Enhanced Magnetic Resonance Imaging
- 2013
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The present study aims at demonstrating phosphorus metabolite concentration changes and alterations in uptake/excretion of a hepatocyte specific contrast agent in patients with diffuse - or suspected diffuse - liver disease by applying two non-invasive quantitative MR techniques and to compare the results with histo-pathological findings, with focus on liver fibrosis.In the first study phosphorus-31 MR spectroscopy using slice selection (DRESS) was implemented. Patients with histopathologically proven diffuse liver disease (n = 9) and healthy individuals (n = 12) were examined. The patients had significantly lower concentrations of phosphodiesters (PDE) and ATP compared with controls. Constructing an ‘anabolic charge’ (AC) based on absolute concentrations, [PME] / ([PME] + [PDE]), the patients had a significant larger AC than the control subjects.The MRS technique was then, in a second study, applied on two distinct groups of patients, one group with steatosis and none-to-moderate inflammation (n = 13) and one group with severe fibrosis or cirrhosis (n = 16). A control group (n = 13) was also included. Lower concentrations of PDE and a higher AC were found in the cirrhosis group compared to the control group. Also compared to the steatosis group, the cirrhosis group had lower concentrations of PDE and a higher AC. A significant correlation between fibrosis stage and PDE and fibrosis stage and AC was found. Using an AC cut-off value of 0.27 to discriminate between mild (stage 0-2) and advanced (stage 3-4) fibrosis yielded an AUROC value of 0.78, similar as for discriminating between F0-1 vs. F2-4.Dynamic contrast enhanced MRI (DCE-MRI) was performed prospectively in a third study on 38 patients referred for evaluation of elevated serum alanine aminotransferase (ALT) and/or alkaline phosphatase (ALP) levels. Data were acquired from regions of interest in the liver and spleen by using single-breath-hold symmetrically sampled two-point Dixon 3D images time-series (non-enhanced, arterial and venous portal phase; 3, 10, 20 and 30 min) following a bolus injection of Gd-EOB-DTPA (0.025 mmol/kg). A new quantification procedure for calculation of the ‘hepatocyte specific uptake rate’, KHep, was applied on a two-compartment pharmacokinetic model. Liver-to-spleen contrast ratios (LSC_N) were also calculated. AUROC values of 0.71, 0.80 and 0.78, respectively, were found for KHep, LSC_N10 and LSC_N20 with regard to severe versus mild fibrosis. Significant group differences were found for KHep (borderline), LSC_N10 and LSC_N20.In study four no significant correlation between visual assessments of bile ducts excretion of Gd-EOB-DTPA and histo-pathological grading of fibrosis or the quantified uptake of Gd-EOB-DTPA defined as KHep and LSC_N.In conclusion 31P-MRS and DCE-MRI show promising results for achieving a non-invasive approach in discriminating different levels of fibrosis from each other.
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| 22. |
- Peden, John F., et al.
(författare)
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A genome-wide association study in Europeans and South Asians identifies five new loci for coronary artery disease
- 2011
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 43:4, s. 339-344
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies have identified 11 common variants convincingly associated with coronary artery disease (CAD)(1-7), a modest number considering the apparent heritability of CAD(8). All of these variants have been discovered in European populations. We report a meta-analysis of four large genome-wide association studies of CAD, with similar to 575,000 genotyped SNPs in a discovery dataset comprising 15,420 individuals with CAD (cases) (8,424 Europeans and 6,996 South Asians) and 15,062 controls. There was little evidence for ancestry-specific associations, supporting the use of combined analyses. Replication in an independent sample of 21,408 cases and 19,185 controls identified five loci newly associated with CAD (P < 5 x 10(-8) in the combined discovery and replication analysis): LIPA on 10q23, PDGFD on 11q22, ADAMTS7-MORF4L1 on 15q25, a gene rich locus on 7q22 and KIAA1462 on 10p11. The CAD-associated SNP in the PDGFD locus showed tissue-specific cis expression quantitative trait locus effects. These findings implicate new pathways for CAD susceptibility.
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| 23. |
- Sator, Lea, et al.
(författare)
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Overdiagnosis of COPD in Subjects With Unobstructed Spirometry A BOLD Analysis
- 2019
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Ingår i: Chest. - : Elsevier BV. - 0012-3692 .- 1931-3543. ; 156:2, s. 277-288
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: There are several reports on underdiagnosis of COPD, while little is known about COPD overdiagnosis and overtreatment. We describe the overdiagnosis and the prevalence of spirometrically defined false positive COPD, as well as their relationship with overtreatment across 23 population samples in 20 countries participating in the BOLD Study between 2003 and 2012.METHODS: A false positive diagnosis of COPD was considered when participants reported a doctor's diagnosis of COPD, but postbronchodilator spirometry was unobstructed (FEV1/FVC > LLN). Additional analyses were performed using the fixed ratio criterion (FEV1/FVC < 0.7).RESULTS: Among 16,177 participants, 919 (5.7%) reported a previous medical diagnosis of COPD. Postbronchodilator spirometry was unobstructed in 569 subjects (61.9%): false positive COPD. A similar rate of overdiagnosis was seen when using the fixed ratio criterion (55.3%). In a subgroup analysis excluding participants who reported a diagnosis of "chronic bronchitis" or "emphysema" (n = 220), 37.7% had no airflow limitation. The site-specific prevalence of false positive COPD varied greatly, from 1.9% in low- to middle-income countries to 4.9% in high-income countries. In multivariate analysis, overdiagnosis was more common among women, and was associated with higher education; former and current smoking; the presence of wheeze, cough, and phlegm; and concomitant medical diagnosis of asthma or heart disease. Among the subjects with false positive COPD, 45.7% reported current use of respiratory medication. Excluding patients with reported asthma, 34.4% of those with normal spirometry still used a respiratory medication.CONCLUSIONS: False positive COPD is frequent. This might expose nonobstructed subjects to possible adverse effects of respiratory medication.
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| 24. |
- Sikkema, Lisa, et al.
(författare)
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An integrated cell atlas of the lung in health and disease
- 2023
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Ingår i: Nature Medicine. - : Springer Nature. - 1078-8956 .- 1546-170X. ; 29:6, s. 1563-1577
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Tidskriftsartikel (refereegranskat)abstract
- Single-cell technologies have transformed our understanding of human tissues. Yet, studies typically capture only a limited number of donors and disagree on cell type definitions. Integrating many single-cell datasets can address these limitations of individual studies and capture the variability present in the population. Here we present the integrated Human Lung Cell Atlas (HLCA), combining 49 datasets of the human respiratory system into a single atlas spanning over 2.4 million cells from 486 individuals. The HLCA presents a consensus cell type re-annotation with matching marker genes, including annotations of rare and previously undescribed cell types. Leveraging the number and diversity of individuals in the HLCA, we identify gene modules that are associated with demographic covariates such as age, sex and body mass index, as well as gene modules changing expression along the proximal-to-distal axis of the bronchial tree. Mapping new data to the HLCA enables rapid data annotation and interpretation. Using the HLCA as a reference for the study of disease, we identify shared cell states across multiple lung diseases, including SPP1 + profibrotic monocyte-derived macrophages in COVID-19, pulmonary fibrosis and lung carcinoma. Overall, the HLCA serves as an example for the development and use of large-scale, cross-dataset organ atlases within the Human Cell Atlas.
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| 25. |
- Thomsen, Henrik S., et al.
(författare)
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Nephrogenic systemic fibrosis and gadolinium-based contrast media: updated ESUR Contrast Medium Safety Committee guidelines
- 2013
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Ingår i: European Radiology. - : Springer Science and Business Media LLC. - 0938-7994 .- 1432-1084. ; 23:2, s. 307-318
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Tidskriftsartikel (refereegranskat)abstract
- To update the guidelines of the Contrast Media Safety Committee (CMSC) of the European Society of Urogenital Radiology (ESUR) on nephrogenic systemic fibrosis and gadolinium-based contrast media. Topics reviewed include the history, clinical features and prevalence of nephrogenic systemic fibrosis and the current understanding of its pathophysiology. The risk factors for NSF are discussed and prophylactic measures are recommended. The stability of the different gadolinium-based contrast media and the potential long-term effects of gadolinium in the body have also been reviewed. aEuro cent Clinical features, risk factors and prevention of nephrogenic systemic fibrosis are reviewed aEuro cent Patients with GFR below 30 ml/min/1.73 m (2) have increased risk of developing NSF aEuro cent Low stability gadolinium contrast media show the strongest association with NSF aEuro cent Following guidelines regarding gadolinium contrast agents minimises the risk of NSF aEuro cent Potential long-term harm from gadolinium accumulation in the body is discussed.
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| 26. |
- Abdelraheem, Mohamed Ahmed, et al.
(författare)
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On The Distribution of Linear Biases: Three Instructive Examples
- 2012
-
Ingår i: Lecture Notes in Computer Science : Advances in Cryptology – CRYPTO 2012 32nd Annual Cryptology Conference, Santa Barbara, CA, USA, August 19-23, 2012. Proceedings - Advances in Cryptology – CRYPTO 2012 32nd Annual Cryptology Conference, Santa Barbara, CA, USA, August 19-23, 2012. Proceedings. - Berlin, Heidelberg : Springer Berlin Heidelberg. - 0302-9743 .- 1611-3349. - 9783642320088 - 9783642320095 ; 7417, s. 50-67
-
Konferensbidrag (refereegranskat)abstract
- Despite the fact that we evidently have very good block ciphers at hand today, some fundamental questions on their security are still unsolved. One such fundamental problem is to precisely assess the security of a given block cipher with respect to linear cryptanalysis. In by far most of the cases we have to make (clearly wrong) assumptions, e.g., assume independent round-keys. Besides being unsatisfactory from a scientific perspective, the lack of fundamental understanding might have an impact on the performance of the ciphers we use. As we do not understand the security sufficiently enough, we often tend to embed a security margin -- from an efficiency perspective nothing else than wasted performance. The aim of this paper is to stimulate research on these foundations of block ciphers. We do this by presenting three examples of ciphers that behave differently to what is normally assumed. Thus, on the one hand these examples serve as counter examples to common beliefs and on the other hand serve as a guideline for future work.
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| 27. |
- Aho Fält, Tobias, et al.
(författare)
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Simulated Dose Reduction for Abdominal CT With Filtered Back Projection Technique: Effect on Liver Lesion Detection and Characterization
- 2019
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Ingår i: American Journal of Roentgenology: diagnostic imaging and related sciences. - 0361-803X. ; 212:1, s. 84-93
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE. Previous studies have shown the possibility to reduce radiation dose in abdominal CT by 25–50% without negatively affecting detection of liver lesions. How radiation dose reduction affects characterization of liver metastases is not as well known. The objective of this study was to investigate how different levels of simulated dose reduction affect the detection and characterization of liver lesions, primarily hypovascular metastases. A secondary objective was to analyze the relationship between the lesion size and contrast-to-noise ratio (CNR) and the detection rate.MATERIALS AND METHODS. Thirty-nine patients (19 with metastases and 20 without) were retrospectively selected. The following radiation dose levels (DLs) were simulated: 100% (reference level), 75%, 50%, and 25%. Five readers were asked to mark liver lesions and rate the probability of malignancy on a 5-grade Likert scale. Noninferiority analysis using the jackknife free-response ROC (JAFROC) method was performed as well as direct comparison of detection rates and grades.RESULTS. JAFROC analysis showed noninferior detection and characterization of metastases at DL75 as compared with DL100. However, the number of benign lesions and false-positive localizations rated as “suspected malignancy” was significantly higher at DL75.CONCLUSION. Radiation dose can be reduced by 25% without negatively affecting diagnosis of hypovascular liver metastases. Characterization of benign lesions, however, is impaired at DL75, which may lead to unnecessary follow-up examinations. Finally, increased image noise seems to affect the detection of small lesions to a degree that cannot be explained solely by the reduction in CNR.
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| 28. |
- Alhadad, Alaa, et al.
(författare)
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Incidence of nephrogenic systemic fibrosis at a large university hospital in Sweden.
- 2012
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Ingår i: Scandinavian Journal of Urology and Nephrology. - : Informa UK Limited. - 1651-2065 .- 0036-5599. ; 46, s. 48-53
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Tidskriftsartikel (refereegranskat)abstract
- Objective. Nephrogenic systemic fibrosis (NSF) is a rare condition that may follow administration of gadolinium-based contrast media (Gd-CM) in patients with renal insufficiency. This study was initiated to determine the incidence of NSF at Skåne University Hospital, Malmö, in Sweden. Material and methods. During the period January 2001 to December 2008 10 650 patients underwent magnetic resonance imaging (MRI) examinations. The re-expressed four-variable Modification of Diet in Renal Disease (MDRD) equation was used to calculate the estimated glomerular filtration rate (eGFR). The 272 patients with an eGFR <30 ml/min/1.73 m2 who were given Gd-CM were selected for final analysis. A diagnosis of NSF or other dermatological diagnoses in the 272 patients was searched for in the database of the Departments of Dermatology and Pathology. Results. The 272 patients, of whom 26 patients were on dialysis, had undergone 406 MRI examinations with Gd-CM. Mean follow-up time was 3.9 (±2.7 SD) years. Assuming a mean body weight of 70 kg, the overall median dose of the 406 examinations with Gd-CM was 0.14 mmol/kg body weight (0.06, 0.34; 2.5-97.5 percentiles). In this retrospective study of patients with eGFR <30 ml/min/1.73 m(2), none developed NSF (the upper 95% confidence limit for zero cases of NSF in the 272 patients was 2.3%). Conclusion. Although it is premature to claim that Gd-CM using the regimen employed in this institution is safe to use in all patients with eGFR <30 ml/min/1.73 m(2), the results.indicate that development of NSF is extremely uncommon.
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| 29. |
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| 30. |
- Arthur Hvidtfeldt, Ulla, et al.
(författare)
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Long-term exposure to fine particle elemental components and lung cancer incidence in the ELAPSE pooled cohort
- 2021
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Ingår i: Environmental Research. - : Elsevier BV. - 0013-9351 .- 1096-0953. ; 193
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Tidskriftsartikel (refereegranskat)abstract
- Background: An association between long-term exposure to fine particulate matter (PM2.5) and lung cancer has been established in previous studies. PM2.5 is a complex mixture of chemical components from various sources and little is known about whether certain components contribute specifically to the associated lung cancer risk. The present study builds on recent findings from the Effects of Low-level Air Pollution: A Study in Europe (ELAPSE) collaboration and addresses the potential association between specific elemental components of PM2.5 and lung cancer incidence.Methods: We pooled seven cohorts from across Europe and assigned exposure estimates for eight components of PM2.5 representing non-tail pipe emissions (copper (Cu), iron (Fe), and zinc (Zn)), long-range transport (sulfur (S)), oil burning/industry emissions (nickel (Ni), vanadium (V)), crustal material (silicon (Si)), and biomass burning (potassium (K)) to cohort participants' baseline residential address based on 100 m by 100 m grids from newly developed hybrid models combining air pollution monitoring, land use data, satellite observations, and dispersion model estimates. We applied stratified Cox proportional hazards models, adjusting for potential confounders (age, sex, calendar year, marital status, smoking, body mass index, employment status, and neighborhood-level socio-economic status).Results: The pooled study population comprised 306,550 individuals with 3916 incident lung cancer events during 5,541,672 person-years of follow-up. We observed a positive association between exposure to all eight components and lung cancer incidence, with adjusted HRs of 1.10 (95% CI 1.05, 1.16) per 50 ng/m(3) PM2.5 K, 1.09 (95% CI 1.02, 1.15) per 1 ng/m3 PM2.5 Ni, 1.22 (95% CI 1.11, 1.35) per 200 ng/m(3) PM2.5 S, and 1.07 (95% CI 1.02, 1.12) per 200 ng/m(3) PM2.5 V. Effect estimates were largely unaffected by adjustment for nitrogen dioxide (NO2). After adjustment for PM2.5 mass, effect estimates of K, Ni, S, and V were slightly attenuated, whereas effect estimates of Cu, Si, Fe, and Zn became null or negative.Conclusions: Our results point towards an increased risk of lung cancer in connection with sources of combustion particles from oil and biomass burning and secondary inorganic aerosols rather than non-exhaust traffic emissions. Specific limit values or guidelines targeting these specific PM2.5 components may prove helpful in future lung cancer prevention strategies.
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| 31. |
- Bach-Gansmo, T, et al.
(författare)
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Motion associated susceptibility artifacts
- 1992
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Ingår i: Acta Radiologica. - 1600-0455. ; 33:6, s. 606-610
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Tidskriftsartikel (refereegranskat)abstract
- A bowel labeling agent is important for improving abdominal MR. Besides providing contrast between the bowel and other organs, the contrast agent itself is a potential source of artifacts. The artifacts created by superparamagnetic particles (SPP) subjected to motion have been studied in vitro at 0.5 T, and compared to artifacts created by a paramagnetic compound. Apart from the expected static effects of the SPP, movement induced additional artifacts were seen as signal displacements in the phase-encoding direction. The artifacts were obvious at an iron concentration of 1 mg Fe/ml, barely visible at 0.2 mg Fe/ml, and completely absent at 0.1 mg Fe/ml. Artifacts were also evident with the SPP outside the imaging slice. This further emphasizes the importance of choosing the lowest effective dose when using SPP contrast agents. For the paramagnetic agent, motion propagated artifacts consisted of high and low signal regions in a mosaic pattern.
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| 32. |
- Carrasquilla, Germán D, et al.
(författare)
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Postmenopausal hormone therapy and risk of stroke : A pooled analysis of data from population-based cohort studies.
- 2017
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Ingår i: PLoS Medicine. - : Public Library of Science (PLoS). - 1549-1277 .- 1549-1676. ; 14:11
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Recent research indicates a favourable influence of postmenopausal hormone therapy (HT) if initiated early, but not late, on subclinical atherosclerosis. However, the clinical relevance of timing of HT initiation for hard end points such as stroke remains to be determined. Further, no previous research has considered the timing of initiation of HT in relation to haemorrhagic stroke risk. The importance of the route of administration, type, active ingredient, and duration of HT for stroke risk is also unclear. We aimed to assess the association between HT and risk of stroke, considering the timing of initiation, route of administration, type, active ingredient, and duration of HT.METHODS AND FINDINGS: Data on HT use reported by the participants in 5 population-based Swedish cohort studies, with baseline investigations performed during the period 1987-2002, were combined in this observational study. In total, 88,914 postmenopausal women who reported data on HT use and had no previous cardiovascular disease diagnosis were included. Incident events of stroke (ischaemic, haemorrhagic, or unspecified) and haemorrhagic stroke were identified from national population registers. Laplace regression was employed to assess crude and multivariable-adjusted associations between HT and stroke risk by estimating percentile differences (PDs) with 95% confidence intervals (CIs). The fifth and first PDs were calculated for stroke and haemorrhagic stroke, respectively. Crude models were adjusted for age at baseline only. The final adjusted models included age at baseline, level of education, smoking status, body mass index, level of physical activity, and age at menopause onset. Additional variables evaluated for potential confounding were type of menopause, parity, use of oral contraceptives, alcohol consumption, hypertension, dyslipidaemia, diabetes, family history of cardiovascular disease, and cohort. During a median follow-up of 14.3 years, 6,371 first-time stroke events were recorded; of these, 1,080 were haemorrhagic. Following multivariable adjustment, early initiation (<5 years since menopause onset) of HT was associated with a longer stroke-free period than never use (fifth PD, 1.00 years; 95% CI 0.42 to 1.57), but there was no significant extension to the time period free of haemorrhagic stroke (first PD, 1.52 years; 95% CI -0.32 to 3.37). When considering timing as a continuous variable, the stroke-free and the haemorrhagic stroke-free periods were maximal if HT was initiated approximately 0-5 years from the onset of menopause. If single conjugated equine oestrogen HT was used, late initiation of HT was associated with a shorter stroke-free (fifth PD, -4.41 years; 95% CI -7.14 to -1.68) and haemorrhagic stroke-free (first PD, -9.51 years; 95% CI -12.77 to -6.24) period than never use. Combined HT when initiated late was significantly associated with a shorter haemorrhagic stroke-free period (first PD, -1.97 years; 95% CI -3.81 to -0.13), but not with a shorter stroke-free period (fifth PD, -1.21 years; 95% CI -3.11 to 0.68) than never use. Given the observational nature of this study, the possibility of uncontrolled confounding cannot be excluded. Further, immortal time bias, also related to the observational design, cannot be ruled out.CONCLUSIONS: When initiated early in relation to menopause onset, HT was not associated with increased risk of incident stroke, regardless of the route of administration, type of HT, active ingredient, and duration. Generally, these findings held also for haemorrhagic stroke. Our results suggest that the initiation of HT 0-5 years after menopause onset, as compared to never use, is associated with a decreased risk of stroke and haemorrhagic stroke. Late initiation was associated with elevated risks of stroke and haemorrhagic stroke when conjugated equine oestrogen was used as single therapy. Late initiation of combined HT was associated with haemorrhagic stroke risk.
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| 33. |
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| 34. |
- Dreja, Julia, et al.
(författare)
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Volumetric analysis of small bowel motility in an unselected cohort of patients with Crohn’s disease
- 2020
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Ingår i: Neurogastroenterology and Motility. - : Wiley. - 1350-1925 .- 1365-2982. ; 32:10
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Tidskriftsartikel (refereegranskat)abstract
- Background: Quantified terminal ileal motility during magnetic resonance enterography (MRE) has been suggested to be used as a biomarker of Crohn's disease (CD). The aim of the present study was to evaluate this method in clinical practice. Methods: Healthy volunteers and all consecutive patients referred to MRE during a 2-year period were asked to participate and complete the Irritable Bowel Syndrome-Symptom Severity Scale (IBS-SSS) to assess gastrointestinal symptoms. Medical records were scrutinized, and motility indices (MIs) were calculated from MR images. Key Results: Twenty-two healthy controls and 134 examinations with CD were included (inclusion rate: 76.3%). Patients with CD had increased mural thickness of the terminal ileum, increased fecal calprotectin, and more symptoms than controls. Patients with active CD had increased mural thickness of ileum and terminal ileum, higher MR activity indices, and signs of inflammation in laboratory analyses, but similar symptoms, compared with inactive disease. After exclusion of sole colon disease (n = 13), MI inversely correlated with mural thickness in terminal ileum, and MI was lower in active disease versus controls in ileum (P =.019) and terminal ileum (P =.005), and versus inactive disease in terminal ileum (P =.044). The area under the curve of MI in terminal ileum was 0.736 for active CD against healthy controls (P =.002) and 0.682 for active against inactive CD (P =.001). MIs were similar in controls and inactive CD. Conclusions and Interferences: MI reflects inflammatory activity in the intestine. Alterations in MI did not explain symptomatology in inactive CD, without measurable inflammatory parameters in morphology or laboratory analyses.
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| 35. |
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| 36. |
- Elmståhl, Barbara, et al.
(författare)
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Gadolinium contrast media are more nephrotoxic than iodine media. The importance of osmolality in direct renal artery injections
- 2006
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Ingår i: European Radiology. - : Springer Science and Business Media LLC. - 0938-7994 .- 1432-1084. ; 16:12, s. 2712-2720
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Tidskriftsartikel (refereegranskat)abstract
- A study was undertaken of the role of osmotoxicity in gadolinium (Gd) and iodine contrast media (CM) nephrotoxicity in ischemic porcine kidneys. Test solutions: mannitol iso-osmotic to 0.5 M: gadopentetate (1.96 Osm/kg H2O), 0.5 M: gadodiamide (0.78 Osm/kg H2O) and 0.5 M: iohexol (190 mg I/ml, 0.42 Osm/kg H2O). Each solution was injected [3 ml/kg body weight (BW)] into the balloon-occluded (10 min) renal artery of eight left-sided nephrectomized pigs. The plasma half-life of a glomerular filtration rate (GFR) marker was used to compare their effects on GFR 1-3 h post-injection. The median half-lives of the GFR marker after injection of gadopentetate (1,730 min) and mannitol 1.96 Osm/kg H2O (2,782 min) did not differ statistically (P = 0.28), but were significantly longer than after all other solutions (P < 0.001). There was no significant difference (P = 0.06) between gadodiamide (218 min) and mannitol 0.82 Osm/kg H2O (169 min), while there was (P = 0.03) between iohexol (181 min) and mannitol 0.43 Osm/kg H2O (148 min). The difference between gadodiamide and iohexol was significant (P = 0.01). Reduction in GFR, as a marker of nephrotoxicity, induced by gadopentetate correlated with its high osmolality, while the effect of gadodiamide and iohexol may include chemotoxicity. Iohexol molecules were less nephrotoxic than the Gd-CM molecules and contain three-times the number of attenuating atoms per molecule.
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| 37. |
- Elmståhl, Barbara, et al.
(författare)
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Histomorphological Changes after Renal X-Ray Arteriography Using Iodine and Gadolinium Contrast Media in an Ischemic Porcine Model.
- 2007
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Ingår i: Acta Radiologica. - : SAGE Publications. - 1600-0455 .- 0284-1851. ; 48:10, s. 1109-1119
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Tidskriftsartikel (refereegranskat)abstract
- Background: Gadolinium contrast media (Gd-CM) are regarded as non-nephrotoxic or considerably less nephrotoxic than iodine contrast media (I-CM), and have therefore come to be used as a substitute for I-CM in patients with renal insufficiency in a variety of radiographic examinations. Purpose: To investigate renal histomorphological changes caused by Gd-CM in comparison with I-CM after renal X-ray arteriography in an ischemic porcine model, and to evaluate these changes in relation to the nephrotoxicity of the CM used. Material and Methods: Test solutions: gadopentetate, gadodiamide, iohexol, gadobutrol, iopromide, iodixanol, mannitol, and saline. The experiments were performed on 152 animals. Each pig was randomized to receive one test solution injected into the balloon-occluded (10 min) right renal artery. The kidneys were evaluated histomorphologically. The severity of histomorphological changes was graded subjectively: 1 = minimal, 2 = mild, 3 = moderate, and 4 = marked. Results: The main histological changes were 1) proximal tubular and glomerular necrosis, 2) hemorrhage/congestion of the cortex, medulla, and glomeruli, 3) proximal tubular vacuolation, and 4) protein-filled tubules in the cortex and medulla. Necrosis and hemorrhage/congestion were more frequent after injections with gadopentetate, mannitol solution iso-osmotic to gadopentetate, and gadobutrol compared to all other groups (P<0.001). The degree of necrosis and hemorrhage/congestion was related to the degree of impairment of renal function, but inversely related to vacuolation and tubular protein filling. Conclusion: In ischemic porcine kidneys, the histomorphological changes caused by Gd-CM are similar to those caused by I-CM. Vacuolation appears to be independent of the osmolality and viscosity of the CM, and does not seem to be an indicator of renal impairment. “High-osmolal” Gd-CM are more nephrotoxic than “low- and iso-osmolal” I-CM when compared in equal volumes of concentrations, resulting in equal X-ray attenuation.
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| 38. |
- Elmståhl, Barbara, et al.
(författare)
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Iodixanol 320 results in better renal tolerance and radiodensity than do gadolinium-based contrast media: Arteriography in ischemic porcine kidneys
- 2008
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Ingår i: Radiology. - : Radiological Society of North America (RSNA). - 1527-1315 .- 0033-8419. ; 247:1, s. 88-97
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: To prospectively compare nephrotoxicity and radiodensity of plasma hyperosmotic gadolinium chelates (attenuation-osmotic ratio of 1: 1) with those of plasma iso-osmotic iodine-based contrast media (attenuation-osmotic ratio of 3: 1 or 6: 1) after renal arteriography in ischemic porcine kidneys. Materials and Methods: The local animal care committee approved this study. The following contrast media were used: (a) iodixanol (150 mg of iodine per milliliter and 320 mg I/mL, 0.29 osm/kg H2O), (b) iopromide (150 mg I/mL, 0.34 osm/kg), (c) 0.5 mol/L gadodiamide (0.78 osm/kg), and (d) 1.0 mol/L gadobutrol (1.6 osm/kg). After left-sided nephrectomy, contrast media (3 mL per kilogram of body weight) were injected (20 mL/min) in a noncrossover design into the right renal artery of pigs during a 10-minute ischemic period. There were eight pigs in each group and one group for each contrast medium. We compared histomorphology, radiographic contrast medium excretion, subjective radiodensity of nephrograms (70 kVp) at the end of injection, and contrast medium plasma half-life elimination times 1-3 hours after injection. Longer elimination times resulted in lower glomerular filtration rates. Results: Gadobutrol caused extensive tubular necrosis and moderate glomerular necrosis; gadodiamide and iopromide, minimal to mild tubular necrosis; and iodixanol, no necrosis. Gadobutrol was the only contrast medium to show no sign of excretion, and its plasma half-life elimination time (median, 1103 minutes; P = .001) was significantly longer than that of other contrast agents. Gadodiamide had a significantly longer plasma half-life elimination time (median, 209 minutes; P = .01) than did iodine-based contrast media (median, 136-142 minutes). The 320 mg I/mL dose of iodixanol had the highest radiodensity, whereas gadodiamide had the lowest radiodensity. The radiodensity of the 320 mg I/mL dose of iodixanol was greater than that of the 150 mg I/mL dose of iodixanol, which was equal to the radiodensities of the 150 mg I/mL dose of iopromide and 1.0 mol/L gadobutrol, which in turn were greater than that of 0.5 mol/L gadodiamide. Conclusion: Plasma iso-osmotic iodine-based contrast media used at commercially available concentrations have superior attenuation and nephrotoxic profiles compared with equal volumes of hyperosmotic nonionic 0.5-1.0 mol/L gadolinium-based contrast media when performing renal arteriographic procedures. (c) RSNA, 2008.
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| 39. |
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| 40. |
- Eriksson, Per-Olof, et al.
(författare)
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Novel Nano-Sized MR Contrast Agent Mediates Strong Tumor Contrast Enhancement in an Oncogene-Driven Breast Cancer Model.
- 2014
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 9:10
-
Tidskriftsartikel (refereegranskat)abstract
- The current study was carried out to test the potential of a new nanomaterial (Spago Pix) as a macromolecular magnetic MR contrast agent for tumor detection and to verify the presence of nanomaterial in tumor tissue. Spago Pix, synthesized by Spago Nanomedical AB, is a nanomaterial with a globular shape, an average hydrodynamic diameter of 5 nm, and a relaxivity (r1) of approximately 30 (mM Mn)-1 s-1 (60 MHz). The material consists of an organophosphosilane hydrogel with strongly chelated manganese (II) ions and a covalently attached PEG surface layer. In vivo MRI of the MMTV-PyMT breast cancer model was performed on a 3 T clinical scanner. Tissues were thereafter analyzed for manganese and silicon content using inductively coupled plasma-atomic emission spectroscopy (ICP-AES). The presence of nanomaterial in tumor and muscle tissue was assessed using an anti-PEG monoclonal antibody. MR imaging of tumor-bearing mice (n = 7) showed a contrast enhancement factor of 1.8 (tumor versus muscle) at 30 minutes post-administration. Contrast was retained and further increased 2-4 hours after administration. ICP-AES and immunohistochemistry confirmed selective accumulation of nanomaterial in tumor tissue. A blood pharmacokinetics analysis showed that the concentration of Spago Pix gradually decreased over the first hour, which was in good agreement with the time frame in which the accumulation in tumor occurred. In summary, we demonstrate that Spago Pix selectively enhances MR tumor contrast in a clinically relevant animal model. Based on the generally higher vascular leakiness in malignant compared to benign tissue lesions, Spago Pix has the potential to significantly improve cancer diagnosis and characterization by MRI.
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| 41. |
- Fahlvik, A K, et al.
(författare)
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Magnetic starch microspheres, efficacy and elimination. A new organ-specific contrast agent for magnetic resonance imaging
- 1990
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Ingår i: Investigative Radiology. - 0020-9996. ; 25:2, s. 113-120
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Tidskriftsartikel (refereegranskat)abstract
- A new particulate magnetic resonance (MR) contrast agent was prepared by controlled precipitation of iron oxide in an aqueous starch solution. The potential of the magnetic starch microspheres (MSM) as a hepatosplenic contrast enhancer was studied by MR spectroscopy and MR imaging. Intravascular administration of MSM to rodents showed an effective blood clearance and a tissue-specific localization of the substance. MSM doses in a range of 0.3-1.5 mg Fe/kg caused a 50% alteration in sensitive contrast parameters (ED50 doses) of liver and spleen. The contrast effect of MSM in liver and spleen was halved within 2 to 5 days. The approximated lethal MSM dose in mice was 150-200 mg Fe/kg. MSM is a tissue-specific MR contrast substance with high efficacy, rapid bioelimination, and low acute toxicity.
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| 42. |
- Flodmark, Carl-Erik, et al.
(författare)
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Laser beam measurement of abdominal sagittal diameter in obese children: a validation study.
- 2013
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Ingår i: Pediatric obesity. - : Wiley. - 2047-6310 .- 2047-6302. ; 8:2, s. 112-117
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Tidskriftsartikel (refereegranskat)abstract
- What is already known about this subject Sagittal diameter (SAD), i.e. the mid height of the abdomen when lying down, has been reported to correlate to visceral fat, insulin resistance and cardiovascular risk factors in adults. SAD seems to be the best anthropometric predictor of cardiovascular risk, and also of more importance than waist circumference (WC) in adults. There has been no validation studies comparing SAD measured with anthropometric tools (e.g. ruler) to measurements made with more exact devices such as magnetic resonance imaging (MRI) in pediatric age. What this study adds This new reliable method is ideal for children due to limited body contact and no radiation. It is accurate, less expensive than MRI, and also easier to perform than measuring WC. It is easily available for screening purposes making future epidemiological studies possible evaluating health risks related to regional distribution of abdominal tissue. OBJECTIVES: Sagittal diameter (SAD) has been reported to correlate to visceral fat and cardiovascular risk factors. SAD is measured with the individual lying down, halfway between the lower rib margin and the iliac crest; it represents the mid-height of the abdomen. The aim of this study was to validate SAD measured using a recently-developed laser beam device (SAD(LDB) ) against SAD measured using MRI (SAD(MRI) ). METHODS: Of 48 obese children (25 boys, 23 girls) aged 9-11 years on the waiting list for obesity treatment, 34 agreed to a baseline measurement, which was followed by repeated measurements 6 and 12 months later in 31 and 22 children respectively. MRI was used to examine SAD(MRI) at 5 cm above (SAD(MRI) (,cra) ) and below (SAD(MRI) (,cau) ) the mid plane of the L4-5 intervertebral disc. RESULTS: Each of the differences SAD(LBD) - SAD(MRI) (,cau) and SAD(LBD) - SAD(MRI) (,cra) was subjected to a repeated-measurements ANOVA; the visit did not have a statistically significant effect in either case (p = 0.19 and p = 0.72, respectively). The difference SAD(LBD) - SAD(MRI) (,cau) was 1.50 on average (p < 0.0001; CI 1.26-1.74) while the corresponding figure for SAD(LBD) - SAD(MRI) (,cra) was 1.26 (p < 0.0001; CI 1.04-1.49). Regression of the difference on the mean gave slopes of -0.09 (p = 0.25) and -0.04 (p = 0.57) respectively. Prediction of SAD(MRI) from SAD(LDB) can be performed in different ways: by means of linear regression or by means of an additive correction. CONCLUSIONS: Thus, this laser device can be used instead of MRI to estimate SAD by using a simple correction.
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| 46. |
- Fält, Tobias, et al.
(författare)
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Seesaw Balancing Radiation Dose and IV Contrast Dose: Evaluation of a New Abdominal CT Protocol for Reducing Age-Specific Risk.
- 2013
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Ingår i: American Journal of Roentgenology: diagnostic imaging and related sciences. - 1546-3141. ; 200:2, s. 383-388
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Tidskriftsartikel (refereegranskat)abstract
- The purpose of this study was to evaluate an abdominal CT protocol in which radiation dose was reduced and IV contrast dose increased for young patients and radiation dose was increased and IV medium dose decreased for elderly patients. The hypothesis was that these adjustments would result in constant image quality and a reduction in age-specific risk.
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- Hakansson, K, et al.
(författare)
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MR and ultrasound in screening of patients with suspected biliary tract disease
- 2002
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Ingår i: Acta Radiologica. - : SAGE Publications. - 1600-0455 .- 0284-1851. ; 43:1, s. 80-86
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Tidskriftsartikel (refereegranskat)abstract
- Purpose The diagnostic value and cost-efficiency of MR imaging were compared with US before endoscopic retrograde cholangiopancreatography (ERCP) in patients with clinically suspected biliary tract disease. Material and Methods: In a prospective study of 219 patients, 85 were examined with both MR and US before ERCP. Results: To find the correct diagnosis in the jaundiced patients the sensitivity of US, MR and FRCP was 53%, 93%, and 89%, respectively. In the patients with abdominal upper quadrant pain and normal serum bilirubin, the sensitivity of US, MR and ERCP was 50%, 100% and 70%, respectively. Examination with MR costs four times more than US. Screening with US and supplemental MR in non-diagnostic cases would cost 80% of the total amount compared to screening with MR only. Conclusion: MR had a higher sensitivity than US for diagnosing biliary tract disease and MR was superior to US in visualising stones in the common bile duct and in diagnosing the cause of cholestasis. However, screening with US and supplemental MR in non-diagnostic cases is at present most cost-effective. With increased accessibility and slightly lower costs, MR will probably replace US as screening method in patients with suspected biliary tract disease.
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| 49. |
- Hakansson, K, et al.
(författare)
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MR characteristics of acute cholangitis
- 2002
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Ingår i: Acta Radiologica. - : SAGE Publications. - 1600-0455 .- 0284-1851. ; 43:2, s. 175-179
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: To describe the MR appearance of acute cholangitis and discuss the role of MR imaging as a diagnostic method in this disease. Material and Methods: Of 60 patients with clinical acute cholangitis, 12 were examined with MR before endoscopic retrograde pancreatography (ERCP). A retrospective review was performed of MR and ERCP findings. The MR findings registered were presence of biliary duct dilatation, intraluminal filling defects due to stones or sludge, bands of mucosal oedema of the biliary ducts, intra- and retroperitoneal oedema/fluid, and definition of the cause of obstruction, e.g. stones, stenosis or tumour was made. Results: Acute cholangitis was related to obstruction from choledocholithiasis (n = 8), pancreatic cancer (n = 1), benign biliary duct stricture (n = 1), papillary stenosis (n = 1) and without evidence of an obstructing cause (n = 1). One patient had an acute obstructive suppurative (toxic) cholangitis. Conclusion: MR imaging has a role in the non-invasive radiographic arsenal of techniques to confirm or exclude the diagnosis of acute cholangitis, especially in older patients where the clinical symptoms may be vague.
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| 50. |
- Hakansson, K, et al.
(författare)
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MR imaging in clinically suspected acute cholecystitis. A comparison with ultrasonography
- 2000
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Ingår i: Acta Radiologica. - : SAGE Publications. - 1600-0455 .- 0284-1851. ; 41:4, s. 322-328
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: The diagnostic value of fast pulse sequences in MR imaging was compared with US in patients with clinically suspected acute cholecystitis. MATERIAL AND METHODS: In a prospective study of 94 patients, 35 were examined with both MR and US within 24 h. RESULTS: MR diagnoses were acute cholecystitis in 23, gallbladder and common bile duct stones in 3, other pathologic conditions of the abdomen in 7 and normal in 2 patients. US diagnoses were acute cholecystitis in 17, gallbladder stones in 8, other pathologic conditions of the abdomen in 2, normal in 5 and non-conclusive in 3 patients. CONCLUSION: MR has a higher sensitivity than US for diagnosing acute cholecystitis and, with increased accessibility, may be the first imaging method.
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