Einfluss von Indomethazin auf die adulte hippocampale Neurogenese und viskoelastische Eigenschaften des Gehirns im MPTP-Mausmodell für Dopamindepletion

Die Neurogenese im Gyrus dentatus (DG) des Hippocampus kann durch diverse Faktoren wie eine modulierte Transmitterhomöostase oder Entzündung beeinflusst werden und ist auch in neurodegenerativen Erkrankungen verändert. Mediatoren einer Entzündung sind zum Beispiel Zytokine oder Prostaglandine, wobei letztere durch das Enzym Cyclooxygenase (COX) erzeugt werden. Ob eine COX-Hemmung und dadurch modulierte Entzündungsreaktionen die adulte Neurogenese im DG in neurodegenerativen Erkrankungen beeinflussen, ist bisher unklar. Eine veränderte Neurogenese oder ein neuronaler Zellverlust in neurodegenerativen Erkrankungen könnte außerdem zu einer modifizierten Zusammensetzung des zellulären Netzwerks führen und sich in den viskoelastischen Eigenschaften widerspiegeln, welche durch die Messparameter des neuen bildgebenden Verfahrens Magnetresonanz-Elastographie (MRE) ermittelt werden könnten. Veränderte viskoelastische Parameter des Gehirns wurden bereits in Patienten mit neurodegenerativen Erkrankungen beobachtet, aber bisher gibt es nur wenige Studien zur Untersuchung der zugrundeliegenden zellulären Mechanismen. In der vorliegenden Arbeit wurden die Veränderungen viskoelastischer Eigenschaften mittels MRE und mögliche basierende zelluläre Mechanismen im Hippocampus (Studie 1) und in der SN (Studie 2) im 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridin (MPTP)-Mausmodell für Neurodegeneration mit resultierender Dopamindepletion untersucht. Des Weiteren wurde der Einfluss des nichtselektiven COX-Hemmers Indomethazin auf die adulte hippocampale Neurogenese und deren regulatorische Signalwege sowie die Entzündungsreaktionen im DG und SN eruiert (Studie 3). Die hippocampale Neurogenese und zelluläre Entzündungsreaktion wurden unter Zuhilfenahme immunhistochemischer Färbungen beurteilt. Ferner wurden Veränderungen neurogeneserelevanter Signalwege mit Hilfe der quantitativen Polymerase-Kettenreaktion und in Zytokinkonzentrationen mittels enzymatischen Immunadsorptionsverfahrens bestimmt. Nach MPTP-Behandlung zeigte sich im Hippocampus eine transient höhere Anzahl neuer Vorläuferzellen, welche in einem kurzfristig gesteigerten prozentualen Anteil neuer Neurone resultierte und somit zu einer transient höheren Viskoelastizität führte. In der SN hatte der Verlust dopaminerger Neurone eine Verringerung viskoelastischer Eigenschaften zur Folge. Die Anzahl neuer reifer Neurone im DG war zu einem späteren Zeitpunkt nach MPTP-Gabe vermindert, welches durch Indomethazinbehandlung, unterstützt durch hochregulierte proneurogene Signalwege, verhindert werden konnte. Dies war zudem mit einer verringerten zellulären Entzündungsreaktion assoziiert. Zusammenfassend weisen die Ergebnisse darauf hin, dass Neurone zu den biomechanischen Eigenschaften eines Gewebes beitragen. Daher könnte die MRE durch Erfassung verminderter viskoelastischer Eigenschaften bei neurodegenerativen Erkrankungen ein mögliches klinisch diagnostisches Werkzeug sein. Ferner verhinderte der COX-Hemmer Indomethazin eine geschädigte Neurogenese und Entzündung nach Dopamindepletion. Dies trägt dazu bei nichtselektive COX-Hemmer als mögliche Medikamente zur Verbesserung der Neurogenese in neurodegenerativen Erkrankungen in Betracht zu ziehen.Neurogenesis in the dentate gyrus (DG) of the hippocampus can be influenced by diverse factors, such as altered transmitter homeostasis or inflammation, and is also changed in neurodegenerative diseases. Mediators of inflammation are, for example, cytokines or prostaglandins. Last-mentioned mediators are catalyzed by the enzyme cyclooxygenase (COX). However, it is still not clear if COX inhibition and thus modulated inflammatory reactions influence adult neurogenesis in the DG in neurodegenerative diseases. In neurodegenerative diseases, altered neurogenesis or the loss of neurons could also lead to a changed composition of the cellular network and could be displayed in viscoelastic properties, which could be detected by parameters of the novel imaging technique magnetic resonance elastography (MRE). Altered viscoelastic parameters of the brain have already been observed in patients with neurodegenerative diseases, but to date only a few studies have researched the underlying cellular mechanisms. Here, we investigated the alterations of viscoelastic properties using MRE and possible underlying cellular mechanism in the hippocampus (study 1) and in the SN (study 2) by applying the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of dopamine depletion. Moreover, we evaluated the influence of the nonselective COX inhibitor indomethacin on adult hippocampal neurogenesis and neurogenic signaling pathways as well as inflammation in the DG and SN (study 3). Hippocampal neurogenesis and cellular inflammation were investigated using immunohistochemical stainings. Furthermore, alterations in neurogenesis-relevant signaling pathways were analyzed using quantitative polymerase chain reaction, and concentrations of cytokines were quantified by enzyme-linked immunosorbent assay. In the hippocampus, MPTP treatment caused a transiently increased amount of new progenitor cells resulting in a transiently increased percentage of new neurons leading to a temporarily higher viscoelasticity. In the SN, the loss of dopaminergic neurons led to a decrease of viscoelastic properties. At a later time point after MPTP administration, the number of new mature neurons was decreased in the DG. This could be prevented by indomethacin treatment, which was supported by upregulated proneurogenic signaling pathways, and was associated with a decreased cellular inflammation. In conclusion, the MRE and histological results show that neurons contribute to the biomechanical tissue characteristics. Thus, decreased viscoelastic properties in neurodegenerative diseases observed by MRE may be a potential approach for clinical diagnosis. Furthermore, the COX inhibitor indomethacin prevented impaired adult neurogenesis and inflammation after dopamine depletion. This contributes to the validation of nonselective COX inhibitors as a potential therapeutic drug to restore neurogenesis in neurodegenerative diseases

Total Pelvic Exenteration for Gynecologic Malignancies

Total pelvic exenteration (PE) is a radical operation, involving en bloc resection of pelvic organs, including reproductive structures, bladder, and rectosigmoid. In gynecologic oncology, it is most commonly indicated for the treatment of advanced primary or locally recurrent cancer. Careful patient selection and counseling are of paramount importance when considering someone for PE. Part of the evaluation process includes comprehensive assessment to exclude unresectable or metastatic disease. PE can be curative for carefully selected patients with gynecologic cancers. Major complications can be seen in as many as 50% of patients undergoing PE, underscoring the need to carefully discuss risks and benefits of this procedure with patients considering exenterative surgery

Robust methylation‐based classification of brain tumours using nanopore sequencing

Background DNA methylation-based classification of cancer provides a comprehensive molecular approach to diagnose tumours. In fact, DNA methylation profiling of human brain tumours already profoundly impacts clinical neuro-oncology. However, current implementation using hybridisation microarrays is time consuming and costly. We recently reported on shallow nanopore whole-genome sequencing for rapid and cost-effective generation of genome-wide 5-methylcytosine profiles as input to supervised classification. Here, we demonstrate that this approach allows us to discriminate a wide spectrum of primary brain tumours. Results Using public reference data of 82 distinct tumour entities, we performed nanopore genome sequencing on 382 tissue samples covering 46 brain tumour (sub)types. Using bootstrap sampling in a cohort of 55 cases, we found that a minimum set of 1000 random CpG features is sufficient for high-confidence classification by ad hoc random forests. We implemented score recalibration as a confidence measure for interpretation in a clinical context and empirically determined a platform-specific threshold in a randomly sampled discovery cohort (N = 185). Applying this cut-off to an independent validation series (n = 184) yielded 148 classifiable cases (sensitivity 80.4%) and demonstrated 100% specificity. Cross-lab validation demonstrated robustness with concordant results across four laboratories in 10/11 (90.9%) cases. In a prospective benchmarking (N = 15), the median time to results was 21.1 h. Conclusions In conclusion, nanopore sequencing allows robust and rapid methylation-based classification across the full spectrum of brain tumours. Platform-specific confidence scores facilitate clinical implementation for which prospective evaluation is warranted and ongoing

Increased nutrient supply to the Southern Ocean during the Holocene and its implications for the pre-industrial atmospheric CO₂ rise

A rise in the atmospheric CO2 concentration of ~20 parts per million over the course of the Holocene has long been recognized as exceptional among interglacials and is in need of explanation. Previous hypotheses involved natural or anthropogenic changes in terrestrial biomass, carbonate compensation in response to deglacial outgassing of oceanic CO2, and enhanced shallow water carbonate deposition. Here, we compile new and previously published fossil-bound nitrogen isotope records from the Southern Ocean that indicate a rise in surface nitrate concentration through the Holocene. When coupled with increasing or constant export production, these data suggest an acceleration of nitrate supply to the Southern Ocean surface from underlying deep water. This change would have weakened the ocean’s biological pump that stores CO2 in the ocean interior, possibly explaining the Holocene atmospheric CO2 rise. Over the Holocene, the circum-North Atlantic region cooled, and the formation of North Atlantic Deep Water appears to have slowed. Thus, the ‘seesaw’ in deep ocean ventilation between the North Atlantic and the Southern Ocean that has been invoked for millennial-scale events, deglaciations and the last interglacial period may have also operated, albeit in a more gradual form, over the Holocene

Supralevator Abscess Presenting With Pneumoarthrosis And Retroperitoneal Air, A Case Report

Abstract 74-year-old male presented to the emergency department with complaint of fever, weakness, and fatigue and was admitted to the hospital for further workup. The patient was found to have gram negative bacteremia and Clostridioides difficile infection. Computed tomography imaging of the abdomen and pelvis was obtained and demonstrated air in the retroperitoneal/ presacral space tracking to the left hemipelvis and femoral joint. Concern for possible septic joint lead to an Orthopedic surgery evaluation and magnetic resonance imaging of the left hip and pelvis which revealed a complicated perirectal infection tracking to the left hemipelvis. The patient was taken to the operating room with colorectal surgery for further management and treatment.</jats:p

Surgical Management of Neuroendocrine Tumours of the Pancreas

Neuroendocrine tumours of the pancreas (pNET) are rare, accounting for 1–2% of all pancreatic neoplasms. They develop from pancreatic islet cells and cover a wide range of heterogeneous neoplasms. While most pNETs are sporadic, some are associated with genetic syndromes. Furthermore, some pNETs are ‘functioning’ when there is clinical hypersecretion of metabolically active peptides, whereas others are ‘non-functioning’. pNET can be diagnosed at a localised stage or a more advanced stage, including regional or distant metastasis (in 50% of cases) mainly located in the liver. While surgical resection is the cornerstone of the curative treatment of those patients, pNET management requires a multidisciplinary discussion between the oncologist, radiologist, pathologist, and surgeon. However, the scarcity of pNET patients constrains centralised management in high-volume centres to provide the best patient-tailored approach. Nonetheless, no treatment should be initiated without precise diagnosis and staging. In this review, the steps from the essential comprehensive preoperative evaluation of the best surgical approach (open versus laparoscopic, standard versus sparing parenchymal pancreatectomy, lymphadenectomy) according to pNET staging are analysed. Strategies to enhance the short- and long-term benefit/risk ratio in these particular patients are discussed.</jats:p

Surgical Management of Neuroendocrine Tumours of the Pancreas

International audienceNeuroendocrine tumours of the pancreas (pNET) are rare, accounting for 1-2% of all pancreatic neoplasms. They develop from pancreatic islet cells and cover a wide range of heterogeneous neoplasms. While most pNETs are sporadic, some are associated with genetic syndromes. Furthermore, some pNETs are 'functioning' when there is clinical hypersecretion of metabolically active peptides, whereas others are 'non-functioning'. pNET can be diagnosed at a localised stage or a more advanced stage, including regional or distant metastasis (in 50% of cases) mainly located in the liver. While surgical resection is the cornerstone of the curative treatment of those patients, pNET management requires a multidisciplinary discussion between the oncologist, radiologist, pathologist, and surgeon. However, the scarcity of pNET patients constrains centralised management in high-volume centres to provide the best patient-tailored approach. Nonetheless, no treatment should be initiated without precise diagnosis and staging. In this review, the steps from the essential comprehensive preoperative evaluation of the best surgical approach (open versus laparoscopic, standard versus sparing parenchymal pancreatectomy, lymphadenectomy) according to pNET staging are analysed. Strategies to enhance the short- and long-term benefit/risk ratio in these particular patients are discussed

Complicated Diverticulitis and Pelvic Radiation Leading to Colonic Stricture, Colorectal Fistula, and Anal Stenosis

The purpose of this case is to highlight a rare case of sigmoid colon-to-rectum fistula. A 66-year-old man with a history of pelvic radiation and diverticulosis presented to the emergency department with a 3-week history of abdominal pain and watery diarrhea. Computed tomography (CT) imaging was significant for a sigmoid-to-rectum fistula with sigmoid stricture. The patient underwent a laparoscopic colectomy with end colostomy. Pathology revealed perforated diverticulitis. To date, there have been no cases reported in literature describing sigmoid-to-rectum fistula. In conclusion, it is important to consider the development of complex diverticular disease in patients with history of pelvic radiation

Xyr1 (Xylanase Regulator 1) Regulates both the Hydrolytic Enzyme System and d-Xylose Metabolism in Hypocrea jecorina

Xyr1 (xylanase regulator 1) of the ascomycete Hypocrea jecorina (anamorph Trichoderma reesei) was recently demonstrated to play an essential role in the transcriptional regulation of the xyn1 (xylanase 1-encoding) gene expression. Consequently, this study reports on the deletion of the xyr1 gene from the H. jecorina genome. Comparative studies of the growth behavior of the different mutant strains (deleted and retransformed xyr1) grown on various carbon sources pointed to the strongly reduced ability of the xyr1 deletion strain to utilize d-xylose and xylan. Transcriptional analysis of the xyl1 (d-xylose reductase 1-encoding) gene as well as measurements of corresponding enzymatic activities gave evidence that Xyr1 takes part in the control of the fungal d-xylose pathway, in particular in the regulation of d-xylose reductase. It could be demonstrated that the uptake of d-xylose into the fungal cell is uninfluenced in the Δxyr1 strain. Furthermore, transcriptional regulation of the major hydrolytic enzyme-encoding genes xyn1 and xyn2 (xylanases 1 and 2), cbh1 and cbh2 (cellobiohydrolases 1 and 2), and egl1 (endoglucanase 1) is strictly dependent on Xyr1. Regulation of the respective genes via Xyr1 is not affected by the substances mediating induction (xylose, xylobiose, and sophorose) and is indispensable for all modes of gene expression (basal, derepressed, and induced). Moreover, Xyr1, it was revealed, activated transcriptional regulation of inducer-providing enzymes such as β-xylosidase BXLI and β-glucosidase BGLI but was not shown to be involved in the regulation of BGLII