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Bei Kindern mit akuter lymphoblastischer Leukämie ist eine möglichst frühe und genaue Diagnostik der Infiltration des Zentralen Nervensystems für die Festlegung der weiteren Therapie von essenzieller Bedeutung. Ziel dieser Studie war es, die diagnostische Wertigkeit der Schädel-MRT im Vergleich zum Standarddiagnostikum Lumbalpunktion bezüglich einer leukämischen Beteiligung des ZNS zu untersuchen. Außerdem sollte die Häufigkeit relevanter Zufallsbefunde festgestellt werden, um den Nutzen einer zusätzlich zur Lumbalpunktion durchgeführten MRT zu beurteilen. Es erfolgte eine retrospektive Analyse der Daten von 277 Patienten mit Erstdiagnose und 56 Patienten mit Rezidiv einer ALL, die zwischen 1998 und 2016 an der Klinik für Kinder- und Jugendmedizin des Universitätsklinikums Frankfurt am Main behandelt worden waren. Sie hatten im Rahmen der initialen Diagnostik zusätzlich zur Lumbalpunktion eine Schädel-MRT mit Kontrastmittel erhalten.
Der durchschnittliche zeitliche Abstand zwischen Diagnosestellung und MRT betrug 11 Tage (39,5 Tage bei Rezidivpatienten). Die Sensitivitäten und Spezifitäten der beiden diagnostischen Mittel MRT und Liquor wurden berechnet.
Dazu diente als Goldstandard die endgültige Diagnose des ZNS-Status, die entweder durch die Liquordiagnostik, die Bildgebung oder die Klinik (RetinaInfiltration, Fazialisparese) gestellt wurde.
Insgesamt fanden sich bei 14 der 277 Patienten mit Erstdiagnose Leukämie eine Infiltration des ZNS. Davon waren 2 Patienten in der MRT, 11 Patienten in der Lumbalpunktion und 2 Patienten durch eine Retina-Infiltration als positiv diagnostiziert worden. Nur ein Patient, der in der MRT positiv befundet worden war, hatte in der Liquordiagnostik ein negatives Ergebnis. Bei den 56 Patienten mit Rezidiv ergab die MRT 6 positive Befunde und die Liquordiagnostik zeigte 13 positive Befunde. 3 Patienten waren zudem klinisch mit Fazialisparese (n=2) und retinaler Infiltration (n=1) positiv zu werten. Diese 3 hatten jedoch auch in der Lumbalpunktion ein positives Ergebnis. Von den Patienten, die in der MRT positiv befundet wurden, hatte 1 Patient ein negatives Ergebnis in der Lumbalpunktion.
Dieser zeigte allerdings Symptome und hätte somit die Bildgebung ohnehin erhalten. Für die MRT ergibt sich bei den Patienten mit Erstdiagnose eine Sensitivität von 14,3%, bei den Rezidivpatienten eine Sensitivität von 43%. Die Spezifität liegt bei den Patienten mit Erstdiagnose ALL bei 99,6% und bei den Rezidivpatienten bei 100%. Für die Lumbalpunktion errechnet sich bei den Patienten mit Erstdiagnose eine Sensitivität von 78,6% und bei den Rezidivpatienten eine Sensitivität von 92,9%, mit einer Falsch-negativ-Rate von 21,4% und 7,1%. Die Spezifität der Lumbalpunktion liegt in beiden Gruppen bei 100%.
Bezüglich relevanter Zufallsbefunde ist bei den Patienten mit Erstdiagnose eine Sinusvenenthrombose bei einer klinisch unauffälligen Patientin zu nennen.
Weitere Nebenbefunde, die keine Auswirkungen auf die Therapie hatten, waren Schleimhautschwellungen der Nasennebenhöhlen (n=188), Verlegung der Mastoidzellen (n=45), Hirnvolumenminderung (n=27), Blutungen ohne Therapiebedürftigkeit (n=5), Zysten (n=11) und angeborene Fehlbildungen (n=7). Außerdem wurde bei 6 Rezidivpatienten eine chronische therapieassoziierte Leukenzephalopathie diagnostiziert.
Die vorliegende Studie stellt unseres Wissens nach die bisher umfangreichste Schädel-MRT-Studie bei Kindern mit ALL unter dieser Fragestellung dar. Ihre Nachteile ergeben sich durch die retrospektive Betrachtung und dadurch bedingte eingeschränkte Einheitlichkeit.
Aus unseren Ergebnissen lässt sich schlussfolgern, dass die Schädel-MRT keinen zusätzlichen Nutzen zur alleinigen Lumbalpunktion bringt. Nur ein einziger Patient hatte in der MRT ein positives Ergebnis, welches weder durch die Lumbalpunktion noch durch die Klinik erkannt worden war. Auch in Hinblick auf die geringe Rate an relevanten Nebenbefunden bei asymptomatischen Patienten ergibt sich keine grundsätzliche Notwendigkeit zur Durchführung dieser Bildgebung. Die zusätzliche Belastung einer kontrastmittelgestützten MRT, für die bei kleinen Kindern zudem häufig eine Sedierung erforderlich ist, kann klinisch neurologisch unauffälligen Patienten mit ALL also erspart werden.
Stellenwert der Teststreifen-basierten Analyse der INR für die Behandlung von Blutungskomplikationen
(2020)
Das Ziel der hier vorliegenden Studie war es einen Zusammenhang zwischen den Ergebnissen von konventioneller versus Teststreifen-basierter INR-Messung zu untersuchen und die Analysedauern der beiden Methoden zu vergleichen. Wir haben in dieser prospektiven Mono-Center Studie 24 hämorrhagische Patienten und Patientinnen inkludiert und aus infrastrukturellen Gesichtspunkten in zwei Gruppenkollektive aufgeteilt. Das eine Studienkollektiv bildeten 12 hämorrhagische Patientinnen der Klinik für Gynäkologie und Geburtshilfe des Universitätsklinikums Frankfurt. Die Blutproben dieser Patientinnen wurden mittels einem personengebundenen Transportdienst in das Zentrallabor der Universitätsklinik geliefert. Das zweite Gruppenkollektiv bildeten 12 Patienten aus dem Schockraum der zentralen Notaufnahme. Die Blutproben dieses Kollektivs wurden mittels Rohrpost direkt in das Zentrallabor übermittelt. Wir untersuchten mittels konventioneller Gerinnungsdiagnostik und mittels Teststreifen-basierter POC-Diagnostik (CoaguChek II Pro®, PT Test, Roche Diagnostics AG) die INR eines jeden Patienten. Zudem erfolgte die Erfassung von Transport- und Analysedauer. Für die Auswertung der Daten errechneten wir die Spearman-Korrelationskoeffizienten sowohl auf Gruppenebene als auch für das Gesamtkollektiv und führten eine Bland-Altman Analyse zum direkten Methodenvergleich durch.
Es zeigte sich, dass die mittels POCT ermittelte INR im Gesamtkollektiv signifikant mit den im Zentrallabor gemessenen Werten korreliert (r=0,79). Auch auf Gruppenebene zeigte sich in Gruppe 1 (Schockraum) r=0,91 und in Gruppe 2 (Kreißsaal) r=0,83 eine signifikante Korrelation. Die Bland-Altmann Analyse ergab, dass die Ergebnisse der Teststreifen-basierten POC-Methode um 0,082 (SD±0,19) niedriger waren als die Ergebnisse der konventionellen Gerinnungstests. Die Untersuchung der Analyse- und Transportzeiten brachte hervor, dass die Bereitstellungsdauer der POC-Messmethode signifikant kürzer war (2 (1,04/2,85) Minuten) als die Dauer bis zur elektronischen Ergebnisbereitstellung nach laboranalytischen Untersuchungen (58,2 (38,28/88) Minuten). Es ergab sich zudem, dass die Transportdauer mittels Rohrpost mit 8 (3,25/10,1) Minuten signifikant kürzer war als die des personengebundenen Transportdienstes 18,5 (14,5/33) Minuten (p<0,001).Die in der Studie ermittelten konsistenten Ergebnisse lassen vermuten, dass Teststreifen-basierte Systeme als Methoden zur Notfalldiagnostik hämorrhagischer Patienten geeignet sein können, weil ihre Messergebnisse verglichen mit der klassischen Gerinnungsdiagnostik im Zentrallabor deutlich schneller und mit vergleichbarer Ergebnisqualität vorliegen. Die Teststreifen-basierten Methoden können als diagnostische Elemente in Hämotherapie-Algorithmen eingesetzt werden und dazu beitragen, eine zeitnahe und zielgerichtete Hämotherapie umzusetzen, die sich positiv auf das klinische Ergebnis der Patienten auswirken kann.
Perioperative Blutungskomplikationen stellen, insbesondere für neurochirurgisch behandelte Patienten, eine schwerwiegende Komplikation dar und sind mit einer signifikant erhöhten Morbidität und Mortalität assoziiert [1]. Der perioperative Blutverlust ist einer der Hauptgründe für die Transfusion allogener Blutprodukte [2, 3]. Transfusionen von Erythrozytenkonzentraten (EK), Gefrorenem Frischplasma (GFP) und Thrombozytenkonzentraten (TK) sind dabei unabhängige Risikofaktoren für die Entwicklung thromboembolischer, pulmonaler, hämodynamischer oder septischer Komplikationen und selbst mit einer erhöhten perioperativen Morbidität und Mortalität assoziiert [3-10]. In der Literatur wird die Prävalenz von Blutungskomplikationen im Rahmen von intrakraniellen Eingriffen (Raten zwischen 0,8% bis 50%) sehr unterschiedlich beschrieben [1, 11-13]. Gleichwertige Voraussetzungen für die Bildung und Aufrechterhaltung eines stabilen Blutgerinnsels sind, neben einer effizienten primären Hämostase (Thrombozytenzahl und –funktion, Von-Willebrand-Faktor), auch die plasmatische Gerinnung (extrinsische und intrinsische Gerinnungsfaktoren) und der Schutz vor (Hyper)fibrinolyse [14].
The recently developed stereospecific sodium salt glycosylation procedure has been successfully applied to the synthesis of the β-ᴅ-2′-deoxyribofuranosides of benzimidazole, 5,6-dihalogeno benzimidazoles, and some 2-substituted analogues in high yield. The 5,6-dibromo analogue was obtained by bromination of the parent nucleoside. These have all been characterized by spectroscopic methods, including 1H NMR, which permitted analyses of their solution conformations and comparison with those of the corresponding ribofuranosides. Some biological aspects, including preliminary results on cytotoxicity and antiviral activity, are briefly considered.
Fanyiwi, Prasakti Tenri ; Agayby, Beshoy ; Kienitz, Ricardo ; Haag, Marcus ; Schmid, Michael Christoph
A growing body of psychophysical research reports theta (3-8 Hz) rhythmic fluctuations in visual perception that are often attributed to an attentional sampling mechanism arising from theta rhythmic neural activity in mid- to high-level cortical association areas. However, it remains unclear to what extent such neuronal theta oscillations might already emerge at early sensory cortex like the primary visual cortex (V1), e.g. from the stimulus filter properties of neurons. To address this question, we recorded multi-unit neural activity from V1 of two macaque monkeys viewing a static visual stimulus with variable sizes, orientations and contrasts. We found that among the visually responsive electrode sites, more than 50 % showed a spectral peak at theta frequencies. Theta power varied with varying basic stimulus properties. Within each of these stimulus property domains (e.g. size), there was usually a single stimulus value that induced the strongest theta activity. In addition to these variations in theta power, the peak frequency of theta oscillations increased with increasing stimulus size and also changed depending on the stimulus position in the visual field. Further analysis confirmed that this neural theta rhythm was indeed stimulus-induced and did not arise from small fixational eye movements (microsaccades). When the monkeys performed a detection task of a target embedded in a theta-generating visual stimulus, reaction times also tended to fluctuate at the same theta frequency as the one observed in the neural activity. The present study shows that a highly stimulus-dependent neuronal theta oscillation can be elicited in V1 that appears to influence the temporal dynamics of visual perception.
Under natural conditions, the visual system often sees a given input repeatedly. This provides an opportunity to optimize processing of the repeated stimuli. Stimulus repetition has been shown to strongly modulate neuronal-gamma band synchronization, yet crucial questions remained open. Here we used magnetoencephalography in 30 human subjects and find that gamma decreases across ~10 repetitions and then increases across further repetitions, revealing plastic changes of the activated neuronal circuits. Crucially, changes induced by one stimulus did not affect responses to other stimuli, demonstrating stimulus specificity. Changes partially persisted when the inducing stimulus was repeated after 25 minutes of intervening stimuli. They were strongest in early visual cortex and increased interareal feedforward influences. Our results suggest that early visual cortex gamma synchronization enables adaptive neuronal processing of recurring stimuli. These and previously reported changes might be due to an interaction of oscillatory dynamics with established synaptic plasticity mechanisms.
Um die Rolle von potentiell schmerzauslösenden Substanzen bei der Entstehung von menschlichem Muskelschmerz und von muskulärer Hyperalgesie zu beurteilen, wurde bei dieser Arbeit das DOMS Muskelschmerzmodell und das hypertone NaCl Muskelschmerzmodell in Kombination mit der Mikrodialysetechnik verwendet. Dabei wurden bei 10 gesunden, untrainierten Probanden metabolische Änderungen im Glucosestoffwechsel (Glucose, Laktat) und Fettstoffwechsel (Glycerol), Änderung der Glutamat Freisetzung und Änderungen von inflammatorischen Mediatoren (PGE2, NO, Substanz P) in den schmerzhaften und in den Kontrollmuskeln untersucht. Studienbegleitend erfolgte zur Beurteilung der Effektivität der Übungen und des dabei entstandenen Muskelschadens die Bestimmung von Serum CK, Serum Laktat, des Muskelumfangs und der Muskeldruckschmerzschwelle (PPT). Die Probanden gaben regelmäßig die Schmerzintensität auf einer visuellen Analogskala (VAS) an. Die DOMS Muskelschmerzen wurden 24 Stunden vor dem Beginn der Mikrodialyse durch konzentrisch/ exzentrische Kontraktionen der Wadenmuskulatur im Verum Bein ausgelöst. Während der Mikrodialyse erfolgte die Schmerzstimulation der Wadenmuskulatur durch Plantar- und Dorsalflexion des Fußes. Die Schmerzauslösung beim hypertonen NaCl Modell geschah während der Mikrodialyse durch sequentielle Injektionen von hypertoner NaCl Lösung ( 5 ∗ 200 µl 5.8% NaCl Lösung in 2 Minuten Intervallen) in den Bizepsmuskel am Oberarm. Die Zuordnung der Behandlung (Verum vs. Kontrollmuskel) erfolgte jeweils nach dem Zufallsprinzip.
Direkt nach den DOMS Übungen kam es zu einem signifikanten Anstieg von Laktat im Serum, nach 24 Stunden zu einem signifikanten Ansteigen der CK Aktivität und einer Zunahme des Muskelumfangs. Mit beiden Modellen konnte zuverlässig ein Muskelschmerz erzeugt werden, wobei die Schmerzintensität bei wiederholter Stimulierung abnahm und dies im DOMS Modell stärker ausgeprägt war. Eine mechanische Hyperalgesie konnte nur an den Waden beobachtet werden, die dort aber beidseitig auftrat und damit eine Art „zentraler Übererregbarkeit“ vermuten lässt. Die Dialysatkonzentrationen von Glutamat, PGE2 und Substanz P zeigten aufgrund der Schmerzstimulation im DOMS Bein einen lokalen Anstieg (Glutamat 125 ± 20 µM [p=0.005], PGE2 239 ± 45 pg/ml, Substanz P 64 ± 11 pg/ml). Dabei traten im Kontrollbein keine signifikanten Änderungen auf. Während der Mikrodialyseperiode war die NO Konzentration im DOMS Bein signifikant geringer als im Kontrollbein (p = 0.02), zeigte dabei aber keine Beeinflussung durch die Schmerzstimulation. Gleichzeitig war dabei die Laktatkonzentration im DOMS Bein im Vergleich zum Kontrollbein erhöht. Die Glucose- und Glycerolkonzentrationen wiesen durch die Schmerzauslösung keine bedeutenden Veränderungen auf.
Im Bizepsmuskel kam es infolge der hypertonen NaCl Injektionen zu einem signifikanten Anstieg der Glutamat Konzentration im Dialysat (50 ± 3 µM, p = 0.003), wobei diese im Kontrollmuskel konstant blieb. Die Injektionen hatten aber keinen Einfluss auf die Werte von Glucose, Laktat, Glycerol, NO, PGE2, des Muskelumfangs und der PPT.
Möglicherweise ist ein inflammatorischer Prozess an den peripheren Mechanismen der Muskelschmerzentstehung beim DOMS Modell beteiligt. Die Injektion von hypertoner NaCl Lösung löst den Muskelschmerz vermutlich direkt durch die hohe extrazelluläre Natrium Konzentration aus, wobei es zu einer Depolarisation der Nozizeptormembran mit einer nachfolgenden Glutamat Freisetzung aus den aktivierten Nozizeptoren kommt. Die Vorteile dieses Modells sind die Wiederholbarkeit und die kurze Dauer des Muskelschmerzes. Die dem ausgelösten Schmerz zugrundeliegenden Mechanismen ähneln jedoch nicht den Mechanismen die dem klinischen Muskelschmerz zugrunde liegen. Deshalb könnte es sein, dass die Bedeutungen der Ergebnisse aus diesem Modell relativ beschränkt sind und die Nützlichkeit insbesondere für pharmakologische Studien damit auch eingeschränkt ist.
Der Neurotransmitter Glutamat ist an den peripheren Mechanismen der Muskelschmerzentstehung beteiligt, da die Glutamat Freisetzung direkt mit dem Muskelschmerz beim DOMS Modell und beim Hypertonen NaCl Modell assoziiert war. Die beim DOMS Modell erhöhten Konzentrationen von Laktat, PGE2, sowie die Änderungen von Substanz P und die erniedrigten NO Konzentrationen könnten auch zu der Entstehung von Muskelschmerz beitragen.
Der beobachtete Rückgang der Schmerzintensität bei wiederholter Stimulierung lässt auf eine Art „Gewöhnung“ schließen, die bei Anwendung des DOMS Modells für pharmakologische Untersuchungen einen Nachteil darstellen könnte.
Mücke, Marcus Maximilian ; Rüschenbaum, Sabrina ; Mayer, Amelie ; Mücke, Victoria Therese ; Schwarzkopf, Katharina M. ; Zeuzem, Stefan ; Kehrmann, Jan ; Scholtysik, René ; Lange, Christian
Introduction: Quinolone prophylaxis is recommended for patients with advanced cirrhosis at high risk of spontaneous bacterial peritonitis (SBP) or with prior SBP. Yet, the impact of long-term antibiotic prophylaxis on the microbiome of these patients is poorly characterized.
Methods: Patients with liver cirrhosis receiving long-term quinolone prophylaxis to prevent SBP were prospectively included and sputum and stool samples were obtained at baseline, 1, 4 and 12 weeks thereafter. Both bacterial DNA and RNA were assessed with 16S rRNA sequencing. Relative abundance, alpha and beta diversity were calculated and correlated with clinical outcome.
Results: Overall, 35 stool and 19 sputum samples were obtained from 11 patients. Two patients died (day 9 and 12) all others were followed for 180 days. Reduction of Shannon diversity and bacterial richness was insignificant after initiation of quinolone prophylaxis (p > 0.05). Gut microbiota were significantly different between patients (p < 0.001) but non-significantly altered between the different time points before and after initiation of antibiotic prophylaxis (p > 0.05). A high relative abundance of Enterobacteriaceae > 20% during quinolone prophylaxis was found in three patients. Specific clinical scenarios (development of secondary infections during antibiotic prophylaxis or the detection of multidrug-resistant Enterobacteriaceae) characterized these patients. Sputum microbiota were not significantly altered in individuals during prophylaxis.
Conclusion: The present exploratory study with small sample size showed that inter-individual differences in diversity of gut microbiota were high at baseline, yet quinolone prophylaxis had only a moderate impact. High relative abundances of Enterobacteriaceae during follow-up might indicate failure of or non-adherence to quinolone prophylaxis. However, our results may not be clinically significant given the limitations of the study and therefore future studies are needed to further investigate this phenomenon.
Gerhardt, Sarah ; Luderer, Mathias ; Bumb, Jan Malte ; Sobanski, Esther ; Moggi, Franz ; Kiefer, Falk ; Vollstädt-Klein, Sabine
Rationale: Both attention deficit-/hyperactivity disorder (ADHD) and alcohol use disorder (AUD) are accompanied by deficits in response inhibition. Furthermore, the prevalence of comorbidity of ADHD and AUD is high. However, there is a lack of research on whether the same neuronal subprocesses of inhibition (i.e., interference inhibition, action withholding and action cancellation) exhibit deficits in both psychiatric disorders. Methods: We examined these three neural subprocesses of response inhibition in patient groups and healthy controls: non-medicated individuals with ADHD (ADHD; N = 16), recently detoxified and abstinent individuals with alcohol use disorder (AUD; N = 15), and healthy controls (HC; N = 15). A hybrid response inhibition task covering interference inhibition, action withholding, and action cancellation was applied using a 3T functional magnetic resonance imaging (fMRI). Results: Individuals with ADHD showed an overall stronger hypoactivation in attention related brain areas compared to AUD or HC during action withholding. Further, this hypoactivation was more accentuated during action cancellation. Individuals with AUD recruited a broader network, including the striatum, compared to HC during action withholding. During action cancellation, however, they showed hypoactivation in motor regions. Additionally, specific neural activation profiles regarding group and subprocess became apparent. Conclusions: Even though deficits in response inhibition are related to both ADHD and AUD, neural activation and recruited networks during response inhibition differ regarding both neuronal subprocesses and examined groups. While a replication of this study is needed in a larger sample, the results suggest that tasks have to be carefully selected when examining neural activation patterns of response inhibition either in research on various psychiatric disorders or transdiagnostic questions.
Although immune checkpoint inhibitors such as anti-PD-1 antibodies have shown remarkable clinical success in many different tumor types, the proportion of patients benefiting from this treatment option remains low. Therefore, there is a need to sensitize tumors for immune checkpoint blockade. In this study two approaches were tested, a chemoimmunotherapy approach combining PD-1 checkpoint blockade with doxorubicin (DOX) chemotherapy, and ablation of the sphingosine-1-phosphate (S1P) receptor (S1PR4) based on the following rationale. Chemotherapy was shown to induce immune paralysis which contributes to tumor relapse, while PD-1 signaling was shown to facilitate the acquisition of chemoresistance. Thus, combinatorial chemoimmunotherapy is expected to be beneficial by maintaining or even activating anti-tumor immunity during chemotherapy. S1PR4 is an immune cell specific receptor, whose ablation slowed tumor progression by activating anti-tumor immunity in a mouse model that was previously insensitive to anti-PD-1 monotherapy. This suggested that S1PR4 ablation might pre-activate immunity to sensitize for anti-PD-1 therapy.
To test these combinatorial approaches, two tumor mouse models were employed, namely the MC38 murine adenocarcinoma model as well as the transgenic polyoma middle T oncogene (PyMT) breast cancer model. In the MC38 model, a mild synergistic effect of PD-1 immune checkpoint blockade and S1PR4 ablation was observed, indicated by improved tumor progression and survival as compared to the WT control, and an increased number of tumor-free mice compared to anti-PD-1 therapy alone in WT mice. These observations correlated with an enhanced natural killer (NK) cell infiltrate and increased CXCL9 and CXCL10 production in anti-PD-1 treated S1PR4 KO tumors. As noted before, the PyMT model was largely resistant to anti-PD-1 monotherapy in a therapeutic setting. S1PR4 ablation alone showed significant tumor reduction that was not further enhanced by anti-PD-1 treatment. The same was observed when chemotherapy with DOX was added, where WT tumors relapsed, while S1PR4 KO tumor did not. Addition of anti-PD-1 did only mildly increase tumor control in S1PR4 KO mice, indicating that S1PR4 KO per se very efficiently re-activated anti-tumor immunity. Since S1PR4 KO induces type I 12 interferon (IFN-1) over-production in S1PR4 KO PyMT tumors, a link between high IFN-1 levels and tumor immunity was tested by using mice deficient in the IFN-1 receptor (IFNAR1). Unexpectedly, DOX chemotherapy was most efficient in mice with IFNAR ablation only as compared to WT, S1PR4 KO or S1PR4 and IFNAR1 double KO mice, although deficiency in IFNAR signaling is predominantly regarded as tumor promoting. The underlying mechanisms need to be tested in future studies. Interestingly, chemoimmunotherapy in WT mice prevented tumor relapse to a similar extent than S1PR4 KO and was superior to chemotherapy or immune checkpoint blockade alone. To investigate mechanisms of chemoimmunotherapy success compared to monotherapy, whole transcriptome analysis was used, which identified a set of genes that were upregulated specifically upon chemoimmunotherapy. This gene signature and, more specifically, a condensed four-gene signature predicted favorable survival of human mammary carcinoma patients in the METABRIC cohort.
Moreover, PyMT tumors treated with chemoimmunotherapy contained higher levels of cytotoxic lymphocytes, particularly NK cells. Gene set enrichment analysis and ELISA measurements revealed increased IL-27 production and signaling in PyMT tumors upon chemoimmunotherapy. Moreover, IL-27 improved NK cell cytotoxicity against PyMT cells in vitro. These data supported recent clinical observations indicating a benefit of chemoimmunotherapy compared to monotherapy in breast cancer and suggested potential underlying mechanisms.
Taken together the present work revealed new strategies to reactivate tumor immunity leading to improved chemotherapy response, namely a combination with immune checkpoint blockade and ablation of S1PR4, which activated different lymphocyte compartments within tumors.
Sawicki, Olga Anastasia ; Müller, Angelina ; Klaaßen-Mielke, Renate ; Glushan, Anastasiya ; Gerlach, Ferdinand M. ; Beyer, Martin ; Wensing, Michel ; Karimova, Kateryna
In 2004, Germany introduced a program based on voluntary contracting to strengthen the role of general practice care in the healthcare system. Key components include structured management of chronic diseases, coordinated access to secondary care, data-driven quality improvement, computerized clinical decision-support, and capitation-based reimbursement. Our aim was to determine the long-term effects of this program on the risk of hospitalization of specific categories of high-risk patients. Based on insurance claims data, we conducted a longitudinal observational study from 2011 to 2018 in Baden-Wuerttemberg, Germany. Patients were assigned to one or more of four open cohorts (in 2011, elderly, n = 575,363; diabetes mellitus, n = 163,709; chronic heart failure, n = 82,513; coronary heart disease, n = 125,758). Adjusted for key patient characteristics, logistic regression models were used to compare the hospitalization risk of the enrolled patients (intervention group) with patients receiving usual primary care (control group). At the start of the study and throughout long-term follow-up, enrolled patients in the four cohorts had a lower risk of all-cause hospitalization and ambulatory, care-sensitive hospitalization. Among patients with chronic heart failure and coronary heart disease, the program was associated with significantly reduced risk of cardiovascular-related hospitalizations across the eight observed years. The effect of the program also increased over time. Over the longer term, the results indicate that strengthening primary care could be associated with a substantial reduction in hospital utilization among high-risk patients.
Structural brain morphometry as classifier and predictor of ADHD and reward-related comorbidities
(2022)
Rooij, Daan van ; Zhang-James, Yanli ; Buitelaar, Jan K. ; Faraone, Stephen V. ; Reif, Andreas ; Grimm, Oliver
Attention deficit/hyperactivity disorder (ADHD) is one of the most common neurodevelopmental disorders, and around two-thirds of affected children report persisting problems in adulthood. This negative trajectory is associated with high comorbidity with disorders like obesity, depression, or substance use disorder (SUD). Decreases in cortical volume and thickness have also been reported in depression, SUD, and obesity, but it is unclear whether structural brain alterations represent unique disorder-specific profiles. A transdiagnostic exploration of ADHD and typical comorbid disorders could help to understand whether specific morphometric brain changes are due to ADHD or, alternatively, to the comorbid disorders. In the current study, we studied the brain morphometry of 136 subjects with ADHD with and without comorbid depression, SUD, and obesity to test whether there are unique or common brain alterations. We employed a machine-learning-algorithm trained to classify subjects with ADHD in the large ENIGMA-ADHD dataset and used it to predict the diagnostic status of subjects with ADHD and/or comorbidities. The parcellation analysis demonstrated decreased cortical thickness in medial prefrontal areas that was associated with presence of any comorbidity. However, these results did not survive correction for multiple comparisons. Similarly, the machine learning analysis indicated that the predictive algorithm grouped most of our ADHD participants as belonging to the ADHD-group, but no systematic differences between comorbidity status came up. In sum, neither a classical comparison of segmented structural brain metrics nor an ML model based on the ADHD ENIGMA data differentiate between ADHD with and without comorbidities. As the ML model is based in part on adolescent brains, this might indicate that comorbid disorders and their brain changes are not captured by the ML model because it represents a different developmental brain trajectory.
Hellmuth, Nadine ; Brat, Camilla Anethe Sandra ; Awad, Omar ; George, Sven ; Kahnt, Astrid Stefanie ; Bauer, Tom ; Phuoc, Hai Phong Huynh ; Steinhilber, Dieter ; Angioni, Carlo ; Hassan, Mohamed ; Hock, Katharina Julia ; Manolikakes, Georg ; Zacharowski, Kai ; Roos, Jessica ; Maier, Thorsten Jürgen
Endogenous nitro-fatty acids (NFA) are potent electrophilic lipid mediators that exert biological effects in vitro and in vivo via selective covalent modification of thiol-containing target proteins. The cytoprotective, anti-inflammatory, and anti-tumorigenic effects of NFA in animal models of disease caused by targeted protein nitroalkylation are a valuable basis for the development of future anti-phlogistic and anti-neoplastic drugs. Considering the complexity of diseases and accompanying comorbidities there is an urgent need for clinically effective multifunctional drugs. NFA are composed of a fatty acid backbone containing a nitroalkene moiety triggering Michael addition reactions. However, less is known about the target-specific structure–activity relationships and selectivities comparing different NFA targets. Therefore, we analyzed 15 NFA derivatives and compared them with the lead structure 9-nitro-oleic acid (9NOA) in terms of their effect on NF-κB (nuclear factor kappa B) signaling inhibition, induction of Nrf-2 (nuclear factor erythroid 2-related factor 2) gene expression, sEH (soluble epoxide hydrolase), LO (lipoxygenase), and COX-2 (cyclooxygenase-2) inhibition, and their cytotoxic effects on colorectal cancer cells. Minor modifications of the Michael acceptor position and variation of the chain length led to drugs showing increased target preference or enhanced multi-targeting, partly with higher potency than 9NOA. This study is a significant step forward to better understanding the biology of NFA and their enormous potential as scaffolds for designing future anti-inflammatory drugs.
Hahn, Alexander ; Parey, Kristian ; Bublitz, Maike ; Mills, Deryck J. ; Zickermann, Volker ; Vonck, Janet ; Kühlbrandt, Werner ; Meier, Thomas Kurt
Highlights
• Cryo-EM structure of a yeast F1Fo-ATP synthase dimer
• Inhibitor-free X-ray structure of the F1 head and rotor complex
• Mechanism of ATP generation by rotary catalysis
• Structural basis of cristae formation in the inner mitochondrial membrane
Summary
We determined the structure of a complete, dimeric F1Fo-ATP synthase from yeast Yarrowia lipolytica mitochondria by a combination of cryo-EM and X-ray crystallography. The final structure resolves 58 of the 60 dimer subunits. Horizontal helices of subunit a in Fo wrap around the c-ring rotor, and a total of six vertical helices assigned to subunits a, b, f, i, and 8 span the membrane. Subunit 8 (A6L in human) is an evolutionary derivative of the bacterial b subunit. On the lumenal membrane surface, subunit f establishes direct contact between the two monomers. Comparison with a cryo-EM map of the F1Fo monomer identifies subunits e and g at the lateral dimer interface. They do not form dimer contacts but enable dimer formation by inducing.
Tesch, Roberta ; Rak, Marcel ; Raab, Monika ; Berger, Lena Marie ; Kronenberger, Thales ; Jörger, Andreas C. ; Berger, Benedict-Tilman ; Abdi, Ismahan ; Hanke, Thomas ; Poso, Antti ; Strebhardt, Klaus ; Sanhaji, Mourad ; Knapp, Stefan
Salt-inducible kinases (SIKs) are key metabolic regulators. Imbalance of SIK function is associated with the development of diverse cancers, including breast, gastric and ovarian cancer. Chemical tools to clarify the roles of SIK in different diseases are, however, sparse and are generally characterized by poor kinome-wide selectivity. Here, we have adapted the pyrido[2,3-d]pyrimidin-7-one-based PAK inhibitor G-5555 for the targeting of SIK, by exploiting differences in the back-pocket region of these kinases. Optimization was supported by high-resolution crystal structures of G-5555 bound to the known off-targets MST3 and MST4, leading to a chemical probe, MRIA9, with dual SIK/PAK activity and excellent selectivity over other kinases. Furthermore, we show that MRIA9 sensitizes ovarian cancer cells to treatment with the mitotic agent paclitaxel, confirming earlier data from genetic knockdown studies and suggesting a combination therapy with SIK inhibitors and paclitaxel for the treatment of paclitaxel-resistant ovarian cancer.
Kramer, Isabelle Marie ; Baral, Sunita ; Gautam, Ishan ; Braun, Markus ; Magdeburg, Axel ; Phuyal, Parbati ; Kadel, Indira ; Dhimal, Meghnath ; Ahrens, Bodo ; Groneberg, Jan David Alexander ; Müller, Ruth
Container-breeding Aedes spp. (Diptera: Culicidae) mosquitoes can be surveilled at low cost using ovitraps. Hence, this method is a preferred monitoring approach of dengue vectors in low-resource settings. The ovitraps consist of a cup filled with water and an oviposition substrate for female mosquitoes. The attractiveness of the substrates for female mosquitoes can greatly differ due to differences in texture, color, and smell of the materials used. We compare four oviposition substrates, which are all low priced, easy to transport, and easy to purchase, to maximize the success of Aedes egg sampling. Sampled egg material is often reared to adulthood for further taxonomic identification and transported to (international) laboratories for specialized vector research. Here we introduce a transport technique for sampled eggs. In addition, we explored the impact of international transport by means of a bilateral hatching experiment in Nepal, the country of origin, and in Germany, in a laboratory specialized in ecophysiological research. The best low-cost oviposition substrate for the dengue vectors Aedes albopictus (Skuse) and Aedes aegypti (L.) was found to be a white cotton sheet. The introduced transport technique of sampled eggs is easy to build from laboratory and household materials and ensures good transport conditions (i.e., temperature and relative humidity). Even under good temperature (17.4–31.0 °C) and humidity conditions (58.9–94.2%), hatching success of eggs was found to be reduced after international transport to Germany when compared to the hatching success of eggs in Nepal. We postulate that air pressure during international transport may have reduced the hatching success and strongly recommend pressure-regulated transport boxes for egg transport via airplane. As the proposed operation procedure is useful in assisting the monitoring of Ae. albopictus and Ae. aegypti in low-resource settings, Aedes researchers are encouraged to follow it for the sampling and transport of Aedes eggs.
Ziel: Ziel dieser Studie war es die Verweildauerraten, sowie die komplikationslosen Verweil-dauerraten von rein zahn, rein implantat und kombiniert zahn-implantatgetragenen Galvano-Konusprothesen auf keramischen Primärteilen im Oberkiefer zu untersuchen. Zusätzlich wurden durchgeführte Reparaturen, sowie die Patientenzufriedenheit ausgewertet.
Methode: 83 Patienten, welche im Zeitraum von 1999-2012 am ZZMK eine Galvano-Konusprothese im Oberkiefer erhalten haben wurden retrospektiv nachuntersucht. Die Patientenzufriedenheit wurde anhand eines Fragebogens erhoben, welcher mittels 22 Fragen die Bereiche „Ästhetik“, „Prothesenhalt-bzw. funktion“ und die „Reinigungsmöglichkeit der Prothese“ aus Patientensicht evaluiert. Als Zielereignis der Kaplan-Meier Verweildaueranalyse wurde die erste Reparatur, das Versagen der Prothese, sowie der Pfeiler- bzw. der Implantatverlust definiert. Reparatur- und Nachsorgemaßnahmen wurden deskriptiv erhoben.
Ergebnisse: Es konnten 83 Prothesen und 477 Pfeiler nachuntersucht werden. Der mittlere Beobachtungszeitraum betrug 3,9 Jahre. Die 3- ,5- und 10- Jahres Verweildauerraten der Prothesen lagen bei 98,2%, 95,5% bzw. 70,7%. Die konstruktionsbezogene Pfeilerüberlebensrate bis zum ersten Pfeilerzahnverlust betrug 98,2% nach 3 Jahren, 92,9% nach 5 Jahren und 29,2% nach 10 Jahren. Die häufigste Ursache eines Versagens war der Mehrfachverlust von Pfeilern (n=5). Eine Prothese versagte aufgrund eines Gerüstbruchs (n=1). Es konnte keine signifikanten Unterschiede in der Verweildauerrate bis zum Prothesenverlust, sowie in der komplikationslosen Verweildauerrate zwischen rein zahn, rein implantat und kombiniert zahn-implantagetragenen Prothesen festgestellt werden. Zu den häufigsten Reparaturen zählten Erweiterungen nach Pfeilerverlusten, Verblendreparaturen, Dezementierungen der Primärkronen und Frakturen von Prothesenzähnen. Die häufigste Nachsorgemaßnahme war die Druckstellenentfernung. Die Patientenzufriedenheit mit der Galvano-Konusprothese erwies sich als sehr hoch. Die Ästhetik, der Prothesenhalt und die Reinigungsmöglichkeit des Zahnersatzes wurden unabhängig der Verankerungsart durchgängig positiv bewertet.
Schlussfolgerung: Die Galvano-Konusprothese hat sich als hochwertiger herausnehmbarer Zahnersatz bewährt, welcher hohe Verweildauerraten aufweist und dessen Reparaturanfälligkeit vergleichbar mit anderen Doppelkronenversorgungen ist.