Cofilin-2 in der dilatativen Kardiomyopathie: Implikationen für die molekulare Pathogenese

Eine der häufigsten Ursachen für die Entwicklung einer Herzinsuffizienz ist die dilatative Kardiomyopathie. Deren Entstehung liegt in bis zu 50% eine genetische Ursache zugrunde. Die dabei wirkenden molekularen Mechanismen sind nicht zufriedenstellend verstanden. In Vorversuchen unserer Arbeitsgruppe ist mit dem Calsarcin 1 defizienten Mausmodell gearbeitet worden, welche eine dilatative Kardiomyopathie mit linksventrikulärer Dilatation und Induktion der Hypertrophie assoziierten fötalen Gene ohne Hypertrophie der Kardiomyozyten entwickeln. Ausgehend von diesem Modell ist die microRNA, miR 301 3p, als herunterreguliert identifiziert worden. Ziel dieser Studie war nun die Identifizierung kardialer Zielstrukturen der miR 301a und deren Charakterisierung. Im Verlauf ist Cofilin 2 als Zielstruktur der miR 301a entdeckt worden, was durch Mutation der Bindestellen und Nachweis der in vitro Regulation verifiziert worden ist. Passend zu der verminderten Expression der miR 301a in den Calsarcin 1 defizienten Tieren zeigt sich eine verstärkte Cofilin 2 Expression bei gleichem Phosphorylierungsstatus, welcher auf eine vermehrte Cofilin¬ 2 Aktivität hindeuten kann. Weitere Mausmodelle des Herzversagens haben ebenfalls erhöhte Expressionsniveaus von Cofilin 2 gezeigt. Im Widerspruch zu den Calsarcin 1-/- Tieren ist hier auch miR 301a vermehrt exprimiert. Die hauptsächliche Expression sowohl von miR-301a als auch von Cofilin 2 findet sich dabei in Kardiomyozyten und weniger in kardialen Fibroblasten. Funktionell zeigen miR 301a und Cofilin 2 eine Übereinstimmung in der Regulierung des Serum Response Faktors, da miR 301a inhibierend und Cofilin 2 stimulierend auf die Aktivität des Serum Response Faktors wirken. In neonatalen Kardiomyozyten führt Cofilin 2 zu einer Induktion der Hypertrophie assoziierten Gene ohne Hypertrophie zu induzieren. Zusammenfassend implizieren die erhobenen Daten eine Beteiligung der miR 301a und Cofilin 2 in der Pathogenese der dilatativen Kardiomyopathie

Predicting hypotension in perioperative and intensive care medicine

Blood pressure is the main determinant of organ perfusion. Hypotension is common in patients having surgery and in critically ill patients. The severity and duration of hypotension are associated with hypoperfusion and organ dysfunction. Hypotension is mostly treated reactively after low blood pressure values have already occurred. However, prediction of hypotension before it becomes clinically apparent would allow the clinician to treat hypotension pre-emptively, thereby reducing the severity and duration of hypotension. Hypotension cannowbepredictedminutes before it actually occurs from the blood pressure waveform using machine-learning algorithms that can be trained to detect subtle changes in cardiovascular dynamics preceding clinically apparent hypotension. However, analyzing the complex cardiovascular system is a challenge because cardiovascular physiology is highly interdependent, works within complicated networks, and is influenced by compensatory mechanisms. Improved hemodynamic data collection and integration will be a key to improve current models and develop new hypotension prediction models. (C) 2019 Elsevier Ltd. All rights reserved

Cardiac output estimation using pulse wave analysis-physiology, algorithms, and technologies:a narrative review

Pulse wave analysis (PWA) allows estimation of cardiac output (CO) based on continuous analysis of the arterial blood pressure (AP) waveform. We describe the physiology of the AP waveform, basic principles of PWA algorithms for CO estimation, and PWA technologies available for clinical practice. The AP waveform is a complex physiological signal that is determined by interplay of left ventricular stroke volume, systemic vascular resistance, and vascular compliance. Numerous PWA algorithms are available to estimate CO, including Windkessel models, long time interval or multi-beat analysis, pulse power analysis, or the pressure recording analytical method. Invasive, minimally-invasive, and noninvasive PWA monitoring systems can be classified according to the method they use to calibrate estimated CO values in externally calibrated systems, internally calibrated systems, and uncalibrated systems

Identification of Novel Potential Inhibitors of Pteridine Reductase 1 in Trypanosoma brucei via Computational Structure-Based Approaches and in Vitro Inhibition Assays

Pteridine reductase 1 (PTR1) is a trypanosomatid multifunctional enzyme that provides a mechanism for escape of dihydrofolate reductase (DHFR) inhibition. This is because PTR1 can reduce pterins and folates. Trypanosomes require folates and pterins for survival and are unable to synthesize them de novo. Currently there are no anti-folate based Human African Trypanosomiasis (HAT) chemotherapeutics in use. Thus, successful dual inhibition of Trypanosoma brucei dihydrofolate reductase (TbDHFR) and Trypanosoma brucei pteridine reductase 1 (TbPTR1) has implications in the exploitation of anti-folates. We carried out molecular docking of a ligand library of 5742 compounds against TbPTR1 and identified 18 compounds showing promising binding modes. The protein-ligand complexes were subjected to molecular dynamics to characterize their molecular interactions and energetics, followed by in vitro testing. In this study, we identified five compounds which showed low micromolar Trypanosome growth inhibition in in vitro experiments that might be acting by inhibition of TbPTR1. Compounds RUBi004, RUBi007, RUBi014, and RUBi018 displayed moderate to strong antagonism (mutual reduction in potency) when used in combination with the known TbDHFR inhibitor, WR99210. This gave an indication that the compounds might inhibit both TbPTR1 and TbDHFR. RUBi016 showed an additive effect in the isobologram assay. Overall, our results provide a basis for scaffold optimization for further studies in the development of HAT anti-folates

Continuous noninvasive pulse wave analysis using finger cuff technologies for arterial blood pressure and cardiac output monitoring in perioperative and intensive care medicine:a systematic review and meta-analysis

Background: Finger cuff technologies allow continuous noninvasive arterial blood pressure (AP) and cardiac output/index (CO/CI) monitoring. Methods: We performed a meta-analysis of studies comparing finger cuff-derived AP and CO/CI measurements with invasive measurements in surgical or critically ill patients. We calculated overall random effects model-derived pooled estimates of the mean of the differences and of the percentage error (PE; CO/CI studies) with 95%-confidence intervals (95%-CI), pooled 95%-limits of agreement (95%-LOA), Cochran's Q and I2 (for heterogeneity). Results: The pooled mean of the differences (95%-CI) was 4.2 (2.8 to 5.62) mm Hg with pooled 95%-LOA of –14.0 to 22.5 mm Hg for mean AP (Q=230.4 [P<0.001], I2=91%). For mean AP, the mean of the differences between finger cuff technologies and the reference method was ≤5±8 mm Hg in 9/27 data sets (33%). The pooled mean of the differences (95%-CI) was –0.13 (–0.43 to 0.18) L min−1 with pooled 95%-LOA of –2.56 to 2.23 L min−1 for CO (Q=66.7 [P<0.001], I2=90%) and 0.07 (0.01 to 0.13) L min−1 m−2 with pooled 95%-LOA of –1.20 to 1.15 L min−1 m−2 for CI (Q=5.8 [P=0.326], I2=0%). The overall random effects model-derived pooled estimate of the PE (95%-CI) was 43 (37 to 49)% (Q=48.6 [P<0.001], I2=63%). In 4/19 data sets (21%) the PE was ≤30%, and in 10/19 data sets (53%) it was ≤45%. Conclusions: Study heterogeneity was high. Several studies showed interchangeability between AP and CO/CI measurements using finger cuff technologies and reference methods. However, the pooled results of this meta-analysis indicate that AP and CO/CI measurements using finger cuff technologies and reference methods are not interchangeable in surgical or critically ill patients. Clinical trial number: PROSPERO registration number: CRD42019119266

Predicted risks of radiogenic cardiac toxicity in two pediatric patients undergoing photon or proton radiotherapy

BACKGROUND: Hodgkin disease (HD) and medulloblastoma (MB) are common malignancies found in children and young adults, and radiotherapy is part of the standard treatment. It was reported that these patients who received radiation therapy have an increased risk of cardiovascular late effects. We compared the predicted risk of developing radiogenic cardiac toxicity after photon versus proton radiotherapies for a pediatric patient with HD and a pediatric patient with MB. METHODS: In the treatment plans, each patient’s heart was contoured in fine detail, including substructures of the pericardium and myocardium. Risk calculations took into account both therapeutic and stray radiation doses. We calculated the relative risk (RR) of cardiac toxicity using a linear risk model and the normal tissue complication probability (NTCP) values using relative seriality and Lyman models. Uncertainty analyses were also performed. RESULTS: The RR values of cardiac toxicity for the HD patient were 7.27 (proton) and 8.37 (photon), respectively; the RR values for the MB patient were 1.28 (proton) and 8.39 (photon), respectively. The predicted NTCP values for the HD patient were 2.17% (proton) and 2.67% (photon) for the myocardium, and were 2.11% (proton) and 1.92% (photon) for the whole heart. The predicted ratios of NTCP values (proton/photon) for the MB patient were much less than unity. Uncertainty analyses revealed that the predicted ratio of risk between proton and photon therapies was sensitive to uncertainties in the NTCP model parameters and the mean radiation weighting factor for neutrons, but was not sensitive to heart structure contours. The qualitative findings of the study were not sensitive to uncertainties in these factors. CONCLUSIONS: We conclude that proton and photon radiotherapies confer similar predicted risks of cardiac toxicity for the HD patient in this study, and that proton therapy reduced the predicted risk for the MB patient in this study

CEACAM6 is upregulated by <i>Helicobacter pylori</i> CagA and is a biomarker for early gastric cancer

Early detection of gastric cancers saves lives, but remains a diagnostic challenge. In this study, we aimed to identify cell-surface biomarkers of early gastric cancer. We hypothesized that a subset of plasma membrane proteins induced by the Helicobacter pylori oncoprotein CagA will be retained in early gastric cancers through non-oncogene addiction. An inducible system for expression of CagA was used to identify differentially upregulated membrane protein transcripts in vitro. The top hits were then analyzed in gene expression datasets comparing transcriptome of gastric cancer with normal tissue, to focus on markers retained in cancer. Among the transcripts enriched upon CagA induction in vitro, a significant elevation of CEACAM6 was noted in gene expression datasets of gastric cancer. We used quantitative digital immunohistochemistry to measure CEACAM6 protein levels in tissue microarrays of gastric cancer. We demonstrate an increase in CEACAM6 in early gastric cancers, when compared to matched normal tissue, with an AUC of 0.83 for diagnostic validity. Finally, we show that a fluorescently conjugated CEACAM6 antibody binds avidly to freshly resected gastric cancer xenograft samples and can be detected by endoscopy in real time. Together, these results suggest that CEACAM6 upregulation is a cell surface response to H. pylori CagA, and is retained in early gastric cancers. They highlight a novel link between CEACAM6 expression and CagA in gastric cancer, and suggest CEACAM6 to be a promising biomarker to aid with the fluorescent endoscopic diagnosis of early neoplastic lesions in the stomach

The Oldest Case of Decapitation in the New World (Lapa do Santo, East-Central Brazil)

We present here evidence for an early Holocene case of decapitation in the New World (Burial 26), found in the rock shelter of Lapa do Santo in 2007. Lapa do Santo is an archaeological site located in the Lagoa Santa karst in east-central Brazil with evidence of human occupation dating as far back as 11.7-12.7 cal kyBP (95.4% interval). An ultra-filtered AMS age determination on a fragment of the sphenoid provided an age range of 9.1-9.4 cal kyBP (95.4% interval) for Burial 26. The interment was composed of an articulated cranium, mandible and first six cervical vertebrae. Cut marks with a v-shaped profile were observed in the mandible and sixth cervical vertebra. The right hand was amputated and laid over the left side of the face with distal phalanges pointing to the chin and the left hand was amputated and laid over the right side of the face with distal phalanges pointing to the forehead. Strontium analysis comparing Burial 26's isotopic signature to other specimens from Lapa do Santo suggests this was a local member of the group. Therefore, we suggest a ritualized decapitation instead of trophy-taking, testifying for the sophistication of mortuary rituals among hunter-gatherers in the Americas during the early Archaic period. In the apparent absence of wealth goods or elaborated architecture, Lapa do Santo's inhabitants seemed to use the human body to express their cosmological principles regarding death

Non-invasive measurement of pulse pressure variation using a finger-cuff method in obese patients having laparoscopic bariatric surgery

Pulse pressure variation (PPV) is a dynamic cardiac preload variable used to predict fluid responsiveness. PPV can be measured non-invasively using innovative finger-cuff systems allowing for continuous arterial pressure waveform recording, e.g., the Nexfin system [BMEYE B.V., Amsterdam, The Netherlands; now Clearsight (Edwards Lifesciences, Irvine, CA, USA)] (PP