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Tobacco smoke-associated particulate matter emissions in a car cabin using the TAPaC platform
(2023)
Zigarettenrauch enthält bis zu 5000 Inhaltsstoffe, von denen mindestens 250 gesundheits-schädlich und 98 krebserregend sind. Der freigesetzte Feinstaub erreicht hohe Konzentrati-onen in Innenräumen und ist somit besonders schädlich für Passivraucher (z.B. Kinder).
Ziel war es eine Messplattform zu etablieren, mit dessen Hilfe die Feinstaubexposition durch Zigarettenrauch im Fahrzeuginnenraum unter unterschiedlichen ventilatorischen Szenarien untersucht werden konnte. Zudem sollte der Einfluss verschiedener Tabakprodukte auf die Feinstaubkonzentration getestet werden.
Im ersten Teil dieser Dissertation wird die neuartige TAPaC Messplattform (tobacco-associated particulate matter emissions inside a car cabin: establishment of a new measuring platform) vorgestellt. Sie erlaubt die Auswirkungen verschiedener ventilatorischer Sze-narien auf die Feinstaubemission von Zigarettenrauch im Auto besser beurteilen zu können. Da niemand gesundheitsschädlichem Tabakrauch ausgesetzt wird, kann sie ohne jegliche ethische Bedenken eingesetzt werden. Die Zigaretten werden hierbei einzeln auf der Beifahrerseite verraucht. Der beim Rauchen freigesetzte Feinstaub wird auf der Fahrerseite gemessen und in PM10 (Partikel mit einem aerodynamischen Durchmesser <10 µm), PM2,5 (Partikel mit einem aerodynamischen Durchmesser <2,5 µm), und PM1 (Partikel mit einem aerodynamischen Durchmesser <1 µm) unterteilt. Hierbei konnten unter der Verwendung von 3R4F Research Cigarettes extrem hohe Feinstaubmesswerte bei geschlossenen Fenstern und ausgeschalteter Lüftung nachgewiesen werden (PM10: 1608 µg/m3, PM2,5: 1583 µg/m3, PM1: 1133 µg/m3). Diese Daten stellen Durchschnittwerte nach 10-minütiger Messung dar. Auch konnte eine Reduktion der Feinstaubkonzentration (PM10: -70,8 bis -74,4%, PM2,5: -70,6 bis -74,3%, PM1: -64,0 bis -68,0%) durch den Einsatz der Lüftung nachgewiesen werden.
Der zweite Teil dieser Dissertation befasste sich maßgeblich mit dem Einfluss unterschiedlicher ventilatorischer Szenarien auf die Feinstaubkonzentrationen im Auto. Unter Verwen-dung von drei unterschiedlichen Zigarettenprodukten (3R4F Research Cigarettes, Marlboro Red, Marlboro Gold) wurden insgesamt 7 ventilatorische Szenarien (Condition C1b–C7b) getestet. Für alle Szenarien, mit Ausnahme von C1b, war die Autolüftung auf Stufe 2/4 ge-stellt und in Richtung der Windschutzscheibe gerichtet. Die Szenarien beinhalteten: Condition 1 (C1b) Fenster geschlossen, Autolüftung aus und externer Ventilator aus, Condition 2 (C2b) Fenster 10 cm geöffnet und externer Ventilator aus, Condition 3 (C3b) Fenster 10 cm geöffnet und externer Ventilator auf höchster Stufe (3/3) an, Condition 4 (C4b) Fenster halb geöffnet und externer Ventilator aus, Condition 5 (C5b) Fenster halb geöffnet und externer Ventilator auf höchster Stufe (3/3) an, Condition 6 (C6b) Fenster vollständig geöffnet und externer Ventilator aus und Condition 7 (C7b) Fenster vollständig geöffnet und externer Ventilator auf höchster Stufe (3/3) an.
Es zeigten sich besonders hohe Feinstaubkonzentrationen bei Zigaretten, welche ohne Ventilation bei geschlossenem Fenster verraucht wurden. Unabhängig von der verwendeten Marke war die Feinstaubbelastung nach 10 min unter C1b (PM10: 1272–1697 µg/m3, PM2,5: 1253–1659 µg/m3, PM1: 964–1263 µg/m3) deutlich höher als unter C2b (PM10: 67–84 µg/m3, PM2,5: 68–83 µg/m3, PM1: 66–79 µg/m3), C3b (PM10: 100–139 µg/m3, PM2,5: 99–138 µg/m3, PM1: 95–132 µg/m3), C4b (PM10: 84–94 µg/m3, PM2,5: 84–93 µg/m3, PM1: 81–89 µg/m3), C5b (PM10: 94–120 µg/m3, PM2,5: 93–119 µg/m3, PM1: 90–114 µg/m3), C6b (PM10: 155–196 µg/m3, PM2,5: 154–195 µg/m3, PM1: 148–184 µg/m3), und C7b (PM10: 74–99 µg/m3, PM2,5: 72–97 µg/m3, PM1: 69–93 µg/m3). Ebenfalls wurden Feinstaubspitzenwerte bei 4,5 min und 10 min ausgewertet. Bei 4,5 min konnte PM10 unter C2b–C7b um 81,6–93,3% im Vergleich zu C1b reduziert werden. Bei 10 min sogar um 92,9–99,3%. Die 3R4F Zigarette hatte die höchste Feinstaubemission gefolgt von Marlboro Rod und Marlboro Gold. Zudem zeigte sich, dass die Feinstaubemission auch von den Tabakinhaltsstoffen und dessen Konzentrationen abhängig ist.
Die Etablierung der neuen Messplattform ermöglicht die Erforschung von Feinstaubexpositionen durch Zigarettenrauch im Auto ohne potentiell gesundheitliche Folgen. In Zusammenschau der Daten ließ sich nach Öffnen des Fensters und unter Einflussnahme verschiedener ventilatorischer Einstellungen eine deutliche Reduktion der Feinstaubkonzentration im Auto feststellen. Nichtsdestotrotz bleibt die Feinstaubbelastung im Autoinnenraum zu hoch und übersteigt die Richtwerte der Air Quality Guidelines aus dem Jahre 2021 der WHO. Die experimentell untersuchten Belüftungsszenarien sind somit insuffizient, da sie nicht vor der toxischen Feinstaubexposition durch Passivrauch beim Autofahren schützen können.
Background/aim: The aim of this study was to analyze a population of patients who had suffered from traumatic dental injuries (TDIs) by using different patient-, trauma- and treatment-related parameters.
Material and methods: All dental records of patients ≥ 3 years old who had presented at the dental emergency service between Jan 1, 2009 and Dec 31, 2016 for the treatment of dental trauma were analyzed. A total of 2758 patients were invited for a recall examination at the Department for Dental Surgery and Implantology, ZZMK Carolinum, Goethe University Frankfurt, Germany; of these, 269 patients attended their recall appointments.
Results: The enrolled patient population consisted of 1718 males and 1040 females, with a mean age of 19.63 years (median 12.00 ± 17.354 years). A total of 4909 injured teeth were assessed, with a mean of 1.78 injured teeth per patient (median 2.00 ± 1.279). Males were found to be more frequently affected by TDIs compared to females (1.65:1). The majority of these injuries occurred in the first two decades of life (66.1%; n = 1824). The majority of the patients presented for initial treatment within 24 h of their accident (95.7%). The most frequent TDIs were isolated luxation injuries 49.4% (n = 2426) and isolated crown fractures 30% (n = 1472). Combination injuries were diagnosed in 20.6% of the cases (n = 1011).
Conclusions: Based on the findings of the present analysis, it can be concluded that males were more frequently affected by TDIs than females. Most patients had suffered from TDI before they had turned 10 years of age. Overall, the enamel–dentin fracture was found to be the most frequent injury, followed by concussions and lateral luxations.
Andlauer, Till ; Guzman-Parra, José ; Streit, Fabian ; Strohmaier, Jana ; González, Maria José ; Flores, Susana Gil ; Cabaleiro Fabeiro, Francisco J. ; Rı́o Noriega, Francisco del ; Perez, Fermin Perez ; González, Jesus Haro ; Orozco Diaz, Guillermo ; de Diego-Otero, Yolanda ; Moreno-Kuestner, Berta ; Auburger, Georg ; Degenhardt, Franziska ; Heilmann-Heimbach, Stefanie ; Herms, Stefan ; Hoffmann, Per ; Frank, Josef ; Foo, Jerome Clifford ; Treutlein, Jens ; Witt, Stephanie H. ; Cichon, Sven ; Kogevinas, Manolis ; Rivas, Fabio ; Mayoral, Fermı́n ; Müller-Myhsok, Bertram ; Forstner, Andreas Josef ; Nöthen, Markus Maria ; Rietschel, Marcella
Multiplex families with a high prevalence of a psychiatric disorder are often examined to identify rare genetic variants with large effect sizes. In the present study, we analysed whether the risk for bipolar disorder (BD) in BD multiplex families is influenced by common genetic variants. Furthermore, we investigated whether this risk is conferred mainly by BD-specific risk variants or by variants also associated with the susceptibility to schizophrenia or major depression. In total, 395 individuals from 33 Andalusian BD multiplex families (166 BD, 78 major depressive disorder, 151 unaffected) as well as 438 subjects from an independent, BD case/control cohort (161 unrelated BD, 277 unrelated controls) were analysed. Polygenic risk scores (PRS) for BD, schizophrenia (SCZ), and major depression were calculated and compared between the cohorts. Both the familial BD cases and unaffected family members had higher PRS for all three psychiatric disorders than the independent controls, with BD and SCZ being significant after correction for multiple testing, suggesting a high baseline risk for several psychiatric disorders in the families. Moreover, familial BD cases showed significantly higher BD PRS than unaffected family members and unrelated BD cases. A plausible hypothesis is that, in multiplex families with a general increase in risk for psychiatric disease, BD development is attributable to a high burden of common variants that confer a specific risk for BD. The present analyses demonstrated that common genetic risk variants for psychiatric disorders are likely to contribute to the high incidence of affective psychiatric disorders in the multiplex families. However, the PRS explained only part of the observed phenotypic variance, and rare variants might have also contributed to disease development.
Dongen, Jenny van ; Hagenbeek, Fiona A. ; Suderman, Matthew ; Roetman, Peter J. ; Sugden, Karen ; Geburtig-Chiocchetti, Andreas ; Ismail, Khadeeja ; Mulder, Rosa H. ; Hafferty, Jonathan D. ; Adams, Mark J. ; Walker, Rosie M. ; Morris, Stewart W. ; Lahti, Jari ; Küpers, Leanne K. ; Escaramis, Georgia ; Alemany, Silvia ; Bonder, Marc Jan ; Meijer, Mandy ; Ip, Hill F. ; Jansen, Rick ; Baselmans, Bart M. L. ; Parmar, Priyanka ; Lowry, Estelle ; Streit, Fabian ; Sirignano, Lea ; Send, Tabea S. ; Frank, Josef ; Jylhävä, Juulia ; Wang, Yunzhang ; Mishra, Pashupati Prasad ; Colins, Olivier F. ; Corcoran, David L. ; Poulton, Richie ; Mill, Jonathan ; Hannon, Eilis ; Arseneault, Louise ; Korhonen, Tellervo ; Vuoksimaa, Eero ; Felix, Janine F. ; Bakermans-Kranenburg, Marian J. ; Campbell, Archie ; Czamara, Darina ; Binder, Elisabeth ; Corpeleijn, Eva ; González Ruiz, Juan Ramon ; Grazuleviciene, Regina ; Gutzkow, Kristine B. ; Evandt, Jorunn ; Vafeiadi, Marina ; Klein, Marieke ; Meer, Dennis van der ; Ligthart, Lannie ; Heijmans, Bastiaan Theodoor ; Hoen, Peter A. C. 't ; Meurs, Joyce Berdina Josepha van ; Franke, Lude ; Boomsma, Dorret I. ; Pool, René ; Hottenga, Jouke J. ; Greevenbroek, Marleen M. J. van ; Stehouwer, Coen D. A. ; Kallen, Carla J. H. van der ; Schalkwijk, Casper G. ; Wijmenga, Cisca ; Zhernakova, Sasha ; Tigchelaar, Ettje F. ; Slagboom, P. Eline ; Beekman, Marian ; Deelen, Joris ; Heemst, Diana van ; Veldink, Jan H. ; Berg, Leonard H. van den ; Duijn, Cornelia M. van ; Hofman, Bert A. ; Isaacs, Aaron ; Uitterlinden, André G. ; Jhamai, P. Mila ; Verbiest, Michael ; Suchiman, H. Eka D. ; Verkerk, Marijn ; Breggen, Ruud van der ; Rooij, Jeroen van ; Lakenberg, Nico ; Mei, Hailiang ; Iterson, Maarten van ; Galen, Michiel van ; Bot, Jan ; Zhernakova, Dasha V. ; Hof, Peter van ’t ; Deelen, Patrick ; Nooren, Irene ; Moed, Matthijs ; Vermaat, Martijn ; Luijk, René ; Dijk, Freerk van ; Arindrarto, Wibowo ; Kielbasa, Szymon M. ; Swertz, Morris A. ; Zwet, Erik. W. van ; Hoen, Peter-Bram ’t ; Kluft, Cornelis ; Davies, Gareth E. ; Hakulinen, Christian ; Keltikangas-Järvinen, Liisa ; Franke, Barbara ; Freitag, Christine M. ; Konrad, Kerstin ; Hervás, Amaia ; Fernández-Rivas, Aranzazu ; Vetro, Agnes ; Raitakari, Olli ; Lehtimäki, Terho ; Vermeiren, Robert ; Strandberg, Timo ; Räikkönen, Katri ; Snieder, Harold ; Witt, Stephanie H. ; Deuschle, Michael ; Pedersen, Nancy L. ; Hägg, Sara ; Sunyer, Jordi ; Kaprio, Jaakko ; Ollikainen, Miina ; Moffitt, Terrie E. ; Tiemeier, Henning ; IJzendoorn, Marinus H. van ; Relton, Caroline ; Vrijheid, Martine ; Sebert, Sylvain ; Jarvelin, Marjo-Riitta ; Caspi, Avshalom ; Evans, Kathryn L. ; McIntosh, Andrew M. ; Bartels, Meike
DNA methylation profiles of aggressive behavior may capture lifetime cumulative effects of genetic, stochastic, and environmental influences associated with aggression. Here, we report the first large meta-analysis of epigenome-wide association studies (EWAS) of aggressive behavior (N = 15,324 participants). In peripheral blood samples of 14,434 participants from 18 cohorts with mean ages ranging from 7 to 68 years, 13 methylation sites were significantly associated with aggression (alpha = 1.2 × 10−7; Bonferroni correction). In cord blood samples of 2425 children from five cohorts with aggression assessed at mean ages ranging from 4 to 7 years, 83% of these sites showed the same direction of association with childhood aggression (r = 0.74, p = 0.006) but no epigenome-wide significant sites were found. Top-sites (48 at a false discovery rate of 5% in the peripheral blood meta-analysis or in a combined meta-analysis of peripheral blood and cord blood) have been associated with chemical exposures, smoking, cognition, metabolic traits, and genetic variation (mQTLs). Three genes whose expression levels were associated with top-sites were previously linked to schizophrenia and general risk tolerance. At six CpGs, DNA methylation variation in blood mirrors variation in the brain. On average 44% (range = 3–82%) of the aggression–methylation association was explained by current and former smoking and BMI. These findings point at loci that are sensitive to chemical exposures with potential implications for neuronal functions. We hope these results to be a starting point for studies leading to applications as peripheral biomarkers and to reveal causal relationships with aggression and related traits.
The compulsive habit of cars
(2014)
The car dependence of people living in contemporary cities is a major concern for policy makers, who often find it difficult to persuade people into more sustainable transport modes. By contrast, recent insights from neuroscience have shown that a broad spectrum of behaviors can become habitual and, thus, resistant to change. Here, we outline the potential of collaboration between neuroscience and human geography aiming at a better understanding of habits that determine everyday commuting routines.
Bei 166 Patienten wurde eine perkutane transluminale Angioplastie (PTA) der A. carotis interna bzw. communis durchgeführt. 37/166 Patienten hatten symptomatische Stenosen (22,3 %). Der Stenosegrad lag bei 76,0 ± 9,9 % (57- 97 %). Bei 165/166 Patienten (99,4 %) wurde die PTA erfolgreich durchgeführt und der Stenosegrad auf 5,8 ± 21,2 % ( -73- 79 %) gesenkt. Perioperativ traten bei 8/166 Patienten neurologische Komplikationen auf (4,8 %), darunter fünf cerebrale Infarkte (3,0 %). Perioperative verstarben vier Patienten (2,4 %), zwei an Folgen einer Apoplexie, zwei an Folgen eines Myokardinfarktes. 152/166 Patienten wurden durchschnittlich 16 ± 18 Monate (ein Tag nach PTA bis maximal 87 Monaten) nachuntersucht. Bei 17 Patienten kam es zu Rezidivstenosen (10,2 %), drei davon zeigten neurologische Symptome, drei weitere bedurften einer wiederholten PTA (Re-PTA).
Die perioperativen Ergebnisse der vorgelegten Arbeit deckten sich weitgehend mit denen anderer Studien zur PTA 5, sowie zu denen bedeutender Studien zur Thrombendarteriektomie (TEA) 6. Diese Ergebnisse wurden durch die randomisierte CAVATAS- Studie
bestätigt, in der keine signifikanten Unterschiede bezüglich der Inzidenz neurologischer Symptome und der Mortalität der PTA und TEA nachgewiesen wurden [18]. Größer angelegte Studien hierzu werden zur Zeit in Europa und Nordamerika durchgeführt (CREST, SPACE). Rezidivstenosen scheinen häufiger nach PTAs aufzutreten, wobei Verbesserungen durch neue Techniken für die PTA und auch die TEA zu erwarten sind. Die klinische Bedeutung der Rezidivstenosen erwies sich bei der PTA als relativ unbedeutend.
Bei der Ermittlung von Risikofaktoren (Patientenalter; Stenoselänge; Kalzifikationen, Ulcerationen und Thromben in der Läsion) wurde festgestellt, dass bei der PTA andere Faktoren bedeutsam sind als bei der TEA. Zukünftig könnten Komplikationen vermieden werden, wenn Patienten aufgrund ihres Risikoprofils zur jeweils vorteilhafteren Behandlung zugewiesen würden.
Bei 91/166 Patienten wurde ein Embolieprotektionssystem verwandt. Es wurden verschiedene Methoden angewendet: distale Occlusion (PercuSurge™ System, n = 46), Filtersysteme (4 verschiedene Typen, n = 43) und proximale Occlusion (Arteriasystem, n = 2). Die Erfolgsrate lag bei 95,6 % und unterschied sich nicht signifikant innerhalb der einzelnen Systeme (PercuSurge™ System: 95,7 %; Filter: 95,3 %). Bei 67/91 Patienten wurde thrombotisches Material in den Filtern, bzw. im Aspirat festgestellt (73,6 %), wobei die Filter häufiger Partikel zurückhielten als das PercuSurge™ System (81,4 % versus 69,6 %). Bei vier Patienten kam es während der Protektion zu neurologischen Komplikationen, wobei in keinem dieser Fälle ein kausaler Zusammenhang zu den Protektionssysteme nachgewiesen werden konnte. Bei allen vier Patienten wurde thrombotisches Material nachgewiesen und entfernt. Die perioperative Inzidenz neurologischer Komplikationen lag bei 2,7 % (2/75 Patienten) ohne und bei 6,6 % (6/91 Patienten) mit Protektion. Die Mortalität lag bei 1,3 % (1/75 Patienten) ohne und bei 3,3 % (3/91 Patienten) mit Protektion. Diese Ergebnisse waren nicht signifikant. Die Ergebnisse der Filter und des PercuSurge™ Systems unterschieden sich ebenfalls nicht signifikant voneinander (PercuSurge™ System, Inzidenz neurologischer Komplikationen und Mortalität: 4,3 %; Filtersysteme, Inzidenz neurologischer Komplikationen: 9,3 %, Mortalität: 2,3 %). Während der PTA traten periprocedurale neurologische Symptome (PNS) bei Benutzung von Filtersystemen bei 8/43 Patienten (18,6 %), beim PercuSurge™ System bei 17/46 Patienten (37,0 %) auf.
Alle Protektionssysteme erwiesen sich in der vorliegenden Arbeit als praktikabel und für die klinische Routine geeignet. Der häufige Nachweis von Partikeln bestätigte den Nutzen der Protektion. In dieser Arbeit zeigte sich jedoch eine höhere Inzidenz neurologischer Komplikationen und Mortalität. Aufgrund der durchweg positiven Erfahrungen in vielen anderen Studien ist jedoch der klinische Nutzen der Protektion unzweifelhaft [70, 90, 132]. Kein signifikanter Unterschied konnte zwischen dem PercuSurge™ System den Filtersystemen festgestellt werden. Das PercuSurge™ System zeichnete eine geringere Inzidenz neurologischer Komplikationen und eine höhere technische Erfolgsrate aus, die Filter eine geringere Inzidenz von PNS und eine größere Effektivität beim Zurückhalten von thromboembolischen Partikeln.
Gerade in der Medizin besteht die Diagnostik nicht nur aus Zahlen und Werten, die Gesamtheit einer Diagnostik setzt sich häufig auch aus Bildern zusammen. Die bildgebende Diagnostik lässt nur wenig Spielraum für eine platzsparende Arbeitsweise, zu wichtig ist der wissenschaftliche Aussagewert feinster Details, seien es nun radiologische Aufnahmen, klinische Bilder oder Histologien. Moderne Computernetzwerke bieten eine geeignete Infrastruktur zum Austausch relevanter Daten in akzeptabler Geschwindigkeit bei guter Datenqualität. So ist die EDV nicht nur Datenverwalter, sondern ein aktives Hilfsmittel im medizinischen Alltagsgebrauch.
Diese Arbeit soll zeigen, welche technischen Voraussetzungen erfüllt sein müssen, um durch Einsatz digitaler Bilderfassungsgeräte eine optimale Datengrundlage für Forschung, Lehre und Dokumentation zu schaffen.
Die gezeigten Systeme sind grundsätzlich in statische „solid-state“ Systeme und dynamische „remote“-Systeme zu unterteilen.
Statische Systeme sind der asynchronen Telemedizin zuzuordnen und arbeiten nach dem store and forward Prinzip. Die Aufnahme ist nicht erweiterbar, in der Ferne wird zeitlich unabhängig die Diagnose gestellt. Dieses System bietet sich in strukturschwachen Regionen an.
Remotesysteme sind technisch sehr viel aufwendiger. Die sogenannte synchrone Telemedizin ist auch räumlich getrennt, findet jedoch zeitgleich statt. Das heißt, über eine Kamera und Datenleitung sind die Experten direkt mit dem Präparat oder dem Patienten verbunden. Aufgrund des technischen Aufwandes sind solche Systeme in der Regel in strukturstarken Regionen zu finden.
Beide Varianten messen sich bezüglich ihrer Validität an dem sogenannten „GoldStandard“, dem direkten Kontakt von Facharzt oder Pathologen zu Patient oder Präparat. Abhängig von der technischen Qualität haben sich beide telemedizinischen Prinzipien als in hohem Maße valide dargestellt.
Die Wahl der Kamera als zentrales Übersetzungsmedium von Bild in Daten setzt ein exaktes Studium der technischen Grundlagen voraus, wenn man bezüglich Auflösung und Lichtempfindlichkeit keine Kompromisse eingehen möchte, aber auch, wenn die physikalischen Grenzen, wie etwa die optische Auflösung eines Systems, die Notwendigkeit eines hochauflösendsten Systems nicht sinnvoll erscheinen lässt. Die Archivierung der Daten erfordert zudem Speicherplatz. Die Kompression von Bildern kann verlustfrei, aber auch verlustbehaftet stattfinden. Je nach Anwendungszweck gilt es daher abzuwägen, ob objektive Verlustfreiheit bei höherem Speicherbedarf oder wenig Platzbedarf bei einem eventuellen Qualitätsverlust gewünscht ist. Im hier gestellten Vergleich zwischen einem hochauflösenden Single-Shot System und einem Multishotaufbau hat sich gezeigt, dass die Qualität des Bildes bei einem hochauflösenden Einzelbild homogener ist, während das gekachelte Bild durch das Merging-Verfahren Belichtungs- und Schärfeunterschiede aufweist und die Bereiche der Bildteilzusammenführung erkennen lassen kann. Als Vorteil eines solchen Aufbaus ist sicherlich die technisch nahezu unbegrenzte Bildfläche zu nennen, da das aufgenommene Areal nicht von einem Einzelbild, sondern der Zahl der Segmente abhängt. Insofern haben beide Konzepte abhängig vom Einsatzanspruch ihre Existenzberechtigung.
Multilevel-Untersuchung des nitrinergen Systems bei affektiven Störungen und schizophrenen Psychosen
(2023)
Das nitrinerge System und damit auch NOx als Neurotransmitter werden mit der Entstehung verschiedener psychischer Erkrankungen in Verbindung gebracht. Die genaue Rolle des Botenstoffs ist jedoch nicht ausreichend geklärt und auch die Frage, ob dieser als diagnostischer oder prädiktiver Biomarker nützlich sein könnte, ist unbeantwortet. In der vorliegenden Arbeit wurde folglich untersucht, ob es Unterschiede zwischen den Diagnosegruppen MDD, BIP, SCZ und der Kontrollgruppe bezüglich peripherer NOx- Konzentrationen gibt. Darüber hinaus wurden Unterschiede innerhalb der Diagnosegruppen im Krankheitsverlauf im Sinne von Phasenunterschieden mittels zweier Messzeitpunkte untersucht und analysiert, ob es Korrelationen mit genetischen Variationen in NOS-Genabschnitten gibt. Insgesamt wurden 185 Probanden in die Studie mitaufgenommen: 52 gesunde CTRL, 43 Patienten mit MDD, 41 Patienten mit BIP und 49 Patienten mit SCZ. Biochemische, genetische und klinische Daten wurden bei Aufnahme und Entlassung in der psychiatrischen Abteilung des Universitätsklinikums Frankfurt erhoben. Klinische Daten, die den Symptomverlauf 90 und die Erkrankungsschwere beurteilten, nutzten dazu standardisierte teilstrukturierte klinische Interviews. Biochemische Daten wurden mittels im Serum gemessener NOx- Spiegel quantifiziert. Bezüglich der Untersuchung der Risikogenvarianten wurden Probanden anhand des NOS1 ex1f-VNTR-Polymorphismus sowie SNPs in den Genen NOS1, NOS3 und NOS1AP genotypisiert. Bei Aufnahme wiesen SCZ-Patienten im Vergleich zu CTRL-, MDD- und BIP-Gruppen signifikant höhere NOx- Konzentrationen auf. Während NOx- Spiegel im Behandlungsverlauf bei MDD- und BIP-Patienten signifikant zunahmen, konnte dies bei SCZ-Patienten nicht beobachtet werden. Weiterhin konnte gezeigt werden, dass Patienten, deren depressive Beschwerden nicht relevant zurückgingen, bei Entlassung signifikant höhere NOx- Konzentrationen aufwiesen, was durch die Beobachtung einer signifikant positiven Korrelation zwischen NOx- Serumspiegeln und depressiven Symptomen bei Entlassung unterstützt wurde. Bei der genetischen Untersuchung der Daten fiel auf, dass homozygote Träger des kurzen VNTR-Allels signifikant erhöhte NOx- Konzentrationen besaßen. Diese Ergebnisse blieben bei jenen Trägern auch nach Entlassung signifikant. Insgesamt gibt es Hinweise darauf, dass erhöhte periphere NOx- Metabolitkonzentrationen mit einer Zunahme der Psychopathologie bzw. der Erkrankungsschwere einhergehen könnten, was möglicherweise auf den NOS1 ex1f-VNRT-Polymorphismus zurückzuführen ist. Außerdem zeigten zwei SNPs, welche beide im NOS1AP-Gen lokalisiert sind, bei BIP Patienten signifikant gesteigerte NOx- Werte. Die vorliegenden Ergebnisse deuten darauf hin, dass NO-Signalübertragung und NOS-Genotypen in der Pathogenese psychischer Erkrankungen eine Rolle spielen könnten. Ob diese Veränderungen allerdings kausal mit Krankheitsprozessen zu tun haben oder ob es eher Epiphänomene der Erkrankungen sind, kann mit dieser Studie nicht geklärt werden. Die Genvarianten könnten wiederum bei der Regulierung von peripheren NOx- Konzentrationen von Bedeutung sein. Die Arbeit liefert zudem Hinweise, die Verwendung von NOx als möglichen peripheren Biomarker weiter zu verfeinern und zu untersuchen. Zukünftige Studien, die die Wirksamkeit von NOx- modulierenden Pharmaka untersuchen, könnten davon profitieren, Diagnosegruppen nach Subgruppen einzuteilen, die sowohl NOS Risikogenvarianten als auch periphere NOx- Spiegel im Sinne eines Biomarker beachten.
Polyunsaturated fatty acids (PUFAs) play essential roles in mediating inflammation and its resolution. PUFA metabolites generated by the cytochrome P450 (CYP) - soluble epoxide hydrolase (sEH) axis are known to regulate macrophage activation/polarization but little is known about their role in the resolution of inflammation. Monocytes were isolated from murine bone marrow or human peripheral blood and differentiated to naïve macrophages (M0). Thereafter cells were polarized using LPS and IFNγ (M1), IL-4 (M2a), or TGFβ1 (M2c). Gene expression was analyzed by RNA sequencing, RT-qPCR and Western blotting. Phagocytosis of zymosan and oxo-LDL were also assessed in vitro. Zymosan-induced peritonitis combined with immune cell profiling was used to evaluate the resolution of inflammation in vivo. The expression of sEH was comparable in M0, M1 and M2a macrophages but markedly elevated in M2c polarized cells. The increase in sEH expression elicited by TGFβ relied on the TGFβ receptor ALK5 and the phosphorylation of SMAD2, which was able to bind to the sEH promoter. In macrophages lacking sEH, M2c polarization was incomplete and characterized by lower levels of pro-resolving phagocytosis associated receptors (Tlr2 and Mrc1), as well as higher levels of the pro-inflammatory markers; Nlrp3, IL-1β and TNFα. Fitting with the failure to upregulate phagocytosis associated receptors, the uptake of zymosan and ox-LDL was less efficient in M2c macrophages from sEH-/- mice. The latter animals also demonstrated a retarded resolution of inflammation (zymosan-induced peritonitis) in vivo with fewer resident macrophages and recruited macrophages. PUFA profile analysis indicated decreased sEH substrates e.g., 11, 12-EET, as well as increased sEH products e.g., 11, 12-DHET, indicating an increased sEH activity in M2c macrophages. Taken together, our data indicates that sEH expression is required for the effective M2c polarization of macrophages and thus the resolution of inflammation.