| 1. |
- Blauw, Hylke M, et al.
(författare)
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A large genome scan for rare CNVs in amyotrophic lateral sclerosis
- 2010
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Ingår i: Human Molecular Genetics. - : Oxford Journals. - 0964-6906 .- 1460-2083. ; 19:20, s. 4091-4099
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Tidskriftsartikel (refereegranskat)abstract
- Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease selectively affecting motor neurons in the brain and spinal cord. Recent genome-wide association studies (GWASs) have identified several common variants which increase disease susceptibility. In contrast, rare copy-number variants (CNVs), which have been associated with several neuropsychiatric traits, have not been studied for ALS in well-powered study populations. To examine the role of rare CNVs in ALS susceptibility, we conducted a CNV association study including over 19,000 individuals. In a genome-wide screen of 1875 cases and 8731 controls, we did not find evidence for a difference in global CNV burden between cases and controls. In our association analyses, we identified two loci that met our criteria for follow-up: the DPP6 locus (OR = 3.59, P = 6.6 × 10(-3)), which has already been implicated in ALS pathogenesis, and the 15q11.2 locus, containing NIPA1 (OR = 12.46, P = 9.3 × 10(-5)), the gene causing hereditary spastic paraparesis type 6 (HSP 6). We tested these loci in a replication cohort of 2559 cases and 5887 controls. Again, results were suggestive of association, but did not meet our criteria for independent replication: DPP6 locus: OR = 1.92, P = 0.097, pooled results: OR = 2.64, P = 1.4 × 10(-3); NIPA1: OR = 3.23, P = 0.041, pooled results: OR = 6.20, P = 2.2 × 10(-5)). Our results highlight DPP6 and NIPA1 as candidates for more in-depth studies. Unlike other complex neurological and psychiatric traits, rare CNVs with high effect size do not play a major role in ALS pathogenesis.
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| 2. |
- Koellensperger, Martin, et al.
(författare)
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Presentation, Diagnosis, and Management of Multiple System Atrophy in Europe: Final Analysis of the European Multiple System Atrophy Registry
- 2010
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Ingår i: Movement Disorders. - : Wiley. - 0885-3185. ; 25:15, s. 2604-2612
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Tidskriftsartikel (refereegranskat)abstract
- Multiple system atrophy (MSA) is a Parkinson's Disease (PD)-like alpha-synucleinopathy clinically characterized by dysautonomia, parkinsonism, cerebellar ataxia, and pyramidal signs in any combination. We aimed to determine whether the clinical presentation of MSA as well as diagnostic and therapeutic strategies differ across Europe and Israel. In 19 European MSA Study Group centres all consecutive patients with a clinical diagnosis of MSA were recruited from 2001 to 2005. A standardized minimal data set was obtained from all patients. Four-hundred thirty-seven MSA patients from 19 centres in 10 countries were included. Mean age at onset was 57.8 years; mean disease duration at inclusion was 5.8 years. According to the consensus criteria 68% were classified as parkinsonian type (MSA-P) and 32% as cerebellar type (MSA-C) (probable MSA: 72%, possible MSA: 28%). Symptomatic dysautonomia was present in almost all patients, and urinary dysfunction (83%) more common than symptomatic orthostatic hypotension (75%). Cerebellar ataxia was present in 64%, and parkinsonism in 87%, of all cases. No significant differences in the clinical presentation were observed between the participating countries. In contrast, diagnostic work up and therapeutic strategies were heterogeneous. Less than a third of patients with documented orthostatic hypotension or neurogenic bladder disturbance were receiving treatment. This largest clinical series of MSA patients reported so far shows that the disease presents uniformly across Europe. The observed differences in diagnostic and therapeutic management including lack of therapy for dysautonomia emphasize the need for future guidelines in these areas. (C) 2010 Movement Disorder Society
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| 3. |
- Auer, Martin, et al.
(författare)
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Automatic Displacement and Strain measuring in the Aorta from dynamic electrocardiographically-gated Computed Tomographic Angiography
- 2010
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Konferensbidrag (refereegranskat)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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| 4. |
- Biasetti, Jacopo, et al.
(författare)
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A Blood Flow based model for Platelet Activation in Abdominal Aortic Aneurisms
- 2010
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Konferensbidrag (refereegranskat)abstract
- Introduction Thrombus formation is the physiological response to vascular injury, it prevents loss of blood and permits wound healing, however, it is also associated with pathological conditions like hypoxia, anoxia and infarction [1]. Consequently, thrombus development must be carefully modulated to avoid uncontrolled growth, which in turn could lead to organ malfunctions. Specifically, an Intra-Luminal Thrombus (ILT) is found in almost all larger (clinically relevant) Abdominal Aortic Aneurysms (AAAs) and multiple biochemical [2] and biomechanical [3] implications on the underlying wall tissue have been reported. Despite the dominant role played by the ILT in AAA disease little is known regarding its development, and hence, the present study investigates ILT formation with particular emphasis on platelet activation triggered by biomechanical and biochemical field variables. Method The proposed model assumes that platelet activation is defined by a single field variable representing the accumulation of mechanical [4] and chemical [5] factors as the platelet moves along its path line. Platelet activation is given as soon asovercomes a certain threshold thought to be a constitutive property of blood. Specifically, the rate of the activation variable is determined by the maximum shear stress and the local concentrations of agonists and antagonists. To implement the model the fluid mechanical problem was solved in (COMSOL, COMSOL AB) and a particle tracking analysis (MATLAB, The MathWorks) was applied as a post processing step. The flow in a circular tube and the Backward Facing Step (BFS) problem under varying initial conditions were used for a basic investigation of the model and to relate its predictions to available data in the literature. Finally, platelet activation in patient specific AAAs was predicted and related to ILT development, which was estimated from Computer Tomography-Angiography (CT-A) data recorded from patient follow-up studies. Results and Conclusions The platelet activation variable is complex distributed (highly heterogeneous) in the flow field, where, specifically, at the boundary of vortexes [6] and in the boundary layer of the non- endothelialized wall highest values were predicted. Continuous release of antagonists from the endothelialized wall lowers in its vicinity, and hence, despite the high shear stress platelet activation is prevented. The proposed model links biomechanical and biochemical mechanisms of platelet activation and is able to predict the onset of thrombus formation of the BFS problem. The model is also able to predict some features of ILT development in the AAA, however, the change in luminal geometry is a cumulative effect of ILT growth, wall growth and their mechanical interactions, and hence, data recorded form patient follow-up studies needs to be analyzed carefully when validating the present model. References [1] J. D. Humphrey, Springer-Verlag, New York, 2002. [2] M. Kazi, et. al. J. Vasc. Surg., 38:1283-1292, 2003. [3] W. R. Mower et. al., J. Vasc. Surg., 33:602-608, 1997. [4] J. D. Hellums, Ann. Biomed. Eng., 22: 445-455, 1994. [5] B. Alberts et. al. Molecular Biology of the cell, 2002. [6] J. Biasetti et. al. Ann. Biomed. Eng., 38: 380–390 2010.
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| 5. |
- Giampaolo, Martufi, et al.
(författare)
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Abdominal Aortic Aneurysm development over time : Experimental evidence and constitutive modeling
- 2010
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Ingår i: Proceedings of the 6th World Congress of Biomechanics. - : Springer. - 9783642145148
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Konferensbidrag (refereegranskat)abstract
- Abdominal Aortic Aneurysms (AAAs) are defined as a localized permanent dilatation of the infrarenal aorta at least 50 % of its normal diameter. AAAs are frequently diagnosed in the elderly male population and evaluating rupture risk is critically important as aneurysm rupture carries high mortality rates. Growth predictors might be helpful to assess AAA rupture risk and could therefore give a better graded indication for elective repair in order to reduce related mortality without unnecessarily increasing the rate of interventions. Factors associated with AAA growth are still limited but there are some evidence that higher initial AAA diameter is related to faster AAA expansion [1]. The initial dilatation is dependent on elastin degradation, but strength of the AAA is maintained by increased production of collagen. It has been suggested that rupture occurs when collagen production is insufficient to counteract load-bearing at high pressure [2]. AAA growth quantification 30 patients with infrarenal AAAs were included in this study. Criteria for inclusion were 1-year follow-up and availability of at least two high-resolution Computer Tomography-Angiography (CTA) scans. Consequently, 60 CT-A scans were systematically segmented, reconstructed and analyzed (A4research, VASCOPS GmbH), in order to investigate geometrical and mechanical factors likely to be correlated with AAA growth. Derived results were analyzed with an especially developed (automatic) analyzing schema (MatLab, The MathWorks), and the derived information aims at guiding the development of an analytical growth model for AAAs. Constitutive Modeling Collagen is a structural protein responsible for the mechanical strength, stiffness and toughness of biological tissues like skin, tendon, bone, cornea, lung and vasculature. In the present study we considered the enlargement of the aneurysm as a consequence of a pathological degradation and synthesis of collagen, i.e. malfunction of collagen turn-over. Consequently, the vascular wall is modeled by an (inert) matrix material representing the elastin, which is reinforced by a dynamic structure of bundles of collagen. Specifically, collagen is formed by a continuous stress-mediated process and deposited in the current configuration [3] and removed by a constant degradation rate. Finally the micro-plane concept [4] is used for the Finite Element implementation [5] of the constitutive model. Results and conclusions The quantitative description of AAA growth by examining patient follow-up data revealed novel insights into the natural history of this disease. Most interestingly not all portions of the AAA seem to enlarge, some might be stable or even shrink over time; a feature that has not yet been considered by models reported in the literature. The model proposed within this study has a strong biological motivation and captures saline feature of AAA growth. Besides that, the micro-plane approach allows a straight forward FE implementation and preliminary results indicate its numerical robustness. References [1] F.J.V. Schlösser, et al., J Vasc Surg, 47:1127–1133 2008. [2] E. Choke, et al., Eur.j.Vasc.endovasc.surg, 30(3):227-44 2005. [3] J.D.Humphrey, J Biomech Eng, 121:591–597 1999. [4] Z.P. Bazant and P.C. Prat, J Eng Mech, 113(7) 1050-1064 1987. [5] S. Federico and T.C Gasser, J R Soc Interface (in press)
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| 6. |
- Hyhlik-Dürr, A., et al.
(författare)
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Finite-Elemente-Analyse abdomineller Aortenaneurysmen : Erste Ergebnisse der Intra- und Interobserver Validierung
- 2010
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Konferensbidrag (refereegranskat)abstract
- Hintergrund: Die Therapie des abdominellen Aortenaneurysmas (AAA) ist indiziert, wenn das Rupturrisiko das Risiko der elektiven Operation übersteigt. Die Abschätzung des individuellen Rupturrisikos gilt als Basis der Indikationsstellung zur offenen oder endovaskulären Chirurgie. Bisher wird der Durchmesser des AAA als maßgeblicher Risikofaktor für die Ruptur herangezogen. Für eine sensitivere Indikationsstellung sollten jedoch andere morphologische oder biomechanische Faktoren wie die Volumenveränderung im Verlauf und/oder die Wandspannung im Aneurysma untersucht werden. Ziel dieser Studie ist die Analyse der Reproduzierbarkeit der Durchmesserbestimmung sowie der Volumen- und Wandspannungsberechnung anhand eines geometrischen Modells, basierend auf der Finite Elemente Methode. Methode: Computertomographische Daten von vier gesunden und zehn Patienten mit infrarenalen abdominellen Aneurysmen werden von drei unabhängigen Untersuchern analysiert. Die abdominelle Aorta wird semiautomatisch von Computertomographie-Angiographie (CTA) Bilddaten segmentiert, wobei zwei und drei-dimensionale aktive Konturmodelle, wie sie aus der Bildverarbeitung bekannt sind, zum Einsatz kommen. Der maximale Durchmesser (cernterline-basiert) sowie das aortale Volumen werden aus den rekonstruierten dreidimensionalen Modellen berechnet. Zusätzlich werden nicht-lineare Finite Elemente Modelle verwendet, um die mechanische Spannung in der Aortenwand zwischen der Aortenbifurkation und den Nierenarterien zu bestimmen. Zu diesen Zweck wird der mittlere arterielle Druck als Belastung angenommen und nicht-lineare isotrope Materialmodelle erfassen die mechanischen Eigenschaften der Aortenwand und des Thrombusgewebes. Die Intra- und Interobserver Variabilität der fünf Messungen des maximalen Durchmessers, des Volumens und der maximalen Wandspannung wurden durch die Berechnung des Variationskoeffizienten (CV=SD*100/Arithmethisches Mittel in %) ausgedrückt. Die methodische Variation berechnet sich aus der Abweichung des Duchmessers (mm), des Volumens (ml) und der maximalen Wandspannung (kPA) zwischen den drei Untersuchern. Ergebnisse: Die Reproduzierbarkeit gesunder Gefäßen lag bei einem Durchmesser zwischen 16.1mm und 16.6mm zwischen CV=2,5% und CV=4,9%. Das aortale Volumen lag zwischen 14ml und 15ml, die Reproduzierbarkeit bei den gesunden Gefäßen streute zwischen CV=5.8% und CV=11.5%. Die maximale Wandspannung variierte zwischen 53 kPA and 55 kPa, der CV% lag hierbei zwischen 3 und 13. Die Interobserver Variabilität lag < 10% für den Durchmesser, die Volumenbestimmung und die Bestimmung der maximale Wandspannung. Der maximale Durchmesser der Aorta bei 3 Patienten mit infrarenalem Aneurysma wurde mit durchschnittlich 58.9mm, 54.6mm und 71.2mm berechnet (Stand bei Abstracteinreichung). Der Variationskoeffizient zeigte dabei eine hohe Übereinstimmung mit Werten unter 5%. Das Volumen der Aneurysmen schwankte zwischen 130 ml und 300 ml (CV<10%), die berechnete Wandspannung lag zwischen 172 kPA und 296 kPA (CV<10%). Die Variabilität zwischen den drei Untersuchern betrug 0,7-6,0 mm für den Durchmesser, 11-28 ml für das Volumen und 4-27 kPA für die maximale Wandspannung. Zusammenfassung: Sowohl an gesunden als auch an degenerativ veränderten Gefäßen ergibt die Reproduzierbarkeit des Aortendurchmessers und des aortalen Volumens basierend auf dem dreidimensionalen rekonstruierten Modellen eine hohe Übereinstimmung. Die berechnete Wandspannung basierend auf den Finiten Elemente Modellen zeigt einen geringen Grad an Variabilität sowohl zwischen verschiedenen Untersuchern als auch bei wiederholter Messung. Daher könnten die Volumenbestimmung und die Analyse der Wandspannung zusätzliche Größen bei der Bestimmung des individuellen Rupturrisikos bei Patienten mit Aortenaneurysmen darstellen, um eine präzisere Indikationsstellung zu ermöglichen.
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