Pantoprazole Does not Affect Serum Trough Levels of Tacrolimus and Everolimus in Liver Transplant Recipients

Background: Liver transplant recipients are frequently treated with proton pump inhibitors. Drug interactions have been described especially with respect to omeprazole. Due to the lower binding capacity of pantoprazole to CYP2C19 this drug became preferred and became the most used proton pump inhibitor in Germany. The data on the influence of pantoprazole on immunosuppressive drugs in liver transplant recipients a very scarce.Methods: The authors performed a single center analysis in liver transplant recipients on the effect of pantoprazole on the serum trough levels of different immunosuppressants. The trough levels were compared over a period of 1 year before and after start or stop of a continuous oral co-administration of 40 mg pantoprazole once daily.Results: The serum trough levels of tacrolimus (n = 30), everolimus (n = 7), or sirolimus (n = 3) remain constant during an observation period of at least 1 year before and after co-administration of pantoprazole. None of the included patients needed a change of dosage of the observed immunosuppressants during the observation period.Conclusions: The oral co-administration of pantoprazole is safe in immunosuppressed liver transplant recipients according to the serum trough levels of tacrolimus, everolimus, and sirolimus. This analysis provides first data on the influence of pantoprazole on immunosuppressive drugs in liver transplant recipients

Host Shifts from Lamiales to Brassicaceae in the Sawfly Genus Athalia

Plant chemistry can be a key driver of host shifts in herbivores. Several species in the sawfly genus Athalia are important economic pests on Brassicaceae, whereas other Athalia species are specialized on Lamiales. These host plants have glucosides in common, which are sequestered by larvae. To disentangle the possible direction of host shifts in this genus, we examined the sequestration specificity and feeding deterrence of iridoid glucosides (IGs) and glucosinolates (GSs) in larvae of five species which either naturally sequester IGs from their hosts within the Plantaginaceae (Lamiales) or GSs from Brassicaceae, respectively. Furthermore, adults were tested for feeding stimulation by a neo-clerodane diterpenoid which occurs in Lamiales. Larvae of the Plantaginaceae-feeders did not sequester artificially administered p-hydroxybenzylGS and were more deterred by GSs than Brassicaceae-feeders were by IGs. In contrast, larvae of Brassicaceae-feeders were able to sequester artificially administered catalpol (IG), which points to an ancestral association with Lamiales. In line with this finding, adults of all tested species were stimulated by the neo-clerodane diterpenoid. Finally, in a phylogenetic tree inferred from genetic marker sequences of 21 Athalia species, the sister species of all remaining 20 Athalia species also turned out to be a Lamiales-feeder. Fundamental physiological pre-adaptations, such as the establishment of a glucoside transporter, and mechanisms to circumvent activation of glucosides by glucosidases are therefore necessary prerequisites for successful host shifts between Lamiales and Brassicaceae

A time-resolved proteomic and prognostic map of COVID-19

COVID-19 is highly variable in its clinical presentation, ranging from asymptomatic infection to severe organ damage and death. We characterized the time-dependent progression of the disease in 139 COVID-19 inpatients by measuring 86 accredited diagnostic parameters, such as blood cell counts and enzyme activities, as well as untargeted plasma proteomes at 687 sampling points. We report an initial spike in a systemic inflammatory response, which is gradually alleviated and followed by a protein signature indicative of tissue repair, metabolic reconstitution, and immunomodulation. We identify prognostic marker signatures for devising risk-adapted treatment strategies and use machine learning to classify therapeutic needs. We show that the machine learning models based on the proteome are transferable to an independent cohort. Our study presents a map linking routinely used clinical diagnostic parameters to plasma proteomes and their dynamics in an infectious disease

About the influence of the Calcineurin and Ras binding protein (Carabin) on the growth regulation of cardiomyocytes

In Kardiomyozyten spielen sowohl der Calcineurin-NFAT-Signalweg, als auch der ERK/MAPK-Signalweg essentielle Rollen bei der Entstehung von Herzhypertrophie und Herzinsuffizienz. Das Calcineurin-and-Ras-binding-Protein (Carabin) wurde in T-Lymphozyten als dualer Inhibitor von Calcineurin und Ras beschrieben, so dass Carabin ein möglicher Antagonist von Herzhypertrophie und Herzinsuffizienz sein könnte. Diese Dissertation liefert erste Charakterisierungen der Funktion von Carabin in Kardiomyozyten. Ziel war es, die Hypothese zu prüfen, dass eine gesteigerte Carabin-Expression in Kardiomyozyten antihypertroph wirksam ist. Mittels planimetrischer Oberflächenanalysen isolierter Kardiomyozyten konnte gezeigt werden, dass Carabin in Kardiomyozyten in vitro, unter Phenylephrin- und unter Angiotensin-II-Stimulation antihypertroph wirksam ist. Entsprechend der Ergebnisse einer subzellulären Lokalisation eines NFATc3-GFP-Fusionsproteins ist dieser Effekt durch Inhibition der NFAT-Dephosphorylierung erklärbar. Eine chronische Angiotensin-II-vermittelte Herzhypertrophie-Induktion in Mäusen mit Kardiomyozyten-spezifisch gesteigerter Carabin-Expression konnte jedoch nicht beeinflusst werden. Ein Einfluss von Carabin auf den ERK/MAPK-Signalweg konnte in Kardiomyozyten sowohl in vitro, als auch in vivo nicht bestätigt werden. Pan et al. beschrieben Carabin in T-Lymphozyten als Feedbackinhibitor des Calcineurin-NFAT-Signalwegs. Dieser Effekt konnte in Kardiomyozyten ebenfalls nicht bestätigt werden. Für ein vollständiges Verständnis des Einflusses von Carabin auf die Wachstumsregulation von Kardiomyozyten sind jedoch noch weiterführende Untersuchungen notwendig

Kinetics of Bilirubin and Ammonia Elimination during Hemadsorption Therapy in Secondary Sclerosing Cholangitis Following ECMO Therapy and Severe COVID-19

In critically ill patients, liver dysfunction often results in coagulopathy and encephalopathy and is associated with high mortality. Extracorporeal clearance of hepatotoxic metabolites, including bilirubin and ammonia, aims to attenuate further hepatocyte damage and liver injury, resulting in decreased mortality. The efficacy of hemadsorption combined with conventional hemodialysis to eliminate bilirubin and ammonia to support the liver’s excretory function in acute liver injury has been described previously. However, the optimal use of liver support systems in chronic liver dysfunction due to secondary sclerosing cholangitis in critically ill patients (SSC-CIP) has not been defined yet. We herein describe the kinetics of successful bilirubin and ammonia elimination by hemadsorption in a patient with SSC-CIP after extracorporeal membrane oxygenation (ECMO) therapy for severe acute respiratory distress syndrome (ARDS) in a patient with coronavirus disease 2019 (COVID-19). During the course of the disease, the patient developed laboratory signs of liver injury during ECMO therapy before clinically detectable jaundice or elevated bilirubin levels. A diagnosis of SSC-CIP was confirmed by endoscopic retrograde cholangiopancreatography (ERCP) based on intraductal filling defects in the intrahepatic bile ducts due to biliary casts. The patient showed stable elevations of bilirubin and ammonia levels thereafter, but presented with progressive nausea, vomiting, weakness, and exhaustion. Based on these laboratory findings, hemadsorption was combined with hemodialysis treatment and successfully eliminated bilirubin and ammonia. Moreover, direct comparison revealed that ammonia is more efficiently eliminated by hemadsorption than bilirubin levels. Clinical symptoms of nausea, vomiting, weakness, and exhaustion improved. In summary, bilirubin and ammonia were successfully eliminated by hemadsorption combined with hemodialysis treatment in SSC-CIP following ECMO therapy and severe COVID-19. This observation is particularly relevant since it has been reported that a considerable subset of critically ill patients with COVID-19 suffer from liver dysfunction associated with high mortality

Diagnostic accuracy of B-Mode ultrasound and Hepatorenal Index for graduation of hepatic steatosis in patients with chronic liver disease.

BACKGROUND/AIMS:The aim of our study was to evaluate the diagnostic accuracy of B-Mode ultrasound and Hepatorenal Index (HRI) by high-end devices for the detection and classification of hepatic steatosis in patients with various causes of chronic liver disease (CLD). METHODS:We retrospectively enrolled patients with CLD who underwent liver biopsy and baseline ultrasound between March 2016 and May 2019. Sonographic graduation of steatosis (0°-III°) using B-Mode criteria and HRI were correlated with the histological graduation (S0 (33-66%) and S3 (>66%). Interobserver agreement was calculated. RESULTS:157 patients were evaluated. B-Mode ultrasound had a sensitivity of 75.6% and a specificity of 76.0% to differentiate between steatosis and no steatosis (AUROC 0.758). Using B-Mode criteria for advanced steatosis (≥II°), specificity for presence of histological steatosis was ≥98.7%. For detection of advanced steatosis (≥S2), sensitivity of B-mode criteria was 90.9%. In a subgroup of patients with advanced liver fibrosis, sensitivity of B-mode criteria was 95.0% for detection of advanced steatosis (S≥2). A HRI cut-off-value of 1.46 differentiates between patients with steatosis and patients without steatosis with a sensitivity of 42.7% and a specificity of 90.7% (AUROC 0.680). Interobserver agreement of both B-Mode and HRI was good to excellent. CONCLUSION:B-Mode ultrasound using high-end devices is an excellent method to detect advanced steatosis in patients with various CLD. For diagnosis of mild steatosis, modern ultrasound devices may have higher sensitivity but at the expense of specificity. Stage of fibrosis and etiology of CLD seem not to impact on diagnostic accuracy. The additional calculation of HRI seems to have no additional benefit with regard to detect or grade hepatic steatosis in our study population

Endoscopic submucosal dissection with an additional working channel (ESD+): a novel technique to improve procedure time and safety of ESD

Background and aims!#!A new external additional working channel (AWC) was recently introduced by which endoscopic submucosal dissection (ESD) can be converted to a technique termed 'ESD+ '. We aim to systematically evaluate this novel technique in flat gastric lesions and compare it to classical ESD.!##!Methods!#!The study was prospectively conducted in a pre-clinical ex vivo animal model (EASIE-R simulator) with porcine stomachs. Prior to intervention, we set standardized lesions measuring 3 cm or 4 cm in antegrade as well as in retrograde positions.!##!Results!#!Overall, 64 procedures were performed by an experienced endoscopist. Both techniques were reliable and showed en bloc resection rates of 100%. Overall, ESD+ reduced time of procedure compared to ESD (24.5 vs. 32.5 min, p = 0.025*). Particularly, ESD+ was significantly faster in retrograde lesions with a median of 22.5 vs. 34.0 min in 3 cm retrograde lesions (p = 0.002*) and 34.5 vs. 41.0 min (p = 0.011*) in 4 cm retrograde lesions. There were 0 perforations with both techniques. In ESD+ , 1 muscularis damage occurred (3.13%) compared to 6 muscularis damages with ESD (18.75%, p = 0.045*).!##!Conclusions!#!By its grasp-and-mobilize technique, ESD+ allows potentially faster and safer resections of flat gastric lesions compared to conventional ESD in an ex vivo porcine model. The potential advantages of ESD+ in terms of procedure time may be particularly relevant for difficult lesions in retrograde positions

Enhancer of Zeste Homolog 2 (EZH2) Is a Marker of High-Grade Neuroendocrine Neoplasia in Gastroenteropancreatic and Pulmonary Tract and Predicts Poor Prognosis

Tumor grading is a robust prognostic predictor in patients with neuroendocrine neoplasms (NEN) and guides therapy, especially in tumors with high proliferation. NEN can be separated into well-differentiated and poorly differentiated types. The more aggressive NEN have been further separated into neuroendocrine tumors (NET G3) with a better prognosis and neuroendocrine carcinomas (NEC) with a worse prognosis. Despite this distinction’s tremendous clinical and therapeutic relevance, optimal diagnostic biomarkers are still lacking. In this study, we analyzed the protein expression and prognostic impact of Enhancer of Zeste Homolog 2 (EZH2) by immunohistochemistry in 219 tissue samples of gastroenteropancreatic (GEP-NEN) and pulmonary NEN (P-NEN). EZH2 was almost exclusively expressed in NEN with a proliferation rate above 20% (G3), while all low-grade tumors were nearly negative. Among high-grade NEN, 65% showed high and 35% low expression of EZH2. In this group, the high expression of EZH2 was significantly associated with poor overall survival and NEC histology. Interestingly, EZH2 seems to act independently of Polycomb Repressive Complex 2 (PRC2) in NEN. In conclusion, we propose EZH2 as a robust biomarker for distinguishing between NET G3 and NEC among gastroenteropancreatic and pulmonary NEN