| 1. |
- Rajewsky, N., et al.
(författare)
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LifeTime and improving European healthcare through cell-based interceptive medicine
- 2020
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Ingår i: Nature. - : Springer Nature. - 0028-0836 .- 1476-4687. ; 587:7834, s. 377-386
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Tidskriftsartikel (refereegranskat)abstract
- LifeTime aims to track, understand and target human cells during the onset and progression of complex diseases and their response to therapy at single-cell resolution. This mission will be implemented through the development and integration of single-cell multi-omics and imaging, artificial intelligence and patient-derived experimental disease models during progression from health to disease. Analysis of such large molecular and clinical datasets will discover molecular mechanisms, create predictive computational models of disease progression, and reveal new drug targets and therapies. Timely detection and interception of disease embedded in an ethical and patient-centered vision will be achieved through interactions across academia, hospitals, patient-associations, health data management systems and industry. Applying this strategy to key medical challenges in cancer, neurological, infectious, chronic inflammatory and cardiovascular diseases at the single-cell level will usher in cell-based interceptive medicine in Europe over the next decade.
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| 2. |
- Manning, Alisa, et al.
(författare)
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A Low-Frequency Inactivating AKT2 Variant Enriched in the Finnish Population Is Associated With Fasting Insulin Levels and Type 2 Diabetes Risk
- 2017
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Ingår i: Diabetes. - : AMER DIABETES ASSOC. - 0012-1797 .- 1939-327X. ; 66:7, s. 2019-2032
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Tidskriftsartikel (refereegranskat)abstract
- To identify novel coding association signals and facilitate characterization of mechanisms influencing glycemic traits and type 2 diabetes risk, we analyzed 109,215 variants derived from exome array genotyping together with an additional 390,225 variants from exome sequence in up to 39,339 normoglycemic individuals from five ancestry groups. We identified a novel association between the coding variant (p.Pro50Thr) in AKT2 and fasting plasma insulin (FI), a gene in which rare fully penetrant mutations are causal for monogenic glycemic disorders. The low-frequency allele is associated with a 12% increase in FI levels. This variant is present at 1.1% frequency in Finns but virtually absent in individuals from other ancestries. Carriers of the FI-increasing allele had increased 2-h insulin values, decreased insulin sensitivity, and increased risk of type 2 diabetes (odds ratio 1.05). In cellular studies, the AKT2-Thr50 protein exhibited a partial loss of function. We extend the allelic spectrum for coding variants in AKT2 associated with disorders of glucose homeostasis and demonstrate bidirectional effects of variants within the pleckstrin homology domain of AKT2.
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| 3. |
- van der Lee, S. J., et al.
(författare)
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A nonsynonymous mutation in PLCG2 reduces the risk of Alzheimer's disease, dementia with Lewy bodies and frontotemporal dementia, and increases the likelihood of longevity
- 2019
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Ingår i: Acta Neuropathologica. - : Springer Science and Business Media LLC. - 0001-6322 .- 1432-0533. ; 138:2, s. 237-250
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Tidskriftsartikel (refereegranskat)abstract
- The genetic variant rs72824905-G (minor allele) in the PLCG2 gene was previously associated with a reduced Alzheimer's disease risk (AD). The role of PLCG2 in immune system signaling suggests it may also protect against other neurodegenerative diseases and possibly associates with longevity. We studied the effect of the rs72824905-G on seven neurodegenerative diseases and longevity, using 53,627 patients, 3,516 long-lived individuals and 149,290 study-matched controls. We replicated the association of rs72824905-G with reduced AD risk and we found an association with reduced risk of dementia with Lewy bodies (DLB) and frontotemporal dementia (FTD). We did not find evidence for an effect on Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS) risks, despite adequate sample sizes. Conversely, the rs72824905-G allele was associated with increased likelihood of longevity. By-proxy analyses in the UK Biobank supported the associations with both dementia and longevity. Concluding, rs72824905-G has a protective effect against multiple neurodegenerative diseases indicating shared aspects of disease etiology. Our findings merit studying the PLC gamma 2 pathway as drug-target.
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| 4. |
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| 5. |
- Emery-Corbin, Samantha J., et al.
(författare)
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Eukaryote-Conserved Methylarginine Is Absent in Diplomonads and Functionally Compensated in Giardia
- 2020
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Ingår i: Molecular biology and evolution. - : OXFORD UNIV PRESS. - 0737-4038 .- 1537-1719. ; 37:12, s. 3525-3549
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Tidskriftsartikel (refereegranskat)abstract
- Methylation is a common posttranslational modification of arginine and lysine in eukaryotic proteins. Methylproteomes are best characterized for higher eukaryotes, where they are functionally expanded and evolved complex regulation. However, this is not the case for protist species evolved from the earliest eukaryotic lineages. Here, we integrated bioinformatic, proteomic, and drug-screening data sets to comprehensively explore the methylproteome of Giardia duodenalis-a deeply branching parasitic protist. We demonstrate that Giardia and related diplomonads lack arginine-methyltransferases and have remodeled conserved RGG/RG motifs targeted by these enzymes. We also provide experimental evidence for methylarginine absence in proteomes of Giardia but readily detect methyllysine. We bioinformatically infer 11 lysine-methyltransferases in Giardia, including highly diverged Su(var)3-9, Enhancer-of-zeste and Trithorax proteins with reduced domain architectures, and novel annotations demonstrating conserved methyllysine regulation of eukaryotic elongation factor 1 alpha. Using mass spectrometry, we identifymore than 200methyllysine sites in Giardia, including in species-specific gene families involved in cytoskeletal regulation, enriched in coiled-coil features. Finally, we use known methylation inhibitors to show that methylation plays key roles in replication and cyst formation in this parasite. This study highlights reduced methylation enzymes, sites, and functions early in eukaryote evolution, including absent methylarginine networks in the Diplomonadida. These results challenge the view that arginine methylation is eukaryote conserved and demonstrate that functional compensation of methylarginine was possible preceding expansion and diversification of these key networks in higher eukaryotes.
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| 6. |
- Sailer, Anna, et al.
(författare)
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A genome-wide association study in multiple system atrophy
- 2016
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Ingår i: Neurology. - 0028-3878. ; 87:15, s. 1591-1598
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To identify genetic variants that play a role in the pathogenesis of multiple system atrophy (MSA), we undertook a genome-wide association study (GWAS). Methods: We performed a GWAS with >5 million genotyped and imputed single nucleotide polymorphisms (SNPs) in 918 patients with MSA of European ancestry and 3,864 controls. MSA cases were collected from North American and European centers, one third of which were neuropathologically confirmed. Results: We found no significant loci after stringent multiple testing correction. A number of regions emerged as potentially interesting for follow-up at p < 1 × 10-6, including SNPs in the genes FBXO47, ELOVL7, EDN1, and MAPT. Contrary to previous reports, we found no association of the genes SNCA and COQ2 with MSA. Conclusions: We present a GWAS in MSA. We have identified several potentially interesting gene loci, including the MAPT locus, whose significance will have to be evaluated in a larger sample set. Common genetic variation in SNCA and COQ2 does not seem to be associated with MSA. In the future, additional samples of well-characterized patients with MSA will need to be collected to perform a larger MSA GWAS, but this initial study forms the basis for these next steps.
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| 7. |
- Ansell, Brendan R. E., et al.
(författare)
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Divergent Transcriptional Responses to Physiological and Xenobiotic Stress in Giardia duodenalis
- 2016
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Ingår i: Antimicrobial Agents and Chemotherapy. - 0066-4804 .- 1098-6596. ; 60:10, s. 6034-6045
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Tidskriftsartikel (refereegranskat)abstract
- Understanding how parasites respond to stress can help to identify essential biological processes. Giardia duodenalis is a parasitic protist that infects the human gastrointestinal tract and causes 200 to 300 million cases of diarrhea annually. Metronidazole, a major antigiardial drug, is thought to cause oxidative damage within the infective trophozoite form. However, treatment efficacy is suboptimal, due partly to metronidazole-resistant infections. To elucidate conserved and stress-specific responses, we calibrated sublethal metronidazole, hydrogen peroxide, and thermal stresses to exert approximately equal pressure on trophozoite growth and compared transcriptional responses after 24 h of exposure. We identified 252 genes that were differentially transcribed in response to all three stressors, including glycolytic and DNA repair enzymes, a mitogen-activated protein (MAP) kinase, high-cysteine membrane proteins, flavin adenine dinucleotide (FAD) synthetase, and histone modification enzymes. Transcriptional responses appeared to diverge according to physiological or xenobiotic stress. Downregulation of the antioxidant system and alpha-giardins was observed only under metronidazole-induced stress, whereas upregulation of GARP-like transcription factors and their subordinate genes was observed in response to hydrogen peroxide and thermal stressors. Limited evidence was found in support of stress-specific response elements upstream of differentially transcribed genes; however, antisense derepression and differential regulation of RNA interference machinery suggest multiple epigenetic mechanisms of transcriptional control.
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| 8. |
- Ansell, Brendan R. E., et al.
(författare)
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Drug resistance in Giardia duodenalis
- 2015
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Ingår i: Biotechnology Advances. - : Elsevier BV. - 0734-9750 .- 1873-1899. ; 33:6, s. 888-901
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Forskningsöversikt (refereegranskat)abstract
- Giardia duodenalis is a microaerophilic parasite of the human gastrointestinal tract and a major contributor to diarrheal and post-infectious chronic gastrointestinal disease world-wide. Treatment of G. duodenalis infection currently relies on a small number of drug classes. Nitroheterocyclics, in particular metronidazole, have represented the front line treatment for the last 40 years. Nitroheterocyclic-resistant G. duodenalis have been isolated from patients and created in vitro, prompting considerable research into the biomolecular mechanisms of resistance. These compounds are redox-active and are believed to damage proteins and DNA after being activated by oxidoreductase enzymes in metabolically active cells. In this review, we explore the molecular phenotypes of nitroheterocyclic-resistant G. duodenalis described to date in the context of the protisfs unusual glycolytic and antioxidant systems. We propose that resistance mechanisms are likely to extend well beyond currently described resistance-associated enzymes (i.e., pyruvate ferredoxin oxidoreductases and nitroreductases), to include NAD(P)H- and flavin-generating pathways, and possibly redox-sensitive epigenetic regulation. Mechanisms that allow G. duodenalis to tolerate oxidative stress may lead to resistance against both oxygen and nitroheterocyclics, with implications for clinical control. The present review highlights the potential for systems biology tools and advanced bioinformatics to further investigate the multifaceted mechanisms of nitroheterocyclic resistance in this important pathogen.
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| 9. |
- Ansell, Brendan R. E., et al.
(författare)
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Time-Dependent Transcriptional Changes in Axenic Giardia duodenalis Trophozoites
- 2015
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Ingår i: PLoS Neglected Tropical Diseases. - : Public Library of Science (PLoS). - 1935-2727 .- 1935-2735. ; 9:12
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Tidskriftsartikel (refereegranskat)abstract
- Giardia duodenalis is the most common gastrointestinal protozoan parasite of humans and a significant contributor to the global burden of both diarrheal disease and post-infectious chronic disorders. Although G. duodenalis can be cultured axenically, significant gaps exist in our understanding of the molecular biology and metabolism of this pathogen. The present study employed RNA sequencing to characterize the mRNA transcriptome of G. duodenalis trophozoites in axenic culture, at log (48 h of growth), stationary (60 h), and declining (96 h) growth phases. Using similar to 400-times coverage of the transcriptome, we identified 754 differentially transcribed genes (DTGs), mainly representing two large DTG groups: 438 that were down-regulated in the declining phase relative to log and stationary phases, and 281 that were up-regulated. Differential transcription of prominent antioxidant and glycolytic enzymes implicated oxygen tension as a key factor influencing the transcriptional program of axenic trophozoites. Systematic bioinformatic characterization of numerous DTGs encoding hypothetical proteins of unknown function was achieved using structural homology searching. This powerful approach greatly informed the differential transcription analysis and revealed putative novel antioxidant-coding genes, and the presence of a nearcomplete two-component-like signaling system that may link cytosolic redox or metabolite sensing to the observed transcriptional changes. Motif searching applied to promoter regions of the two large DTG groups identified different putative transcription factor-binding motifs that may underpin global transcriptional regulation. This study provides new insights into the drivers and potential mediators of transcriptional variation in axenic G. duodenalis and provides context for static transcriptional studies.
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| 10. |
- Ansell, Brendan R. E., et al.
(författare)
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Transcriptomics Indicates Active and Passive Metronidazole Resistance Mechanisms in Three Seminal Giardia Lines
- 2017
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Ingår i: Frontiers in Microbiology. - : Frontiers Media SA. - 1664-302X. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- Giardia duodenalis is an intestinal parasite that causes 200-300 million episodes of diarrhoea annually. Metronidazole (Mtz) is a front-line anti-giardial, but treatment failure is common and clinical resistance has been demonstrated. Mtz is thought to be activated within the parasite by oxidoreductase enzymes, and to kill by causing oxidative damage. In G. duodenalis, Mtz resistance involves active and passive mechanisms. Relatively low activity of iron-sulfur binding proteins, namely pyruvate: ferredoxin oxidoreductase (PFOR), ferredoxins, and nitroreductase-1, enable resistant cells to passively avoid Mtz activation. Additionally, low expression of oxygen-detoxification enzymes can allow passive (non-enzymatic) Mtz detoxification via futile redox cycling. In contrast, active resistance mechanisms include complete enzymatic detoxification of the pro-drug by nitroreductase-2 and enhanced repair of oxidized biomolecules via thioredoxin-dependent antioxidant enzymes. Molecular resistance mechanisms may be largely founded on reversible transcriptional changes, as some resistant lines revert to drug sensitivity during drug-free culture in vitro, or passage through the life cycle. To comprehensively characterize these changes, we undertook strand-specific RNA sequencing of three laboratory-derived Mtz-resistant lines, 106-2ID(10), 713-M3, and WB-M3, and compared transcription relative to their susceptible parents. Common up-regulated genes encoded variant-specific surface proteins (VSPs), a high cysteine membrane protein, calcium and zinc channels, a Mad-2 cell cycle regulator and a putative fatty acid a alpha-oxidase. Down-regulated genes included nitroreductase-1, putative chromate and quinone reductases, and numerous genes that act proximal to PFOR. Transcriptional changes in 106-2ID(10) diverged from those in 713-r and WB-r (r <= 0.2), which were more similar to each other (r = 0.47). In 106-2ID(10), a nonsense mutation in nitroreductase-1 transcripts could enhance passive resistance whereas increased transcription of nitroreductase-2, and a MATE transmembrane pump system, suggest active drug detoxification and efflux, respectively. By contrast, transcriptional changes in 713-M3 and WB-M3 indicated a higher oxidative stress load, attributed to Mtz- and oxygen-derived radicals, respectively. Quantitative comparisons of orthologous gene transcription between Mtz-resistant G. duodenalis and Trichomonas vaginalis, a closely related parasite, revealed changes in transcripts encoding peroxidases, heat shock proteins, and FMN-binding oxidoreductases, as prominent correlates of resistance. This work provides deep insight into Mtz-resistant G. duodenalis, and illuminates resistance-associated features across parasitic species.
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| 11. |
- Bedran, Georges, et al.
(författare)
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The Immunopeptidome from a Genomic Perspective : Establishing the Noncanonical Landscape of MHC Class I–Associated Peptides
- 2023
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Ingår i: Cancer immunology research. - 2326-6066. ; 11:6, s. 742-762
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Tidskriftsartikel (refereegranskat)abstract
- Tumor antigens can emerge through multiple mechanisms, including translation of noncoding genomic regions. This noncanonical category of tumor antigens has recently gained attention; however, our understanding of how they recur within and between cancer types is still in its infancy. Therefore, we developed a proteogenomic pipeline based on deep learning de novo mass spectrometry (MS) to enable the discovery of noncanonical MHC class I–associated peptides (ncMAP) from noncoding regions. Considering that the emergence of tumor antigens can also involve posttranslational modifications (PTM), we included an open search component in our pipeline. Leveraging the wealth of MS-based immunopeptidomics, we analyzed data from 26 MHC class I immunopeptidomic studies across 11 different cancer types. We validated the de novo identified ncMAPs, along with the most abundant PTMs, using spectral matching and controlled their FDR to 1%. The noncanonical presentation appeared to be 5 times enriched for the A03 HLA supertype, with a projected population coverage of 55%. The data reveal an atlas of 8,601 ncMAPs with varying levels of cancer selectivity and suggest 17 cancer-selective ncMAPs as attractive therapeutic targets according to a stringent cutoff. In summary, the combination of the open-source pipeline and the atlas of ncMAPs reported herein could facilitate the identification and screening of ncMAPs as targets for T-cell therapies or vaccine development.
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| 12. |
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| 13. |
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| 14. |
- Geser, F, et al.
(författare)
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The European Multiple System Atrophy-Study Group (EMSA-SG)
- 2005
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Ingår i: Journal of Neural Transmission. - : Springer Science and Business Media LLC. - 0300-9564 .- 1435-1463. ; 112:12, s. 1677-1686
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Tidskriftsartikel (refereegranskat)abstract
- Introduction. The European Multiple System Atrophy-Study Group (EMSA-SG) is an academic network comprising 23 centers across Europe and Israel that has constituted itself already in January 1999. This international forum of established experts under the guidance of the University Hospital of Innsbruck as coordinating center is supported by the 5th framework program of the European Union since March 2001 (QLK6-CT-2000-00661). Objectives. Primary goals of the network include (1) a central Registry for European multiple system atrophy (MSA) patients, (2) a decentralized DNA Bank, (3) the development and validation of the novel Unified MSA Rating Scale (UMSARS), (4) the conduction of a Natural History Study (NHS), and (5) the planning or implementation of interventional therapeutic trials. Methods. The EMSA-SG Registry is a computerized data bank localized at the coordinating centre in Innsbruck collecting diagnostic and therapeutic data of MSA patients. Blood samples of patients and controls are recruited into the DNA Bank. The UMSARS is a novel specific rating instrument that has been developed and validated by the EMSA-SG. The NHS comprises assessments of basic anthropometric data as well as a range of scales including the UMSARS, Unified Parkinson's Disease Rating Scale (UPDRS), measures of global disability, Red Flag list, MMSE (Mini Mental State Examination), quality of live measures, i.e. EuroQoL 5D (EQ-5D) and Medical Outcome Study Short Form (SF-36) as well as the Beck Depression Inventory (BDI). In a subgroup of patients dysautonomic features are recorded in detail using the Queen Square Cardiovascular Autonomic Function Test Battery, the Composite Autonomic Symptom Scale (COMPASS) and measurements of residual urinary volume. Most of these measures are repeated at 6-monthly follow up visits for a total study period of 24 months. Surrogate markers of the disease progression are identified by the EMSA-SG using magnetic resonance and diffusion weighted imaging (MRI and DWI, respectively). Results. 412 patients have been recruited into the Registry so far. Probable MSA-P was the most common diagnosis (49% of cases). 507 patients donated DNA for research. 131 patients have been recruited into the NHS. There was a rapid deterioration of the motor disorder (in particular akinesia) by 26.1% of the UMSARS II, and - to a lesser degree - of activities of daily living by 16.8% of the UMSARS I in relation to the respective baseline scores. Motor progression was associated with low motor or global disability as well as low akinesia or cerebellar subscores at baseline. Mental function did not deteriorate during this short follow up period. Conclusion. For the first time, prospective data concerning disease progression are available. Such data about the natural history and prognosis of MSA as well as surrogate markers of disease process allow planning and implementation of multi-centre phase II/III neuroprotective intervention trials within the next years more effectively. Indeed, a trial on growth hormone in MSA has just been completed, and another on minocycline will be completed by the end of this year.
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| 15. |
- Hansen, Eline P., et al.
(författare)
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Exploration of extracellular vesicles from Ascaris suum provides evidence of parasite-host cross talk
- 2019
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Ingår i: Journal of Extracellular Vesicles. - : Wiley. - 2001-3078. ; 8:1
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Tidskriftsartikel (refereegranskat)abstract
- The prevalent porcine helminth, Ascaris suum, compromises pig health and reduces farm productivity worldwide. The closely related human parasite, A. lumbricoides, infects more than 800 million people representing a disease burden of 1.31 million disability-adjusted life years. The infections are often chronic in nature, and the parasites have a profound ability to modulate their hosts' immune responses. This study provides the first in-depth characterisation of extracellular vesicles (EVs) from different developmental stages and body parts of A. suum and proposes the role of these vesicles in the host-parasite interplay. The release of EVs from the third- (L3) and fourth-stage (L4) larvae and adults was demonstrated by transmission electron microscopy (TEM), and sequencing of EV-derived RNA identified a number of microRNAs (miRNAs) and transcripts of potential host immune targets, such as IL-13, IL-25 and IL-33, were identified. Furthermore, proteomics of EVs identified several proteins with immunomodulatory properties and other proteins previously shown to be associated with parasite EVs. Taken together, these results suggest that A. suum EVs and their cargo may play a role in host-parasite interactions. This knowledge may pave the way to novel strategies for helminth infection control and knowledge of their immune modulatory potential.
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| 16. |
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| 17. |
- Polzer, S., et al.
(författare)
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Automatic identification and validation of planar collagen organization in the aorta wall with application to abdominal aortic aneurysm
- 2013
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Ingår i: Microscopy and Microanalysis. - 1431-9276 .- 1435-8115. ; 19:6, s. 1395-1404
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Tidskriftsartikel (refereegranskat)abstract
- Arterial physiology relies on a delicate three-dimensional (3D) organization of cells and extracellular matrix, which is remarkably altered by vascular diseases like abdominal aortic aneurysms (AAA). The ability to explore the micro-histology of the aorta wall is important in the study of vascular pathologies and in the development of vascular constitutive models, i.e., mathematical descriptions of biomechanical properties of the wall. The present study reports and validates a fast image processing sequence capable of quantifying collagen fiber organization from histological stains. Powering and re-normalizing the histogram of the classical fast Fourier transformation (FFT) is a key step in the proposed analysis sequence. This modification introduces a powering parameter w, which was calibrated to best fit the reference data obtained using classical FFT and polarized light microscopy (PLM) of stained histological slices of AAA wall samples. The values of w = 3 and 7 give the best correlation (Pearson's correlation coefficient larger than 0.7, R 2 about 0.7) with the classical FFT approach and PLM measurements. A fast and operator independent method to identify collagen organization in the arterial wall was developed and validated. This overcomes severe limitations of currently applied methods like PLM to identify collagen organization in the arterial wall.
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| 18. |
- Polzer, S., et al.
(författare)
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Importance of material model in wall stress prediction in abdominal aortic aneurysms
- 2013
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Ingår i: Medical Engineering and Physics. - : Elsevier BV. - 1350-4533 .- 1873-4030. ; 35:9, s. 1282-1289
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Tidskriftsartikel (refereegranskat)abstract
- Background: Results of biomechanical simulation of the abdominal aortic aneurysm (AAA) depend on the constitutive description of the wall. Based on in vitro and in vivo experimental data several constitutive models for the AAA wall have been proposed in the literature. Those models differ strongly from each other and their impact on the computed stress in biomechanical simulation is not clearly understood. Methods: Finite element (FE) models of AAAs from 7 patients who underwent elective surgical repair were used to compute wall stresses. AAA geometry was reconstructed from CT angiography (CT-A) data and patient-specific (PS) constitutive descriptions of the wall were derived from planar biaxial testing of anterior wall tissue samples. In total 28 FE models were used, where the wall was described by either patient-specific or previously reported study-average properties. This data was derived from either uniaxial or biaxial in vitro testing. Computed wall stress fields were compared on node-by-node basis. Results: Different constitutive models for the AAA wall cause significantly different predictions of wall stress. While study-average data from biaxial testing gives globally the same stress field as the patient-specific wall properties, the material model based on uniaxial test data overestimates the wall stress on average by 30. kPa or about 67% of the mean stress. A quasi-linear description based on the in vivo measured distensibility of the AAA wall leads to a completely altered stress field and overestimates the wall stress by about 75. kPa or about 167% of the mean stress. Conclusion: The present study demonstrated that the constitutive description of the wall is crucial for AAA wall stress prediction. Consequently, results obtained using different models should not be mutually compared unless different stress gradients across the wall are not taken into account. Highly nonlinear material models should be preferred when the response of AAA to increased blood pressure is investigated, while the quasi-linear model with high initial stiffness produces negligible stress gradients across the wall and thus, it is more appropriate when response to mean blood pressure is calculated.
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| 19. |
- Rowbotham, S. E., et al.
(författare)
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Inositol in the MAnaGemENt of abdominal aortic aneurysm (IMAGEN) : Study protocol for a randomised controlled trial
- 2017
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Ingår i: Trials. - : BioMed Central Ltd.. - 1745-6215. ; 18:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: An abdominal aortic aneurysm (AAA) is a focal dilation of the abdominal aorta and is associated with a risk of fatal rupture. Experimental studies suggest that myo-inositol may exert beneficial effects on AAAs through favourable changes to biological pathways implicated in AAA pathology. The aim of the Inositol in the MAnaGemENt of abdominal aortic aneurysm (IMAGEN) trial is to assess if myo-inositol will reduce AAA growth. Methods/design: IMAGEN is a multi-centre, prospective, parallel-group, randomised, double-blind, placebo-controlled trial. A total of 164 participants with an AAA measuring ≥ 30 mm will be randomised to either 2 g of myo-inositol or identical placebo twice daily for 12 months. The primary outcome measure will be AAA growth estimated by increase in total infrarenal aortic volume measured on computed tomographic scans. Secondary outcome measures will include AAA diameter assessed by computed tomography and ultrasound, AAA peak wall stress and peak wall rupture index, serum lipids, circulating AAA biomarkers, circulating RNAs and health-related quality of life. All analysis will be based on the intention-to-treat principle at the time of randomisation. All patients who meet the eligibility criteria, provide written informed consent and are enrolled in the study will be included in the primary analysis, regardless of adherence to dietary allocation. Discussion: Currently, there is no known medical therapy to limit AAA progression. The IMAGEN trial will be the first randomised trial, to our knowledge, to assess the value of myo-inositol in limiting AAA growth.
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| 20. |
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| 21. |
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| 22. |
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| 23. |
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| 24. |
- van Es, Michael A, et al.
(author)
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Angiogenin variants in Parkinson disease and amyotrophic lateral sclerosis
- 2011
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In: Annals of Neurology. - : Wiley-Blackwell. - 0364-5134 .- 1531-8249. ; 70:6, s. 964-973
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Journal article (peer-reviewed)abstract
- OBJECTIVE: Several studies have suggested an increased frequency of variants in the gene encoding angiogenin (ANG) in patients with amyotrophic lateral sclerosis (ALS). Interestingly, a few ALS patients carrying ANG variants also showed signs of Parkinson disease (PD). Furthermore, relatives of ALS patients have an increased risk to develop PD, and the prevalence of concomitant motor neuron disease in PD is higher than expected based on chance occurrence. We therefore investigated whether ANG variants could predispose to both ALS and PD.METHODS: We reviewed all previous studies on ANG in ALS and performed sequence experiments on additional samples, which allowed us to analyze data from 6,471 ALS patients and 7,668 controls from 15 centers (13 from Europe and 2 from the USA). We sequenced DNA samples from 3,146 PD patients from 6 centers (5 from Europe and 1 from the USA). Statistical analysis was performed using the variable threshold test, and the Mantel-Haenszel procedure was used to estimate odds ratios.RESULTS: Analysis of sequence data from 17,258 individuals demonstrated a significantly higher frequency of ANG variants in both ALS and PD patients compared to control subjects (p = 9.3 × 10(-6) for ALS and p = 4.3 × 10(-5) for PD). The odds ratio for any ANG variant in patients versus controls was 9.2 for ALS and 6.7 for PD.INTERPRETATION: The data from this multicenter study demonstrate that there is a strong association between PD, ALS, and ANG variants. ANG is a genetic link between ALS and PD.
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| 25. |
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| 26. |
- Auer, Martin, et al.
(author)
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Automatic Displacement and Strain measuring in the Aorta from dynamic electrocardiographically-gated Computed Tomographic Angiography
- 2010
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Conference paper (peer-reviewed)abstract
- Introduction Image modalities like Duplex Ultrasound, Transesophageal Echocardiography, Intravascular Ultrasound, Computed Tomography and Magnetic Resonance provide vascular interventionists and surgeons with useful diagnostic information for treatment planning. Recent developments in cross-sectional imaging, including multi-modality image fusion and new contrast agents have resulted in improved spatial resolution. Specifically, dynamic Electrocardiographically-Gated Computed Tomographic Angiography (ECG-gated CTA) provides valuable information regarding motion and deformation of the normal and diseased aorta during the cardiac cycle. Extracting and presenting (visualization) of accurate quantitative information from the recorded image data, however remains a challenging task of image post processing. Method The algorithm proposed within this paper processes ECG-gated CTA data (here goes the scanner model and manufacturer) in DICOM (digital imaging and communication in medicine) format, within which the user manually defines an Eulerian Region of Interest (ROI). 2D deformable (active) contour models are used to pre-segment the luminal surfaces of the selected vessels at an arbitrary time point during the cardiac cycle. A tessellation algorithm is used to define the initial configuration of a 3D deformable (active) contour model, which in turn is used for the final segmentation of the luminal surfaces continuously during the cardiac cycle. Specifically, Finite Element (FE) formulations [1] for frames and shells, as known from structural mechanics, are used to define the deformable contour modes. This allows a direct mechanical interpretation of the applied set of reconstruction parameters and leads to an efficient FE implementation of the models [2]; parallel processor architecture is used to solve the global set of non-linear FE equations. Finally displacement and strain measures are derived from the dynamic segmentations and color coded plots are used to visualize them. Results and Conclusions The clinical relevance of dynamic imaging has not been fully exploited and accurate and fast image processing tools are critical to extract valuable information from ECG-gated CTA data. Such information is not only of direct clinical relevance but also critical to process our current understanding regarding normal and pathological aortic motions and deformations. The image processing concept proposed in this paper leads to efficient and clinically applicable software that facilitates an analysis of the entire aorta on a standard Personal Computer within a few minutes. Deformable (active) contour models are known to be more accurate compared to threshold based segmentation concepts [3] and the accuracy of the present approach is in the range of the in-plane image resolution. Apart from direct diagnostic information the extracted geometrical data could also be used (once enriched by accurate pressure measurements) for none invasive (minimal invasive) estimation of biomechanical aortic tissue properties. References [1] O. C. Zienkiewicz and R. L. Taylor, vol.1,2, 5th ed. Oxford: Butterworth Heinemann, 2000. [2] M. Auer and T. C. Gasser, IEEE T. Med. Imaging, 2010 (in press). [3] M. Sonka and J. M. Fitzpatrick, editors., Bellingham: Spie press, 2000
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- Gasser, T. Christian, et al.
(author)
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Hyperelastic modelling of arterial layers with distributed collagen fibre orientations
- 2006
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In: Journal of the Royal Society Interface. - : The Royal Society. - 1742-5689 .- 1742-5662. ; 3:6, s. 15-35
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Research review (peer-reviewed)abstract
- Constitutive relations are fundamental to the solution of problems in continuum mechanics, and are required in the study of, for example, mechanically dominated clinical interventions involving soft biological tissues. Structural continuum constitutive models of arterial layers integrate information about the tissue morphology and therefore allow investigation of the interrelation between structure and function in response to mechanical loading. Collagen fibres are key ingredients in the structure of arteries. In the media (the middle layer of the artery wall) they are arranged in two helically distributed families with a small pitch and very little dispersion in their orientation (i.e. they are aligned quite close to the circumferential direction). By contrast, in the adventitial and intimal layers, the orientation of the collagen fibres is dispersed, as shown by polarized light microscopy of stained arterial tissue. As a result, continuum models that do not account for the dispersion are not able to capture accurately the stress-strain response of these layers. The purpose of this paper, therefore, is to develop a structural continuum framework that is able to represent the dispersion of the collagen fibre orientation. This then allows the development of a new hyperelastic free-energy function that is particularly suited for representing the anisotropic elastic properties of adventitial and intimal layers of arterial walls, and is a generalization of the fibre-reinforced structural model introduced by Holzapfel & Gasser (Holzapfel & Gasser 2001 Comput. Meth. Appl. Mech. Eng. 190, 4379-4403) and Holzapfel et al. (Holzapfel et al. 2000 J. Elast. 61, 1-48). The model incorporates an additional scalar structure parameter that characterizes the dispersed collagen orientation. An efficient finite element implementation of the model is then presented and numerical examples show that the dispersion of the orientation of collagen fibres in the adventitia of human iliac arteries has a significant effect on their mechanical response.
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- Grover, Sandeep, et al.
(author)
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Replication of a Novel Parkinson's Locus in a European Ancestry Population
- 2021
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In: Movement Disorders. - : Wiley. - 0885-3185 .- 1531-8257. ; 36:7, s. 1689-1695
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Journal article (peer-reviewed)abstract
- BACKGROUND: A recently published East Asian genome-wide association study of Parkinson;s disease (PD) reported 2 novel risk loci, SV2C and WBSCR17.OBJECTIVES: The objective of this study were to determine whether recently reported novel SV2C and WBSCR17 loci contribute to the risk of developing PD in European and East Asian ancestry populations.METHODS: We report an association analysis of recently reported variants with PD in the COURAGE-PD cohort (9673 PD patients; 8465 controls) comprising individuals of European and East Asian ancestries. In addition, publicly available summary data (41,386 PD patients; 476,428 controls) were pooled.RESULTS: Our findings confirmed the role of the SV2C variant in PD pathogenesis (rs246814, COURAGE-PD PEuropean = 6.64 × 10-4 , pooled PD P = 1.15 × 10-11 ). The WBSCR17 rs9638616 was observed as a significant risk marker in the East Asian pooled population only (P = 1.16 × 10-8 ).CONCLUSIONS: Our comprehensive study provides an up-to-date summary of recently detected novel loci in different PD populations and confirmed the role of SV2C locus as a novel risk factor for PD irrespective of the population or ethnic group analyzed. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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- Holzapfel, Gerhard A., et al.
(author)
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A new constitutive framework for arterial wall mechanics and a comparative study of material models
- 2000
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In: Journal of elasticity. - 0374-3535 .- 1573-2681. ; 61:03-jan, s. 1-48
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Journal article (peer-reviewed)abstract
- In this paper we develop a new constitutive law for the description of the (passive) mechanical response of arterial tissue. The artery is modeled as a thick-walled nonlinearly elastic circular cylindrical tube consisting of two layers corresponding to the media and adventitia (the solid mechanically relevant layers in healthy tissue). Each layer is treated as a fiber-reinforced material with the fibers corresponding to the collagenous component of the material and symmetrically disposed with respect to the cylinder axis. The resulting constitutive law is orthotropic in each layer. Fiber orientations obtained from a statistical analysis of histological sections from each arterial layer are used. A specific form of the law, which requires only three material parameters for each layer, is used to study the response of an artery under combined axial extension, inflation and torsion. The characteristic and very important residual stress in an artery in vitro is accounted for by assuming that the natural (unstressed and unstrained) configuration of the material corresponds to an open sector of a tube, which is then closed by an initial bending to form a load-free, but stressed, circular cylindrical configuration prior to application of the extension, inflation and torsion. The effect of residual stress on the stress distribution through the deformed arterial wall in the physiological state is examined. The model is fitted to available data on arteries and its predictions are assessed for the considered combined loadings. It is explained how the new model is designed to avoid certain mechanical, mathematical and computational deficiencies evident in currently available phenomenological models. A critical review of these models is provided by way of background to the development of the new model.
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| 38. |
- Holzapfel, Gerhard A., et al.
(author)
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Comparison of a multi-layer structural model for arterial walls with a fung-type model, and issues of material stability
- 2004
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In: Journal of Biomechanical Engineering. - : ASME International. - 0148-0731 .- 1528-8951. ; 126:2, s. 264-275
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Journal article (peer-reviewed)abstract
- The goals of this paper are (i) to re-examine the constitutive law for the description of the (passive) highly nonlinear and anisotropic response of healthy elastic arteries introduced recently by the authors, (ii) to show how the mechanical response of a carotid artery under inflation and extension predicted by the structural model compares with that for a three-dimensional form of Fung-type strain-energy function, (iii) to provide a new set of material parameters that can be used in a finite element program, and (iv) to show that the model has certain mathematical features that are important from the point of view of material and numerical stability.
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- Khosla, S., et al.
(author)
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Meta-analysis of peak wall stress in ruptured, symptomatic and intact abdominal aortic aneurysms
- 2014
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In: British Journal of Surgery. - : Oxford University Press (OUP). - 0007-1323 .- 1365-2168. ; 101:11, s. 1350-1357
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Research review (peer-reviewed)abstract
- Background: Abdominal aortic aneurysm (AAA) is an important cause of sudden death; however, there are currently incomplete means to predict the risk of AAA rupture. AAA peak wall stress (PWS) can be estimated using finite element analysis (FEA) methods from computed tomography (CT) scans. The question is whether AAA PWS can predict AAA rupture. The aim of this systematic review was to compare PWS in patients with ruptured and intact AAA. Methods: The MEDLINE database was searched on 25 May 2013. Case-control studies assessing PWS in asymptomatic intact, and acutely symptomatic or ruptured AAA from CT scans using FEA were included. Data were extracted independently. A random-effects model was used to calculate standard mean differences (SMDs) for PWS measurements. Results: Nine studies assessing 348 individuals were identified and used in the meta-analysis. Results from 204 asymptomatic intact and 144 symptomatic or ruptured AAAs showed that PWS was significantly greater in the symptomatic/ruptured AAAs compared with the asymptomatic intact AAAs (SMD 0.95, 95 per cent confidence interval 0. 71 to 1.18; P < 0. 001). The findings remained significant after adjustment for mean systolic blood pressure, standardized at 120 mmHg(SMD 0.68, 0.39 to 0.96; P < 0. 001). Minimal heterogeneity between studies was noted (I-2 = 0 per cent). Conclusion: This study suggests that PWS is greater in symptomatic or ruptured AAA than in asymptomatic intact AAA.
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- Lindquist Liljeqvist, M., et al.
(author)
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Volume growth of abdominal aortic aneurysms correlates with baseline volume and increasing finite element analysis-derived rupture risk
- 2016
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In: Journal of Vascular Surgery. - : Elsevier. - 0741-5214 .- 1097-6809. ; 63:6, s. 1434-1442
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Journal article (peer-reviewed)abstract
- Background: The diagnosis and management of abdominal aortic aneurysms (AAAs) currently relies on the aortic maximal diameter, which grows in an unpredictable manner. Infrarenal aortic volume has recently become clinically feasible to measure, and an estimate of biomechanical rupture risk derived from finite element analysis, the peak wall rupture index (PWRI), has been shown to predict AAA rupture. Our objective was to ascertain how well volume growth correlates with baseline volume and increasing PWRI, compared with the maximal diameter. Methods: We retrospectively identified 41 AAA patients (nine women, 32 men) at our institution who had undergone two computed tomography angiographies with an interval of 8 to 17 months. Digital three-dimensional reproductions of the aneurysms were segmented from the 82 computed tomography angiographies. AAA diameter, volume, and PWRI were measured and calculated with finite element analysis software. Growth rates of diameter and volume were related to baseline diameter and volume as well as to change rates of PWRI. Significant growth was defined as growth exceeding our interobserver 95% limits of agreement. Results: Diameter growth rate did not correlate with baseline diameter (r = 0.15, 95% confidence interval [CI], -0.17 to 0.45), but volume growth rate correlated with baseline volume (r = 0.56; 95% CI, 0.30-0.75). The correlation between baseline volume and volume growth rate was stronger than the correlation between baseline diameter and diameter growth rate (95% CI, 0.086-0.71). Increasing PWRI correlated with volume growth rate (r = 0.70; 95% CI, 0.40-0.87) but not with diameter growth rate (r = 0.044; 95% CI, -0.44 to 0.51), and the difference between the correlation coefficients was significant (95% CI, 0.11-1.16). Conclusions: Volume better predicts aneurysm growth rate and correlates stronger with increasing estimated biomechanical rupture risk compared with diameter. Our results support the notion of monitoring all three dimensions of an AAA.
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