Minimal long-term neurobehavioral impairments after endovascular perforation subarachnoid hemorrhage in mice

AbstractCognitive deficits are among the most severe and pervasive consequences of aneurysmal subarachnoid hemorrhage (SAH). A critical step in developing therapies targeting such outcomes is the characterization of experimentally-tractable pre-clinical models that exhibit multi-domain neurobehavioral deficits similar to those afflicting humans. We therefore searched for neurobehavioral abnormalities following endovascular perforation induction of SAH in mice, a heavily-utilized model. We instituted a functional screen to manage variability in injury severity, then assessed acute functional deficits, as well as activity, anxiety-related behavior, learning and memory, socialization, and depressive-like behavior at sub-acute and chronic time points (up to 1 month post-injury). Animals in which SAH was induced exhibited reduced acute functional capacity and reduced general activity to 1 month post-injury. Tests of anxiety-related behavior including central area time in the elevated plus maze and thigmotaxis in the open field test revealed increased anxiety-like behavior at subacute and chronic time-points, respectively. Effect sizes for subacute and chronic neurobehavioral endpoints in other domains, however, were small. In combination with persistent variability, this led to non-significant effects of injury on all remaining neurobehavioral outcomes. These results suggest that, with the exception of anxiety-related behavior, alternate mouse models are required to effectively analyze cognitive outcomes after SAH.</jats:p

modCHIMERA: A novel murine closed-head model of moderate traumatic brain injury

AbstractTraumatic brain injury is a major source of global disability and mortality. Preclinical TBI models are a crucial component of therapeutic investigation. We report a tunable, monitored model of murine non-surgical, diffuse closed-head injury—modCHIMERA—characterized by impact as well as linear and rotational acceleration. modCHIMERA is based on the Closed-Head Impact Model of Engineered Rotational Acceleration (CHIMERA) platform. We tested this model at 2 energy levels: 1.7 and 2.1 Joules—substantially higher than previously reported for this system. Kinematic analysis demonstrated linear acceleration exceeding injury thresholds in humans, although outcome metrics tracked impact energy more closely than kinematic parameters. Acute severity metrics were consistent with a complicated-mild or moderate TBI, a clinical population characterized by high morbidity but potentially reversible pathology. Axonal injury was multifocal and bilateral, neuronal death was detected in the hippocampus, and microglial neuroinflammation was prominent. Acute functional analysis revealed prolonged post-injury unconsciousness, and decreased spontaneous behavior and stimulated neurological scores. Neurobehavioral deficits were demonstrated in spatial learning/memory and socialization at 1-month. The overall injury profile of modCHIMERA corresponds with the range responsible for a substantial portion of TBI-related disability in humans. modCHIMERA should provide a reliable platform for efficient analysis of TBI pathophysiology and testing of treatment modalities.</jats:p

TRICHLOROETHYLENE EXPOSURE AND TRAUMATIC BRAIN INJURY INTERACT AND PRODUCE DUAL INJURY BASED PATHOLOGY AND PIOGLITAZONE CAN ATTENUATE DEFICITS FOLLOWING TRAUMATIC BRAIN INJURY

The development of Parkinson\u27s disease (PD) in humans has been linked to genetic and environmental factors for many years. However, finding common single insults which can produce pathology in humans has proved difficult. Exposure to trichloroethylene (TCE) or traumatic brain injury (TBI) has been shown to be linked to PD and it has also been proposed that multiple insults may be needed for disease development. The present studies show that exposure to TCE prior to a TBI can result in pathology similar to early PD and that the interaction of both insults is required for impairment in behavioral function, and cell loss. Following exposure to TCE for 2 weeks there is a 75% impairment in mitochondrial function but it has yet to be shown if the addition of a TBI can make this worse. If the exposure to TCE is reduced to 1 week and combined with TBI a 50% reduction in mitochondrial function is observed following the dual injury which requires both insults. These studies provide further support for the hypothesis that PD may result from a multifactorial mechanism. It had been established that regional differences exist in mitochondrial function across brain regions. The present studies indicate that previous findings are not likely to be the result of differences in individual mitochondria isolated from the cortex, striatum, and hippocampus. Further analysis of the effect of mitochondrial inhibitors on enzyme activity and oxygen consumption reveal that the different regions of the brain are similarly affected by the inhibitors. These results suggest that findings from previous studies indicating regionally specific deficits following systemic toxin exposure, such as with TCE, are not the result of regional differences in the individual mitochondria. Given that TBI results in significant dysfunction, finding effective therapeutics for TBI will provide substantial benefits to individuals suffering an insult. Treatment with Pioglitazone following TBI reduced mitochondrial dysfunction, cognitive impairment, cortical tissue loss, and inflammation. These findings provide initial evidence that treatment with Pioglitazone may be an effective intervention for TBI

Screening for brain aneurysm in the Familial Intracranial Aneurysm study: frequency and predictors of lesion detection

Object Approximately 20% of patients with an intracranial saccular aneurysm report a family history of intracranial aneurysm (IA) or subarachnoid hemorrhage. A better understanding of predictors of aneurysm detection in familial IA may allow more targeted aneurysm screening strategies. Methods The Familial Intracranial Aneurysm (FIA) study is a multicenter study, in which the primary objective is to define the susceptibility genes related to the formation of IA. First-degree relatives (FDRs) of those affected with IA are offered screening with magnetic resonance (MR) angiography if they were previously unaffected, are ≥ 30 years of age, and have a history of smoking and/or hypertension. Independent predictors of aneurysm detection on MR angiography were determined using the generalized estimating equation version of logistic regression. Results Among the first 303 patients screened with MR angiography, 58 (19.1%) had at least 1 IA, including 24% of women and 11.7% of men. Ten (17.2%) of 58 affected patients had multiple aneurysms. Independent predictors of aneurysm detection included female sex (odds ratio [OR] 2.46, p = 0.001), pack-years of cigarette smoking (OR 3.24 for 20 pack-years of cigarette smoking compared with never having smoked, p < 0.001), and duration of hypertension (OR 1.26 comparing those with 10 years of hypertension to those with no hypertension, p = 0.006). Conclusions In the FIA study, among the affected patients’ FDRs who are > 30 years of age, those who are women or who have a history of smoking or hypertension are at increased risk of suffering an IA and should be strongly considered for screening

Bioavailability in soils

The consumption of locally-produced vegetables by humans may be an important exposure pathway for soil contaminants in many urban settings and for agricultural land use. Hence, prediction of metal and metalloid uptake by vegetables from contaminated soils is an important part of the Human Health Risk Assessment procedure. The behaviour of metals (cadmium, chromium, cobalt, copper, mercury, molybdenum, nickel, lead and zinc) and metalloids (arsenic, boron and selenium) in contaminated soils depends to a large extent on the intrinsic charge, valence and speciation of the contaminant ion, and soil properties such as pH, redox status and contents of clay and/or organic matter. However, chemistry and behaviour of the contaminant in soil alone cannot predict soil-to-plant transfer. Root uptake, root selectivity, ion interactions, rhizosphere processes, leaf uptake from the atmosphere, and plant partitioning are important processes that ultimately govern the accumulation ofmetals and metalloids in edible vegetable tissues. Mechanistic models to accurately describe all these processes have not yet been developed, let alone validated under field conditions. Hence, to estimate risks by vegetable consumption, empirical models have been used to correlate concentrations of metals and metalloids in contaminated soils, soil physico-chemical characteristics, and concentrations of elements in vegetable tissues. These models should only be used within the bounds of their calibration, and often need to be re-calibrated or validated using local soil and environmental conditions on a regional or site-specific basis.Mike J. McLaughlin, Erik Smolders, Fien Degryse, and Rene Rietr

Literaturrecherche und -analyse zur Genetik der altersabhängigen Makuladegeneration (AMD)

Die aktuell umfassenste GWAS zur Genetik der altersabhängigen Makuladegeneration (AMD), einer komplexen progressiv-degenerativen Erkrankung der zentralen Netzhaut, fand über 7.000 assoziierte Varianten in 52 unabhängigen Signalen, die in 34 Genorte des Genoms verteilt sind. Die Interpretation von GWAS-Ergebnissen weist jedoch Limitationen auf. Von einer genetischen Assoziation alleine kann nicht auf Kausalität geschlossen werden. Daher sind weiterführende Analysen wichtig, um die GWAS-Befunde genauer zu analysieren und die kausalen Varianten und deren Konsequenzen zu identifizieren. Solche Folgestudien, die sich auf eine umfassende GWAS stützen, sind Objekt der Forschung dieser Arbeit. Es soll ausgehend von der gegenwärtig umfassensten und aktuellsten GWAS zur AMD (Fritsche et al. 2016) ein Überblick über den Stand der laufenden Forschung zur Pathogenese der AMD erstellt werden. Weiter sollen mit Hilfe der zweitjüngsten GWAS zur AMD von 2013 (Fritsche et al. 2013) zeitliche Trends in der Forschung ermittelt werden. Zuletzt werden Bereiche herausgearbeitet, denen in der ophthalmologischen Forschung bisher wenig Aufmerksamkeit zuteil wurde, so dass weitere Forschung wünschenswert wäre. Im Fokus dieser Arbeit steht eine systematische Literaturrecherche mittels des Web of Science (WoS), einer Online-Zitationsdatenbank von Clarivate Analytics. Diese enthält Zugänge zu über 18.000 verschiedenen Zeitschriften und über eine Milliarde Querverweise bezüglich Zitationen. Die Daten werden durch die im WoS integrierte Suche nach zitierenden Referenzen gefiltert und anschließend händisch analysiert und kategorisiert. Unter den Studientypen der Folgestudien finden sich vor allem genetische Assoziationsstudien und Übersichtsarbeiten, gefolgt von experimentellen Studien. Die Studienkohorten der genetischen Assoziationsstudien waren größtenteils von europäischer Ethnizität oder transethnisch, wobei in keiner Arbeit beispielsweise eine rein afrikanische Studienpopulation untersucht wurde. In Sachen Krankheitsstatus wurde meist die AMD ohne weitere Differenzierung betrachtet. Analysen von Subgruppen der AMD konzentrierten sich fast ausnahmslos auf die Spätform oder deren Unterform, die NV-AMD. Im zeitlichen Verlauf von 2013 auf 2016 konnte unter den Genotypisierungsdaten eine Veränderung von der Genotypisierung einzelner SNPs in einem Gen hin zu Genotypisierungs-Microarrays, die SNPs aus dem kompletten Genom untersuchten, festgestellt werden. Als Mosdellsysteme für funktionelle Untersuchungen waren Tierversuche führend, gefolgt von Zellversuchen, menschlichem Spendergewebe und Bioproben. Dabei wurden vor allem Locusuntersuchungen verfolgt, jedoch auch Therapieoptionen, Stoffwechsel, Stressreaktion, Genexpression und Biomarker. Unter den in dieser Arbeit genauer betrachteten Loci der Arbeiten, die Fritsche et al. (2016) zitierten, wurden fünf schon vor 2016 bekannte Loci in den Folgejahren nicht weiter untersucht. In der kombinierten Analyse der GWAS aus dem Jahr 2013 und 2016 fällt auf, dass alle bekannten Loci bereits untersucht wurden, unter den 16 Loci, die 2016 erstmals neu berichtet wurden, jedoch lediglich zwei. Zusammenfassend ist zu sagen, dass die Forschung zur Genetik der AMD in viele verschiedene Richtungen erfolgt, wobei eine vergleichende Analyse dieser Richtungen sinnvoll wäre. Dies gestaltet sich jedoch kompliziert. Neu gefundene Assoziationen finden dabei in die weiterführende Forschung nur sehr wenig Eingang, obwohl eine funktionelle Validierung und Abklärung vielversprechend wären

FlexMap Fusion: Georeferencing and Automated Conflation of HD Maps with OpenStreetMap

Today's software stacks for autonomous vehicles rely on HD maps to enable sufficient localization, accurate path planning, and reliable motion prediction. Recent developments have resulted in pipelines for the automated generation of HD maps to reduce manual efforts for creating and updating these HD maps. We present FlexMap Fusion, a methodology to automatically update and enhance existing HD vector maps using OpenStreetMap. Our approach is designed to enable the use of HD maps created from LiDAR and camera data within Autoware. The pipeline provides different functionalities: It provides the possibility to georeference both the point cloud map and the vector map using an RTK-corrected GNSS signal. Moreover, missing semantic attributes can be conflated from OpenStreetMap into the vector map. Differences between the HD map and OpenStreetMap are visualized for manual refinement by the user. In general, our findings indicate that our approach leads to reduced human labor during HD map generation, increases the scalability of the mapping pipeline, and improves the completeness and usability of the maps. The methodological choices may have resulted in limitations that arise especially at complex street structures, e.g., traffic islands. Therefore, more research is necessary to create efficient preprocessing algorithms and advancements in the dynamic adjustment of matching parameters. In order to build upon our work, our source code is available at https://github.com/TUMFTM/FlexMap_Fusion.Comment: 7 page