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1.	Locke, Adam E, et al. (författare) Genetic studies of body mass index yield new insights for obesity biology. 2015 Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 518:7538, s. 197-401 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.
2.	Shungin, Dmitry, et al. (författare) New genetic loci link adipose and insulin biology to body fat distribution. 2015 Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 518:7538, s. 187-378 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.
3.	Speliotes, Elizabeth K., et al. (författare) Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index 2010 Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:11, s. 937-948 Tidskriftsartikel (refereegranskat)abstract Obesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between body mass index and ~2.8 million SNPs in up to 123,865 individuals with targeted follow up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity susceptibility loci and identified 18 new loci associated with body mass index (P < 5 × 10−8), one of which includes a copy number variant near GPRC5B. Some loci (at MC4R, POMC, SH2B1 and BDNF) map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor. Furthermore, genes in other newly associated loci may provide new insights into human body weight regulation.
4.	Kilpeläinen, Tuomas O, et al. (författare) Genome-wide meta-analysis uncovers novel loci influencing circulating leptin levels 2016 Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7 Tidskriftsartikel (refereegranskat)abstract Leptin is an adipocyte-secreted hormone, the circulating levels of which correlate closely with overall adiposity. Although rare mutations in the leptin (LEP) gene are well known to cause leptin deficiency and severe obesity, no common loci regulating circulating leptin levels have been uncovered. Therefore, we performed a genome-wide association study (GWAS) of circulating leptin levels from 32,161 individuals and followed up loci reaching P<10(-6) in 19,979 additional individuals. We identify five loci robustly associated (P<5 × 10(-8)) with leptin levels in/near LEP, SLC32A1, GCKR, CCNL1 and FTO. Although the association of the FTO obesity locus with leptin levels is abolished by adjustment for BMI, associations of the four other loci are independent of adiposity. The GCKR locus was found associated with multiple metabolic traits in previous GWAS and the CCNL1 locus with birth weight. Knockdown experiments in mouse adipose tissue explants show convincing evidence for adipogenin, a regulator of adipocyte differentiation, as the novel causal gene in the SLC32A1 locus influencing leptin levels. Our findings provide novel insights into the regulation of leptin production by adipose tissue and open new avenues for examining the influence of variation in leptin levels on adiposity and metabolic health.
5.	Ntalla, Ioanna, et al. (författare) Multi-ancestry GWAS of the electrocardiographic PR interval identifies 202 loci underlying cardiac conduction 2020 Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11:1 Tidskriftsartikel (refereegranskat)abstract The electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality. Here we report a multi-ancestry (N=293,051) genome-wide association meta-analysis for the PR interval, discovering 202 loci of which 141 have not previously been reported. Variants at identified loci increase the percentage of heritability explained, from 33.5% to 62.6%. We observe enrichment for cardiac muscle developmental/contractile and cytoskeletal genes, highlighting key regulation processes for atrioventricular conduction. Additionally, 8 loci not previously reported harbor genes underlying inherited arrhythmic syndromes and/or cardiomyopathies suggesting a role for these genes in cardiovascular pathology in the general population. We show that polygenic predisposition to PR interval duration is an endophenotype for cardiovascular disease, including distal conduction disease, AF, and atrioventricular pre-excitation. These findings advance our understanding of the polygenic basis of cardiac conduction, and the genetic relationship between PR interval duration and cardiovascular disease. On the electrocardiogram, the PR interval reflects conduction from the atria to ventricles and also serves as risk indicator of cardiovascular morbidity and mortality. Here, the authors perform genome-wide meta-analyses for PR interval in multiple ancestries and identify 141 previously unreported genetic loci.
6.	Roselli, Carolina, et al. (författare) Multi-ethnic genome-wide association study for atrial fibrillation 2018 Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 50:9, s. 1225-1233 Tidskriftsartikel (refereegranskat)abstract Atrial fibrillation (AF) affects more than 33 million individuals worldwide(1) and has a complex heritability(2). We conducted the largest meta-analysis of genome-wide association studies (GWAS) for AF to date, consisting of more than half a million individuals, including 65,446 with AF. In total, we identified 97 loci significantly associated with AF, including 67 that were novel in a combined-ancestry analysis, and 3 that were novel in a European-specific analysis. We sought to identify AF-associated genes at the GWAS loci by performing RNA-sequencing and expression quantitative trait locus analyses in 101 left atrial samples, the most relevant tissue for AF. We also performed transcriptome-wide analyses that identified 57 AF-associated genes, 42 of which overlap with GWAS loci. The identified loci implicate genes enriched within cardiac developmental, electrophysiological, contractile and structural pathways. These results extend our understanding of the biological pathways underlying AF and may facilitate the development of therapeutics for AF.
7.	van de Vegte, Yordi, et al. (författare) Genetic insights into resting heart rate and its role in cardiovascular disease 2023 Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 14:1 Tidskriftsartikel (refereegranskat)abstract The genetics and clinical consequences of resting heart rate (RHR) remain incompletely understood. Here, the authors discover new genetic variants associated with RHR and find that higher genetically predicted RHR decreases risk of atrial fibrillation and ischemic stroke. Resting heart rate is associated with cardiovascular diseases and mortality in observational and Mendelian randomization studies. The aims of this study are to extend the number of resting heart rate associated genetic variants and to obtain further insights in resting heart rate biology and its clinical consequences. A genome-wide meta-analysis of 100 studies in up to 835,465 individuals reveals 493 independent genetic variants in 352 loci, including 68 genetic variants outside previously identified resting heart rate associated loci. We prioritize 670 genes and in silico annotations point to their enrichment in cardiomyocytes and provide insights in their ECG signature. Two-sample Mendelian randomization analyses indicate that higher genetically predicted resting heart rate increases risk of dilated cardiomyopathy, but decreases risk of developing atrial fibrillation, ischemic stroke, and cardio-embolic stroke. We do not find evidence for a linear or non-linear genetic association between resting heart rate and all-cause mortality in contrast to our previous Mendelian randomization study. Systematic alteration of key differences between the current and previous Mendelian randomization study indicates that the most likely cause of the discrepancy between these studies arises from false positive findings in previous one-sample MR analyses caused by weak-instrument bias at lower P-value thresholds. The results extend our understanding of resting heart rate biology and give additional insights in its role in cardiovascular disease development.
8.	Appelros, Stefan, et al. (författare) Short and long term outcome of severe acute pancreatitis. 2001 Ingår i: European Journal of Surgery. - : Oxford University Press (OUP). - 1102-4151. ; 167:4, s. 281-286 Tidskriftsartikel (refereegranskat)abstract OBJECTIVE: Between 1985 and 1994, 883 cases of acute pancreatitis were treated in Malmö, Sweden (population 233,000). The purpose of this study was to report the short- and long-term outcome of the 79 cases that were severe, according to the Atlanta classification. DESIGN: Retrospective and follow-up study a median time of 7 years since the attack. SETTING: University hospital, Sweden. SUBJECTS: 79 patients with severe acute pancreatitis. MAIN OUTCOME MEASURES: Mortality, cause of death, organ failure, local complications, surgical procedures, mortality since the attack, and endocrine and exocrine dysfunction. RESULTS: Twenty-one patients died from their attack. Organ failure was the predominant cause of death in the 13 patients who died during the first 10 days after admission, whereas infection was the most common cause of death in patients who died later. Mortality was low under the age of 60 and increased with age. Organ failure developed in 72 patients. Twenty-four patients developed pancreatic necrosis or abscesses and 18 patients were treated by necrosectomy and open or closed drainage. At follow-up, 13 patients had died, 2 from pancreatic carcinoma. 35 patients were included in the follow-up survey. 15 of these had diabetes and an additional 4 had impaired glucose tolerance. 9 patients had signs of severe exocrine dysfunction. CONCLUSIONS: There was a high incidence of endocrine and exocrine dysfunction together with, in many patients, ongoing social problems related to chronic alcoholism several years after an attack of severe acute pancreatitis.
9.	Berndt, Sonja I., et al. (författare) Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture 2013 Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 45:5, s. 501-U69 Tidskriftsartikel (refereegranskat)abstract Approaches exploiting trait distribution extremes may be used to identify loci associated with common traits, but it is unknown whether these loci are generalizable to the broader population. In a genome-wide search for loci associated with the upper versus the lower 5th percentiles of body mass index, height and waist-to-hip ratio, as well as clinical classes of obesity, including up to 263,407 individuals of European ancestry, we identified 4 new loci (IGFBP4, H6PD, RSRC1 and PPP2R2A) influencing height detected in the distribution tails and 7 new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3 and ZZZ3) for clinical classes of obesity. Further, we find a large overlap in genetic structure and the distribution of variants between traits based on extremes and the general population and little etiological heterogeneity between obesity subgroups.
10.	Broadaway, K Alaine, et al. (författare) Loci for insulin processing and secretion provide insight into type 2 diabetes risk. 2023 Ingår i: American Journal of Human Genetics. - : Elsevier. - 0002-9297 .- 1537-6605. ; 110:2, s. 284-299 Tidskriftsartikel (refereegranskat)abstract Insulin secretion is critical for glucose homeostasis, and increased levels of the precursor proinsulin relative to insulin indicate pancreatic islet beta-cell stress and insufficient insulin secretory capacity in the setting of insulin resistance. We conducted meta-analyses of genome-wide association results for fasting proinsulin from 16 European-ancestry studies in 45,861 individuals. We found 36 independent signals at 30 loci (p value < 5 × 10-8), which validated 12 previously reported loci for proinsulin and ten additional loci previously identified for another glycemic trait. Half of the alleles associated with higher proinsulin showed higher rather than lower effects on glucose levels, corresponding to different mechanisms. Proinsulin loci included genes that affect prohormone convertases, beta-cell dysfunction, vesicle trafficking, beta-cell transcriptional regulation, and lysosomes/autophagy processes. We colocalized 11 proinsulin signals with islet expression quantitative trait locus (eQTL) data, suggesting candidate genes, including ARSG, WIPI1, SLC7A14, and SIX3. The NKX6-3/ANK1 proinsulin signal colocalized with a T2D signal and an adipose ANK1 eQTL signal but not the islet NKX6-3 eQTL. Signals were enriched for islet enhancers, and we showed a plausible islet regulatory mechanism for the lead signal in the MADD locus. These results show how detailed genetic studies of an intermediate phenotype can elucidate mechanisms that may predispose one to disease.
11.	Do, Ron, et al. (författare) Common variants associated with plasma triglycerides and risk for coronary artery disease 2013 Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 45:11, s. 1345- Tidskriftsartikel (refereegranskat)abstract Triglycerides are transported in plasma by specific triglyceride-rich lipoproteins; in epidemiological studies, increased triglyceride levels correlate with higher risk for coronary artery disease (CAD). However, it is unclear whether this association reflects causal processes. We used 185 common variants recently mapped for plasma lipids (P < 5 x 10(-8) for each) to examine the role of triglycerides in risk for CAD. First, we highlight loci associated with both low-density lipoprotein cholesterol (LDL-C) and triglyceride levels, and we show that the direction and magnitude of the associations with both traits are factors in determining CAD risk. Second, we consider loci with only a strong association with triglycerides and show that these loci are also associated with CAD. Finally, in a model accounting for effects on LDL-C and/or high-density lipoprotein cholesterol (HDL-C) levels, the strength of a polymorphism's effect on triglyceride levels is correlated with the magnitude of its effect on CAD risk. These results suggest that triglyceride-rich lipoproteins causally influence risk for CAD.
12.	Dörr, Marcus, et al. (författare) Common Genetic Variation in Relation to Brachial Vascular Dimensions and Flow-Mediated Vasodilation 2019 Ingår i: Circulation. - : LIPPINCOTT WILLIAMS & WILKINS. - 2574-8300. ; 12:2 Tidskriftsartikel (refereegranskat)
13.	Ek, Weronica E, et al. (författare) Genome-wide DNA methylation study identifies genes associated with the cardiovascular biomarker GDF-15 2016 Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 25:4, s. 817-827 Tidskriftsartikel (refereegranskat)abstract Growth-differentiation factor 15 (GDF-15) is expressed in low to moderate levels in most healthy tissues and increases in response to inflammation. GDF-15 is associated with cardiovascular dysfunction and over-expressed in the myocardium of patients with myocardial infarction (MI). However, little is known about the function of GDF-15 in cardiovascular disease, and the underlying regulatory network of GDF-15 is not known. To investigate a possible association between GDF-15 levels and DNA methylation, we performed a genome-wide DNA methylation study of white blood cells in a population-based study (N = 717). Significant loci where replicated in an independent cohort (N = 963). We also performed a gene ontology (GO) enrichment analysis. We identified and replicated 16 CpG-sites (false discovery rate [FDR] < 0.05), at 11 independent loci including MIR21. MIR21 encodes a microRNA (miR-21) that has previously been shown to be associated with the development of heart disease. Interestingly, GDF15 mRNA contains a binding site for miR-21. Four sites were also differentially methylated in blood from participants previously diagnosed with MI and 14 enriched GO terms (FDR < 0.05, enrichment > 2) were identified, including 'cardiac muscle cell differentiation'. This study shows that GDF-15 levels are associated with differences in DNA methylation in blood cells, and a subset of the loci are also differentially methylated in participants with MI. However, there might be interactions between GDF-15 levels and methylation in other tissues not addressed in this study. These results provide novel links between GDF-15 and cardiovascular disease.
14.	Folkersen, Lasse, et al. (författare) Genomic and drug target evaluation of 90 cardiovascular proteins in 30,931 individuals. 2020 Ingår i: Nature metabolism. - : Springer Science and Business Media LLC. - 2522-5812. ; 2:10, s. 1135-1148 Tidskriftsartikel (refereegranskat)abstract Circulating proteins are vital in human health and disease and are frequently used as biomarkers for clinical decision-making or as targets for pharmacological intervention. Here, we map and replicate protein quantitative trait loci (pQTL) for 90 cardiovascular proteins in over 30,000 individuals, resulting in 451 pQTLs for 85 proteins. For each protein, we further perform pathway mapping to obtain trans-pQTL gene and regulatory designations. We substantiate these regulatory findings with orthogonal evidence for trans-pQTLs using mouse knockdown experiments (ABCA1 and TRIB1) and clinical trial results (chemokine receptors CCR2 and CCR5), with consistent regulation. Finally, we evaluate known drug targets, and suggest new target candidates or repositioning opportunities using Mendelian randomization. This identifies 11 proteins with causal evidence of involvement in human disease that have not previously been targeted, including EGF, IL-16, PAPPA, SPON1, F3, ADM, CASP-8, CHI3L1, CXCL16, GDF15 and MMP-12. Taken together, these findings demonstrate the utility of large-scale mapping of the genetics of the proteome and provide a resource for future precision studies of circulating proteins in human health.
15.	Folkersen, Lasse, et al. (författare) Mapping of 79 loci for 83 plasma protein biomarkers in cardiovascular disease 2017 Ingår i: PLOS Genetics. - : PUBLIC LIBRARY SCIENCE. - 1553-7390 .- 1553-7404. ; 13:4 Tidskriftsartikel (refereegranskat)abstract Recent advances in highly multiplexed immunoassays have allowed systematic large-scale measurement of hundreds of plasma proteins in large cohort studies. In combination with genotyping, such studies offer the prospect to 1) identify mechanisms involved with regulation of protein expression in plasma, and 2) determine whether the plasma proteins are likely to be causally implicated in disease. We report here the results of genome-wide association (GWA) studies of 83 proteins considered relevant to cardiovascular disease (CVD), measured in 3,394 individuals with multiple CVD risk factors. We identified 79 genome-wide significant (p<5e-8) association signals, 55 of which replicated at P<0.0007 in separate validation studies (n = 2,639 individuals). Using automated text mining, manual curation, and network-based methods incorporating information on expression quantitative trait loci (eQTL), we propose plausible causal mechanisms for 25 trans-acting loci, including a potential post-translational regulation of stem cell factor by matrix metalloproteinase 9 and receptor-ligand pairs such as RANK-RANK ligand. Using public GWA study data, we further evaluate all 79 loci for their causal effect on coronary artery disease, and highlight several potentially causal associations. Overall, a majority of the plasma proteins studied showed evidence of regulation at the genetic level. Our results enable future studies of the causal architecture of human disease, which in turn should aid discovery of new drug targets.
16.	Hallström, Hadar, et al. (författare) Probiotic supplements and debridement of peri-implant mucositis : a randomized controlled trial 2015 Ingår i: Acta Odontologica Scandinavica. - : Taylor & Francis. - 0001-6357 .- 1502-3850. ; 74:1, s. 60-66 Tidskriftsartikel (refereegranskat)abstract Objective. The aim of this double-blind randomized placebo-controlled trial was to evaluate the effects of probiotic supplements in adjunct to conventional management of peri-implant mucositis.Materials and methods.Forty-nine adult patients with peri-implant mucositis were consecutively recruited after informed consent. After initial mechanical debridement and oral hygiene instructions, the patients received a topical oil application (active or placebo) followed by twice-daily intake of lozenges (active or placebo) for 3 months. The active products contained a mix of two strains of Lactobacillus reuteri. Patients were clinically monitored and sampled at baseline and after 1, 2, 4, 12 and 26 weeks. The clinical end-points were pocket-probing depth (PPD), plaque index (PI) and bleeding on probing (BOP). In addition, the subgingival microbiota was processed with checkerboard DNA-DNA hybridization and samples of gingival crevicular fluid (GCF) were analyzed for selected cytokines with the aid of multiplex immunoassays.Results.After 4 and 12 weeks, all clinical parameters were improved in both the test and the placebo group. PPD and BOP were significantly reduced compared with baseline (p < 0.05), but no significant differences were displayed between the groups. The clinical improvements persisted 3 months after the intervention. No major alterations of the subgingival microflora were disclosed and the levels of inflammatory mediators in GCF did not differ between the groups.Conclusions.Mechanical debridement and oral hygiene reinforcement resulted in clinical improvement of peri-implant mucositis and a reduction in cytokine levels. Probiotic supplements did not provide added benefit to placebo.
17.	Heid, Iris M, et al. (författare) Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution 2010 Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:11, s. 949-960 Tidskriftsartikel (refereegranskat)abstract Waist-hip ratio (WHR) is a measure of body fat distribution and a predictor of metabolic consequences independent of overall adiposity. WHR is heritable, but few genetic variants influencing this trait have been identified. We conducted a meta-analysis of 32 genome-wide association studies for WHR adjusted for body mass index (comprising up to 77,167 participants), following up 16 loci in an additional 29 studies (comprising up to 113,636 subjects). We identified 13 new loci in or near RSPO3, VEGFA, TBX15-WARS2, NFE2L3, GRB14, DNM3-PIGC, ITPR2-SSPN, LY86, HOXC13, ADAMTS9, ZNRF3-KREMEN1, NISCH-STAB1 and CPEB4 (P = 1.9 × 10⁻⁹ to P = 1.8 × 10⁻⁴⁰) and the known signal at LYPLAL1. Seven of these loci exhibited marked sexual dimorphism, all with a stronger effect on WHR in women than men (P for sex difference = 1.9 × 10⁻³ to P = 1.2 × 10⁻¹³). These findings provide evidence for multiple loci that modulate body fat distribution independent of overall adiposity and reveal strong gene-by-sex interactions.
18.	Lethagen, Stefan, et al. (författare) Clinical spectrum of hepatitis C-related liver disease and response to treatment with interferon and ribavirin in haemophilia or von Willebrand disease 2001 Ingår i: British Journal of Haematology. - : Wiley. - 0007-1048. ; 113:1, s. 87-93 Tidskriftsartikel (refereegranskat)abstract Our aim was to evaluate the severity of liver disease resulting from chronic hepatitis C in haemophilia or von Willebrand disease and the efficacy of 6 months treatment with interferon alpha and ribavirin. Fifty-five liver biopsies were performed in 43 patients without any bleeding complications, as seen with ultrasound immediately after the biopsy and 48 h thereafter. Histological changes were mild, with low scores for both inflammation and fibrosis, in spite of long exposure to blood products (mean 27 years). Two patients had compensated cirrhosis. Thirty-five out of 39 included patients completed study treatment. Hepatitis C virus (HCV)-RNA was negative in 77% (30/39) of patients at the end of treatment, and 36% (14/39) achieved a complete sustained response at follow-up 6 months after treatment. Treatment failure was more frequent in patients with virus genotype 1 compared with non-1 (P = 0.0003). The response rate correlated well with that of non-haemophilic patients. In summary: (1) liver biopsy was safe with our regimen; (2) liver disease in our patients was usually mild and had a slow progress; (3) only HCV genotype 1 predicted treatment failure; (4) our treatment results agreed with those from non-haemophilic patients.
19.	Lind, Lars, et al. (författare) Atrial fibrillation genetic risk differentiates cardioembolic stroke from other stroke subtypes 2018 Ingår i: Neurology. Genetics. - : LIPPINCOTT WILLIAMS & WILKINS. - 2376-7839. ; 4:6, s. e293- Tidskriftsartikel (refereegranskat)
20.	Lindgren, A, et al. (författare) Environmental management of dive organizations and –operators 2007 Ingår i: New frontiers in marine tourism: diving experiences, management and sustainability. ; , s. 115-136 Bokkapitel (övrigt vetenskapligt/konstnärligt)
21.	Lindgren, Stefan, et al. (författare) 24-GHz modulation bandwidth and passive alignment of flip-chip mounted DFB laser diodes 1997 Ingår i: IEEE Photonics Technology Letters. - : Institute of Electrical and Electronics Engineers (IEEE). - 1041-1135 .- 1941-0174. ; 9:3, s. 306-308 Tidskriftsartikel (refereegranskat)
22.	Lindgren, Stefan, et al. (författare) Intravenous iron sucrose is superior to oral iron sulphate for correcting anaemia and restoring iron stores in IBD patients : A randomized, controlled, evaluator-blind, multicentre study 2009 Ingår i: Scandinavian Journal of Gastroenterology. - : Informa UK Limited. - 0036-5521 .- 1502-7708. ; 44:7, s. 838-845 Tidskriftsartikel (refereegranskat)abstract Objective. Patients with inflammatory bowel disease (IBD) often have low iron stores or anaemia. There is controversy about whether iron should be supplemented orally or intravenously (i.v.). The purpose of this study was to investigate whether treatment with intravenous iron is superior to treatment with oral iron. The primary end-points were response and remaining anaemia at the end of treatment (EOT).Material and methods. Ninety-one patients with IBD and anaemia (B-Hb <115 g/L) were randomized to oral iron sulphate (n=46) or intravenous iron sucrose (n=45) treatment for 20 weeks.Results. Forty-three patients in the intravenous iron group completed the study compared to 35 patients in the oral iron group (p=0.0009). Only 22 patients (48%) tolerated the prescribed oral dose, and 52% reduced the dose or withdrew from treatment because of poor tolerance. At EOT, 47% patients in the oral iron group increased their B-Hb by ≥20 g/L, compared with 66% in the intravenous iron group (p=0.07). In the oral iron group, 41% still had anaemia versus 16% of the patients in the intravenous iron group (p=0.007), and 22% versus 42% reached their reference B-Hb level (p=0.04). Treatment with intravenous iron sucrose improved iron stores faster and more effectively than oral iron (p=0.002). Under treatment with intravenous iron, 74% of the patients had no anaemia and normal S-ferritin levels (>25 µg/L) at EOT compared with 48% of patients receiving oral iron (p=0.013).Conclusions. Treatment with intravenous iron sucrose is effective, safe, well tolerated and superior to oral iron in correcting haemoglobin and iron stores in patients with IBD.
23.	Ljung, Tryggve, et al. (författare) Granulocyte, monocyte/macrophage apheresis for inflammatory bowel disease : the first 100 patients treated in Scandinavia 2007 Ingår i: Scandinavian Journal of Gastroenterology. - Oslo : Taylor & Francis. - 0036-5521 .- 1502-7708. ; 42:2, s. 221-227 Tidskriftsartikel (refereegranskat)abstract OBJECTIVE: Selective leukocyte apheresis is a new type of non-pharmacological treatment for patients with active ulcerative colitis and Crohn's disease. Preliminary data have indicated that this type of therapy is safe and efficacious, and large sham-controlled studies are currently in progress. In Scandinavia, a substantial number of patients with chronic inflammatory bowel disease have already received leukocyte apheresis on a compassionate use basis and the aim of this study was to report the clinical outcome and adverse events in the first patients treated. MATERIAL AND METHODS: Clinical details of the first consecutive 100 patients with inflammatory bowel disease treated with granulocyte, monocyte/macrophage (Adacolumn) apheresis in Scandinavia were prospectively registered. Median length of follow-up was 17 months, (range 5-30). RESULTS: The study population comprised 52 patients with ulcerative colitis, 44 patients with Crohn's disease and 4 patients with indeterminate colitis. In 97 patients the indication for Adacolumn treatment was steroid-refractory or steroid-dependent disease. Clinical remission was attained in 48% of the patients with ulcerative colitis, and an additional 27% had a clinical response to the apheresis treatment. The corresponding figures for patients with Crohn's disease were 41% and 23%, respectively. Complete steroid withdrawal was achieved in 27 out of the 50 patients taking corticosteroids at baseline. Adverse events were reported in 15 patients and headache was most frequently reported (n=7). CONCLUSIONS: Granulocyte, monocyte/macrophage apheresis treatment seems to be a valuable adjuvant therapy in selected patients with refractory inflammatory bowel disease. The risk for toxicity or severe adverse events appears to be low.
24.	Lu, Yingchang, et al. (författare) New loci for body fat percentage reveal link between adiposity and cardiometabolic disease risk 2016 Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7 Tidskriftsartikel (refereegranskat)abstract To increase our understanding of the genetic basis of adiposity and its links to cardiometabolic disease risk, we conducted a genome-wide association meta-analysis of body fat percentage (BF%) in up to 100,716 individuals. Twelve loci reached genome-wide significance (P<5 × 10(-8)), of which eight were previously associated with increased overall adiposity (BMI, BF%) and four (in or near COBLL1/GRB14, IGF2BP1, PLA2G6, CRTC1) were novel associations with BF%. Seven loci showed a larger effect on BF% than on BMI, suggestive of a primary association with adiposity, while five loci showed larger effects on BMI than on BF%, suggesting association with both fat and lean mass. In particular, the loci more strongly associated with BF% showed distinct cross-phenotype association signatures with a range of cardiometabolic traits revealing new insights in the link between adiposity and disease risk.
25.	Malik, R, et al. (författare) Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes 2018 Ingår i: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 50:4, s. 524- Tidskriftsartikel (refereegranskat)
26.	Marouli, Eirini, et al. (författare) Rare and low-frequency coding variants alter human adult height 2017 Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 542:7640, s. 186-190 Tidskriftsartikel (refereegranskat)abstract Height is a highly heritable, classic polygenic trait with approximately 700 common associated variants identified through genome-wide association studies so far. Here, we report 83 height-associated coding variants with lower minor-allele frequencies (in the range of 0.1-4.8%) and effects of up to 2 centimetres per allele (such as those in IHH, STC2, AR and CRISPLD2), greater than ten times the average effect of common variants. In functional follow-up studies, rare height increasing alleles of STC2 (giving an increase of 1-2 centimetres per allele) compromised proteolytic inhibition of PAPP-A and increased cleavage of IGFBP-4 in vitro, resulting in higher bioavailability of insulin-like growth factors. These 83 height-associated variants overlap genes that are mutated in monogenic growth disorders and highlight new biological candidates (such as ADAMTS3, IL11RA and NOX4) and pathways (such as proteoglycan and glycosaminoglycan synthesis) involved in growth. Our results demonstrate that sufficiently large sample sizes can uncover rare and low-frequency variants of moderate-to-large effect associated with polygenic human phenotypes, and that these variants implicate relevant genes and pathways.
27.	Nordanstig, Joakim, et al. (författare) Mortality with Paclitaxel-Coated Devices in Peripheral Artery Disease. 2020 Ingår i: The New England journal of medicine. - : Massachusetts Medical Society. - 1533-4406 .- 0028-4793. ; 383, s. 2538-46 Tidskriftsartikel (refereegranskat)abstract The results of a recent meta-analysis aroused concern about an increased risk of death associated with the use of paclitaxel-coated angioplasty balloons and stents in lower-limb endovascular interventions for symptomatic peripheral artery disease.We conducted an unplanned interim analysis of data from a multicenter, randomized, open-label, registry-based clinical trial. At the time of the analysis, 2289 patients had been randomly assigned to treatment with drug-coated devices (the drug-coated-device group, 1149 patients) or treatment with uncoated devices (the uncoated-device group, 1140 patients). Randomization was stratified according to disease severity on the basis of whether patients had chronic limb-threatening ischemia (1480 patients) or intermittent claudication (809 patients). The single end point for this interim analysis was all-cause mortality.No patients were lost to follow-up. Paclitaxel was used as the coating agent for all the drug-coated devices. During a mean follow-up of 2.49 years, 574 patients died, including 293 patients (25.5%) in the drug-coated-device group and 281 patients (24.6%) in the uncoated-device group (hazard ratio, 1.06; 95% confidence interval, 0.92 to 1.22). At 1 year, all-cause mortality was 10.2% (117 patients) in the drug-coated-device group and 9.9% (113 patients) in the uncoated-device group. During the entire follow-up period, there was no significant difference in the incidence of death between the treatment groups among patients with chronic limb-threatening ischemia (33.4% [249 patients] in the drug-coated-device group and 33.1% [243 patients] in the uncoated-device group) or among those with intermittent claudication (10.9% [44 patients] and 9.4% [38 patients], respectively).In this randomized trial in which patients with peripheral artery disease received treatment with paclitaxel-coated or uncoated endovascular devices, the results of an unplanned interim analysis of all-cause mortality did not show a difference between the groups in the incidence of death during 1 to 4 years of follow-up. (Funded by the Swedish Research Council and others; ClinicalTrials.gov number, NCT02051088.).
28.	Scott, Robert A., et al. (författare) Large-scale association analyses identify new loci influencing glycemic traits and provide insight into the underlying biological pathways 2012 Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 44:9, s. 991-1005 Tidskriftsartikel (refereegranskat)abstract Through genome-wide association meta-analyses of up to 133,010 individuals of European ancestry without diabetes, including individuals newly genotyped using the Metabochip, we have increased the number of confirmed loci influencing glycemic traits to 53, of which 33 also increase type 2 diabetes risk (q < 0.05). Loci influencing fasting insulin concentration showed association with lipid levels and fat distribution, suggesting impact on insulin resistance. Gene-based analyses identified further biologically plausible loci, suggesting that additional loci beyond those reaching genome-wide significance are likely to represent real associations. This conclusion is supported by an excess of directionally consistent and nominally significant signals between discovery and follow-up studies. Functional analysis of these newly discovered loci will further improve our understanding of glycemic control.
29.	Steen Carlsson, Katarina, et al. (författare) Costs of on-demand and prophylactic treatment for severe haemophilia in Norway and Sweden. 2004 Ingår i: Haemophilia. - : Wiley. - 1351-8216 .- 1365-2516. ; 10:5, s. 515-526 Tidskriftsartikel (refereegranskat)abstract The expected annual cost (in the year 2000 prices) for a 30-year-old patient with average individual and treatment characteristics for on-demand EUR 51 832 (95% CI: 44 324-59 341) and for prophylaxis EUR 146 118 (95% CI: 129 965-162 271), was obtained from panel-data analysis of an 11-year retrospective panel of 156 patients with severe haemophilia in Norway and Sweden. Costs included haemophilia-related treatment costs within the health-care sector (factor concentrate, doctors' visits, diagnostic procedures, hospitalisation, invasive procedures, etc.) and cost for haemophilia-related resource use in other sectors (lost production, use of special equipment, adaptation of workplace and domicile, etc). Although costs of lost production, reconstructive surgery and hospitalisation were higher for on-demand, they did not balance out the higher costs of factor-concentrate consumption in prophylaxis. The cut-off risk of premature death, where on-demand and prophylaxis would have been equally costly, was 3.7 percentage units higher for on-demand than for prophylaxis. Such a great risk difference has not been reported elsewhere to our knowledge. Estimated cost-elasticities indicated that annual costs of prophylaxis would increase by approximately the same proportion as a potential increase in the price of factor concentrate and decrease less than proportionately with a reduction in prescribed dose kg-1. For on-demand, the annual costs would increase by approximately the same proportion as an increase in the prescribed dose kg-1.
30.	Steen Carlsson, Katarina, et al. (författare) On-demand vs. prophylactic treatment for severe haemophilia in Norway and Sweden: differences in treatment characteristics and outcome. 2003 Ingår i: Haemophilia. - : Wiley. - 1351-8216. ; 9:5, s. 555-566 Tidskriftsartikel (refereegranskat)abstract Using an 11-year panel of 156 Norwegian and Swedish patients with severe haemophilia, and including retrospective case-book data from birth, we compared the differences in the haemophilia-related resource use between on-demand and prophylactic treatment. Patients treated on-demand had more surgery (arthrodeses, prostheses implantations and synovectomies) and more days lost from work. Median annual factor-concentrate consumption among adults (18+) was 211 000 IU [interquartile range (IQR) 154 000-268 000] or 3 024 IU kg-1 year-1 for patients on prophylactic treatment and 55 000 IU (IQR 28 000-91 000) for on-demand patients (780 IU kg-1 year-1). This was partly explained by the fact that the median dose per kg body weight was twice as great 28, (IQR 24-32) for prophylaxis compared with 14 (IQR 12-16) for on-demand. Prescribed dose per kg body weight was found to be an important factor explaining the variation in total annual factor-concentrate consumption per patient for both types of treatment. Other variables included in the panel-data regression analysis were the number of weeks on secondary prophylaxis for on-demand patients and age, body weight and type of haemophilia for children (0-17 years) on prophylaxis. Differences were consistently substantial and will affect both costs and benefits of the two treatment strategies.
31.	Steen Carlsson, Katarina, et al. (författare) Willingness to pay for on-demand and prophylactic treatment for severe haemophilia in Sweden. 2004 Ingår i: Haemophilia. - : Wiley. - 1351-8216 .- 1365-2516. ; 10:5, s. 527-541 Tidskriftsartikel (refereegranskat)abstract The objective of the present paper was to provide an estimate of the benefits of on-demand and prophylaxis treatment strategies for severe haemophilia in monetary terms. Using the contingent-valuation method, which simulates a missing market by asking people about their willingness to pay (WTP), we asked a representative sample (n = 609) of the Swedish population if they would be willing to pay a specific amount (bid) so that patients with severe haemophilia could receive on-demand treatment and another bid for prophylactic treatment. Different respondents were offered different bids and the bid vector ranged from 71 Euro cents to EUR 130. The order of the bid questions was randomized so that half of the respondents were asked first about their WTP for on-demand treatment, and then about their WTP for prophylaxis, while the order was reversed for the other half of the respondents. The mean estimated WTP (year 2002) was EUR 39 (95% CI 31-47) for on-demand and EUR 65 (95% CI 55-73) for prophylaxis. Our sensitivity analysis showed that the ranking of the two treatment alternatives was robust in that the WTP was greater for prophylaxis in all possible subsets. The point estimates of WTP varied somewhat in subsets defined by individual characteristics, but confidence intervals always overlapped that of the main results. The WTP for on-demand and prophylaxis exceeded the calculated cost of treatment per taxpayer of providing on-demand and prophylactic treatment, respectively, based on our previous results
32.	Surendran, Praveen, et al. (författare) Discovery of rare variants associated with blood pressure regulation through meta-analysis of 1.3 million individuals 2020 Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 52:12, s. 1314-1332 Tidskriftsartikel (refereegranskat)abstract Genetic studies of blood pressure (BP) to date have mainly analyzed common variants (minor allele frequency > 0.05). In a meta-analysis of up to similar to 1.3 million participants, we discovered 106 new BP-associated genomic regions and 87 rare (minor allele frequency <= 0.01) variant BP associations (P < 5 x 10(-8)), of which 32 were in new BP-associated loci and 55 were independent BP-associated single-nucleotide variants within known BP-associated regions. Average effects of rare variants (44% coding) were similar to 8 times larger than common variant effects and indicate potential candidate causal genes at new and known loci (for example, GATA5 and PLCB3). BP-associated variants (including rare and common) were enriched in regions of active chromatin in fetal tissues, potentially linking fetal development with BP regulation in later life. Multivariable Mendelian randomization suggested possible inverse effects of elevated systolic and diastolic BP on large artery stroke. Our study demonstrates the utility of rare-variant analyses for identifying candidate genes and the results highlight potential therapeutic targets.
33.	Turcot, Valerie, et al. (författare) Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity 2018 Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 50:1, s. 26-41 Tidskriftsartikel (refereegranskat)abstract Genome-wide association studies (GWAS) have identified >250 loci for body mass index (BMI), implicating pathways related to neuronal biology. Most GWAS loci represent clusters of common, noncoding variants from which pinpointing causal genes remains challenging. Here we combined data from 718,734 individuals to discover rare and low-frequency (minor allele frequency (MAF) < 5%) coding variants associated with BMI. We identified 14 coding variants in 13 genes, of which 8 variants were in genes (ZBTB7B, ACHE, RAPGEF3, RAB21, ZFHX3, ENTPD6, ZFR2 and ZNF169) newly implicated in human obesity, 2 variants were in genes (MC4R and KSR2) previously observed to be mutated in extreme obesity and 2 variants were in GIPR. The effect sizes of rare variants are similar to 10 times larger than those of common variants, with the largest effect observed in carriers of an MC4R mutation introducing a stop codon (p.Tyr35Ter, MAF = 0.01%), who weighed similar to 7 kg more than non-carriers. Pathway analyses based on the variants associated with BMI confirm enrichment of neuronal genes and provide new evidence for adipocyte and energy expenditure biology, widening the potential of genetically supported therapeutic targets in obesity.
34.	Walford, G. A., et al. (författare) Genome-wide association study of the modified stumvoll insulin sensitivity index identifies BCL2 and FAM19A2 as novel insulin sensitivity loci 2016 Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 65:10, s. 3200-3211 Tidskriftsartikel (refereegranskat)abstract Genome-wide association studies (GWAS) have found few common variants that influence fasting measures of insulin sensitivity. We hypothesized that a GWAS of an integrated assessment of fasting and dynamic measures of insulin sensitivity would detect novel common variants. We performed a GWAS of the modified Stumvoll Insulin Sensitivity Index (ISI) within the Meta-Analyses of Glucose and Insulin-Related Traits Consortium. Discovery for genetic association was performed in 16,753 individuals, and replication was attempted for the 23 most significant novel loci in 13,354 independent individuals. Association with ISI was tested in models adjusted for age, sex, and BMI and in a model analyzing the combined influence of the genotype effect adjusted for BMI and the interaction effect between the genotype and BMI on ISI (model 3). In model 3, three variants reached genome-wide significance: Rs13422522 (NYAP2; P = 8.87 × 10-11), rs12454712 (BCL2; P = 2.7 × 10-8), and rs10506418 (FAM19A2; P = 1.9 × 10-8). The association at NYAP2 was eliminated by conditioning on the known IRS1 insulin sensitivity locus; the BCL2 and FAM19A2 associations were independent of known cardiometabolic loci. In conclusion, we identified two novel loci and replicated known variants associated with insulin sensitivity. Further studies are needed to clarify the causal variant and function at the BCL2 and FAM19A2 loci. © 2016 by the American Diabetes Association.
35.	Wessel, Jennifer, et al. (författare) Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility 2015 Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 6 Tidskriftsartikel (refereegranskat)abstract Fasting glucose and insulin are intermediate traits for type 2 diabetes. Here we explore the role of coding variation on these traits by analysis of variants on the HumanExome BeadChip in 60,564 non-diabetic individuals and in 16,491 T2D cases and 81,877 controls. We identify a novel association of a low-frequency nonsynonymous SNV in GLP1R (A316T; rs10305492; MAF = 1.4%) with lower FG (beta = -0.09 +/- 0.01 mmol l(-1), P = 3.4 x 10(-12)), T2D risk (OR[95% CI] = 0.86[0.76-0.96], P = 0.010), early insulin secretion (beta = -0.07 +/- 0.035 pmol(insulin) mmol(glucose)(-1), P = 0.048), but higher 2-h glucose (beta = 0.16 +/- 0.05 mmol l(-1), P = 4.3 x 10(-4)). We identify a gene-based association with FG at G6PC2 (p(SKAT) = 6.8 x 10(-6)) driven by four rare protein-coding SNVs (H177Y, Y207S, R283X and S324P). We identify rs651007 (MAF = 20%) in the first intron of ABO at the putative promoter of an antisense lncRNA, associating with higher FG (beta = 0.02 +/- 0.004 mmol l(-1), P = 1.3 x 10(-8)). Our approach identifies novel coding variant associations and extends the allelic spectrum of variation underlying diabetes-related quantitative traits and T2D susceptibility.
36.	Willer, Cristen J., et al. (författare) Discovery and refinement of loci associated with lipid levels 2013 Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 45:11, s. 1274-1283 Tidskriftsartikel (refereegranskat)abstract Levels of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides and total cholesterol are heritable, modifiable risk factors for coronary artery disease. To identify new loci and refine known loci influencing these lipids, we examined 188,577 individuals using genome-wide and custom genotyping arrays. We identify and annotate 157 loci associated with lipid levels at P < 5 x 10(-8), including 62 loci not previously associated with lipid levels in humans. Using dense genotyping in individuals of European, East Asian, South Asian and African ancestry, we narrow association signals in 12 loci. We find that loci associated with blood lipid levels are often associated with cardiovascular and metabolic traits, including coronary artery disease, type 2 diabetes, blood pressure, waist-hip ratio and body mass index. Our results demonstrate the value of using genetic data from individuals of diverse ancestry and provide insights into the biological mechanisms regulating blood lipids to guide future genetic, biological and therapeutic research.
37.	Williamson, Alice, et al. (författare) Genome-wide association study and functional characterization identifies candidate genes for insulin-stimulated glucose uptake 2023 Ingår i: Nature Genetics. - : Springer Nature. - 1061-4036 .- 1546-1718. ; 55:6, s. 973-983 Tidskriftsartikel (refereegranskat)abstract Distinct tissue-specific mechanisms mediate insulin action in fasting and postprandial states. Previous genetic studies have largely focused on insulin resistance in the fasting state, where hepatic insulin action dominates. Here we studied genetic variants influencing insulin levels measured 2 h after a glucose challenge in >55,000 participants from three ancestry groups. We identified ten new loci (P < 5 × 10-8) not previously associated with postchallenge insulin resistance, eight of which were shown to share their genetic architecture with type 2 diabetes in colocalization analyses. We investigated candidate genes at a subset of associated loci in cultured cells and identified nine candidate genes newly implicated in the expression or trafficking of GLUT4, the key glucose transporter in postprandial glucose uptake in muscle and fat. By focusing on postprandial insulin resistance, we highlighted the mechanisms of action at type 2 diabetes loci that are not adequately captured by studies of fasting glycemic traits.
38.	Winkler, TW, et al. (författare) The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape: A Large-Scale Genome-Wide Interaction Study 2015 Ingår i: PLoS genetics. - : Public Library of Science (PLoS). - 1553-7404 .- 1553-7390. ; 11:10, s. e1005378- Tidskriftsartikel (refereegranskat)
39.	Åslund, Andreas, et al. (författare) Novel Pentameric Thiophene Derivatives for in Vitro and in Vivo Optical Imaging of a Plethora of Protein Aggregates in Cerebral Amyloidoses 2009 Ingår i: ACS CHEMICAL BIOLOGY. - : American Chemical Society (ACS). - 1554-8929 .- 1554-8937. ; 4:8, s. 673-684 Tidskriftsartikel (refereegranskat)abstract Molecular probes for selective Identification of protein aggregates are important to advance our understanding of the molecular pathogenesis underlying cerebral amyloidoses. Here we report the chemical design of pentameric thiophene derivatives, denoted luminescent conjugated oligothiophenes (LCOs), which could be used for real-time visualization of cerebral protein aggregates in transgenic mouse models of neurodegenerative diseases by multiphoton microscopy. One of the LCOs, p-FTAA, could be utilized for ex vivo spectral assignment of distinct prion deposits from two, mouse-adapted prion strains. p-FTAA also revealed a transient soluble pre-fibrillar non-thioflavinophilic A beta-assemblies during in vitro fibrillation of A beta peptides. In brain tissue samples, A beta deposits and neurofibrillary tangles (NFTs) were readily identified by a strong fluorescence from p-FTAA and the LCO staining showed complete co-localliation with conventional antibodies (6E10 and AT8). In addition, a patchy islet-like staining of individual A beta plaque was unveiled by the anti-oligomer A11 antibody during co-staining with p-FTAA. The major hallmarks of Alzheimers disease, namely, A beta aggregates versus NFTs, could also be distinguished because of distinct emission spectra from p-FTAA. Overall, we demonstrate that LCOs can be utilized as powerful practical research tools for studying protein aggregation diseases and facilitate the study of amyloid origin, evolution and maturation, A beta-tau interactions, and pathogenesis both ex vivo and in vivo.
40.	Ahlén, Ingemar, et al. (författare) Nya järnvägen hotar unikt naturområde 2002 Ingår i: Aftonbladet. - 1103-9000. Tidskriftsartikel (populärvet., debatt m.m.)
41.	Ahlén, Ingemar, et al. (författare) Nya järnvägen hotar unikt naturområde 2002 Ingår i: Aftonbladet. - 1103-9000. Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
42.	Ahlstrand, Erik, 1974-, et al. (författare) Highly Reduced Survival in Essential Thrombocythemia and Polycythemia Vera Patients with Vascular Complications during Follow-up 2020 Ingår i: European Journal of Haematology. - : Munksgaard Forlag. - 0902-4441 .- 1600-0609. ; 104:3, s. 271-278 Tidskriftsartikel (refereegranskat)abstract OBJECTIVE: To explore the relative importance of risk factors, treatments and blood counts for the occurrence of vascular complications and their impact on life expectancy in Essential Thrombocythemia (ET) and Polycythemia Vera (PV).METHODS: Nested case-control study within the Swedish MPN registry. From a cohort of 922 ET patients and 763 PV patients, 71 ET and 81 PV cases with vascular complications were compared to matched controls.RESULTS: Incidence of vascular complications were 2.0 and 3.4 events per 100 patient-years in ET and PV, respectively. At diagnosis, no significant risk factor differences were observed between cases and controls in neither of the diseases. At the time of vascular event, ET complication cases did not differ significantly from controls but in PV, cases had significantly higher WBCs and were to a lesser extent treated with antithrombotic and cytoreductive therapy. Life expectancy was significantly decreased in both ET and PV cases compared to controls.CONCLUSIONS: The risk of vascular complications is high in both ET and PV and these complications have a considerable impact on life expectancy. The protective effect of antithrombotic and cytoreductive therapy for vascular complications in PV underscores the importance of avoiding undertreatment.
43.	Aleman, Soo, et al. (författare) Health check-ups and family screening allow detection of hereditary hemochromatosis with less advanced liver fibrosis and survival comparable with the general population 2011 Ingår i: Scandinavian Journal of Gastroenterology. - : Informa UK Limited. - 0036-5521 .- 1502-7708. ; 46:9, s. 1118-1126 Tidskriftsartikel (refereegranskat)abstract Objective. The information concerning the morbidity and mortality of hereditary hemochromatosis is based primarily on clinical cohorts of symptomatic patients. The major aim of this study was to analyze the long-term prognosis for Swedish patients with this condition, with respect to both clinical features and survival, in relation to the route by which the disease was detected. Patients and methods. 373 patients with hemochromatosis detected through routine health checkups (n = 153), family screening (n = 44), symptoms of arthralgia (n = 23), investigation of other diseases/symptoms (n = 108) or signs of liver disease (n = 45) were monitored for a mean period of 11.9 +/- 5.8 years. The degree of liver fibrosis and survival were analyzed. Results. Overall survival among these patients was not significantly different from that of a matched normal population. The patients diagnosed through health check-ups and family screening were detected at an earlier age and had the highest rate of survival. Liver biopsy at the time of diagnosis revealed cirrhosis in 9% of those detected through the health check-ups and 5% in the case of family screening, compared with 13% for the group with arthralgia, 17% for other diseases/symptoms and 42% for liver disease. Conclusion. Health check-ups and family screening allow detection of hereditary hemochromatosis at an earlier age and with less advanced liver fibrosis, although a few of these patients have already developed cirrhosis. Our study indicates that iron indices should be included in health check-ups, and if abnormal, should lead to further investigation.
44.	Almer, Sven, 1938-, et al. (författare) Handläggning av svårt skov av ulcerös kolit. In: Löfberg R (ed): Inflammatorisk tarmsjukdom. 2010 Ingår i: Läkartidningen. - 0023-7205 .- 1652-7518. ; 106:45, s. 62-75 Tidskriftsartikel (refereegranskat)abstract Patienter med svårt skov av ulcerös kolit bör vårdas på sjukhus och handläggas av gastroenterolog och kolorektal kirurg i nära samarbete.Skovets svårighetsgrad kan underskattas, varför noggrann bedömning av inflammationens utbredning och svårighetsgrad enligt validerade kriterier är viktigt.Intravenös behandling med kortikosteroider är en av hörnstenarna i den akuta behandlingen.Patienter som inte förbättras på denna behandling, bör erbjudas medicinsk »rescue-behandling« eller kolektomi.Infliximab har visats vara en effektiv rescue-behandling och kan minska behovet av kolektomi inom de första 3 månaderna och upp till 3 år.
45.	Andersson, Bertil, et al. (författare) End-expiratory lung volume and ventilation distribution with different continuous positive airway pressure systems in volunteers. 2011 Ingår i: Acta anaesthesiologica Scandinavica. - : Wiley. - 1399-6576 .- 0001-5172. ; 55:2, s. 157-64 Tidskriftsartikel (refereegranskat)abstract Background: Continuous positive airway pressure (CPAP) has been shown to improve oxygenation and a number of different CPAP systems are available. The aim of this study was to assess lung volume and ventilation distribution using three different CPAP techniques. Methods: A high-flow CPAP system (HF-CPAP), an ejector-driven system (E-CPAP) and CPAP using a Servo 300 ventilator (V-CPAP) were randomly applied at 0, 5 and 10 cmH2O in 14 volunteers. End-expiratory lung volume (EELV) was measured by N2 dilution at baseline; changes in EELV and tidal volume distribution were assessed by electric impedance tomography. Results: Higher end-expiratory and mean airway pressures were found using the E-CPAP vs. the HF-CPAP and the V-CPAP system (P<0.01). EELV increased markedly from baseline, 0 cmH2O, with increased CPAP levels: 1110±380, 1620±520 and 1130±350 ml for HF-, E- and V-CPAP, respectively, at 10 cmH2O. A larger fraction of the increase in EELV occurred for all systems in ventral compared with dorsal regions (P<0.01). In contrast, tidal ventilation was increasingly directed toward dorsal regions with increasing CPAP levels (P<0.01). The increase in EELV as well as the tidal volume redistribution were more pronounced with the E-CPAP system as compared with both the HF-CPAP and the V-CPAP systems (P<0.05) at 10 cmH2O. Conclusion: EELV increased more in ventral regions with increasing CPAP levels, independent of systems, leading to a redistribution of tidal ventilation toward dorsal regions. Different CPAP systems resulted in different airway pressure profiles, which may result in different lung volume expansion and tidal volume distribution.
46.	Angelison, Leif, et al. (författare) Short and long-term efficacy of adalimumab in ulcerative colitis : a real-life study 2020 Ingår i: Scandinavian Journal of Gastroenterology. - : Informa UK Limited. - 0036-5521 .- 1502-7708. ; 55:2, s. 154-162 Tidskriftsartikel (refereegranskat)abstract Objective: Randomized controlled trials have shown the effectiveness of Adalimumab in ulcerative colitis. However, real-life data is scarce. We aimed to assess the effectiveness and predictive factors of effectiveness in a large Swedish cohort. Methods: Retrospective capture of data from local registries at five Swedish IBD centers. Clinical response and remission rates were assessed at three months after starting adalimumab treatment and patients were followed until colectomy or need for another biological. Bio-naive patients were compared to bio experienced patients. Factors associated with short term responses were assessed using logistic regression model. Failure on drug was assessed using a Cox proportional hazards regression model. Results: 118 patients (59 males, 59 females) with median age 34.4 years (IQR 27.0–51.4) were included. Median disease duration was 4.3 years (IQR 2.0–9.0) and follow-up 1.27 years (IQR 0.33–4.1). A clinical corticosteroid-free remission was achieved by 38/118 (32.2%) and response by 91/118 (77%) after three months. CRP >3 mg/l at baseline was predictive of short-term failure to reach corticosteroid-free remission. Factors associated with survival on the drug were male gender, CRP <3 mg/l and absence of primary sclerosing cholangitis. Patients >42 years of age at diagnosis were more likely to respond to adalimumab and remain on treatment compared to patients <20 years. Conclusions: An elevated CRP-level, primary sclerosing cholangitis and female gender were predictors of treatment failure. In contrast older age at diagnosis was a predictor of short-term clinical response and drug survival. Prior infliximab failure, regardless of cause, did not influence the outcome of adalimumab treatment.
47.	Arja, Katriann, et al. (författare) Enhanced Fluorescent Assignment of Protein Aggregates by an Oligothiophene-Porphyrin-Based Amyloid Ligand 2013 Ingår i: Macromolecular rapid communications. - : Wiley-VCH Verlag. - 1022-1336 .- 1521-3927. ; 34:9, s. 723-730 Tidskriftsartikel (refereegranskat)abstract Fluorescent probes identifying protein aggregates are of great interest, as deposition of aggregated proteins is associated with many devastating diseases. Here, we report that a fluorescent amyloid ligand composed of two distinct molecular moieties, an amyloidophilic pentameric oligothiophene and a porphyrin, can be utilized for spectral and lifetime imaging assessment of recombinant A 1-42 amyloid fibrils and A deposits in brain tissue sections from a transgenic mouse model with Alzheimers disease pathology. The enhanced spectral range and distinct lifetime diversity of this novel oligothiopheneporphyrin-based ligand allow a more precise assessment of heterogeneous amyloid morphology compared with the corresponding oligothiophene dye.
48.	Bager, P., et al. (författare) Fatigue in out-patients with inflammatory bowel disease is common and multifactorial 2012 Ingår i: Alimentary Pharmacology and Therapeutics. - : Blackwell Publishing. - 0269-2813 .- 1365-2036. ; 35:1, s. 133-141 Tidskriftsartikel (refereegranskat)abstract Background similar to Patients with inflammatory bowel disease (IBD) often complain of fatigue. Aim similar to To investigate the prevalence and characteristics of fatigue among IBD out-patients in Scandinavia and to provide normative values for fatigue in IBD patients. Methods similar to A cross-sectional study was conducted on 425 IBD patients from six out-patient centres in Denmark, Norway and Sweden. Fatigue was measured using the Multidimensional Fatigue Inventory. The patients were also screened for anaemia and iron deficiency. Each centre included approximately 5% of their IBD cohort. The patients were enrolled consecutively from the out-patient clinics, regardless of disease activity and whether the visit was scheduled. The fatigue analysis was stratified for age and gender. Results similar to Using the 95th percentile of the score of the general population as a cut-off, approximately 44% of the patients were fatigued. When comparing the IBD patients with disease activity to the IBD patients in remission, all dimensions of fatigue were statistically significant (P less than 0.05). Being anaemic or iron deficient was not associated with increased fatigue. Being a male patient with ulcerative colitis treated with corticosteroids was a strong determinant for increased fatigue. The normative ranges for IBD fatigue were calculated. Conclusions similar to Fatigue in IBD is common regardless of anaemia or iron deficiency. Fatigue in IBD is most marked for patients less than60 years of age. Stratifying for gender and age is necessary when analysing fatigue, as fatigue is expressed differently between groups.
49.	Bager, Palle, et al. (författare) High burden of iron deficiency and different types of anemia in inflammatory bowel disease outpatients in Scandinavia: A longitudinal 2-year follow-up study 2013 Ingår i: Scandinavian Journal of Gastroenterology. - : Informa Healthcare. - 0036-5521 .- 1502-7708. ; 48:11, s. 1286-1293 Tidskriftsartikel (refereegranskat)abstract Objective. The prevalence of anemia in inflammatory bowel disease (IBD) has been broadly described. The recurrence, type and burden of anemia remain unenlightened. The primary objective was to describe this. The secondary objective was to evaluate the implementation of European guidelines. Materials and methods. This longitudinal follow-up study included 300 IBD outpatients from six centers in Scandinavia. Patients were enrolled in a research cohort, in which each center included 5% of their IBD cohort. The study was prospectively planned, while data were retrospectively collected. The burden of anemia was calculated as number of months with anemia. A Markov model was used to calculate the probabilities of transitioning between stages. The European guidelines were used as the standard for anemia management. Results. Anemia affected andgt; 50% of IBD outpatients during the 2-year observation period. Totally, 20% of the total observation time was spent in anemia. Over the 7200 months of observation, anemia was found in 1410 months. The most frequent type was combined anemia (63%). Combined anemia covers both anemia of chronic disease (ACD) and iron-deficiency anemia (IDA). Pure ACD was present in 21% of burden time, while pure IDA was present in 16% of burden time. The European guidelines have mainly been implemented. Conclusion. Anemia affected a majority of the IBD outpatients. One in five months, the patients were anemic. Anemia related to inflammation dominated the different types of anemia. Pure IDA was found in for 16%. These findings, despite a fair implementation of guidelines.
50.	Bager, Palle, et al. (författare) The prevalence of anemia and iron deficiency in IBD outpatients in Scandinavia 2011 Ingår i: SCANDINAVIAN JOURNAL OF GASTROENTEROLOGY. - : Informa Healthcare. - 0036-5521 .- 1502-7708. ; 46:3, s. 304-309 Tidskriftsartikel (refereegranskat)abstract Objective. To evaluate the prevalence of anemia and iron deficiency (ID) among patients with inflammatory bowel disease (IBD) in the Scandinavian countries. Material and methods. A cross-sectional study including 429 IBD patients from six centers in Denmark, Norway and Sweden. Patients were screened for anemia and ID. Each center included similar to 5% of their IBD cohort. Patients were consecutively seen in the outpatient clinic, regardless of disease activity and whether the visits were scheduled or not. Results. The overall prevalence of anemia was 19% (95% CI: 16--23%). The prevalence was higher among patients with Crohns disease than among patients with ulcerative colitis (p = 0.01). The etiology of anemia was as follows: iron deficiency anemia (20%), anemia of chronic disease (12%), and both conditions (68%). Less than 5% had folate acid or vitamin B12 deficiency. ID was found in 35% (CI: 31-40%) of the patients. Conclusions. Anemia was present in every fifth IBD patient and ID in every third IBD patient.

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