| 1. |
- 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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| 2. |
- Kamm, C, et al.
(författare)
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The fragile X tremor ataxia syndrome in the differential diagnosis of multiple system atrophy: data from the EMSA Study Group
- 2005
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Ingår i: Brain. - : Oxford University Press (OUP). - 1460-2156 .- 0006-8950. ; 128:8, s. 1855-1860
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Tidskriftsartikel (refereegranskat)abstract
- The recent identification of fragile X-associated tremor ataxia syndrome (FXTAS) associated with premutations in the FMR1 gene and the possibility of clinical overlap with multiple system atrophy (MSA) has raised important questions, such as whether genetic testing for FXTAS should be performed routinely in MSA and whether positive cases might affect the specificity of current MSA diagnostic criteria. We genotyped 507 patients with clinically diagnosed or pathologically proven MSA for FMR1 repeat length. Among the 426 clinically diagnosed cases, we identified four patients carrying FMR1 premutations (0.94%). Within the subgroup of patients with probable MSA-C, three of 76 patients (3.95%) carried premutations. We identified no premutation carriers among 81 patients with pathologically proven MSA and only one carrier among 622 controls (0.16%). Our results suggest that, with proper application of current diagnostic criteria, FXTAS is very unlikely to be confused with MSA. However, slowly progressive disease or predominant tremor are useful red flags and should prompt the consideration of FXTAS. On the basis of our data, the EMSA Study Group does not recommend routine FMR1 genotyping in typical MSA patients.
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| 3. |
- Fuchs, J, et al.
(författare)
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Phenotypic variation in a large Swedish pedigree due to SNCA duplication and triplication.
- 2007
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Ingår i: Neurology. - : Ovid Technologies (Wolters Kluwer Health). - 1526-632X .- 0028-3878. ; 68:12, s. 916-922
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Tidskriftsartikel (refereegranskat)abstract
- Background: The " Lister family complex," an extensive Swedish family with autosomal dominant Parkinson disease, was first described by Henry Mjones in 1949. On the basis of clinical, molecular, and genealogic findings on a Swedish and an American family branch, we provide genetic evidence that explains the parkinsonism in this extended pedigree. Methods: Clinical methods included a detailed neurologic exam of the proband of the Swedish family branch, MRI, and ([ 123] I) - beta - CIT SPECT imaging. Genomic analysis included alpha-synuclein sequencing, SNCA real-time PCR dosage, chromosome 4q21 microsatellite analysis, and high-resolution microarray genotyping. The geographic origin and ancestral genealogy of each pedigree were researched in the medical literature and Swedish Parish records. Results: The proband of the Swedish family branch presented with early dysautonomia followed by progressive parkinsonism suggestive of multiple system atrophy. Molecular analysis identified a genomic duplication of < 0.9 Mb encompassing alpha-synuclein and multimerin 1 ( SNCA- MMRN1), flanked by long interspersed repeat sequences ( LINE L1). Microsatellite variability within the genomic interval was identical to that previously described for a Swedish American family with an alpha- synuclein triplication. Subsequent genealogic investigation suggested that both kindreds are ancestrally related to the Lister family complex. Conclusion: Our findings extend clinical, genetic, and genealogical research on the Lister family complex. The genetic basis for familial parkinsonism is an SNCA- MMRN11 multiplication, but whereas SNCA- MMRN1 duplication in the Swedish proband ( Branch J) leads to late- onset autonomic dysfunction and parkinsonism, SNCA- MMRN1 triplication in the Swedish American family ( Branch I) leads to early- onset Parkinson disease and dementia.
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| 4. |
- Gasser, T. Christian, et al.
(författare)
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3D Crack propagation in unreinforced concrete. A two-step algorithm for tracking 3D crack paths
- 2006
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Ingår i: Computer Methods in Applied Mechanics and Engineering. - : Elsevier BV. - 0045-7825 .- 1879-2138. ; 195:37-40, s. 5198-5219
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Tidskriftsartikel (refereegranskat)abstract
- Tensile failure of unreinforced concrete involves progressive micro-cracking, and the related strain-softening can coalesce into geometrical discontinuities, which separate the material. Advanced mechanical theories and numerical schemes are required to efficiently and adequately represent crack propagation in 3D. In this paper we use the concept of strong discontinuities to model concrete failure. We introduce a cohesive fracture process zone, which is characterized by a transversely isotropic traction-separation law. We combine the cohesive crack concept with the partition of unity finite element method, where the finite element space is enhanced by the Heaviside function. The concept is implemented for tetrahedral elements and the failure initialization is based on the simple (non-local) Rankine criterion. For each element we assume the embedded discontinuity to be flat in the reference configuration, which leads to a non-smooth crack surfaces approximation in 3D, in general; different concepts for tracking non-planar cracks in 3D are reviewed. In addition, we propose a two-step algorithm for tracking the crack path, where a predictor step defines discontinuities according to the (non-local) failure criterion and a corrector step draws in non-local information of the existing discontinuities in order to predict a 'closed' 3D crack surface; implementation details are provided. The proposed framework is used to analyze the predictability of concrete failure by two benchmark examples, i.e. the Nooru-Moharned test, and the Brokenshire test. We compare our numerical results, which are mesh independent, with experimental data and numerical results adopted from the literature.
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| 5. |
- Gasser, T. Christian, et al.
(författare)
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A numerical framework to model 3-D fracture in bone tissue with application to failure of the proximal femur
- 2007
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Ingår i: IUTAM SYMPOSIUM ON DISCRETIZATION METHODS FOR EVOLVING DISCONTINUITIES. - DORDRECHT : SPRINGER. - 9781402065293 ; , s. 199-211
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Konferensbidrag (refereegranskat)abstract
- Bone can be regarded as a quasi-brittle material. Under excessive loading nonlinear fracture zones may occur ahead the crack tips, where, typically, cohesive mechanisms are activated. The finite element method provides a powerful tool to analyze fracture formations on a numerical basis, and to better understand failure mechanisms within complex structures. The present work aims to introduce a particular numerical framework to investigate bone failure. We combine the partition of unity finite element method with the cohesive crack concept, and a two-step predictor-corrector algorithm for tracking 3-D non-interacting crack paths. This approach renders a numerically efficient tool that is able to capture the strong discontinuity kinematics in an accurate way. The prediction of failure propagation in the proximal part of the femur under compressive load demonstrates the suitability of the proposed concept. A 3-D finite element model, which accounts for inhomogeneous fracture properties, was used for the prediction of the 3-D crack surface. The achieved computational results were compared with experimental data available in the literature.
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| 6. |
- Gasser, T. Christian, et al.
(författare)
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Failure mechanisms of ventricular tissue due to deep penetration
- 2009
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Ingår i: Journal of Biomechanics. - : Elsevier BV. - 0021-9290 .- 1873-2380. ; 42:5, s. 626-633
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Tidskriftsartikel (refereegranskat)abstract
- Lead perforation is a rare but serious complication of pacemaker implantations, and in the present study the associated tissue failure was investigated by means of in-vitro penetration of porcine and bovine ventricular tissue. Rectangular patches from the right ventricular free wall and the interventricular were separated, bi-axially stretched and immersed in physiological salt solution at 37 C before load displacement curves of m total 891 penetrations were recorded. To this end flat-bottomed cylindrical punches of different diameters were used, and following mechanical testing the penetration were histological analyzed using light and electron microscopes. Penetration pressure, i.e. penetration force divided by punch cross-sectional area decreased slightly from 2.27(SD 0.66) to 1.76 (SD 0.46) N mm(2) for punches of 1.32 to 2.30 mm in diameter, respectively. Deep penetration formed cleavages aligned with the local fiber orientation of the tissue, and hence, a mode-I crack developed, where the crack faces were wedged open by the advancing punch. The performed study derived novel failure data from ventricular tissue due to deep penetration and uncovered associated failure mechanisms. This provides information to derive mechanical failure models, which are essential to enrich our current understanding of failure of soft biological tissues and to guide medical device development.
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| 7. |
- Gasser, T. Christian, et al.
(författare)
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Failure properties of intraluminal thrombus in abdominal aortic aneurysm under static and pulsating mechanical loads
- 2008
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Ingår i: Journal of Vascular Surgery. - : Elsevier BV. - 0741-5214 .- 1097-6809. ; 48:1, s. 179-188
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: It has been suggested that mechanical failure of intraluminal thrombus (ILT) could play a key role in the rupture of abdominal aortic aneurysms (AAAs), and in the present study, this hypothesis has been investigated. An in vitro experimental approach has been proposed, which provides layer-specific failure data of ILT tissue under static and pulsatile mechanical loads. Methods. In total, 112 bone-shaped test specimens are prepared from luminal, medial, and abluminal layers of eight ILTs harvested during open elective AAA repair. Three different types of mechanical experiments, denoted as control test, ultimate strength test, and fatigue test were performed in Dulbecco's modified eagle's medium (DMEM) supplemented with fetal calf serum, L-ascorbic acid, and antibiotics at 37 degrees C and pH 7.0. In detail, fatigue tests, which are experiments, where the ILT tissue is loaded. in pulsatile manner, were carried out at three different load levels with a natural frequency of 1.0 Hz. Results. ILT's ultimate strength (156.5 kPa, 92.0 kPa, and 47.7 kPa for luminal, medial, and abluminal layers, respectively) and referential stiffness (62.88 kPa, 47.52 kPa, and 41.52 kPa, for luminal, medial, and abluminal layers, respectively) continuously decrease from the inside to the outside. ILT tissue failed within less than 1 hour under pulsatile loading at a load level of 60% ultimate strength, while a load level of about 40% ultimate strength did not cause failure within 13.9 hours. Conclusions. ILT tissue is vulnerable against fatigue failure and shows significant decreasing strength with respect to the number of load cycles. Hence, after a reasonable time of pulsating loading ILT's strength is far below its ultimate strength, and when compared with stress predictions from finite element (FE) studies, this indicates the likelihood of fatigue failure in vivo. Failure within the ILT could propagate towards the weakened vessel wall behind it and could initialize AAA failure thereafter.
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| 8. |
- Gasser, T. Christian, et al.
(författare)
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Finite element modeling of balloon angioplasty by considering overstretch of remnant non-diseased tissues in lesions
- 2007
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Ingår i: Computational Mechanics. - : Springer Science and Business Media LLC. - 0178-7675 .- 1432-0924. ; 40:1, s. 47-60
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Tidskriftsartikel (refereegranskat)abstract
- The paper deals with the modeling of balloon angioplasty by considering the balloon-induced overstretch of remnant non-diseased tissues in atherosclerotic arteries. A stenotic artery is modeled as a heterogenous structure composed of adventitia, media and a model plaque, and residual stresses are considered. The constitutive models are able to capture the anisotropic elastic tissue response in addition to the inelastic phenomena associated with tissue stretches beyond the physiological domain. The inelastic model describes the experimentally-observed changes of the wall during balloon inflation, i.e. non-recoverable deformation, and tissue weakening. The contact of the artery with a balloon catheter is simulated by a point-to-surface strategy. The states of deformations and stresses within the artery before, during and after balloon inflation are computed, compared and discussed. The 3D stress states at physiological loading conditions before and after balloon inflation differ significantly, and even compressive normal stresses may occur in the media after dilation.
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| 9. |
- Gasser, T. Christian, et al.
(författare)
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Hyperelastic modelling of arterial layers with distributed collagen fibre orientations
- 2006
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Ingår i: Journal of the Royal Society Interface. - : The Royal Society. - 1742-5689 .- 1742-5662. ; 3:6, s. 15-35
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Forskningsöversikt (refereegranskat)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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| 10. |
- Gasser, T. Christian, et al.
(författare)
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Modeling 3D crack propagation in unreinforced concrete using PUFEM
- 2005
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Ingår i: Computer Methods in Applied Mechanics and Engineering. - : Elsevier BV. - 0045-7825 .- 1879-2138. ; 194:25-26, s. 2859-2896
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Tidskriftsartikel (refereegranskat)abstract
- Concrete is a quasi-brittle material, where tensile failure involves progressive micro-cracking, debounding and other complex irreversible processes of internal damage. Strain-softening is a dominate feature and advanced numerical schemes have to be applied in order to circumvent the ill-posdness of the Boundary-Value Problem to deal with. Throughout the paper we pursue the cohesive zone approach, where initialization and coalescence of micro-cracks is lumped into the cohesive fracture process zone in terms of accumulation of damage. We develop and employ a (discrete) constitutive description of the cohesive zone, which is based on a transversely isotropic traction separation law. The model reflects an exponential decreasing traction with respect to evolving opening displacement and is based on the theory of invariants. Non-negativeness of the damage dissipation is proven and the associated numerical embedded representation is based on the Partition of Unity Finite Element Method. A consistent linearization of the method is presented, where particular attention is paid to the (cohesive) traction terms. Based on the proposed concept three numerical examples are studied in detail, i.e. a double-notched specimen under tensile loading, a four point shear test and a pull-out test of unreinforced concrete. The computational results show mesh-independency and good correlation with experimental results. © 2004 Elsevier B.V. All rights reserved.
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