Vergleich der analgetischen Wirkung von Fentanyl und Butorphanol unter Anästhesie mit Tricainmethansulfonat beim Krallenfrosch (Xenopus laevis)

Die Schmerzkompetenz von Amphibien wird bis heute kontrovers diskutiert. Ein Stellvertreter dieser Klasse, der Afrikanische Krallenfrosch (Xenopus laevis) hat in der Versuchstierkunde seit langem einen festen Platz eingenommen. Weltweit gelten in der tierexperimentellen Forschung die Prinzipien der 3R. Ziel ist es, Tierversuche möglichst zu vermeiden (Replacement), die Zahl der Tiere zu reduzieren (Reduction) und ihr Leiden in Versuchen auf das unerlässliche Maß zu beschränken (Refinement). In Bezug auf letzteren Punkt war ein Ziel dieser Studie, die Überprüfung, ob Tricainmethansulfonat (MS222) als „ideales Anästhetikum“ alle Komponenten einer Allgemeinanästhesie mit chirurgischer Toleranz – Bewusstlosigkeit (Hypnose), Muskelrelaxation, Unterdrückung vegetativer Reflexe und damit eine adäquate Analgesie induzieren kann. Dazu wurde im ersten Teil des Projekts zunächst untersucht, ob es unter einer MS222-Anästhesie neben der Bewusstlosigkeit und Muskelrelaxation auch zur Ausschaltung bzw. Verringerung der Schmerzweiterleitung (Nozizeption) und damit zu einer effektiven Schmerzreduktion (Analgesie) kommt. Entsprechend wurden drei verschiedene Schmerzreize an narkotisierten Krallenfröschen untersucht, um den am besten reproduzier- und standardisierbaren Schmerzreiz zu finden. Da es für narkotisierte Amphibien kein etabliertes Verfahren gibt, um intraoperative Nozizeption zu messen, wurde auf Methoden, die beim Säuger etabliert sind, zurückgegriffen. Folglich wurde ein Anstieg der Herz-Kreislauf-Parameter Blutdruck und Herzfrequenz in der Studie als Hinweis auf Nozizeption gewertet. Zur Messung dieser Vitalparameter beim Frosch wurde in diesem Projekt ein Mikro-Tip-Katheter verwendet, der direkt im Herzventrikel platziert wurde. Alle drei Schmerzreize erzeugten hämodynamische Veränderungen unter MS222-Nakose. Obwohl kein signifikanter Unterschied zu den anderen Reizen bestand, wurde der sogenannte Essigsäuretest als Schmerzreiz der Wahl festgelegt, da dieser mit den größten Unterschieden zwischen dem Ruhewert und dem reizinduzierten Maximalwert verbunden war. Die in der Literatur zu findenden Angaben zur ergänzenden Schmerztherapie bei Amphibien variieren zum Teil stark. Aus diesem Grund wurde im zweiten Teil des Projekts die Wirkung der beiden Opioide Fentanyl und Butorphanol in jeweils drei unterschiedlichen Konzentrationen untersucht. Die Dosierungen der Analgetika wurde auf der Basis der vorhandenen Literatur ausgewählt. Sie betrugen 0,05 mg/kg, 0,25 mg/kg und 0,5 mg/kg für Fentanyl bzw. 0,05 mg/kg, 1,0 mg/kg und 5,0 mg/kg für Butorphanol. Die Reaktionen des hämodynamischen Systems auf den Essigsäuretest wurden vor und nach Gabe der Analgetika kontinuierlich aufgezeichnet. Wider Erwarten zeigte Fentanyl in allen drei Dosierungen keine Reduktion der Nozizeption unter MS222-Narkose. Mit Butorphanol konnte nur in der hohen Dosierung eine kurzzeitige und signifikante Limitierung des maximalen Blutdruck- und Herzfrequenzanstiegs nach einem Schmerzstimulus gemessen und damit als reduzierte Nozizeption gewertet werden. Nach Verabreichung der Essigsäure stiegen beide Parameter 10 Minuten nach Applikation von Butorphanol deutlich geringer an als im Vergleichsversuch ohne Analgetikum. Doch bereits 20 Minuten nach der Butorphanol-Gabe war dieser Effekt nicht mehr messbar. Die hohe Butorphanol-Dosis kann aufgrund starker Nebenwirkungen auf Blutdruck und Herzfrequenz nicht empfohlen werden. Mit dem Einsatz der beiden Opioide gelang es somit nicht, die intraoperative Analgesie nebenwirkungsarm zu verbessern. Zusammenfassend konnte im ersten Teil der Studie gezeigt werden, dass Tricainmethansulfonat eine gute Hypnose und Muskelrelaxation bewirkt, aber keine ausreichende Schmerzausschaltung induziert. Eine zusätzliche Analgesie ist bei schmerzhaften Operationen entsprechend indiziert. Da internationale Empfehlungen in der Versuchstierkunde aktuell jedoch die alleinige Anwendung von MS222 zur Operation von Krallenfröschen vorsehen, besteht Handlungsbedarf, einerseits diese Empfehlung zu überdenken und andererseits bessere Methoden zur Schmerzausschaltung beim Krallenfrosch zu untersuchen. Die aktuellen Dosierungsempfehlungen zu Fentanyl und Butorphanol in der Literatur konnten in der aktuellen Studie nicht bestätigt werden. Mit dem entwickelten Modell, unter Verwendung von mit MS222 anästhesierten Krallenfröschen, 5%iger Essigsäure als Schmerzreiz und einem genauen Messinstrument für hämodynamische Veränderungen (Tip-Katheter), können in Zukunft weitere Analgetika auf ihre Wirkung beim Krallenfrosch untersucht werden.Until today the ability to percept pain has been controversially discussed in amphibians. Over the years a representative of this class, the African clawed frog (Xenopus laevis), has established his position in laboratory animal science. Worldwide the principles of the 3R apply in animal experimental research, the aim is to avoid the use of animals (Replacement), to minimize the number of animals (Reduction) and to limit their suffering to the essential minimum (Refinement). Focusing on refinement, the aim of this study was to assess if tricaine methanesulfonate (MS222) as an “ideal anaesthetic” guarantees all three components of general anaesthesia including surgical tolerance – hypnosis, muscle relaxation, depression of vegetative responses and an adequate analgesia. In the first part of the study it was therefore determined if MS222 anaesthesia, besides muscle relaxation and hypnosis, induces reduction or rather elimination of the conduction of a noxious stimulus (nociception) and results in a therapeutic reduction of pain (analgesia). First, three different pain stimuli were evaluated to identify the most sensitive and reproducible stimulus for nociception under MS222 anaesthesia. Due to the lack of a well-established method to measure intraoperative nociception in anaesthetized amphibia, the same method as in mammals was used. The increase of the cardiovascular parameters blood pressure and heart rate was considered as a clear indication for nociception. For the continuous monitoring of the vital parameters, a micro-tip-catheter was placed directly in the frog’s heart ventricle. All three pain stimuli caused haemodynamic changes under MS222 anaesthesia. Even though there was no significant difference between the increases of BP and HR after the three different pain stimuli, the Acetic acid test (AAT) was defined as the most reproducible nociceptive stimulus. Currently, very little is known in literature about additional analgesia in amphibians and dosage guidelines vary tremendously. Therefore, in the second part of the study the analgesic potency of the two opioids fentanyl and butorphanol was evaluated with the aim to find a proper dose. Based on current literature, three different dosages (low/medium/high) were chosen. Data of the haemodynamic reactions after a noxious stimulus were continuously recorded before and after administration of the analgesics. Contrary to our expectation, fentanyl in all three doses did not show any reduction of nociception under MS222 anaesthesia. The only significant effects observed were a limitation of blood pressure and heart rate increases after a noxious input. This transient effect was only evident with the high butorphanol dose. In comparison to PS 1 (pain stimulus without analgesia) 10 minutes after application of butorphanol both parameters increased less after administration of acetic acid. However, 20 minutes following administration no difference was measured between treatment groups. Moreover, the high dose of butorphanol was associated with a strong cardiovascular depressant effect. Therefore, this dose cannot be recommended as it would not allow a safe anaesthetic and analgesic management. Consequently, the use of the two opioids could not improve intraoperative analgesia without considerable adverse effects. In summary, we conclude that African clawed frogs have intact and active nociceptive pathways under MS222 anaesthesia. In our study, the current anaesthetic drug of choice in amphibians induced unconsciousness and muscle relaxation but insufficient analgesia. Appropriate additional analgesia is required during painful interventions and procedures. As international recommendations of laboratory animal science currently still suggest the single use of MS222 as anaesthetic agent, the results of this study state, that there is a great need for action not only to adjust these recommendations but also to evaluate further analgesic agents in African clawed frogs. Current dosage recommendations of fentanyl and butorphanol could not be confirmed in our study. However, during this research project, we have developed a methodological basis, that will help to further evaluate other analgesics in future studies

Proimmunogenic impact of MEK inhibition synergizes with agonist anti-CD40 immunostimulatory antibodies in tumor therapy

Cancer types with lower mutational load and a non-permissive tumor microenvironment are intrinsically resistant to immune checkpoint blockade. While the combination of cytostatic drugs and immunostimulatory antibodies constitutes an attractive concept for overcoming this refractoriness, suppression of immune cell function by cytostatic drugs may limit therapeutic efficacy. Here we show that targeted inhibition of mitogen-activated protein kinase (MAPK) kinase (MEK) does not impair dendritic cell-mediated T cell priming and activation. Accordingly, combining MEK inhibitors (MEKi) with agonist antibodies (Abs) targeting the immunostimulatory CD40 receptor results in potent synergistic antitumor efficacy. Detailed analysis of the mechanism of action of MEKi shows that this drug exerts multiple pro-immunogenic effects, including the suppression of M2-type macrophages, myeloid derived suppressor cells and T-regulatory cells. The combination of MEK inhibition with agonist anti-CD40 Ab is therefore a promising therapeutic concept, especially for the treatment of mutant Kras-driven tumors such as pancreatic ductal adenocarcinoma. Immune checkpoint inhibitors have limited efficacy in tumors with lower mutational burden and non-permissive microenvironment. Here, the authors show that combining MEK inhibition with an agonist anti-CD40 immunostimulatory antibody improves antitumor treatment by inducing immunogenic changes in the tumor microenvironment

Central Mongolian lake sediments reveal new insights on climate change and equestrian empires in the Eastern Steppes

The repeated expansion of East Asian steppe cultures was a key driver of Eurasian history, forging new social, economic, and biological links across the continent. Climate has been suggested as important driver of these poorly understood cultural expansions, but paleoclimate records from the Mongolian Plateau often suffer from poor age control or ambiguous proxy interpretation. Here, we use a combination of geochemical analyses and comprehensive radiocarbon dating to establish the first robust and detailed record of paleohydrological conditions for Lake Telmen, Mongolia, covering the past ~ 4000 years. Our record shows that humid conditions coincided with solar minima, and hydrological modeling confirms the high sensitivity of the lake to paleoclimate changes. Careful comparisons with archaeological and historical records suggest that in the vast semi-arid grasslands of eastern Eurasia, solar minima led to reduced temperatures, less evaporation, and high biomass production, expanding the power base for pastoral economies and horse cavalry. Our findings suggest a crucial link between temperature dynamics in the Eastern Steppe and key social developments, such as the emergence of pastoral empires, and fuel concerns that global warming enhances water scarcity in the semi-arid regions of interior Eurasia

A MicroRNA Linking Human Positive Selection and Metabolic Disorders

Postponed access: the file will be accessible after 2021-10-14Positive selection in Europeans at the 2q21.3 locus harboring the lactase gene has been attributed to selection for the ability of adults to digest milk to survive famine in ancient times. However, the 2q21.3 locus is also associated with obesity and type 2 diabetes in humans, raising the possibility that additional genetic elements in the locus may have contributed to evolutionary adaptation to famine by promoting energy storage, but which now confer susceptibility to metabolic diseases. We show here that the miR-128-1 microRNA, located at the center of the positively selected locus, represents a crucial metabolic regulator in mammals. Antisense targeting and genetic ablation of miR-128-1 in mouse metabolic disease models result in increased energy expenditure and amelioration of high-fat-diet-induced obesity and markedly improved glucose tolerance. A thrifty phenotype connected to miR-128-1-dependent energy storage may link ancient adaptation to famine and modern metabolic maladaptation associated with nutritional overabundance.acceptedVersio

Soziale Innovation – Beiträge aus der Innovationsforschung der Technischen Universität Chemnitz

Soziale Innovation – Sie gilt als Lebenselixier moderner Gesellschaften und wird im sozialen Miteinander doch wenig benannt. Politiker und Wissenschaftlicher sehen in ihr den Schlüssel der gesellschaftlichen Neuerung, die durch Bürgerinnen und Bürger veranlasst wird. Und doch birgt die Vergegenständlichung einige Herausforderungen. Mit und in diesem Herausgeberband, der an der Technischen Universität Chemnitz entstanden ist, fragen wir uns: Mit welchem Paradigma wird sie belegt? Können wir das Konstrukt philosophisch fassen? Wie können Prozessmodelle der sozialen Innovation visualisiert werden? Welche Besonderheiten treten bei der Evaluierung und Steuerbarkeit auf? Und sind Non Profit Organisationen ein Inkubator für soziale Innovationen? Somit intendieren wir im vorliegenden Band einen holistischen Blick auf das beschriebene Phänomen für Wissenschaftler, Studierende und Interessierte.Social Innovation - It is regarded as an elixir of modern societies, but sparse named in social togetherness. Politicians and scholars see it as the key to new social practices, which is caused by citizens. However, the clarification contains some challenges. In this publication, which was developed at Technische Universität Chemnitz, we ask: Which paradigm is deposited? Can we comprehend the construct philosophically? How can process models of social innovation be visualized? Are there conditions of evaluation and controllability? Are non-profit organizations an incubator for social innovation? Thus, in the present volume we intend a holistic view of the described phenomenon for scientists, students and interested parties

Living conditions and autonomy levels in COPD patients receiving non-invasive ventilation: impact on health related quality of life

Background!#!Research on health-related quality of life (HRQL) has become increasingly important in recent decades. However, the impact of both living conditions and the level of autonomy impairments on HRQL in COPD patients receiving non-invasive ventilation (NIV) is still unclear.!##!Methods!#!The Severe Respiratory Insufficiency Questionnaire (SRI) was used to measure HRQL in a prospective cohort of COPD patients in whom home NIV was already established. Data on sociodemographics, clinical characteristics and standardized levels of autonomy impairment were evaluated. A multiple linear regression analysis was performed to identify the factors associated with a reduced HRQL.!##!Results!#!A total of 137 patients (67.0 ± 7.8 years, 45% female) were assessed. The mean SRI Summary Score was 54.1 ± 16.9 (95%CI: 51.1-57.1; N = 127). Regular ambulatory care was provided in 76% of patients, but only 37% underwent pulmonary rehabilitation. Overall, 69% of patients lived with family members, while 31% lived alone (family situation). Autonomy impairment levels were most serious in 3%, serious in 14%, and significant in 29% of patients, while 54% had no impairments at all. Of note, higher levels of autonomy impairment were markedly associated with lower SRI scores (regression coefficient - 6.5 ± 1.1 per level; P < 0.001). In contrast, family situation (0.2 ± 3.0; P = 0.959), ambulatory care by a respiratory specialist (1.7 ± 3.6; P = 0.638), and pulmonary rehabilitation (- 0.8 ± 3.1; P = 0.802) did not appear to influence HRQL. Possible subgroup effects were evident for the factors 'impaired autonomy' and 'living in a nursing home' (P = 0.016).!##!Conclusion!#!A higher level of autonomy impairment has been identified as the major determinant of reduced HRQL in COPD-patients receiving long-term NIV, particularly in those living in a nursing home. Trial Registration German Clinical Trials Register (DRKS00008759)

Immunohistochemical profiling of liver metastases and matched-pair analysis in patients with metastatic pancreatic ductal adenocarcinoma

Background The purpose of the current study was to investigate the immunohistochemical (IHC) profile of liver metastases (LM) in patients with pancreatic ductal adenocarcinoma (PDAC). Methods Expression of 15 IHC markers in liver biopsies from 77 patients with PDAC, who were diagnosed between 2010 and 2014, were evaluated. In a separate subgroup analysis (n = 12), paired samples (LM and primary tumor) from the same patient were investigated for IHC profile differences. Results LM samples were classified as pancreatobiliary-type (PB-type) in 72 patients (93.5%), intestinal-type (INT-type) in four patients (5.2%), and squamous in one patient (1.3%). There was no significant difference in overall survival (OS) between LM of the PB-type or INT-type (p = 0.097). In a multivariate analysis, age <70 years (p = 0.047), absence of SMAD4 mutation (p = 0.026), absence of CDX2 expression (p = 0.003), and well to moderate differentiation were significant prognostic factors for better OS in patients with LM (p = 0.031). Analysis of paired tissue samples from LM and the primary tumor revealed a difference in CDX2 (50% increase, p = 0.125) and SMAD4 (33% loss of SMAD4, p = 0.375). Conclusions CDX2 expression and SMAD4 mutation indicate a poor outcome in patients with LM of PDAC. Matched-pair analysis revealed differences in distinct IHC marker expression

The Impact of Non-Invasive Ventilation on Sleep Quality in COPD Patients

Background: Non-invasive ventilation (NIV) has been shown to be the most appropriate therapy for COPD patients with chronic respiratory failure. While physiological parameters and long-term outcome frequently serve as primary outcomes, very few studies have primarily addressed the impact of NIV initiation on sleep quality in COPD. Methods: This single-center prospective cohort study comprised NIV-naïve patients with COPD. All patients underwent polysomnographic evaluation both at baseline and at 3 months follow-up, accompanied by the assessment of health-related quality of life (HRQL) using the Severe Respiratory Insufficiency Questionnaire (SRI) and the Epworth Sleepiness Scale (ESS). A subgroup evaluation was performed to address the impact of comorbid obstructive sleep apnea syndrome (OSAS). Results: Forty-six patients were enrolled and twenty-five patients completed the follow-up period (66.7 ± 7.4 years). NIV resulted in an increase in slow-wave sleep (+2% (−3.5/7.5), p = 0.465) and rapid eye movement sleep (+2.2% (−1.0/5.4), p = 0.174), although no statistical significance could be detected. ESS (−1.7(−3.6/0.1), p = 0.066) also showed a positive trend. Significant improvements in the Respiratory Disturbance Index (RDI) (−12.6(−23.7/−1.5), p = 0.027), lung function parameters, transcutaneous PCO2 and the SRI summary scale (4.5(0.9/8), p = 0.016) were observed. Conclusion: NIV therapy does not decrease sleep quality and is even capable of improving HRQL, transcutaneous PaCO2, daytime sleepiness and RDI, and the latter especially holds true for patients with comorbid OSAS