Pathophysiologisch-serologische, bildgebende und klinische Charakteristika der Neuromyelitis Optica

Hintergrund: Neuromyelitis optica-Spektrum-Erkrankungen (NMOSD) stellen eine Gruppe neuroinflammatorischer Erkrankungen dar, die mit dem klinischen Auftreten von Myelitiden und/oder Optikusneuritiden (ON) einhergeht. Aufgrund zahlreicher überlappender klinischer und paraklinischer Eigenschaften beim Nachweis verschiedener Antikörper, vor allem auch in Abgrenzung zur Multiplen Sklerose (MS), besteht weiterhin der Bedarf nach neuen Biomarkern. Methodik: In zwei Studien wurden NMOSD-Patienten mit positivem Nachweis für Aquaporin-4-Antikörper (AQP-4-Ak) mittels 7 Tesla (T) Magnetresonanztomografie (MRT) hinsichtlich der I) periventrikulären Venendichte (PVA) in T2*-gewichteten Aufnahmen und II) der Phasenverschiebung in suszeptibilitätsgewichteten Sequenzen untersucht. Als Vergleich dienten die Ergebnisse von Patienten mit MS und gesunden Kontrollen (HC). In einer dritten Arbeit (III) erfolgte eine retrospektive Auswertung visueller Parameter im Vergleich von AQP-4-Ak-positiven Patienten und Patienten mit Antikörpern gegen das Myelin-Oligodendrozyten-Glykoprotein (MOG) mittels Optischer Kohärenztomografie (OCT), Visuell Evozierter Potenziale (VEP) und der Fernvisus-Messung. Ergebnisse: Bildmorphologisch zeigte sich in den 7T-T2* gewichteten Aufnahmen bei Patienten mit AQP-4-Ak-positiver NMOSD eine normal große PVA (AQP-4-Ak: PVA = 133 mm2; MS: PVA = 117 mm2; HC: PVA =144 mm2) und überwiegend fehlende paramagnetische Phasenverschiebungen (107 von 112 Läsionen, 96%) in den SWI-Sequenzen. Hinsichtlich des Vergleichs von MOG-Ak- gegenüber von AQP4-Ak-positiven Patienten fiel eine größere absolute Schubrate (Mittelwert, Spannweite, MOG-Ak: 4.5, 1 - 13; APQ4-Ak: 2, 1 -4; p = 0.012), bei insgesamt ähnlichem Verlust der im OCT gemessenen peripapillären retinalen Nervenfaserschicht (pRNFL) der AQP-4-Ak-positiven NMOSD im Vergleich zu den MOG-Ak-positiven Patienten auf (Mittelwert Standardabweichung, MOG-Ak: 59 ± 23 µm, AQP-4-Ak: 59 ± 21 µm). Jedoch waren die Werte der pRNFL nach dem Erstereignis einer ON bei den Patienten mit AQP-4-Ak deutlich stärker reduziert, als bei den MOG-Ak-positiven Patienten (AQP-4-Ak: pRNFL-Verlust = 32.8 μm (p<0.001); MOG-Ak: pRNFL-Verlust = 12.8 μm (p=0.001)). Schlussfolgerung: Mit Hilfe von modernen diagnostischen Verfahren, wie dem Ultrahochfeld-MRT und dem OCT wird die bessere Charakterisierung von phänotypisch ähnlichen neuroinflammatorischen Krankheitsentitäten ermöglicht. Die hierfür zugrundeliegenden unterschiedlichen Pathomechanismen sind bisher nicht vollständig verstanden und bedürfen weiterer Untersuchungen.Introduction: Different neuroinflammatory entities define the group of Neuromyelitis optica spectrum disorders (NMOSD) and are usually associated with the presentation of myelitis and/or optic neuritis. Although various antibodies were verified, there is still the challenge of overlapping clinical and paraclinical phenotypes which ask for further new diagnostic parameters. Methods: By using 7 Tesla (T) magnetic resonance imaging (MRI) patients with aquaporin-4-antibodies (AQP-4-ab) were investigated concerning a) the periventricular venous area (PVA) at T2*-weighted images and b) the phase changes within brain lesions at susceptibility-weighted (SWI)-images. The findings were compared to patients with Multiple Sclerosis (MS) and healthy controls (HC). Further patients with AQP-4-ab and antibodies against myelin oligodendrocyte glycoprotein (MOG-ab) were faced by using retrospective data of retinal optical coherence tomography (OCT), visual acuity and visual evoked potentials (VEP). Results: Patients with AQP-4-ab presented equal results like HC concerning the PVA (AQP-4-ab: PVA = 133 mm2; MS: PVA = 117 mm2; HC: PVA =144 mm2) and predominantly missing phase changes in brain lesions at SWI-images (107 of 112 lesions, 96%). Both, AQP-4-ab- and MOGab-positive patients, presented a loss in peripapillary nerve fiber layer (pRNFL) thickness at the same extend (mean ± standard deviation, MOG-ab: 59 ± 23 ±m, AQP4-ab: 59 ± 21 ±m), while the number of episodes of optic neuritis (ON) was lower in AQP4-ab-positive patients (mean, range, MOG-ab: 4.5, 1 - 13; APQ4-ab: 2, 1 -4; p = 0.012). However, the loss of pRNFL thickness after the first episode of ON was greater in patients with AQP-4-ab (AQP-4-ab: pRNFL-loss = 32.8 µm (p<0.001); MOG-ab pRNFL-loss = 12.8 µm (p=0.001). Conclusion: With the help of novel diagnostic tools, like the ultrahighfield-MRI and OCT, it is possible to distinguish between neuroinflammatory entities with similar phenotypes. For a better understanding of the underlying pathomechanisms further investigations are still needed

Aquaporin-4 Functionality and Virchow-Robin Space Water Dynamics: Physiological Model for Neurovascular Coupling and Glymphatic Flow.

The unique properties of brain capillary endothelium, critical in maintaining the blood-brain barrier (BBB) and restricting water permeability across the BBB, have important consequences on fluid hydrodynamics inside the BBB hereto inadequately recognized. Recent studies indicate that the mechanisms underlying brain water dynamics are distinct from systemic tissue water dynamics. Hydrostatic pressure created by the systolic force of the heart, essential for interstitial circulation and lymphatic flow in systemic circulation, is effectively impeded from propagating into the interstitial fluid inside the BBB by the tightly sealed endothelium of brain capillaries. Instead, fluid dynamics inside the BBB is realized by aquaporin-4 (AQP-4), the water channel that connects astrocyte cytoplasm and extracellular (interstitial) fluid. Brain interstitial fluid dynamics, and therefore AQP-4, are now recognized as essential for two unique functions, namely, neurovascular coupling and glymphatic flow, the brain equivalent of systemic lymphatics

Volume changes during active shape fluctuations in cells

Cells modify their volume in response to changes in osmotic pressure but it is usually assumed that other active shape variations do not involve significant volume fluctuations. Here we report experiments demonstrating that water transport in and out of the cell is needed for the formation of blebs, commonly observed protrusions in the plasma membrane driven by cortex contraction. We develop and simulate a model of fluid mediated membrane-cortex deformations and show that a permeable membrane is necessary for bleb formation which is otherwise impaired. Taken together our experimental and theoretical results emphasize the subtle balance between hydrodynamics and elasticity in actively driven cell morphological changes.Comment: Phys. Rev. Lett. in press. 13 pages 4 figures, 9 supplementary figure

Expression and Localization of aquaporin‐1 in Temporomandibular Joint Disc with Internal Derangement

Background: Internal derangement is the most frequent arthropathy affecting the temporomandibular joint, where its commonest form is anterior disc displacement with or without reduction. Despite the frequency of the disorder, the biochemical features of displaced discs are still unclear. Methods: We investigated the expression pattern and localization of aquaporin‐1, an important channel protein involved in plasma membrane water permeability, in patients with anterior disc displacement (both with and without reduction), with a view to assessing the characteristics of local tissue responses to the microenvironmental changes induced by abnormal mechanical loading of the displaced disc. Protein expression was studied by immunohistochemistry in different areas of discs from 18 patients with anterior disc displacement with or without reduction and in four normal controls. Results: A greater proportion of cells immunopositive for aquaporin‐1 were detected in diseased than in normal discs. Whereas protein expression was substantially similar in the different areas of normal discs, a significantly larger number of immunopositive cells were detected in the posterior band of displaced discs without reduction and in the anterior and intermediate bands of those with reduction. Conclusions: These findings suggest that aquaporin‐1 is expressed and upregulated in temporomandibular joint with anterior disc displacement (both with and without reduction)

VerdictDB: Universalizing Approximate Query Processing

Despite 25 years of research in academia, approximate query processing (AQP) has had little industrial adoption. One of the major causes of this slow adoption is the reluctance of traditional vendors to make radical changes to their legacy codebases, and the preoccupation of newer vendors (e.g., SQL-on-Hadoop products) with implementing standard features. Additionally, the few AQP engines that are available are each tied to a specific platform and require users to completely abandon their existing databases---an unrealistic expectation given the infancy of the AQP technology. Therefore, we argue that a universal solution is needed: a database-agnostic approximation engine that will widen the reach of this emerging technology across various platforms. Our proposal, called VerdictDB, uses a middleware architecture that requires no changes to the backend database, and thus, can work with all off-the-shelf engines. Operating at the driver-level, VerdictDB intercepts analytical queries issued to the database and rewrites them into another query that, if executed by any standard relational engine, will yield sufficient information for computing an approximate answer. VerdictDB uses the returned result set to compute an approximate answer and error estimates, which are then passed on to the user or application. However, lack of access to the query execution layer introduces significant challenges in terms of generality, correctness, and efficiency. This paper shows how VerdictDB overcomes these challenges and delivers up to 171$\times$ speedup (18.45$\times$ on average) for a variety of existing engines, such as Impala, Spark SQL, and Amazon Redshift, while incurring less than 2.6% relative error. VerdictDB is open-sourced under Apache License.Comment: Extended technical report of the paper that appeared in Proceedings of the 2018 International Conference on Management of Data, pp. 1461-1476. ACM, 201

Database Learning: Toward a Database that Becomes Smarter Every Time

In today's databases, previous query answers rarely benefit answering future queries. For the first time, to the best of our knowledge, we change this paradigm in an approximate query processing (AQP) context. We make the following observation: the answer to each query reveals some degree of knowledge about the answer to another query because their answers stem from the same underlying distribution that has produced the entire dataset. Exploiting and refining this knowledge should allow us to answer queries more analytically, rather than by reading enormous amounts of raw data. Also, processing more queries should continuously enhance our knowledge of the underlying distribution, and hence lead to increasingly faster response times for future queries. We call this novel idea---learning from past query answers---Database Learning. We exploit the principle of maximum entropy to produce answers, which are in expectation guaranteed to be more accurate than existing sample-based approximations. Empowered by this idea, we build a query engine on top of Spark SQL, called Verdict. We conduct extensive experiments on real-world query traces from a large customer of a major database vendor. Our results demonstrate that Verdict supports 73.7% of these queries, speeding them up by up to 23.0x for the same accuracy level compared to existing AQP systems.Comment: This manuscript is an extended report of the work published in ACM SIGMOD conference 201