Internes Qualitätsmanagement in der gastrointestinalen Endoskopie: Analyse und Erarbeitung von Qualitätskriterien, Prozessbewertung in der Endoskopie der Universitätsklinik Leipzig sowie Evaluation des aktuellen Status und der Entwicklung in Deutschland

Qualitätsmanagement in der Medizin erhält aus verschiedenen Gründen eine zunehmende Bedeutung im klinischen Alltag. Dabei spielt neben der Bereitstellung der bestmöglichen Versorgungsqualität inklusive reibungsloser und effektiver Zeitabläufe auch die Aufrechterhaltung einer interdisziplinären und überregionalen Wettbewerbsfähigkeit der klinischen Einrichtung eine entscheidende Rolle. Im Zuge dessen wird zunehmend versucht die Qualität einer medizinischen Untersuchung anhand von Qualitätskriterien messbar zu machen, um dadurch standardisierte bzw. einheitlich hochwertige Untersuchungsabläufe und eine überregionale Vergleichbarkeit der Prozeduren zu erreichen. Im Rahmen dieser Arbeit wurden spezifische Vorgaben für die Etablierung eines Qualitätsmanagements in der gastrointestinalen Endoskopie aus der Fachliteratur zusammengetragen und ein entsprechender Überblick der einzelnen Qualitätskriterien erstellt. Dabei konnte gezeigt werden, dass für verschiedene Prozeduren in endoskopischen Abteilungen (Hygiene, Sedierung, Patientenmanagement, …) und insbesondere für die Koloskopie eine Vielzahl an gut evaluierten und etablierten Qualitätskriterien existieren. Beispielsweise ist die Adenomdetektionsrate für die Koloskopie schon ein international anerkannter und vielfach eingesetzter Parameter, der es ermöglicht, Leistungen der Untersucher und ganzer endoskopischer Abteilungen zu bewerten und zu vergleichen. Im Vergleich dazu sind für die Gastroskopie aufgrund einer geringeren Datenlage erheblich weniger Parameter verfügbar. Zusätzlich wurde ein Fragebogen erarbeitet, um einen Überblick über die Nutzung von Qualitätskriterien in endoskopischen Abteilungen in Kliniken unterschiedlicher Größe und gastrointestinalen Praxen zu erlangen und Veränderungen innerhalb eines 1-Jahres-Zeitraums darzulegen. Als wesentliches Ergebnis stellte sich heraus, dass die meisten der befragten Einrichtungen bereits ein Qualitätsmanagement etabliert haben und für einzelne Parameter (z.B. ADR) signifikante Unterschiede in der Nutzung zwischen Endoskopien in Kliniken bzw. Praxen bestehen. Ein weiteres Ziel dieser Arbeit war die Evaluation, auf welche Art und Weise die recherchierten Qualitätskriterien in der interdisziplinären Endoskopie des Universitätsklinikums Leipzig (UKL) umgesetzt werden können. In Zusammenarbeit mit dem Institut für Medizinische Informatik, Statistik und Epidemiologie der Universität Leipzig wurde auf Grundlage der erarbeiteten Qualitätsparameter eine Analyse der Prozesse und Strukturen sowie der verwendeten Dokumentationssoftware Viewpoint erstellt. So wurde evident, dass im Rahmen der täglichen klinischen Routine bereits eine große Menge an nützlichen Daten erfasst und gespeichert wird, in einigen Teilgebieten jedoch auch Anpassungen vorgenommen werden sollten. Eine diesbezügliche Auswertung im Sinne eines Qualitätsmanagements fand bisher nur in wenigen Bereichen statt. Im Zuge der Erstellung dieser Arbeit sind als Grundlage zur Implementierung eines abteilungsinternen Qualitätsmanagements schon erste strukturelle Veränderungen (z.B. die Ernennung eines Qualitätsbeauftragten) in der interdisziplinären Endoskopie des UKL durchgeführt worden

The impact of the AO foundation on fracture care : an evaluation of 60 years AO foundation

Objectives Sixty years ago, the Association of Osteosynthesis (AO) was founded with the aim to improve fracture treatment and has since grown into one of the largest medical associations worldwide. Aim of this study was to evaluate AO's impact on science, education, patient care and the MedTech business. Design/methods Impact evaluations were conducted as appropriate for the individual domains: Impact on science was measured by analyzing citation frequencies of publications promoted by AO. Impact on education was evaluated by analyzing the evolution of number and location of AO courses. Impact on patient care was evaluated with a health economic model analyzing cost changes and years of life gained through the introduction of osteosynthesis in 17 high-income countries (HICs). Impact on MedTech business was evaluated by analyzing sales data of AO-associated products. Results Thirty-five AO papers and 2 major AO textbooks are cited at remarkable frequencies in high ranking journals with up to 2000 citations/year. The number of AO courses steadily increased with a total of 645'000 participants, 20‘000 teaching days and 2‘500 volunteer faculty members so far. The introduction of osteosynthesis saved at least 925 billion Swiss Francs [CHF] in the 17 HICs analyzed and had an impact on avoiding premature deaths comparable to the use of antihypertensive drugs. AO-associated products generated sales of 55 billion CHF. Conclusion AO's impact on science, education, patient care, and the MedTech business was significant because AO addressed hitherto unmet needs by combining activities that mutually enriched and reinforced each other

Evaluation of human first trimester decidual and telomerase-transformed endometrial stromal cells as model systems of in vitro decidualization

<p>Abstract</p> <p>Background</p> <p>Decidualization, the differentiation process of maternal uterine stromal cells into secretory decidual cells, is a prerequisite for successful implantation and progression of pregnancy. For in vitro differentiation mostly primary human endometrial stromal cells (HESC) isolated from uterine samples after hysterectomy for benign gynaecological diseases are utilised. However, a continuous supply of endometrial tissue is often lacking. Hence, we analysed whether cultivated human decidual stromal cells (HDSC) prepared from first trimester pregnancy terminations may represent an alternative model system for in vitro decidualization. Moreover, based on the expression of critical marker genes these cells were compared to a previously established endometrial stromal cell line during in vitro differentiation.</p> <p>Methods</p> <p>HDSC isolated from decidual tissue attached to first trimester placentae, and telomerase-transformed human endometrial stromal cells (THESC) were characterised by immunofluorescence and differentiated in vitro using either cyclic adenosine monophosphate (cAMP) and/or estrogen (E2)/progesterone (P4). Proliferation was measured by analyzing cumulative cell numbers. Expression of mRNAs encoding progesterone receptor (PR), prolactin (PRL), insulin-like growth factor binding protein-1 (IGFBP1), and Dickkopf-1 (DKK1) was evaluated using quantitative PCR after 3, 6, 9 and 12 days of in vitro differentiation. PRL and IGFBP-1 protein expression was investigated by enzyme-linked immunosorbent assay (ELISA) and Western blotting, respectively. Furthermore, forkhead box O1A (FOXO1A), a critical transcription factor in decidualization, was analysed by immunofluorescence and Western blotting at two different time points of differentiation.</p> <p>Results</p> <p>Treatment with cAMP provoked morphological changes and growth arrest of THESC and HDSC, the latter showing loss of cells after 6 days of treatment. E2P4 stimulation did neither affect cell morphology nor proliferation of THESC and HDSC. Upon cAMP stimulation PR mRNA was suppressed in HDSC but not in THESC, whereas E2P4 did not alter transcript levels in both cell types. Protein expression of PR-A and PR-B was detectable in HDSC and diminished under cAMP, whereas THESC failed to produce the nuclear receptors. Supplementation of cAMP induced mRNA and protein expression of PRL and IGFBP-1 in both cell types at day 3, 6, 9, and 12 of treatment. In HDSC stimulation with E2P4 increased PRL and IGFBP-1 mRNA and protein production, whereas hormone treatment did not induce the two factors in THESC. E2P4 increased DKK1 mRNA at all time points in HDSC and cAMP provoked induction at day 9 and 12 of differentiation. In contrast, cAMP suppressed DKK1 mRNA in THESC, whereas E2P4 was ineffective. In both cell types combined treatments with cAMP and E2P4 provoked higher expression levels of PRL and IGFBP1 mRNA and protein as compared to cAMP stimulation alone. FOXO1A protein and its nuclear abundance were increased by cAMP in both cell types. However, reduction of its nuclear localisation upon E2P4 treatment could only be observed in HDSC.</p> <p>Conclusion</p> <p>Both HDSC and THESC may represent suitable model systems for cAMP-dependent in vitro decidualization. Since cAMP decreases cell viability of HDSC after 6 days of incubation, this substance should be preferentially used in short-term experiments. Progesterone treatment of THESC might not be applicable since these cells lack progesterone response and PR protein. In contrast, stimulation of PR-expressing HDSC with E2P4 or cAMP/E2P4 may represent an appropriate protocol for human in vitro decidualization inducing and maintaining expression of critical marker genes in a time-dependent manner.</p

Einfluss von Medikation und Erkrankungen auf funktionelle Eigenschaften mesenchymaler Stammzellen des Knochenmarks

In dieser Arbeit wurde zum einen Eigenschaften der MSC hinsichtlich Proliferation und spontaner ALP-Aktivität ermittelt und diese in Zusammenhang mit der Medikation (Simvastatin, ASS, Ramipril und Bisoprolol) und Vorerkrankungen (art. Hypertonie, die koronare Dreigefäßerkrankung, Hyperlipidämie, Diabetes mellitus Typ II) von 275 Spendern gesetzt. Signifikante Zusammenhänge zeigten sich in der Betrachtung von ASS und Proliferation sowie der spontanen ALP-Aktivität. Alle weiteren untersuchten Medikamente und Vorerkrankungen zeigten keinen Einfluss auf die MSC

Transcriptome analysis of human cancer reveals a functional role of Heme Oxygenase-1 in tumor cell adhesion

<p>Abstract</p> <p>Background</p> <p>Heme Oxygenase-1 (HO-1) is expressed in many cancers and promotes growth and survival of neoplastic cells. Recently, HO-1 has been implicated in tumor cell invasion and metastasis. However, the molecular mechanisms underlying these biologic effects of HO-1 remain largely unknown. To identify a common mechanism of action of HO-1 in cancer, we determined the global effect of HO-1 on the transcriptome of multiple tumor entities and identified a universal HO-1-associated gene expression signature.</p> <p>Results</p> <p>Genome-wide expression profiling of Heme Oxygenase-1 expressing versus HO-1 silenced BeWo choriocarcinoma cells as well as a comparative meta-profiling of the preexisting expression database of 190 human tumors of 14 independent cancer types led to the identification of 14 genes, the expression of which correlated strongly and universally with that of HO-1 (P = 0.00002). These genes included regulators of cell plasticity and extracellular matrix (ECM) remodeling (MMP2, ADAM8, TGFB1, BGN, COL21A1, PXDN), signaling (CRIP2, MICB), amino acid transport and glycosylation (SLC7A1 and ST3GAL2), estrogen and phospholipid biosynthesis (AGPAT2 and HSD17B1), protein stabilization (IFI30), and phosphorylation (ALPPL2). We selected PXDN, an adhesion molecule involved in ECM formation, for further analysis and functional characterization. Immunofluorescence and Western blotting confirmed the positive correlation of expression of PXDN and HO-1 in BeWo cancer cells as well as co-localization of these two proteins in invasive extravillous trophoblast cells. Modulation of HO-1 expression in both loss-of and gain-of function cell models (BeWo and 607B melanoma cells, respectively) demonstrated a direct relationship of HO-1 expression with cell adhesion to Fibronectin and Laminin coated wells. The adhesion-promoting effects of HO-1 were dependent on PXDN expression, as loss of PXDN in HO-1 expressing BeWo and 607B cells led to reduced cell attachment to Laminin and Fibronectin coated wells.</p> <p>Conclusions</p> <p>Collectively, our results show that HO-1 expression determines a distinct 'molecular signature' in cancer cells, which is enriched in genes associated with tumorigenesis. The protein network downstream of HO-1 modulates adhesion, signaling, transport, and other critical cellular functions of neoplastic cells and thus promotes tumor cell growth and dissemination.</p

Endothelin-1 down-regulates matrix metalloproteinase 14 and 15 expression in human first trimester trophoblasts via endothelin receptor type B

$\textbf{STUDY QUESTION}$: Does endothelin-1 (ET-1) regulate matrix metalloproteinase (MMP) 14 and 15 production and invasion of human first trimester trophoblasts? $\textbf{SUMMARY ANSWER}$: ET-1 in pathophysiological concentrations down-regulates MMP14 and MMP15 expression via endothelin receptor (ETR) type B and decreases trophoblast migration and invasion. $\textbf{WHAT IS KNOWN ALREADY}$: MMP14 and MMP15 are involved in trophoblast invasion. Impairment of invasion has been linked to pregnancy complications such as pre-eclampsia (PE). ET-1 is up-regulated in PE. $\textbf{STUDY DESIGN, SIZE, DURATION}$: $\textit{In vitro}$ study using primary human trophoblasts from 50 first trimester placentas (gestational week 7-12). $\textbf{PARTICIPANTS/MATERIALS, SETTING, METHODS}$: Trophoblasts were cultured in the absence or presence of 10-100 nM ET-1. MMP14 and MMP15 mRNA and protein were quantified by RT-qPCR and Western blotting, respectively. Selective antagonists for ETRA (BQ-123) or ETRB (BQ-788) were used to identify ETR subtypes involved. Functional ET-1 effects were tested in first trimester chorionic villous explants and transwell invasion assays. The roles of tumor necrosis factor (TNF)-α (25 ng/ml) and oxygen (1%) in ET-1 regulation of MMP14 and 15 expression were assessed by Western blotting. $\textbf{MAIN RESULTS AND THE ROLE OF CHANCE}$: ET-1 down-regulated MMP14 and MMP15 mRNA (-21% and -26%, respectively, $\textit{P}$ < 0.05) and protein levels (-18% and -22%, respectively, $\textit{P}$ < 0.05). This effect was mediated via ETRB. ET-1 decreased trophoblast outgrowth in placental explants (-24%, $\textit{P}$ < 0.05) and trophoblast invasion (-26%, $\textit{P}$ ≤ 0.01). TNF-α enhanced ET-1 mediated MMP15 down-regulation (by 10%, $\textit{P}$ < 0.05), whereas hypoxia abolished the effect of ET-1 on both MMPs. $\textbf{LARGE SCALE DATA}$: N/A. $\textbf{LIMITATIONS, REASONS FOR CAUTION}$: Only primary trophoblasts were used in this study. Since trophoblast yield from first trimester placental material is limited, further aspects of MMP14 and 15 regulation could not be characterized. Other anti-invasive factors may be altered by ET-1 in trophoblasts and, thus, contribute to the reduced invasion, but have not been investigated. Oxygen levels similar to those found in the decidua (5-8% O2) were not analyzed in this study. $\textbf{WIDER IMPLICATIONS OF THE FINDINGS}$: ET-1 modifies placental function already during the first trimester of pregnancy, the time-window when the placental changes implicated in PE occur. Thus, our results improve the understanding of the placental mechanisms underlying trophoblast invasion and PE.The study was funded by the Oesterreichische Nationalbank (Anniversary Fund, project number: 14796) and the Herzfelder'sche Familienstiftung (to J.P.; number: 00685). AMM received funding from the Austrian Science Fund FWF (W1241) and the Medical University Graz through the PhD Program Molecular Fundamentals of Inflammation (DK-MOLIN)

Control of human endometrial stromal cell motility by PDGF-BB, HB-EGF and trophoblast-secreted factors

Human implantation involves extensive tissue remodeling at the fetal-maternal interface. It is becoming increasingly evident that not only trophoblast, but also decidualizing endometrial stromal cells are inherently motile and invasive, and likely contribute to the highly dynamic processes at the implantation site. The present study was undertaken to further characterize the mechanisms involved in the regulation of endometrial stromal cell motility and to identify trophoblast-derived factors that modulate migration. Among local growth factors known to be present at the time of implantation, heparin-binding epidermal growth factor-like growth factor (HB-EGF) triggered chemotaxis (directed locomotion), whereas platelet-derived growth factor (PDGF)-BB elicited both chemotaxis and chemokinesis (non-directed locomotion) of endometrial stromal cells. Supernatants of the trophoblast cell line AC-1M88 and of first trimester villous explant cultures stimulated chemotaxis but not chemokinesis. Proteome profiling for cytokines and angiogenesis factors revealed neither PDGF-BB nor HB-EGF in conditioned media from trophoblast cells or villous explants, while placental growth factor, vascular endothelial growth factor and PDGF-AA were identified as prominent secretory products. Among these, only PDGF-AA triggered endometrial stromal cell chemotaxis. Neutralization of PDGF-AA in trophoblast conditioned media, however, did not diminish chemoattractant activity, suggesting the presence of additional trophoblast-derived chemotactic factors. Pathway inhibitor studies revealed ERK1/2, PI3 kinase/Akt and p38 signaling as relevant for chemotactic motility, whereas chemokinesis depended primarily on PI3 kinase/Akt activation. Both chemotaxis and chemokinesis were stimulated upon inhibition of Rho-associated, coiled-coil containing protein kinase. The chemotactic response to trophoblast secretions was not blunted by inhibition of isolated signaling cascades, indicating activation of overlapping pathways in trophoblast-endometrial communication. In conclusion, trophoblast signals attract endometrial stromal cells, while PDGF-BB and HB-EGF, although not identified as trophoblast-derived, are local growth factors that may serve to fine-tune directed and non-directed migration at the implantation site