| 1. |
- 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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| 2. |
- 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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| 3. |
- Buervenich, Silvia, et al.
(författare)
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A rare truncating mutation in ADH1C (G78Stop) shows significant association with Parkinson disease in a large international sample.
- 2005
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Ingår i: Archives of neurology. - : American Medical Association (AMA). - 0003-9942. ; 62:1, s. 74-8
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Alcohol dehydrogenases (ADHs) may be involved in the pathogenesis of neurodegenerative disorders because of their multiple roles in detoxification pathways and retinoic acid synthesis. In a previous study, significant association of an ADH class IV allele with Parkinson disease (PD) was found in a Swedish sample. PATIENTS: The previously associated single-nucleotide polymorphism plus 12 further polymorphisms in the ADH cluster on human chromosome 4q23 were screened for association in an extension of the original sample that now included 123 Swedish PD patients and 127 geographically matched control subjects. A rare nonsense single-nucleotide polymorphism in ADH1C (G78stop, rs283413) was identified in 3 of these patients but in no controls. To obtain sufficient power to detect a possible association of this rare variant with disease, we screened a large international sample of 1076 PD patients of European ancestry and 940 matched controls. RESULTS: The previously identified association with an ADH class IV allele remained significant (P<.02) in the extended Swedish study. Furthermore, in the international collaboration, the G78stop mutation in ADH1C was found in 22 (2.0%) of the PD patients but only in 6 controls (0.6%). This association was statistically significant (chi(2)(1) = 7.5; 2-sided P = .007; odds ratio, 3.25 [95% confidence interval, 1.31-8.05]). In addition, the G78stop mutation was identified in 4 (10.0%) of 40 Caucasian index cases with PD with mainly hereditary forms of the disorder. CONCLUSION: Findings presented herein provide further evidence for mutations in genes encoding ADHs as genetic risk factors for PD.
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| 4. |
- Hampel, Harald, et al.
(författare)
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Lithium trial in Alzheimer's disease : a randomized, single-blind, placebo-controlled, multicenter 10-week study
- 2009
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Ingår i: Journal of Clinical Psychiatry. - 0160-6689 .- 1555-2101. ; 70:6, s. 922-931
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Lithium, a first-line drug for the treatment of bipolar depression, has recently been shown to regulate glycogen synthase kinase-3 (GSK-3), a kinase that is involved in the phosphorylation of the tau protein. Since hyperphosphorylation of tau is a core pathological feature in Alzheimer's disease, lithium-induced inhibition of GSK-3 activity may have therapeutic effects in Alzheimer's disease. In the current study, we tested the effect of short-term lithium treatment in patients with Alzheimer's disease. METHOD: A total of 71 patients with mild Alzheimer's disease (Mini-Mental State Examination score > or = 21 and < or = 26) were successfully randomly assigned to placebo (N = 38) or lithium treatment (N = 33) at 6 academic expert memory clinics. The 10-week treatment included a 6-week titration phase to reach the target serum level of lithium (0.5-0.8 mmol/L). The primary outcome measures were cerebrospinal fluid (CSF) levels of phosphorylated tau (p-tau) and GSK-3 activity in lymphocytes. Secondary outcome measures were CSF concentration of total tau and beta-amyloid(1-42) (Abeta(1-42)), plasma levels of Abeta(1-42), Alzheimer's Disease Assessment Scale (ADAS)-Cognitive summary scores, MMSE, and Neuropsychiatric Inventory (NPI). Patients were enrolled in the study from November 2004 to July 2005. RESULTS: No treatment effect on GSK-3 activity or CSF-based biomarker concentrations (P > .05) was observed. Lithium treatment did not lead to change in global cognitive performance as measured by the ADAS-Cog subscale (P = .11) or in depressive symptoms. CONCLUSIONS: The current results do not support the notion that lithium treatment may lead to reduced hyperphosphorylation of tau protein after a short 10-week treatment in the Alzheimer's disease target population.
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| 5. |
- 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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| 6. |
- Koellensperger, Martin, et al.
(författare)
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Red flags for multiple system atrophy
- 2008
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Ingår i: Movement Disorders. - : Wiley. - 0885-3185 .- 1531-8257. ; 23:8, s. 1093-1099
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Tidskriftsartikel (refereegranskat)abstract
- The clinical diagnosis Of Multiple system atrophy (MSA) is fraught with difficulty and there are no pathognomonic features to discriminate the parkinsonian variant (MSA-P) from Parkinson's disease (PD). Besides the poor response to levodopa, and the additional presence of pyramidal or cerebellar signs (ataxia) or autonomic failure as major diagnostic criteria, certain other clinical features known as "red flags" or warning signs may raise the clinical suspicion of MSA. To study the diagnostic role of these features in MSA-P versus PD patients, a standardized red flag check list (RFCL) developed by the European MSA Study Group (EMSA-SG) was administered to 57 patients with probable MSA-P and 116 patients with probable PD diagnosed according to established criteria. Those red flags with a specifity over 95% were selected for further analysis. Factor analysis was applied to reduce the number of red flags. The resulting set was then applied to 17 patients with possible MSA-P who on follow-up fulfilled criteria of probable MSA-P. Red flags were grouped into related categories. With two or more of six red flag categories present specificity was 98.3% and sensitivity was 84.2% in our cohort. When applying these criteria to patients with possible MSA-P, 76.5% of them would have been correctly diagnosed as probable MSA-P 15.9 (+/- 7.0) months earlier than with the Consensus criteria alone. We propose a combination of two out of six red flag categories as additional diagnostic criteria for probable MSA-P. (C) 2008 Movement Disorder Society.
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| 7. |
- Leyhe, Thomas, et al.
(författare)
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Increase of BDNF serum concentration in lithium treated patients with early Alzheimer's disease
- 2009
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Ingår i: Journal of Alzheimer's Disease. - 1387-2877 .- 1875-8908. ; 16:3, s. 649-656
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Tidskriftsartikel (refereegranskat)abstract
- Preclinical and clinical studies gave evidence that lithium could be useful in the treatment of Alzheimer's disease (AD). In experimental investigations, lithium induces brain-derived neurotrophic factor (BDNF). Recent studies have found a decrease of BDNF in the serum and brains of AD patients with potentially consecutive lack of neurotrophic support. We assessed the influence of a lithium treatment on BDNF serum concentration in a subset of a greater sample recruited for a randomized, single-blinded, placebo-controlled, parallel-group multicenter 10-week study, investigating the efficacy of lithium treatment in AD patients. In AD patients treated with lithium, a significant increase of BDNF serum levels, and additionally a significant decrease of ADAS-Cog sum scores in comparison to placebo-treated patients, were found. Diminution of cognitive impairment was inversely correlated with lithium serum concentration. Upregulation of BDNF might be part of a neuroprotective effect of lithium in AD patients. The results of the present investigation encourage performing studies with longer treatment phases to observe potential positive long-term effects of lithium in AD patients.
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| 8. |
- Qiu, Chunjing, et al.
(författare)
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A strong mitigation scenario maintains climate neutrality of northern peatlands
- 2022
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Ingår i: One Earth. - : Elsevier BV. - 2590-3330 .- 2590-3322. ; 5:1, s. 86-97
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Tidskriftsartikel (refereegranskat)abstract
- Northern peatlands store 300–600 Pg C, of which approximately half are underlain by permafrost. Climate warming and, in some regions, soil drying from enhanced evaporation are progressively threatening this large carbon stock. Here, we assess future CO2 and CH4 fluxes from northern peatlands using five land surface models that explicitly include representation of peatland processes. Under Representative Concentration Pathways (RCP) 2.6, northern peatlands are projected to remain a net sink of CO2 and climate neutral for the next three centuries. A shift to a net CO2 source and a substantial increase in CH4 emissions are projected under RCP8.5, which could exacerbate global warming by 0.21°C (range, 0.09–0.49°C) by the year 2300. The true warming impact of peatlands might be higher owing to processes not simulated by the models and direct anthropogenic disturbance. Our study highlights the importance of understanding how future warming might trigger high carbon losses from northern peatlands.
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| 9. |
- Roberts, Sean, et al.
(författare)
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CHIELD: the causal hypotheses in evolutionary linguistics database
- 2020
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Ingår i: Journal of Language Evolution. - : Oxford University Press (OUP). - 2058-458X. ; 5:2, s. 101-120
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Tidskriftsartikel (refereegranskat)abstract
- Language is one of the most complex of human traits. There are many hypotheses about how it originated, what factors shaped its diversity, and what ongoing processes drive how it changes. We present the Causal Hypotheses in Evolutionary Linguistics Database (CHIELD, https://chield.excd.org/), a tool for expressing, exploring, and evaluating hypotheses. It allows researchers to integrate multiple theories into a coherent narrative, helping to design future research. We present design goals, a formal specification, and an implementation for this database. Source code is freely available for other fields to take advantage of this tool. Some initial results are presented, including identifying conflicts in theories about gossip and ritual, comparing hypotheses relating population size and morphological complexity, and an author relation network.
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| 10. |
- Straten, Guido, et al.
(författare)
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Influence of Lithium Treatment on GDNF Serum and CSF Concentrations in Patients with Early Alzheimer΄s Disease
- 2011
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Ingår i: Current Alzheimer research. - : Bentham Science Publishers Ltd.. - 1567-2050 .- 1875-5828. ; 8:8, s. 853-859
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Tidskriftsartikel (refereegranskat)abstract
- Preclinical and clinical studies gave evidence that lithium could be useful in the treatment of Alzheimer΄s disease (AD). One possible mechanism of action might be the induction of neurotrophins. Recently, we found a significant increase of brain-derived neurotrophic factor (BDNF) serum levels in AD patients treated with lithium and a significant decrease of ADAS Cog sum scores in comparison to placebo-treated patients. In another previous study we have shown that glial cell line-derived neurotrophic factor (GDNF) levels in CSF of patients with early AD are increased most probably due to an upregulated expression in CNS as an adaptive process of the impaired brain to enhance neurotrophic support at least in early stages of disease. Here we assessed the influence of a lithium treatment on GDNF serum and cerebrospinal fluid (CSF) concentrations in a subset of a greater sample recruited for a randomized, single-blinded, placebocontrolled, parallel-group multicenter 10-week study, investigating the efficacy of lithium treatment in AD patients. We found a significant negative correlation of lithium concentration in serum with GDNF concentration in CSF at the end of treatment (r = -0.585, p = 0.036) and with the difference of GDNF concentration in CSF before and after treatment (r = - 0.755, p = 0.003). However, we could not show a difference in GDNF concentrations between the patients after the treatment with lithium or placebo (serum, mean ± standard deviation: 434.3 ± 117.9 pg/ml versus 543.8 ± 250.0 pg/ml, p = 0.178; CSF, 62.3 ± 37.4 pg/ml versus 72.8 ± 43.9 pg/ml, p = 0.511). The findings of the present investigation indicated that beneficial effects of the lithium treatment might reduce the necessity of enhanced GDNF expression in the CNS in early AD.
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| 11. |
- Wenning, Gregor K., et al.
(författare)
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The natural history of multiple system atrophy: a prospective European cohort study
- 2013
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Ingår i: Lancet Neurology. - 1474-4465. ; 12:3, s. 264-274
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Tidskriftsartikel (refereegranskat)abstract
- Background Multiple system atrophy (MSA) is a fatal and still poorly understood degenerative movement disorder that is characterised by autonomic failure, cerebellar ataxia, and parkinsonism in various combinations. Here we present the final analysis of a prospective multicentre study by the European MSA Study Group to investigate the natural history of MSA. Methods Patients with a clinical diagnosis of MSA were recruited and followed up clinically for 2 years. Vital status was ascertained 2 years after study completion. Disease progression was assessed using the unified MSA rating scale (UMSARS), a disease-specific questionnaire that enables the semiquantitative rating of autonomic and motor impairment in patients with MSA. Additional rating methods were applied to grade global disease severity, autonomic symptoms, and quality of life. Survival was calculated using a Kaplan-Meier analysis and predictors were identified in a Cox regression model. Group differences were analysed by parametric tests and non-parametric tests as appropriate. Sample size estimates were calculated using a paired two-group t test. Findings 141 patients with moderately severe disease fulfilled the consensus criteria for MSA. Mean age at symptom onset was 56.2 (SD 8.4) years. Median survival from symptom onset as determined by Kaplan-Meier analysis was 9.8 years (95% CI 8.1-11.4). The parkinsonian variant of MSA (hazard ratio [HR] 2.08,95% CI 1.09-3.97; p=0.026) and incomplete bladder emptying (HR 2.10,1.02-4.30; p=0.044) predicted shorter survival. 24-month progression rates of UMSARS activities of daily living, motor examination, and total scores were 49% (9.4 [SD 5.9]), 74% (12.9 [8.5]), and 57% (21.9 [11.9]), respectively, relative to baseline scores. Autonomic symptom scores progressed throughout the follow-up. Shorter symptom duration at baseline (OR 0.68, 0.5-0.9; p=0.006) and absent levodopa response (OR 3.4, 1.1-10.2; p=0.03) predicted rapid UMSARS progression. Sample size estimation showed that an interventional trial with 258 patients (129 per group) would be able to detect a 30% effect size in 1-year UMSARS motor examination decline rates at 80% power. Interpretation Our prospective dataset provides new insights into the evolution of MSA based on a follow-up period that exceeds that of previous studies. It also represents a useful resource for patient counselling and planning of multicentre trials.
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| 12. |
- 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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| 13. |
- 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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| 14. |
- Biasetti, Jacopo, et al.
(författare)
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A Fluid-chemical model of thrombus formation
- 2011
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Ingår i: CMBE2011.
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Konferensbidrag (refereegranskat)abstract
- Our understanding of the genesis and evolution of Abdominal Aortic Aneurysms (AAAs), withparticular emphasis on Intra-Luminal Thrombus’ evolution, may be improved by studying thecomplex interplay between fluid-dynamics and biochemistry. To investigate the evolution of prothromboticchemicals inside the blood flow, in particular thrombin (factor IIa), a fluido-chemicalmodel has been developed. To this end a series of convection-diffusion-reaction (CDR) equationsdescribing the tissue factor pathway to thrombin have been solved on top of the biofluiddynamics problem. The proposed model integrates biochemistry and fluids dynamics, and hence,supports a comprehensive understanding of how ILT in AAAs may develop.
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| 15. |
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| 16. |
- Erhart, P., et al.
(författare)
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Finite Element Analysis in Asymptomatic, Symptomatic, and Ruptured Abdominal Aortic Aneurysms : In Search of New Rupture Risk Predictors
- 2015
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Ingår i: European Journal of Vascular and Endovascular Surgery. - : Elsevier BV. - 1078-5884 .- 1532-2165. ; 49:3, s. 239-245
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: To compare biomechanical rupture risk parameters of asymptomatic, symptomatic and ruptured abdominal aortic aneurysms (AAA) using finite element analysis (FEA). Study design: Retrospective biomechanical single center analysis of asymptomatic, symptomatic, and ruptured AAAs. Comparison of biomechanical parameters from FEA. Materials and methods: From 2011 to 2013 computed tomography angiography (CTA) data from 30 asymptomatic, 15 symptomatic, and 15 ruptured AAAs were collected consecutively. FEA was performed according to the successive steps of AAA vessel reconstruction, segmentation and finite element computation. Biomechanical parameters Peak Wall Rupture Risk Index (PWRI), Peak Wall Stress (PWS), and Rupture Risk Equivalent Diameter (RRED) were compared among the three subgroups. Results: PWRI differentiated between asymptomatic and symptomatic AAAs (p < .0004) better than PWS (p < .1453). PWRI-dependent RRED was higher in the symptomatic subgroup compared with the asymptomatic subgroup (p < .0004). Maximum AAA external diameters were comparable between the two groups (p < .1355). Ruptured AAAs showed the highest values for external diameter, total intraluminal thrombus volume, PWS, RRED, and PWRI compared with asymptomatic and symptomatic AAAs. In contrast with symptomatic and ruptured AAAs, none of the asymptomatic patients had a PWRI value >1.0. This threshold value might identify patients at imminent risk of rupture: Conclusions: From different FEA derived parameter, PWRI distinguishes most precisely between asymptomatic and symptomatic AAAs. If elevated, this value may represent a negative prognostic factor for asymptomatic AAAs.
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| 17. |
- Gasser, Thomas Christian
(författare)
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Aorta
- 2017
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Ingår i: Biomechanics of Living Organs. - : Elsevier. - 9780128040607 - 9780128040096 ; , s. 169-191
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Bokkapitel (refereegranskat)abstract
- The aorta is a dynamic structure that is able to maintain conditions for optimal mechanical operation through the continuous turnover of its internal structure. The aorta's properties are critical to the entire cardiovascular system, and the study of its biomechanics may help us to better understand the role of tissue stress and strain in aortic aging and pathology, help to optimize medical devices, and improve therapeutic and diagnostic methods that are currently used in clinics. The present chapter reviews aortic wall histology and morphology in relation to its key mechanical properties. Specifically, the biomechanical role of cells (endothelial cells, smooth muscle cells, fibroblasts, etc.), as well as the extracellular matrix components (elastin, collagen, proteoglycans, water, etc.), will be discussed. Then this information is related to reported constitutive descriptions for aortic tissues. The focus is on histo-mechanical approaches and modeling frames, related to hyperelasticity as well as a superposition of fiber contributions according to a general theory of fibrous connective tissue. Concluding remarks relate to open problems in aorta biomechanics, such as uncertainty and variability of input information. Remarks are also made on the admissible degree of complexity in aortic simulations, in the context of such uncertainties.
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| 18. |
- 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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| 19. |
- Grover, Sandeep, et al.
(författare)
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Replication of a Novel Parkinson's Locus in a European Ancestry Population
- 2021
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Ingår i: Movement Disorders. - : Wiley. - 0885-3185 .- 1531-8257. ; 36:7, s. 1689-1695
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Tidskriftsartikel (refereegranskat)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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| 20. |
- Grytsan, Andrii, et al.
(författare)
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Growth Description for Vessel Wall Adaptation : A Thick-Walled Mixture Model of Abdominal Aortic Aneurysm Evolution
- 2017
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Ingår i: Materials. - : MDPI AG. - 1996-1944. ; 10:9
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Tidskriftsartikel (refereegranskat)abstract
- (1) Background: Vascular tissue seems to adapt towards stable homeostatic mechanical conditions, however, failure of reaching homeostasis may result in pathologies. Current vascular tissue adaptation models use many ad hoc assumptions, the implications of which are far from being fully understood; (2) Methods: The present study investigates the plausibility of different growth kinematics in modeling Abdominal Aortic Aneurysm (AAA) evolution in time. A structurally motivated constitutive description for the vessel wall is coupled to multi-constituent tissue growth descriptions; Constituent deposition preserved either the constituent's density or its volume, and Isotropic Volume Growth (IVG), in-Plane Volume Growth (PVG), in-Thickness Volume Growth (TVG) and No Volume Growth (NVG) describe the kinematics of the growing vessel wall. The sensitivity of key modeling parameters is explored, and predictions are assessed for their plausibility; (3) Results: AAA development based on TVG and NVG kinematics provided not only quantitatively, but also qualitatively different results compared to IVG and PVG kinematics. Specifically, for IVG and PVG kinematics, increasing collagen mass production accelerated AAA expansion which seems counterintuitive. In addition, TVG and NVG kinematics showed less sensitivity to the initial constituent volume fractions, than predictions based on IVG and PVG; (4) Conclusions: The choice of tissue growth kinematics is of crucial importance when modeling AAA growth. Much more interdisciplinary experimental work is required to develop and validate vascular tissue adaption models, before such models can be of any practical use.
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| 21. |
- Grytsan, Andrii, 1986-, et al.
(författare)
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Growth description for vessel wall adaptation : a thick-walled mixture model of abdominal aortic aneurysm evolution
- 2016
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- Modeling the soft tissue volumetric growth has received considerable attention in the literature.However, due to the lack of experimental observations, the growth kinematics, that are reported in the literature, are based on a number of assumptions.The present study tested the plausibility of different growth descriptions when applied to the abdominal aortic aneurysm (AAA) evolution.A structurally motivated material model and the multi-constituent tissue growth descriptions were utilized. The mass increment of the individual constituents preserved either the density or the volume.Four different growth descriptions were tested, namely isotropic (IVG), in-plane (PVG), in-thickness (TVG) growth and no volume growth (NVG) models.Based on the model sensitivity to the increased collagen deposition, TVG and NVG models were found to be plausible scenarios, while IVG and PVG were found to be implausible. In addition, TVG and NVG models were less sensitive to the initial constituent volume fractions, than IVG and PVG models.In conclusion, the choice of the growth kinematics is of crucial importance when modeling the AAA growth and remodeling, and,probably, also for other soft biological tissues.
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| 22. |
- Holzapfel, Gerhard A., et al.
(författare)
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Computational stress-deformation analysis of arterial walls including high-pressure response
- 2007
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Ingår i: International Journal of Cardiology. - : Elsevier BV. - 0167-5273 .- 1874-1754. ; 116:1, s. 78-85
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Tidskriftsartikel (refereegranskat)abstract
- Background: Changes in the mechanical behavior of arteries after balloon angioplasty cause cell reactions that may be responsible for restenosis. Hence, the study of the stress-deforination changes in arterial walls following supraphysiological tissue loading is an essential task. Methods: A normal LAD coronary artery was modeled and computationally analyzed as a two-layer, thick-walled, anisotropic and inelastic circular tube including residual strains. Each layer was treated as a fibre-matrix composite. The tube was subjected to an axial stretch of 1. 1 and a transmural pressure of 750 min Hg. Since overstretch of rerrmant non-diseased tissue in lesions is a primary mechanism of lumen enlargement this model approach represents a reasonable first step. Results: At physiological loading, the residual stresses led to a significant reduction of the high circumferential stress values at the inner wall, and the stress gradients. At low pressure level the media was the mechanically relevant layer, while at supraphysiological loading, the adventitia was the predominant load-carrying constituent providing a stiff support for 'redistribution' of soft plaque components by means of radial compression. After unloading to physiological loading conditions the stress state in the arterial wall differed significantly from that before inflation; the stress gradient in the media even changed its sign. Complete unloading indicated lumen enlargement, material softening and energy dissipation, which is in agreement with experimental studies. Conclusions: This method may be useful to improve interventional protocols for reducing the dilatational trauma, and thereby the adverse biological reaction in arterial walls following balloon angioplasty.
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| 23. |
- 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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| 24. |
- Kiousis, Dimitrios, et al.
(författare)
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Smooth contact strategies with emphasis on the modeling of balloon angioplasty with stenting
- 2008
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Ingår i: International Journal for Numerical Methods in Engineering. - : Wiley. - 0029-5981 .- 1097-0207. ; 75:7, s. 826-855
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Tidskriftsartikel (refereegranskat)abstract
- Critical to the simulation of balloon angioplasty is the modeling of the contact between the artery wall and the medical devices. In standard approaches, the 3D contact surfaces are described by means of C0-continuous facet-based techniques, which may lead to numerical problems. This work introduces a novel contact algorithm where the target surfaces are described by polynomial expressions with C2-continuity. On the basis of uniform cubic B-splines, two different parametrization techniques are presented and compared, while the related implementation of the algorithm into a finite element analysis program is described. Two numerical examples are selected to demonstrate the special merits of the proposed contact formulation. The first example is a benchmark contact problem selected to point out the special features of the proposed strategies. The second example is concerned with the simulation of balloon angioplasty and stenting, where the contact between the balloon, the stent and the artery wall is numerically modeled. A patient-specific 3D model of a stenotic femoral artery serves as a basis. The study concludes by identifying the changes in the mechanical environment of the artery in terms of contact forces and strains by considering two different stent designs.
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| 25. |
- Krüger, Rejko, et al.
(författare)
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A large-scale genetic association study to evaluate the contribution of Omi/HtrA2 (PARK13) to Parkinson's disease
- 2011
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Ingår i: Neurobiology of Aging. - : Elsevier BV. - 1558-1497 .- 0197-4580. ; 32:3, s. 9-548
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Tidskriftsartikel (refereegranskat)abstract
- High-profile studies have provided conflicting results regarding the involvement of the Omi/HtrA2 gene in Parkinson's disease (PD) susceptibility. Therefore, we performed a large-scale analysis of the association of common Omi/HtrA2 variants in the Genetic Epidemiology of Parkinson's disease (GEO-PD) consortium. GEO-PD sites provided clinical and genetic data including affection status, gender, ethnicity, age at study, age at examination (all subjects); age at onset and family history of PD (patients). Genotyping was performed for the five most informative SNPs spanning the Omi/HtrA2 gene in approximately 2-3 kb intervals (rs10779958, rs2231250, rs72470544, rs1183739, rs2241028). Fixed as well as random effect models were used to provide summary risk estimates of Omi/HtrA2 variants. The 20 GEO-PD sites provided data for 6378 cases and 8880 controls. No overall significant associations for the five Omi/HtrA2 SNPs and PD were observed using either fixed effect or random effect models. The summary odds ratios ranged between 0.98 and 1.08 and the estimates of between-study heterogeneity were not large (non-significant Q statistics for all 5 SNPs; I(2) estimates 0-28%). Trends for association were seen for participants of Scandinavian descent for rs2241028 (OR 1.41, p=0.04) and for rs1183739 for age at examination (cut-off 65 years; OR 1.17, p=0.02), but these would not be significant after adjusting for multiple comparisons and their Bayes factors were only modest. This largest association study performed to define the role of any gene in the pathogenesis of Parkinson's disease revealed no overall strong association of Omi/HtrA2 variants with PD in populations worldwide.
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