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1.
Author Correction: Common variants in Alzheimer's disease and risk stratification by polygenic risk scores.
de Rojas, I, Moreno-Grau, S, Tesi, N, Grenier-Boley, B, Andrade, V, Jansen, IE, Pedersen, NL, Stringa, N, Zettergren, A, Hernández, I, et al
Nature communications. 2023;(1):716
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2.
Common variants in Alzheimer's disease and risk stratification by polygenic risk scores.
de Rojas, I, Moreno-Grau, S, Tesi, N, Grenier-Boley, B, Andrade, V, Jansen, IE, Pedersen, NL, Stringa, N, Zettergren, A, Hernández, I, et al
Nature communications. 2021;(1):3417
Abstract
Genetic discoveries of Alzheimer's disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer's disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer's disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer's disease.
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3.
Physiological fluid interfaces: Functional microenvironments, drug delivery targets, and first line of defense.
Bertsch, P, Bergfreund, J, Windhab, EJ, Fischer, P
Acta biomaterialia. 2021;:32-53
Abstract
Fluid interfaces, i.e. the boundary layer of two liquids or a liquid and a gas, play a vital role in physiological processes as diverse as visual perception, oral health and taste, lipid metabolism, and pulmonary breathing. These fluid interfaces exhibit a complex composition, structure, and rheology tailored to their individual physiological functions. Advances in interfacial thin film techniques have facilitated the analysis of such complex interfaces under physiologically relevant conditions. This allowed new insights on the origin of their physiological functionality, how deviations may cause disease, and has revealed new therapy strategies. Furthermore, the interactions of physiological fluid interfaces with exogenous substances is crucial for understanding certain disorders and exploiting drug delivery routes to or across fluid interfaces. Here, we provide an overview on fluid interfaces with physiological relevance, namely tear films, interfacial aspects of saliva, lipid droplet digestion and storage in the cell, and the functioning of lung surfactant. We elucidate their structure-function relationship, discuss diseases associated with interfacial composition, and describe therapies and drug delivery approaches targeted at fluid interfaces. STATEMENT OF SIGNIFICANCE Fluid interfaces are inherent to all living organisms and play a vital role in various physiological processes. Examples are the eye tear film, saliva, lipid digestion & storage in cells, and pulmonary breathing. These fluid interfaces exhibit complex interfacial compositions and structures to meet their specific physiological function. We provide an overview on physiological fluid interfaces with a focus on interfacial phenomena. We elucidate their structure-function relationship, discuss diseases associated with interfacial composition, and describe novel therapies and drug delivery approaches targeted at fluid interfaces. This sets the scene for ocular, oral, or pulmonary surface engineering and drug delivery approaches.
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4.
Effects of long-term exposure to air pollution on natural-cause mortality: an analysis of 22 European cohorts within the multicentre ESCAPE project.
Beelen, R, Raaschou-Nielsen, O, Stafoggia, M, Andersen, ZJ, Weinmayr, G, Hoffmann, B, Wolf, K, Samoli, E, Fischer, P, Nieuwenhuijsen, M, et al
Lancet (London, England). 2014;(9919):785-95
Abstract
BACKGROUND Few studies on long-term exposure to air pollution and mortality have been reported from Europe. Within the multicentre European Study of Cohorts for Air Pollution Effects (ESCAPE), we aimed to investigate the association between natural-cause mortality and long-term exposure to several air pollutants. METHODS We used data from 22 European cohort studies, which created a total study population of 367,251 participants. All cohorts were general population samples, although some were restricted to one sex only. With a strictly standardised protocol, we assessed residential exposure to air pollutants as annual average concentrations of particulate matter (PM) with diameters of less than 2.5 μm (PM2.5), less than 10 μm (PM10), and between 10 μm and 2.5 μm (PMcoarse), PM2.5 absorbance, and annual average concentrations of nitrogen oxides (NO2 and NOx), with land use regression models. We also investigated two traffic intensity variables-traffic intensity on the nearest road (vehicles per day) and total traffic load on all major roads within a 100 m buffer. We did cohort-specific statistical analyses using confounder models with increasing adjustment for confounder variables, and Cox proportional hazards models with a common protocol. We obtained pooled effect estimates through a random-effects meta-analysis. FINDINGS The total study population consisted of 367,251 participants who contributed 5,118,039 person-years at risk (average follow-up 13.9 years), of whom 29,076 died from a natural cause during follow-up. A significantly increased hazard ratio (HR) for PM2.5 of 1.07 (95% CI 1.02-1.13) per 5 μg/m(3) was recorded. No heterogeneity was noted between individual cohort effect estimates (I(2) p value=0.95). HRs for PM2.5 remained significantly raised even when we included only participants exposed to pollutant concentrations lower than the European annual mean limit value of 25 μg/m(3) (HR 1.06, 95% CI 1.00-1.12) or below 20 μg/m(3) (1.07, 1.01-1.13). INTERPRETATION Long-term exposure to fine particulate air pollution was associated with natural-cause mortality, even within concentration ranges well below the present European annual mean limit value. FUNDING European Community's Seventh Framework Program (FP7/2007-2011).
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5.
Long-term exposure to elemental constituents of particulate matter and cardiovascular mortality in 19 European cohorts: results from the ESCAPE and TRANSPHORM projects.
Wang, M, Beelen, R, Stafoggia, M, Raaschou-Nielsen, O, Andersen, ZJ, Hoffmann, B, Fischer, P, Houthuijs, D, Nieuwenhuijsen, M, Weinmayr, G, et al
Environment international. 2014;:97-106
Abstract
BACKGROUND Associations between long-term exposure to ambient particulate matter (PM) and cardiovascular (CVD) mortality have been widely recognized. However, health effects of long-term exposure to constituents of PM on total CVD mortality have been explored in a single study only. AIMS The aim of this study was to examine the association of PM composition with cardiovascular mortality. METHODS We used data from 19 European ongoing cohorts within the framework of the ESCAPE (European Study of Cohorts for Air Pollution Effects) and TRANSPHORM (Transport related Air Pollution and Health impacts--Integrated Methodologies for Assessing Particulate Matter) projects. Residential annual average exposure to elemental constituents within particle matter smaller than 2.5 and 10 μm (PM2.5 and PM10) was estimated using Land Use Regression models. Eight elements representing major sources were selected a priori (copper, iron, potassium, nickel, sulfur, silicon, vanadium and zinc). Cohort-specific analyses were conducted using Cox proportional hazards models with a standardized protocol. Random-effects meta-analysis was used to calculate combined effect estimates. RESULTS The total population consisted of 322,291 participants, with 9545 CVD deaths. We found no statistically significant associations between any of the elemental constituents in PM2.5 or PM10 and CVD mortality in the pooled analysis. Most of the hazard ratios (HRs) were close to unity, e.g. for PM10 Fe the combined HR was 0.96 (0.84-1.09). Elevated combined HRs were found for PM2.5 Si (1.17, 95% CI: 0.93-1.47), and S in PM2.5 (1.08, 95% CI: 0.95-1.22) and PM10 (1.09, 95% CI: 0.90-1.32). CONCLUSION In a joint analysis of 19 European cohorts, we found no statistically significant association between long-term exposure to 8 elemental constituents of particles and total cardiovascular mortality.
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6.
Folate and Alzheimer: when time matters.
Hinterberger, M, Fischer, P
Journal of neural transmission (Vienna, Austria : 1996). 2013;(1):211-24
Abstract
Folate is necessary for DNA and mtDNA integrity and via folate/B12-dependent methionine cycle for methylation of multiple substrates (epigenetic DNA and enzymes) and methylation of homocysteine. During embryogenesis, folate deficiency is a risk factor for neural tube defects and late in life for cognitive decline and Alzheimer's dementia (AD). It induces several Alzheimer pathomechanisms like oxidative stress, Ca(++) influx, accumulation of hyperphosphorylated tau and β-amyloid. But impact of folic acid supplementation on prevention or delay of dementia is a matter of debate. Six out of seven randomized controlled trials (RCT) with B vitamin intervention periods between 2 and 5.4 years reported about cognitive benefits in the supplemented groups mainly for those subjects with high homocysteine or low folate levels at baseline. This review tries to demonstrate the connection between folate deficiency and AD, analyses selected epidemiologic studies and RCT on folate/B12/homocysteine with long-observation periods (≥ 2 years RCT; ≥ 4 years observational) and attempts to find explanations for the controversy in literature like short follow-up, heterogeneity of subjects concerning age, recruitment, baseline cognition, inclusion criteria and probably "misleading"(not representative for the past) folate/B12/homocysteine levels due to not reported short-term use of multivitamins or food-fortification. Population-based studies-epidemiologic and interventional-starting in the fourth decade would provide the best information about the impact of folate on later development of AD. Mandatory folate fortification areas will be important future field studies for-like neural tube defects-hopefully declining AD incidence and disproving safety concerns.
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7.
One target-two different binding modes: structural insights into gevokizumab and canakinumab interactions to interleukin-1β.
Blech, M, Peter, D, Fischer, P, Bauer, MM, Hafner, M, Zeeb, M, Nar, H
Journal of molecular biology. 2013;(1):94-111
Abstract
Interleukin-1β (IL-1β) is a key orchestrator in inflammatory and several immune responses. IL-1β exerts its effects through interleukin-1 receptor type I (IL-1RI) and interleukin-1 receptor accessory protein (IL-1RAcP), which together form a heterotrimeric signaling-competent complex. Canakinumab and gevokizumab are highly specific IL-1β monoclonal antibodies. Canakinumab is known to neutralize IL-1β by competing for binding to IL-1R and therefore blocking signaling by the antigen:antibody complex. Gevokizumab is claimed to be a regulatory therapeutic antibody that modulates IL-1β bioactivity by reducing the affinity for its IL-1RI:IL-1RAcP signaling complex. How IL-1β signaling is affected by both canakinumab and gevokizumab was not yet experimentally determined. We have analyzed the crystal structures of canakinumab and gevokizumab antibody binding fragment (Fab) as well as of their binary complexes with IL-1β. Furthermore, we characterized the epitopes on IL-1β employed by the antibodies by NMR epitope mapping studies. The direct comparison of NMR and X-ray data shows that the epitope defined by the crystal structure encompasses predominantly those residues whose NMR resonances are severely perturbed upon complex formation. The antigen:Fab co-structures confirm the previously identified key contact residues on IL-1β and provide insight into the mechanisms leading to their distinct modulation of IL-1β signaling. A significant steric overlap of the binding interfaces of IL-1R and canakinumab on IL-1β causes competitive inhibition of the association of IL-1β and its receptor. In contrast, gevokizumab occupies an allosteric site on IL-1β and complex formation results in a minor reduction of binding affinity to IL-1RI. This suggests two different mechanisms of IL-1β pathway attenuation.
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8.
Posttraumatic growth: why do people grow from their trauma?
Kastenmüller, A, Greitemeyer, T, Epp, D, Frey, D, Fischer, P
Anxiety, stress, and coping. 2012;(5):477-89
Abstract
In two experimental studies we found that participants who recalled a highly traumatic autobiographical event (trauma recall) compared with a lesser traumatic event (stress recall) reported having increasingly grown (posttraumatic growth, PTG). Moreover, participants who recalled a traumatic (vs. stressful) event perceived more death-related thoughts (Study 1) and reported coping with this event in a more emotion-focused and in a less problem-focused way (Study 2). Mediation analyzes revealed that the effect of trauma versus stress recall on PTG was mediated by emphasizing the positive, a subscale of emotion-focused coping. These results imply that growth resulting from traumatic events can be traced back to an illusion. No evidence was found that real PTG took place or that the effects shown resulted from death-related thoughts (terror management theory).
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9.
[Consensus statement "Dementia 2010" of the Austrian Alzheimer Society].
Schmidt, R, Marksteiner, M, Dal-Bianco, P, Ransmayr, G, Bancher, C, Benke, T, Wancata, J, Fischer, P, Leblhuber, CF, Psota, G, et al
Neuropsychiatrie : Klinik, Diagnostik, Therapie und Rehabilitation : Organ der Gesellschaft Osterreichischer Nervenarzte und Psychiater. 2010;(2):67-87
Abstract
The Austrian Alzheimer Society developed evidence-based guidelines based on a systematic literature search and criteria-guided assessment with subsequent transparent determination of grades of clinical recommendation. The authors evaluated currently available therapeutic approaches for the most common forms of dementia and focused on diagnosis and pharmacological intervention, taking into consideration the situation in Austria. The purpose of these guidelines is the rational and cost-effective use of diagnostic and therapeutic measures in dementing illnesses. Users are physicians and all other providers of care for patients with dementia in Austria.
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10.
A phase II study on safety and efficacy of high-dose N-acetylcysteine in patients with cystic fibrosis.
Dauletbaev, N, Fischer, P, Aulbach, B, Gross, J, Kusche, W, Thyroff-Friesinger, U, Wagner, TO, Bargon, J
European journal of medical research. 2009;(8):352-8
Abstract
OBJECTIVE We conducted a single-centre, randomised, double-blinded, placebo-controlled phase II clinical study to test safety and efficacy of a 12-week therapy with low-dose (700 mg/daily) or high-dose (2800 mg/daily) of NAC. METHODS Twenty-one patients (DeltaF508 homo/heterozygous, FEV1>40% pred.) were included in the study. After a 3-weeks placebo run-in phase, 11 patients received low-dose NAC, and 10 patients received high-dose NAC. Outcomes included safety and clinical parameters, inflammatory (total leukocyte numbers, cell differentials, TNF-alpha, IL-8) measures in induced sputum, and concentrations of extracellular glutathione in induced sputum and blood. RESULTS High-dose NAC was a well-tolerated and safe medication. High-dose NAC did not alter clinical or inflammatory parameters. However, extracellular glutathione in induced sputum tended to increase on high-dose NAC. CONCLUSIONS High-dose NAC is a well-tolerated and safe medication for a prolonged therapy of patients with CF with a potential to increase extracellular glutathione in CF airways.