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- Vogel, Jacob W., et al.
(author)
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Four distinct trajectories of tau deposition identified in Alzheimer’s disease
- 2021
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In: Nature Medicine. - : Springer Science and Business Media LLC. - 1078-8956 .- 1546-170X. ; 27:5, s. 871-881
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Journal article (peer-reviewed)abstract
- Alzheimer’s disease (AD) is characterized by the spread of tau pathology throughout the cerebral cortex. This spreading pattern was thought to be fairly consistent across individuals, although recent work has demonstrated substantial variability in the population with AD. Using tau-positron emission tomography scans from 1,612 individuals, we identified 4 distinct spatiotemporal trajectories of tau pathology, ranging in prevalence from 18 to 33%. We replicated previously described limbic-predominant and medial temporal lobe-sparing patterns, while also discovering posterior and lateral temporal patterns resembling atypical clinical variants of AD. These ‘subtypes’ were stable during longitudinal follow-up and were replicated in a separate sample using a different radiotracer. The subtypes presented with distinct demographic and cognitive profiles and differing longitudinal outcomes. Additionally, network diffusion models implied that pathology originates and spreads through distinct corticolimbic networks in the different subtypes. Together, our results suggest that variation in tau pathology is common and systematic, perhaps warranting a re-examination of the notion of ‘typical AD’ and a revisiting of tau pathological staging. © 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.
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- Geersing, G. J., et al.
(author)
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Exclusion of deep vein thrombosis using the Wells rule in clinically important subgroups: individual patient data meta-analysis
- 2014
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In: BMJ: British Medical Journal. - : BMJ. - 1756-1833. ; 348, s. 1340-1340
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Journal article (peer-reviewed)abstract
- Objective To assess the accuracy of the Wells rule for excluding deep vein thrombosis and whether this accuracy applies to different subgroups of patients. Design Meta-analysis of individual patient data. Data sources Authors of 13 studies (n=10 002) provided their datasets, and these individual patient data were merged into one dataset. Eligibility criteria Studies were eligible if they enrolled consecutive outpatients with suspected deep vein thrombosis, scored all variables of the Wells rule, and performed an appropriate reference standard. Main outcome measures Multilevel logistic regression models, including an interaction term for each subgroup, were used to estimate differences in predicted probabilities of deep vein thrombosis by the Wells rule. In addition, D-dimer testing was added to assess differences in the ability to exclude deep vein thrombosis using an unlikely score on the Wells rule combined with a negative D-dimer test result. Results Overall, increasing scores on the Wells rule were associated with an increasing probability of having deep vein thrombosis. Estimated probabilities were almost twofold higher in patients with cancer, in patients with suspected recurrent events, and (to a lesser extent) in males. An unlikely score on the Wells rule (<= 1) combined with a negative D-dimer test result was associated with an extremely low probability of deep vein thrombosis (1.2%, 95% confidence interval 0.7% to 1.8%). This combination occurred in 29% (95% confidence interval 20% to 40%) of patients. These findings were consistent in subgroups defined by type of D-dimer assay (quantitative or qualitative), sex, and care setting (primary or hospital care). For patients with cancer, the combination of an unlikely score on the Wells rule and a negative D-dimer test result occurred in only 9% of patients and was associated with a 2.2% probability of deep vein thrombosis being present. In patients with suspected recurrent events, only the modified Wells rule (adding one point for the previous event) is safe. Conclusion Combined with a negative D-dimer test result (both quantitative and qualitative), deep vein thrombosis can be excluded in patients with an unlikely score on the Wells rule. This finding is true for both sexes, as well as for patients presenting in primary and hospital care. In patients with cancer, the combination is neither safe nor efficient. For patients with suspected recurrent disease, one extra point should be added to the rule to enable a safe exclusion.
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- Dalrymple, Annette, et al.
(author)
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Proteomic profiling of plasma in Huntington's disease reveals neuroinflammatory activation and biomarker candidates
- 2007
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In: Journal of Proteome Research. - : American Chemical Society (ACS). - 1535-3893 .- 1535-3907. ; 6:7, s. 2833-2840
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Journal article (peer-reviewed)abstract
- Huntington's disease (HD) causes widespread CNS changes and systemic abnormalities including endocrine and immune dysfunction. HD biomarkers are needed to power clinical trials of potential treatments. We used multiplatform proteomic profiling to reveal plasma changes with HD progression. Proteins of interest were evaluated using immunoblotting and ELISA in plasma from 2 populations, CSF and R6/2 mice. The identified proteins demonstrate neuroinflammation in HD and warrant further investigation as possible biomarkers.
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| 6. |
- Kaminsky, DA, et al.
(author)
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Oscillation mechanics of the human lung periphery in asthma
- 2004
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In: Journal of Applied Physiology. - : American Physiological Society. - 1522-1601 .- 8750-7587. ; 97:5, s. 1849-1858
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Journal article (peer-reviewed)abstract
- To more precisely measure the mechanical properties of the lung periphery in asthma, we have developed a forced oscillation technique that applies a broad-band flow signal through a wedged bronchoscope. We interpreted the data from four healthy and eight mildly asthmatic subjects in terms of an anatomically accurate computer model of the wedged segment. There was substantial overlap in impedance between the two groups, with resistance ( R) showing minimal frequency dependence and elastance (E) showing positive and negative frequency dependence across subjects. After direct instillation of methacholine, R rose in both groups, but compared with healthy subjects, the asthmatic subjects displayed upward, parallel shifts in their dose-response curves. The baseline frequency-response patterns of E were enhanced after methacholine. Frequency dependencies of R and E were well reproduced in two normal subjects by a computational model that employed rigid airways connected to constant-phase tissue units but were better reproduced in the other two normal and three asthmatic subjects when the model employed heterogeneous, peripheral airway narrowing and compliant airways. To capture the frequency dependencies of R and E in the remaining five asthmatic subjects, the model was modified by increasing airway wall stiffness. These results indicate that the lung periphery of mildly asthmatic subjects is not well distinguished from that of healthy subjects by measurement of mechanical impedance at baseline, but group differences are seen after challenge with methacholine. Modeling of the response suggests that variable contributions of airway narrowing and wall compliance are operative in determining overall mechanical impedance of the lung periphery in humans with asthma, likely reflecting the functional consequences of airway inflammation and remodeling.
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- Nowak-Sliwinska, Patrycja, et al.
(author)
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Consensus guidelines for the use and interpretation of angiogenesis assays
- 2018
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In: Angiogenesis. - : Springer. - 0969-6970 .- 1573-7209. ; 21:3, s. 425-532
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Research review (peer-reviewed)abstract
- The formation of new blood vessels, or angiogenesis, is a complex process that plays important roles in growth and development, tissue and organ regeneration, as well as numerous pathological conditions. Angiogenesis undergoes multiple discrete steps that can be individually evaluated and quantified by a large number of bioassays. These independent assessments hold advantages but also have limitations. This article describes in vivo, ex vivo, and in vitro bioassays that are available for the evaluation of angiogenesis and highlights critical aspects that are relevant for their execution and proper interpretation. As such, this collaborative work is the first edition of consensus guidelines on angiogenesis bioassays to serve for current and future reference.
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| 8. |
- Wagers, S, et al.
(author)
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Nonlinearity of respiratory mechanics during bronchoconstriction in mice with airway inflammation
- 2002
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In: Journal of Applied Physiology. - : American Physiological Society. - 1522-1601 .- 8750-7587. ; 92:5, s. 1802-1807
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Journal article (peer-reviewed)abstract
- Respiratory system resistance (R) and elastance (E) are commonly estimated by fitting the linear equation of motion P = EV + R(V) over dot + P-0 (Eq. 1) to measurements of respiratory pressure (P), lung volume (V), and flow (V). However, the respiratory system is unlikely to behave linearly under many circumstances. We determined the importance of respiratory system nonlinearities in two groups of mechanically ventilated Balb/c mice [controls and mice with allergically inflamed airways (ova/ova)], by,g the impact of the addition of nonlinear terms (E2V2 assessing and R-2(V) over dot (V) over dot) on the goodness of model fit seen with Eq. 1. Significant improvement in fit (51.85 +/- 4.19%) was on seen in the ova/ova mice during bronchoconstriction when the E2V2 alone was added. An improvement was also observed with addition of the E2V2 term in mice with both low and high lung volumes ventilated at baseline, suggesting a volume-dependent nonlinearity of E. We speculate that airway closure in the constricted ova/ova mice accentuated the volume-dependent nonlinearity by decreasing lung volume and overdistending the remaining lung.
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| 9. |
- Wagers, S, et al.
(author)
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The allergic mouse model of asthma: normal smooth muscle in an abnormal lung?
- 2004
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In: Journal of Applied Physiology. - : American Physiological Society. - 1522-1601 .- 8750-7587. ; 96:6, s. 2019-2027
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Journal article (peer-reviewed)abstract
- Mice with allergically inflamed airways are widely used as animal models of asthma, but their relevance for human asthma is not understood. We, therefore, examined the time course of changes in respiratory input impedance during induced bronchoconstriction in BALB/c mice sensitized and challenged with ovalbumin. Our results indicate that bronchoconstriction in mice is accompanied by complete closure of substantial regions of the lung and that closure increases markedly when the lungs are allergically inflamed. With the aid of an anatomically accurate computational model of the mouse lung, we show that the hyperresponsiveness of mice with allergically inflamed airways can be explained entirely by a thickening of the airway mucosa and an increased propensity of the airways to close, without the involvement of any increase in the degree of airway smooth muscle shortening. This has implications for the pathophysiology of asthma and suggests that at least some types of asthma may benefit from therapies aimed at manipulating surface tension at the air-liquid interface in the lungs.
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| 10. |
- Zanne, Amy E, et al.
(author)
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Fungal functional ecology: bringing a trait-based approach to plant-associated fungi.
- 2020
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In: Biological reviews of the Cambridge Philosophical Society. - : Wiley. - 1469-185X .- 1464-7931. ; 95:2, s. 409-433
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Journal article (peer-reviewed)abstract
- Fungi play many essential roles in ecosystems. They facilitate plant access to nutrients and water, serve as decay agents that cycle carbon and nutrients through the soil, water and atmosphere, and are major regulators of macro-organismal populations. Although technological advances are improving the detection and identification of fungi, there still exist key gaps in our ecological knowledge of this kingdom, especially related to function. Trait-based approaches have been instrumental in strengthening our understanding of plant functional ecology and, as such, provide excellent models for deepening our understanding of fungal functional ecology in ways that complement insights gained from traditional and -omics-based techniques. In this review, we synthesize current knowledge of fungal functional ecology, taxonomy and systematics and introduce a novel database of fungal functional traits (FunFun ). FunFun is built to interface with other databases to explore and predict how fungal functional diversity varies by taxonomy, guild, and other evolutionary or ecological grouping variables. To highlight how a quantitative trait-based approach can provide new insights, we describe multiple targeted examples and end by suggesting next steps in the rapidly growing field of fungal functional ecology.
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