Managemententlohnung: Das richtige Maß

Aktionäre haben mehr Pflichten bei Vorstandsgehältern.Shareholders' responsibility due to management compensation gets more important

Osteodystrophy in the millennium

Osteodystrophy in the millennium. Despite three decades of intensive research on the derangements of calcium phosphate metabolism of renal failure, several unresolved issues are still with us at the turn of the millennium: poor control of hyperphosphatemia, relative inefficacy of active vitamin D to prevent progressive parathyroid hyperplasia, and persistence of bone disease despite lowering of parathyroid hormone (PTH) and administration of active vitamin D. Although predictions are problematic, it is not unreasonable to hope that, barring unforeseen side effects, calcimimetics will prove to be valuable for suppressing or even preventing hyperparathyroidism, thus potentially replacing, at least in part, active vitamin D. There is also reason to hope that more effective phosphate binders with fewer side effects will become available and that controlled studies will provide a rationale for the administration of estrogens to dialyzed women. As regards understanding the pathological mechanisms, one can anticipate that the disturbances leading to autonomous growth of parathyroid cells will be elucidated and the signals involved in osteoclast/osteoblast differentiation pathways and osteoclast/osteoblast coupling will be clarified, with obvious impact on patient management

A Statistical Model for Risk Stratification on the Basis of Left Ventricular Ejection Fraction and Heart-Rate Turbulence

The MPIP data set was used to obtain a model for mortality risk stratification of acute myocardial infarction patients. The predictors heart rate turbulence (HRT) and left-ventricular ejection fraction (LVEF) were employed. HRT was a categorical variable of three levels; LVEF was continuous and its influence on the relative risk was explained by the natural logarithm function (found using fractional polynomials). Cox - PH model with HRT and lnLVEF was constructed and used for risk stratification. The model can be used to divide the patients into two or more groups according to mortality risk. It also describes the relationship between risk and predictors by a (continuous) function, which allows the calculation of individual mortality risk

Innovationen und Zukunftsperspektiven in der Diagnostik von Bandscheibenpathologien mittels der Computertomographie

In der vorliegenden Arbeit wurden innovative Einsatzmöglichkeiten der Computertomographie (CT) in der Diagnostik von Pathologien der Bandscheibe in den Bereichen traumatischer, infektiöser und degenerativer spinaler Veränderungen untersucht. Im Rahmen traumatischer Verletzungen der Wirbelsäule wurde das CT-morphologische Auftreten eines Fraktur-assoziierten Vakuumphänomens in der Bandscheibe als möglicher Indikator für eine Bandscheibenbeteiligung untersucht, wobei eine Assoziation mit Berstungsfrakturen festgestellt wurde. Gleichzeitig konnte der Nachweis gelingen, dass das Vorhandensein einer Gasansammlung in der Bandscheibe im Gegensatz zur bisherigen Annahme kein Ausschlusskriterium für das Vorhandensein einer spinalen Infektion darstellt. Im Bereich degenerativer spinaler Veränderungen wurden dagegen Kollagen-sensitive Rekonstruktionen basierend auf der Dual-Energy Computertomographie (DECT) hinsichtlich der Darstellung der Bandscheibenmorphologie untersucht. Im nächsten Schritt erfolgte dann die Analyse ihrer Machbarkeit hinsichtlich der Darstellung lumbaler Bandscheibenpathologien sowie Stenosen der Foramina intervertebralia. Die diskutierten Arbeiten zeigen, dass die CT als diagnostisches Mittel wesentlich zu der Beurteilung von Pathologien der Bandscheibe in den untersuchten Bereichen beiträgt, verdeutlichen aber gleichzeitig, dass die Untersuchung mittels einer einzelnen bildgebenden Modalität alleinig in vielen Fällen keine vollumfassende Diagnostik zur Festlegung des therapeutischen Vorgehens erlaubt

Zelluläre Seneszenz induziert durch neue zielgerichtete Therapien

Einleitung: In den letzten Jahren konnte gezeigt werden, dass Therapie-induzierte zelluläre Seneszenz in der Behandlung maligner Erkrankungen eine zweischneidige Rolle einnimmt. Einerseits kommt es durch die Seneszenzauslösung zum Zellzyklusarrest und damit Proliferationsstopp maligner entarteter Zellen. Andererseits fördern persistierende seneszente Zellen über einen spezifischen sekretorischen Phänotyp und über die Akquirierung von Stammzellfunktionen (Stemness), verbunden mit der nicht völlig „terminalen“ Stabilität des Arrestzustandes bei Verlust Seneszenz-essentieller Genexpression, Tumor-Reinitiierungspotential und somit möglicherweise Metastasierung sowie Tumorprogression und Rezidiventwicklung. Trotz dieser weitreichenden biologischen Folgen zellulärer Seneszenz ist kaum untersucht, ob neue zielgerichtete Therapien, die in der personalisierten Krebstherapie bereits vielfach eingesetzt werden, Seneszenz auslösen. Ziel dieser Arbeit war es daher, die Seneszenzauslösung durch diese neuen Medikamente zu untersuchen und mittels Genexpressionsanalysen festzustellen, welche biologischen Folgen eine solche zelluläre Seneszenz hat. Methodik: Vier Zelllinien maligner hämatologischer Erkrankungen (K562, Mec1, RC-K8 und SD-1) wurden mit neun verschiedenen zielgerichteten Inhibitoren (ABT-199, Bortezomib, Gefitinib, Ibrutinib, Idelalisib, Imatinib, Palbociclib, Tipifarnib und Vemurafenib) oder mit dem konventionellen Chemotherapeutikum Adriamycin behandelt und hinsichtlich ihres Wachstumsverhaltens sowie ihrer Viabilität untersucht. Am sechsten Tag nach Behandlung erfolgten die histochemische und fluoreszenzbasierte Färbung der Seneszenz-assoziierten -Galaktosidase. Weiterhin wurde mittels RQ-PCR die Expression von Genen des Seneszenz-assoziierten sekretorischen Phänotyps (SASP) und von Stammzell-Signaling-relevanten Genen quantifiziert. Ergebnisse: Die Behandlungen mit verschiedenen Inhibitoren führten in den Zelllinien K562, RC-K8 und SD-1 jeweils zu statistisch signifikanten Anstiegen des Anteils seneszenter Zellen, wobei Inhibitoren, die über eine Interferenz mit zellulären Kontrollmechanismen wirken, am effektivsten waren. Zusätzlich konnte auch nach der Behandlung mit Seneszenz-auslösenden Inhibitoren ein Anstieg der Expression von Genen, die für Komponenten des SASP kodieren, und von Stemness-Genen gezeigt werden, welcher jedoch meist geringer war als nach Behandlung mit Adriamycin. Diskussion: Die hier dargestellten Ergebnisse zeigen, dass auch die Behandlung mit neuen zielgerichteten, klinisch bereits eingesetzten Inhibitoren zur Auslösung zellulärer Seneszenz in verschiedenen Zelllinien führt. Da es auch hierbei zu einer gesteigerten Expression von SASP- und Stemness-Genen kam, ist zu erwarten, dass auch diese Form der Seneszenz weitreichende biologische Folgen im Rahmen der Tumorbehandlung hat. Sowohl die Ausschüttung von SASP-Faktoren als auch die Entwicklung von Stemness-Funktionen sind potentiell Tumor-promovierend. Gleichzeitig stellen diese seneszenten Zellen aufgrund der zuletzt entwickelten senolytischen und senomorphischen Therapieansätze ein neues Ziel in der Behandlung maligner Erkrankungen dar.Introduction: In the past few years it has been shown that therapy-induced senescence acts as a double-edged sword in the treatment of malignancies. On the one hand, senescence leads to a cell cycle arrest and thus a proliferative halt of malignant cells. On the other hand, due to the secretion of specific senescence-associated factors (senescence-associated secretory phenotype, SASP) and due to the acquisition of stemcell functions (stemness), combined with a loss of essential senescence gene expression and therefore a not entirely terminal stability of the cellular arrest, persistent senescence cells promote tumor reinitiation potential and thereby dissemination as well as tumor progression and relapse. Despite this crucial biological impact of cellular senescence, the ability of novel targeted therapies, which are already applied in the clinic, to induce senescence have hardly been studied. Therefore, it was this project’s aim to investigate whether these targeted therapies induce cellular senescence and to study the biological impact of this therapy-induced senescence. Methods: Four cell lines of hematological malignancies (K562, Mec1, RC-K8 and SD-1) were treated with nine different targeted inhibitors (ABT-199, Bortezomib, Gefitinib, Ibrutinib, Idelalisib, Imatinib, Palbociclib, Tipifarnib und Vemurafenib) or with the convential chemotherapeutic Adriamycin and then studied regarding their growth behavior and viability. On day six after treatment, histochemical and fluorescence-based stainings of the senescence-associated -galactosidase were performed. Additionally, the expression of SASP-genes and genes relevant for stemcell signaling was quantified via RQ-PCR. Results: Treatment with different inhibitors led to a statistically significant increase of the fraction of senescent cells in K562, RC-K8 and SD-1 cell lines. Inhibitors, which intervene with cellular control mechanisms, were most effective. Furthermore, after treatment with senescence-inducing inhibitors an increase of the expression of SASP- and stemness-genes was shown, which however was also smaller than after Adriamycin treatment. Discussion: These results show that treatment with novel targeted, clinically already established therapies leads to cellular senescence in different cell lines. Since this senescence also led to an increased expression of SASP- and stemness-genes, it is to be expected that this form of senescence also has major consequences regarding the treatment of malignant diseases. The secretion of SASP-factors as well as the acquisition of stemness functions are potentially tumor-promoting. At the same time, due to the development of new senolytic and senomorphic therapeutic approaches, these senescent cells themselves pose a novel target in the treatment of malignant diseases

1016-53 An Inexpensive, Easy to Use and Highly Portable Quantitative Angiographic System

Ouantitative angiography is considered the ″gold standard″ for the assessment of coronary arterial dimensions. The presence in the actual systems of one or more disadvantages such as high cost, difficulty in usage and poor portability, have prevented the wide utilization of this method. To implement a similar system, the acquisition of the computer, software, digitizing board and cineprojector with CCD camera is usually required. We developed a system running on every Macintosh computer with only one special requirement, that of a commercially available slide scanner. A public domain software, NIH Image (written by Wayne Rasband) was modified and expanded to perform the following tasks: acquisition and storage of the digitized angiographic frames, automatic edge detection and measurements, and saving of the results in a text format file, readable from every database, spreadsheet or statistical package. Films (courtesy of Dr. Patrick W. Serruys, Rotterdam) of coronary phantoms with known size (0.5, 0.7, 1.0, 1.4, 1.9 mm) implanted in pigs, were used for system validation. The angiographic frames (24 × 18 mm) were digitized with a spatial resolution of 1850 pixels/inch (slide scanners with higher resolution are also available) and 256 gray levels. Using isocenter calibration, the measurements resulted in a correlation coefficient of 0.96 (y=0.86×+0.12), accuracy of –0.03 mm and precision of 0.15 mm. A correlation coefficient of 0.92 (y=0.67x+0.33), an accuracy of –0.03 mm and a precision of 0.23 mm were found using catheter calibration. With the same phantoms, the mean reproducibility was 0.08 mm for the interpolated reference diameter (RD), 0.03 mm for the minimal luminal diameter (MLD), 1.4% for the diameter stenosis (DS) and 0.6 mm for the lesion length. The variability of coronary measurements was also assessed in 23 patients who had 2 angiograms, a median of 21 days apart. The mean (±SD) of the difference between the 2 measurements was 0.09±0.28 mm for RD, 0.06±0.30 mm for MLD, 1.5±9.1% for DS, and 0.32±1.7 mm for lesion length. Less than 1 hour of training was needed for learning how to use this system efficiently

Implant contamination as a cause of surgical site infection in spinal surgery: are single-use implants a reasonable solution? – a systematic review

Background: In spine surgery, surgical site infection (SSI) is one of the main perioperative complications and is associated with a higher patient morbidity and longer patient hospitalization. Most factors associated with SSI are connected with asepsis during the surgical procedure and thus with contamination of implants and instruments used which can be caused by pre- and intraoperative factors. In this systematic review we evaluate the current literature on these causes and discuss possible solutions to avoid implant and instrument contamination. Methods: A systematic literature search of PubMed addressing implant, instrument and tray contamination in orthopaedic and spinal surgery from 2001 to 2019 was conducted following the PRISMA guidelines. All studies regarding implant and instrument contamination in orthopaedic surgery published in English language were included. Results: Thirty-five studies were eligible for inclusion and were divided into pre- and intraoperative causes for implant and instrument contamination. Multiple studies showed that reprocessing of medical devices for surgery may be insufficient and lead to surgical site contamination. Regarding intraoperative causes, contamination of gloves and gowns as well as contamination via air are the most striking factors contributing to microbial contamination. Conclusions: Our systematic literature review shows that multiple factors can lead to instrument or implant contamination. Intraoperative causes of contamination can be avoided by implementing behavior such as changing gloves right before handling an implant and reducing the instruments' intraoperative exposure to air. In avoidance of preoperative contamination, there still is a lack of convincing evidence for the use of single-use implants in orthopaedic surgery

Identification of the Endogenous Key Substrates of the Human Organic Cation Transporter OCT2 and Their Implication in Function of Dopaminergic Neurons

BACKGROUND: The etiology of neurodegenerative disorders, such as the accelerated loss of dopaminergic neurons in Parkinson's disease, is unclear. Current hypotheses suggest an abnormal function of the neuronal sodium-dependent dopamine transporter DAT to contribute to cell death in the dopaminergic system, but it has not been investigated whether sodium-independent amine transporters are implicated in the pathogenesis of Parkinson's disease. METHODOLOGY/PRINCIPAL FINDINGS: By the use of a novel tandem-mass spectrometry-based substrate search technique, we have shown that the dopaminergic neuromodulators histidyl-proline diketopiperazine (cyclo(his-pro)) and salsolinol were the endogenous key substrates of the sodium-independent organic cation transporter OCT2. Quantitative real-time mRNA expression analysis revealed that OCT2 in contrast to its related transporters was preferentially expressed in the dopaminergic regions of the substantia nigra where it colocalized with DAT and tyrosine hydroxylase. By assessing cell viability with the MTT reduction assay, we found that salsolinol exhibited a selective toxicity toward OCT2-expressing cells that was prevented by cyclo(his-pro). A frequent genetic variant of OCT2 with the amino acid substitution R400C reduced the transport efficiency for the cytoprotective cyclo(his-pro) and thereby increased the susceptibility to salsolinol-induced cell death. CONCLUSIONS/SIGNIFICANCE: Our findings indicate that the OCT2-regulated interplay between cyclo(his-pro) and salsolinol is crucial for nigral cell integrity and that a shift in transport efficiency may impact the risk of Parkinson's disease