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Inflammation or injury to the somatosensory nervous system may result in chronic pain conditions, which affect millions of people and often cause major health problems. Emerging lines of evidence indicate that reactive oxygen species (ROS), such as superoxide anion or hydrogen peroxide, are produced in the nociceptive system during chronic inflammatory and neuropathic pain and act as specific signaling molecules in pain processing. Among potential ROS sources in the somatosensory system are NADPH oxidases, a group of electron-transporting transmembrane enzymes whose sole function seems to be the generation of ROS. Interestingly, the expression and relevant function of the Nox family members Nox1, Nox2, and Nox4 in various cells of the nociceptive system have been demonstrated. Studies using knockout mice or specific knockdown of these isoforms indicate that Nox1, Nox2, and Nox4 specifically contribute to distinct signaling pathways in chronic inflammatory and/or neuropathic pain states. As selective Nox inhibitors are currently being developed and investigated in various physiological and pathophysiological settings, targeting Nox1, Nox2, and/or Nox4 could be a novel strategy for the treatment of chronic pain. Here, we summarize the distinct roles of Nox1, Nox2, and Nox4 in inflammatory and neuropathic processing and discuss the effectiveness of currently available Nox inhibitors in the treatment of chronic pain conditions.
Greven, Johannes ; Vollrath, Jan Tilmann ; Bläsius, Felix Marius ; He, Zhizhen ; Bolierakis, Eftychios ; Horst, Klemens ; Störmann, Philipp ; Nowak, Aleksander J. ; Simic, Marija ; Marzi, Ingo ; Hildebrand, Frank ; Relja, Borna
Background: Polytrauma and respiratory tract damage after thoracic trauma cause about 25% of mortality among severely injured patients. Thoracic trauma can lead to the development of severe lung complications such as acute respiratory distress syndrome, and is, therefore, of great interest for monitoring in intensive care units (ICU). In recent years, club cell protein (CC)16 with its antioxidant properties has proven to be a potential outcome-related marker. In this study, we evaluated whether CC16 constitutes as a marker of lung damage in a porcine polytrauma model.
Methods: In a 72 h ICU polytrauma pig model (thoracic trauma, tibial fracture, hemorrhagic shock, liver laceration), blood plasma samples (0, 3, 9, 24, 48, 72 h), BAL samples (72 h) and lung tissue (72 h) were collected. The trauma group (PT) was compared to a sham group. CC16 as a possible biomarker for lung injury in this model, and IL-8 concentrations as known indicator for ongoing inflammation during trauma were determined by ELISA. Histological analysis of ZO-1 and determination of total protein content were used to show barrier disruption and edema formation in lung tissue from the trauma group.
Results: Systemic CC16 levels were significantly increased early after polytrauma compared vs. sham. After 72 h, CC16 concentration was significantly increased in lung tissue as well as in BAL in PT vs. sham. Similarly, IL-8 and total protein content in BAL were significantly increased in PT vs. sham. Evaluation of ZO-1 staining showed significantly lower signal intensity for polytrauma.
Conclusion: The data confirm for the first time in a larger animal polytrauma model that lung damage was indicated by systemic and/or local CC16 response. Thus, early plasma and late BAL CC16 levels might be suitable to be used as markers of lung injury in this polytrauma model.
Fallzahlaufkommen und Qualitätsindikatoren bei der Versorgung des abdominellen Bauchaortenaneurysmas
(2021)
Hintergrund: Der MTL30 ist ein Surrogatparameter, der bisher in visceralchirurgischen Registern verwendet wird, um eine Prognose über die Qualität verschiedener komplikationsträchtiger Eingriffe abzugeben. Der Marker wird als positiv gewertet, wenn ein Patient am 30. postoperativen Tag verstorben (mortality) ist, in ein anderes Akutkrankenhaus verlegt (transfer) werden musste oder weiterhin im Krankenhaus verweilen muss (length of stay >30 days).
Zielsetzung: In dieser Arbeit sollte untersucht werden, ob der MTL30 eine Aussage über die Qualität der operativen Versorgung des Bauchaortenaneurysmas (AAA) abgeben kann. Dazu sollten Kliniken mit unterschiedlichem Fallaufkommen hinsichtlich Letalität und MTL30 miteinander verglichen werden. Zusätzlich sollten Literaturempfehlungen zu Mindestmengen des Fallaufkommens überprüft werden.
Methodik: Insgesamt wurden 18.205 elektive Eingriffe aus dem AAA- Register des Deutschen Instituts für Gefäßmedizinische Gesundheitsforschung (DIGG) der Deutschen Gesellschaft für Gefäßchirurgie und Gefäßmedizin (DGG) analysiert. 14.282 Patienten wurden mittels endovaskulärer Aortenaneurysmaversorgung (EVAR) und 3.923 Patienten mittels offener Versorgung (OAR) behandelt. Die Ergebnisse wurden zum Fallaufkommen der Kliniken in Beziehung gesetzt.
Ergebnisse: Weder für die Letalität noch für den MTL30-Wert konnten Volumen- Ergebnisbeziehungen gefunden werden. Bei EVAR lag die Sterblichkeit im Quintil 1 des Fallaufkommens bei 1,0% und im Quintil 5 bei 1,3%. Auch beim MTL30 ergaben sich keine signifikanten Unterschiede zwischen Quintil 1 und 5, der MTL30 belief sich jeweils auf 5,3%. Bei OAR war die Klinikletalität in dem Quintil mit dem geringsten Fallaufkommen (Quintil 1) mit 5,8% verglichen mit Quintil 5 (höchstes Fallaufkommen, Klinikletalität 3,5%) im Trend höher, aber nicht signifikant unterschiedlich (p= 0,505). Auch bei OAR korrelierte der MTL30 nicht mit dem Fallaufkommen (Quintil 1: 16,4% vs. Quintil 5:12,2%, p=0,110). Jedoch korrelierte die Liegedauer bei EVAR und OAR sowohl mit der Letalität (EVAR: Quintil 1 der Liegezeit 1,69% vs. Quintil 5 1,02%, p= 0,042; OAR: Quintil 1: 6,78% vs. Quintil 5: 2,16%, p= 0,000) als auch mit dem MTL30 (EVAR: Quintil 1 der Liegezeit 7,35% vs. Quintil 5 2,85%, p=0,000; OAR: Quintil 1 26,28% vs. Quintil 5 5,19%, p= 0,000).
Folgerung: Es konnte weder bei EVAR noch bei OAR ein Zusammenhang zwischen dem jährlichen Fallaufkommen und der Letalität bzw. dem MTL30 gefunden werden. Ob der MTL30 gegenüber der alleinigen Erfassung der Klinikletalität als Qualitätsparameter einen Zusatznutzen bietet, muss offenbleiben. Ein vielversprechenderer Marker scheint die stationäre Liegedauer zu sein, die zusätzlich zur Letalität als Qualitätsparameter verwendet werden könnte.
Hintergrund. Patienten mit Gliomen, die das Corpus callosum miteinbeziehen, befinden sich häufig in einem schlechten neurologischen Zustand und werden aufgrund der Antizipation postoperativer neurologischer und neurokognitiver Defizite nur selten einer Tumorresektion unterzogen.
Ziel der Arbeit. Zielsetzung dieser Arbeit war die Untersuchung eines möglichen Vorteils der Resektion von Gliomen im Corpus callosum, unter der Annahme, dass neurokognitive Defizite vor allem durch den Tumor selbst verursacht werden.
Material & Methoden. In diese prospektive Studie wurden zwischen 01/2017 und 01/2020 21 Patienten eingeschlossen, die eine Gliomresektion im Corpus callosum erfuhren. Klinische Routinedaten als auch die neurokognitiven Funktionen der Patienten wurden prä- und postoperative sowie nach 6 Monaten erhoben.
Ergebnisse. In 15 Patienten konnte eine Komplettresektion, in 6 Patienten eine subtotale Resektion mit einem Resektionsausmaß von 97,7% erzielt werden. Während der medianen Beobachtungszeit von 12,6 (2,0 – 30,9) Monaten starben 8 Patienten mit einem Glioblastom ZNS WHO Grad 4 und 1 Patient mit einem Astrozytom ZNS WHO Grad 4 nach im Median von 17 (3,8 – 20,6) Monaten, während 12 Patienten nach im Median 9,4 (2,0 – 30,9) Monaten noch am Leben waren.
Präoperativ wiesen bis zu zwei Drittel aller Patienten Beeinträchtigungen in allen kognitiven Domänen auf, trotz eines medianen Karnofsky Performance Scores von 100% (Spanne 60-100%). Postoperativ wurde in allen neurokognitiven Domänen ein zunehmender Anteil an Patienten mit Einschränkungen beobachtet. Nach 6 Monaten zeigte sich jedoch, dass signifikant weniger Patienten Beeinträchtigungen in den Domänen Aufmerksamkeit, Exekutivfunktionen, Gedächtnis und Depression aufwiesen – Funktionen, die für den Alltag der Patienten von höchster Bedeutung sind.
Fazit. Die Resultate dieser Studie unterstützen unsere Hypothese, dass für Patienten mit Gliomen, die das Corpus callosum miteinbeziehen, der Vorteil einer Tumorresektion das Risiko neuer Defizite überwiegt.
Die Niere ist das in Deutschland am häufigsten transplantierte Organ. Patienten nach Nierentransplantation haben aufgrund der notwendigen Immunsuppression ein erhöhtes Risiko für Infektionen. Die häufigste Infektion nach einer Nierentransplantation ist die Harnwegsinfektion, eine lebensbedrohliche Verlaufsform mit Entwicklung von Organdysfunktionen bezeichnet man als Urosepsis. Durch die Immunsuppression kann die Erkennung des septischen Krankheitsbildes erheblich erschwert sein, da typische körperliche Reaktionen auf eine Infektion unter Immunsuppression (z.B. Fieber, Tachykardie) verändert ablaufen.
Im Rahmen einer Sepsis laufen parallel pro- und antiinflammatorische Prozesse ab. Ein Überwiegen der antiinflammatorischen Prozesse kann zur Entwicklung einer „Sepsis-induzierten Immunsuppression“ führen, welche ein deutliches Mortalitätsrisiko darstellt, da sie zur fehlenden Sanierung des Infektionsfokus sowie zur Entwicklung sekundärer (z.T. opportunistischer) Infektionen führen kann. Ein zentraler antiinflammatorischer Prozess ist die Apoptose von CD4 und CD8 Lymphozyten. Die Möglichkeit der therapeutischen Beeinflussung dieses immunsupprimierten Zustandes ist aktuell Gegenstand zahlreicher Studien. Ziele der vorliegenden Arbeit waren die Überprüfung, ob sich der Abfall der Lymphoyztenzahl/eine Lymphopenie im Rahmen einer Infektionsepsiode auch in der immunsupprimierten Patientenklientel nach Nierentranplantation darstel-len lässt. Des Weiteren sollte diskutiert werden, ob der Nachweis einer reduzierten CD4/8 Lymphozytenzahl geeignet sein kann, diagnostisch die Infektionssituation einzuschätzen und ggf. die immunsuppressive Therapie anzupassen.
In dieser retrospektiven Kohortenanalyse wurden die Daten von nierentransplantierten Patienten ausgewertet, welche in den Jahren 2010 und 2011 im Universitätsklinikum der Goethe-Universität Frankfurt am Main aufgrund einer Harnwegsinfektion (n=47) oder Urosepsis (n=75) behandelt wurden. Es erfolgte ein Ver-gleich der CD4/CD8 Lymphozytenzahl vor, während und nach einer Infektions-episode. Ergänzend wurden die Häufigkeit einer CMV-Reaktivierung/-Infektion sowie das ursächliche bakterielle Erregerspektrum mit zugehörigem Antibiotika-resistenzmuster erhoben.
Sowohl Patienten mit Urosepsis als auch mit Harnwegsinfektion zeigten einen signifikanten Abfall der CD4 Lymphozyten im Rahmen der Infektionsepisode (p<0,01; p<0,05). Patienten mit Urosepsis zeigten zudem einen signifikanten Abfall der CD8 Lymphozyten (p<0,01). Patienten mit Erregernachweis in der Blutkultur zeigten signifikant niedrigere CD4/8 Lymphozyten während der Infek-tionsepisode (p<0,05) als Patienten mit negativer Blutkultur. Eine niedrige CD4/8 Lymphozytenzahl korrelierte besser mit einem Erregernachweis mittels Blutkultur als das Erfüllen der SIRS Kriterien. Mit Behandlung der Infektionsepi-sode zeigte sich ein Wiederanstieg der CD4/8 Lymphozytenzahlen. Unter Re-duktion/Pausieren der immunsuppressiven Therapie kam es zu keiner Abstoßungsreaktion/keinem Versterben eines Patienten im Rahmen der Infektionsepisode. Zu einem CMV-DNA Nachweis kam es bei 15 Patienten (20%) der Gruppe Urosepsis sowie 8 Patienten (17%) der Gruppe Harnwegsinfektion während der Infektionsepisode. Sowohl in Urin- als auch Blutkulturen waren E.coli gefolgt von Enterokokken die häufigsten nachgewiesenen Erreger. E.coli fanden sich signifikant häufiger in Urin- und Blutkulturen bei Urosepsis, Enterokokken signifikant häufiger in Urinkulturen bei Harnwegsinfektionen. Es zeigten sich hohe Antibiotikaresistenzraten insbesondere gegenüber Cotrimoxazol (59% der E.coli) und Fluorchinolonen (45% der E.coli, 82% der Enterokokken). 11% der E.coli und 62% der Klebsiellen waren als 3MRGN Erreger zu klassifizieren, 15% der Klebsiellen als 4MRGN mit Carbapenemresistenz.
Zusammenfassend lässt sich auch bei immunsupprimier-ten/nierentransplantierten Patienten im Rahmen einer Infektionsepisode ein signifikanter Abfall der CD4/8 Lymphozyten nachweisen. Das Reduzieren/Pausieren der immunsupressiven Therapie erscheint anhand der vorgelegten Daten sinnvoll, ein Monitoring der CD4/8 Lymphozytenzahl könnte zur Therapiesteuerung geeignet sein. Im Rahmen weiterer prospektiver Studien könnte eine Erarbeitung eines festen Schemas der Anpassung der immunsuppressiven Therapie an eine bestimmte CD4/8 Lymphozytenzahl sinnvoll sein. Passend zur Vergleichsliteratur waren E.coli und Enterokokken die am häufigsten nachgewiesenen Erreger. Die hohen Antibiotikaresistenzmuster unterstreichen die Notwendigkeit, das lokale Erregermilieu zu kennen, um möglichst passend kalkuliert antibiotisch behandeln zu können.
Many countries have restricted public life during the SARS-CoV2 pandemic. As related measures limited the access to sports facilities, this dissertation aimed (1) to examine changes in physical activity (PA) and well-being in affected countries, and (2) to determine the effectiveness of a digital home exercise program in this context.
Part 1 (PA/well-being) of the dissertation was a digital survey administered in 14 countries. Participants reported a 41 - 42% reduction of PA (NPAQ-SF) during restrictions (n=13,503 valid responses). Compliance with international PA guidelines decreased by nearly 19%. Mental well-being declined substantially (n=14,975 responses; 68.1 to 51.9 points on the WHO5 index) and the proportion of individuals at risk of depression tripled (14.2% to 45.2%). Physical well-being (SF-36 Pain) decreased slightly (85.8% to 81.3%). About two thirds (68.1%) of the respondents reported being interested in digital home exercise.
For Part 2 (digital home exercise) of the dissertation, an international multicenter randomized, controlled trial was performed allocating healthy adults (n=763; 33±12 years) to an intervention (IG) or control (CG) group. In contrast to the CG, the IG was offered live-streamed home exercise for four weeks. Subsequently, both groups had access to pre-recorded workouts for another four weeks. Outcomes were measured weekly using validated questionnaires. Mixed-models data analyses revealed an up to 1.65-fold (95% CI: 1.4-1.94; week 1) increase of PA relative to the CG. Moreover, small improvements in exercise motivation (SKK scale), psychological well-being (WHO-5 index), sleep quality (MOS Sleep Scale), and anxiety symptoms (GAD-7 Scale) were observed for IG.
The results of this dissertation suggest that public life restrictions associated with the pandemic had significant adverse effects on movement behavior and well-being. Digital home exercise can help to maintain and/or increase health- beneficial PA and well-being and may hence represent a supportive element of viral containment efforts.
Emons, Georg ; Auslander, Noam ; Jo, Peter ; Kitz, Julia ; Azizian, Azadeh ; Hu, Yue ; Hess, Clemens F. ; Rödel, Claus ; Sax, Ulrich ; Salinas-Riester, Gabriela ; Ströbel, Philipp ; Kramer, Frank ; Beissbarth, Tim ; Ghadimi, Michael ; Ruppin, Eytan ; Ried, Thomas ; Gaedcke, Jochen Werner Christian ; Grade, Marian
Purpose: Preoperative (neoadjuvant) chemoradiotherapy (CRT) and total mesorectal excision is the standard treatment for rectal cancer patients (UICC stage II/III). Up to one-third of patients treated with CRT achieve a pathological complete response (pCR). These patients could be spared from surgery and its associated morbidity and mortality, and assigned to a “watch and wait” strategy. However, reliably identifying pCR based on clinical or imaging parameters remains challenging.
Experimental design: We generated gene-expression profiles of 175 patients with locally advanced rectal cancer enrolled in the CAO/ARO/AIO-94 and -04 trials. One hundred and sixty-one samples were used for building, training and validating a predictor of pCR using a machine learning algorithm. The performance of the classifier was validated in three independent cohorts, comprising 76 patients from (i) the CAO/ARO/AIO-94 and -04 trials (n = 14), (ii) a publicly available dataset (n = 38) and (iii) in 24 prospectively collected samples from the TransValid A trial.
Results: A 21-transcript signature yielded the best classification of pCR in 161 patients (Sensitivity: 0.31; AUC: 0.81), when not allowing misclassification of non-complete-responders (False-positive rate = 0). The classifier remained robust when applied to three independent datasets (n = 76).
Conclusion: The classifier can identify >1/3 of rectal cancer patients with a pCR while never classifying patients with an incomplete response as having pCR. Importantly, we could validate this finding in three independent datasets, including a prospectively collected cohort. Therefore, this classifier could help select rectal cancer patients for a “watch and wait” strategy.
Translational relevance: Forgoing surgery with its associated side effects could be an option for rectal cancer patients if the prediction of a pathological complete response (pCR) after preoperative chemoradiotherapy would be possible. Based on gene-expression profiles of 161 patients a classifier was developed and validated in three independent datasets (n = 76), identifying over 1/3 of patients with pCR, while never misclassifying a non-complete-responder. Therefore, the classifier can identify patients suited for “watch and wait”.
Greven, Johannes ; Vollrath, Jan Tilmann ; Bläsius, Felix Marius ; He, Zhizhen ; Bolierakis, Eftychios ; Horst, Klemens ; Störmann, Philipp ; Nowak, Aleksander J. ; Simic, Marija ; Marzi, Ingo ; Hildebrand, Frank ; Relja, Borna
Background: Polytrauma and respiratory tract damage after thoracic trauma cause about 25% of mortality among severely injured patients. Thoracic trauma can lead to the development of severe lung complications such as acute respiratory distress syndrome, and is, therefore, of great interest for monitoring in intensive care units (ICU). In recent years, club cell protein (CC)16 with its antioxidant properties has proven to be a potential outcome-related marker. In this study, we evaluated whether CC16 constitutes as a marker of lung damage in a porcine polytrauma model.
Methods: In a 72 h ICU polytrauma pig model (thoracic trauma, tibial fracture, hemorrhagic shock, liver laceration), blood plasma samples (0, 3, 9, 24, 48, 72 h), BAL samples (72 h) and lung tissue (72 h) were collected. The trauma group (PT) was compared to a sham group. CC16 as a possible biomarker for lung injury in this model, and IL-8 concentrations as known indicator for ongoing inflammation during trauma were determined by ELISA. Histological analysis of ZO-1 and determination of total protein content were used to show barrier disruption and edema formation in lung tissue from the trauma group.
Results: Systemic CC16 levels were significantly increased early after polytrauma compared vs. sham. After 72 h, CC16 concentration was significantly increased in lung tissue as well as in BAL in PT vs. sham. Similarly, IL-8 and total protein content in BAL were significantly increased in PT vs. sham. Evaluation of ZO-1 staining showed significantly lower signal intensity for polytrauma.
Conclusion: The data confirm for the first time in a larger animal polytrauma model that lung damage was indicated by systemic and/or local CC16 response. Thus, early plasma and late BAL CC16 levels might be suitable to be used as markers of lung injury in this polytrauma model.
Patil, Shivaprasad Gangadhar ; Linge, Annett ; Hiepe, Hannah ; Grosser, Marianne ; Lohaus, Fabian ; Gudziol, Volker ; Kemper, Max ; Nowak, Alexander ; Haim, Dominik ; Tinhofer, Ingeborg ; Budach, Volker ; Guberina, Maja ; Stuschke, Martin ; Balermpas, Panagiotis ; Müller-von der Grün, Jens ; Schäfer, Henning Sebastian ; Grosu, Anca-Ligia ; Abdollahi, Amir ; Debus, Jürgen ; Ganswindt, Ute ; Belka, Claus ; Pigorsch, Steffi Ulrike ; Combs, Stephanie ; Böke, Simon ; Zips, Daniel ; Jöhrens, Korinna ; Baretton, Gustavo Bruno ; Baumann, Michael ; Krause, Mechthild ; Löck, Steffen
(1) Background: Patients with locally advanced head and neck squamous cell carcinoma (HNSCC) who are biologically at high risk for the development of loco–regional recurrences after postoperative radiotherapy (PORT) but at intermediate risk according to clinical risk factors may benefit from additional concurrent chemotherapy. In this matched-pair study, we aimed to identify a corresponding predictive gene signature. (2) Methods: Gene expression analysis was performed on a multicenter retrospective cohort of 221 patients that were treated with postoperative radiochemotherapy (PORT-C) and 283 patients who were treated with PORT alone. Propensity score analysis was used to identify matched patient pairs from both cohorts. From differential gene expression analysis and Cox regression, a predictive gene signature was identified. (3) Results: 108 matched patient pairs were selected. We identified a 2-metagene signature that stratified patients into risk groups in both cohorts. The comparison of the high-risk patients between the two types of treatment showed higher loco–regional control (LRC) after treatment with PORT-C (p < 0.001), which was confirmed by a significant interaction term in Cox regression (p = 0.027), i.e., the 2-metagene signature was indicative for the type of treatment. (4) Conclusion: We have identified a novel gene signature that may be helpful to identify patients with high-risk HNSCC amongst those at intermediate clinical risk treated with PORT, who may benefit from additional concurrent chemotherapy.
(1) AlphαSynuclein (αSyn) is a synaptic protein which is expressed in the nervous system and has been linked to neurodegenerative diseases, in particular Parkinson’s disease (PD). Symptoms of PD are mainly due to overexpression and aggregation of αSyn and include pain. However, the interconnection of αSyn and pain has not been clarified so far. (2) We investigated the potential effects of a αSyn knock-out on the nociceptive behaviour in mouse models of acute, inflammatory and neuropathic pain. Furthermore, we assessed the impact of αSyn deletion on pain-related cellular and molecular mechanisms in the spinal cord in these models. (3) Our results showed a reduction of acute cold nociception in αSyn knock-out mice while responses to acute heat and mechanical noxious stimulation were similar in wild type and knock-out mice. Inflammatory nociception was not affected by αSyn knock-out which is also mirrored by unaltered inflammatory gene expression. In contrast, in the SNI model of neuropathic pain, αSyn knock-out mice showed decreased mechanical allodynia as compared to wild type mice. This effect was associated with reduced proinflammatory mechanisms and suppressed activation of MAP kinase signalling in the spinal cord while endogenous antinociceptive mechanisms are not inhibited. (4) Our data indicate that αSyn plays a role in neuropathy and its inhibition might be useful to ameliorate pain symptoms after nerve injury.