Der akute arterielle Gefäßverschluss unter Berücksichtigung möglicher Einflussgrößen, insbesondere dem Zusammenhang mit einer Heparin-induzierten Thrombozytopenie

Problemstellung: Der akute arterielle Gefäßverschluss (ALI; Acute Limb Ischemia) ist nach wie vor mit einer hohen Amputations-und Mortalitätsrate verbunden. Seit den 1990er Jahren hat sich zur Behandlung die lokale Lyse-Therapie etabliert, die in einigen Studien Vorteile gegenüber den operativen Verfahren erkennen ließ. Ziel dieser Untersuchung war es, die Ergebnisse der bisher vorliegenden Vergleichsstudien, die meist bereits länger zurücklagen, anhand eigener und aktuellerer Daten zu verifizieren. Patienten und Methoden: Zu diesem Zweck wurden retrospektiv die Daten von 307 Patienten analysiert, bei denen im Zeitraum zwischen März 1999 und Dezember 2006 eine ALI aufgetreten war. Als Grundlage für die Datenerhebung dienten OP-Berichte, Patientenakten und Laborbefunde. Die Datenerfassung erfolgte in der Klinik für Allgemei-ne Chirurgie, Viszeral-, Gefäß- und Kinderchirurgie sowie im Institut für Hämostaseologie und Transfusionsmedizin der Universität des Saarlandes, Medizinische Fakultät Homburg. Die statistische Auswertung wurde mit SPSS vorgenommen. Ergebnisse: In der Studiengruppe waren signifikant mehr Männer als Frauen vertreten (57,0 vs. 43,0 %; p=0,014). Das mittlere Alter der Männer war geringer als jenes der Frau-en (64,1+12,7 vs. 69,6+15,5; p<0,001). Unabhängig davon war zwischen dem 40. und dem 80. Lebensjahr ein kontinuierlicher Anstieg der ALI-Häufigkeit zu beobachten. Das Lyse-Verfahren erwies sich als signifikant effektiver als die OP; Therapieversager (Amputation und/oder Tod) kamen unter Lyse seltener vor (7,2 vs. 27,0 %; p<0,001). Im Hinblick auf weitere mögliche Einflussgrößen ergab sich, dass adipöse Patienten im Vergleich zur Allgemeinbevölkerung unterrepräsentiert waren. Davon abgesehen zeigte sich im Hinblick auf den BMI (Body-Mass-Index), dass sich die geringste Therapieversager-Quote nicht in der Gruppe der Normalgewichtigen, sondern bei den Patienten mit Übergewicht (ohne Adipositas) fand (12,9 vs. 25,8 %; p=0,043). Für andere Faktoren, wie Alter, Geschlecht oder Niereninsuffizienz konnte kein Einfluss auf den Behandlungserfolg festgestellt wer-den. Lediglich hinsichtlich der Thrombozyten konnte gezeigt werden, dass die Reduktion um mehr als 20 % (im Vergleich zu den übrigen Patienten mit einer Reduktion von 0 bis 20 %) mit einer höheren Therapieversager-Quote verbunden war (23,8 vs. 13,7 %; p=0,035). Dem Faktor Heparin-assoziierte Thrombozytopenie kam allerdings keine Bedeu-tung zu. Ein positiver ELISA-Test war nicht mit einer höheren Versager-Quote verbunden. Unter den im Rahmen der univariaten Analyse als signifikant identifizierten Faktoren (Therapieverfahren, BMI, Lokalisation und Thrombozytenverminderung) erwiesen sich alle, außer der Lokalisation, im Rahmen der multivariaten Analyse als signifikante bzw. unabhängige Variablen. Der größte Einfluss kam hierbei dem Therapieverfahren zu (HR für Therapieversagen unter OP: 5,4 [95% CI 1,97-14,6] p=0,001). Schlussfolgerung: Es konnte im Rahmen dieser Studie untermauert werden, dass die Lyse-Therapie gegenüber dem operativen Verfahren vor etwa 10 Jahren Vorteile aufwies. Ein direkter Vergleich zwischen den beiden Gruppen (endovaskuläre vs. offene Revaskula-risation) verbietet sich allerdings, da die Gruppenzuordnung individuell erfolgte und nicht randomisiert war. Unabhängig davon kann vor dem Hintergrund älterer prospektiver Studien jedoch dennoch davon ausgegangen werden, dass die Lyse der OP überlegen war. Aktuell ist jedoch zu berücksichtigen, dass heute interventionelle Maßnahmen im Vorder-grund stehen. Davon abgesehen sollte vor dem Hintergrund der nach wie vor hohen Amputations- und Mortalitätsraten die Prophylaxe stärker berücksichtigt werden. Ziel sollte es sein, die akuten Extremitäten-Ischämie durch frühzeitige Intervention zu vermei-den. Hier wäre auch an eine bessere Beratung und Versorgung der männlichen Patienten zu denken, die in nahezu allen ALI-Studien bisher überrepräsentiert sind. Der Heparin-assoziierten Thrombozytopenie (HIT) kam bemerkenswerterweise im Zusammenhang mit der ALI keine erkennbare Bedeutung zu. Vermutlich wurde in HIT in der Vergangenheit zahlenmäßig deutlich überschätzt, was mit der geringen Spezifität des ELISA-Test in Zu-sammenhang stehen dürfte.Background: Acute limb ischemia (ALI) is still related with high rates of amputation and mortality. Since the 1990th catheter-directed thrombolysis has been well established and some studies indicated advantages in comparison to surgical procedures. The purpose of this study was, to compare results from previous studies with more actual own data. Patients and Methods: We retrospectively analysed the data of 307 patients presented with ALI between March 1999 and December 2006. Assessment was done by review of surgical reports, patient data files, and laboratory results. Data collection was done at Department of General, Visceral, Vascular, and Pediatric Surgery, as well as at Institute of Hemostaseology and Transfusion Medicine of Universität des Saalandes, Medizinische Fakultät Homburg. For statistical analysis the programm SPSS was used. Results: The rate of male patients was significantly higher (57,0 vs. 43,0 %; p=0,014). Mean age of men was lower than mean age of women (64,1+12,7 vs. 69,6+15,5 years; p<0,001). A continuous increase of ALI was observed between patient age of 40 and 80 years. Lysis was significantly more effective than surgical procedure; failures (amputation and/or death) were significantly lower in lysis patients (7,2 vs. 27,0 %; p<0,001). With respect to further putative factors, it was apparent that obese patients were underrepre-sented in comparison with general population. The lowest failure rate was not found in normal weight patients, but in patients with overweight (without obesity) (12,9 vs. 25,8 %; p=0,043). However, age, gender or renal insufficiency did not alter failure rate. Only in respect to thrombocytes, it could be shown that reduction of more than 20 % (in comparison to patients with reduction between 0 and 20 %) was accompanied by higher failure rates (23,8 vs. 13,7 %; p=0,035). Nevertheless, there was no impact of heparin associated thrombocytopenia (HIT). Positive ELISA was not associated with higher failure rate. Three of the four significant factors from univariate analysis (therapeutic interven-tion, BMI, localisation, and thrombocyte reduction) were also significant and therefore independent variables in multivariate analysis. Only localisation was not. Conclusion: It could be confirmed that lysis therapy (catheter directed thrombolysis) was more safe and effective than surgical treatment as shown in previous years (about 10 years ago). It should be noted that there was no randomisation in this study and there- fore a comparison should only be made by precaution. Nevertheless, in view of more previous prospective studies it may be concluded that lysis was superior against operative intervention. However, it should be noted that today interventional strategies are fa-voured. Apart from this, with respect to still high rates of amputation and mortality, the value of prophylaxis should not be underestimated. It should be the aim of all strategies to avoid acute limb ischemia as far as possible. In that regard better informing of male patients were desirable since this patient group is overrepresented in nearly all ALI-Studies. Remarkably, Heparin associated thrombocytopenia was not recognizable associ-ated with ALI in this study. Probably this was because HIT in past was overestimated. And as shown specifity of ELISA was low in identification of HIT

The Serotonin Transporter Gene Alters Sensitivity to Attention Bias Modification: Evidence for a Plasticity Gene

Background - Attention bias modification (ABM) procedures have been shown to modify biased attention with important implications for emotional vulnerability and resilience. The use of ABM to reduce potentially toxic biases, for instance, is a newly emerging therapy for anxiety disorders. A separate line of gene-by-environment interaction research proposes that many so-called vulnerability genes or risk alleles are better seen as plasticity genes, as they seem to make individuals more susceptible to environmental influences for better and for worse. Methods - A standard ABM procedure was used with a sample of 116 healthy adults. Participants were randomly assigned to one of two training groups. One received an ABM procedure designed to induce a bias in attention toward negative material, while the other was trained toward positive pictures. Individuals with low- and high-expressing forms of the serotonin transporter gene (5-HTTLPR) were compared. Results - Those with a low-expression form (S/S, S/Lg, or Lg/Lg) of the 5-HTTLPR gene developed stronger biases for both negative and positive affective pictures relative to those with the high-expression (La/La) form of the gene. Conclusions - Here, we report the first evidence that allelic variation in the promotor region of the 5-HTTLPR gene predicts different degrees of sensitivity to ABM. These results suggest a potential cognitive mechanism for the gene-by-environment interactions that have been found in relation to the serotonin transporter gene. Variation on this genotype may therefore determine who will benefit most (and least) from therapeutic interventions, adversity, and supportive environments

Exposure and harm to combustion-derived wood particles

The human respiratory system is the gateway of entry for inhaled detritus from anthropogenic (e.g. combustion-derived (CD) particulate matter (PM; e.g. diesel exhaust and wood-burning PM). Adult humans inhale 20m3 of air and suspended debris (gases and particles) into the airways daily. Inhalation exposure to CDPM (Figure 1) is known to increase the risk of morbidity and mortality of lung and heart diseases in all exposed individuals. The physicochemical properties of size, surface area and presence of transition metals have been implicated as drivers of the oxidative capacity of CDPM. However, the precise role of reactive organic compounds (ROC) in ambient aerosols, present either in the gas or particle phase has not been fully-investigated for their relevance in the induction of the observed adverse health effects. When addressing the toxicity of inhalation hazards such as wood smoke CDPM, a model that resembles the human lung responding to toxic challenges is required. In our in vitro exposure studies, we utilised normal human bronchial epithelial (NHBE) cells grown at the air-liquid interface (ALI) using filter-well technology (Prytherch et al 2011), to create an in vivo-like 3-dimensional lung model. This model is a fully-differentiated, pseudo-stratified, muco-ciliary epithelium containing basal, serous, Clara, goblet and ciliated cells. NHBE cells were exposed to wood smoke derived from Spruce, Beech and Birch at a dose of 152µg/cm2: carbon black (CB; negative control; Monarch 120, Cabot UK; DQ12 quartz (positive control). Following exposure (24 hours), tissue integrity (i.e. transepithelial electrical resistance (TEER) was measured to reveal minor disruption to bronchial tissue integrity (Figure 2). However, changes in cellular energy levels (i.e. ATP) between the types of wood smokes (Figure 3), could infer the smoke acted as an irritant to the lung environment. Wood smoke exposure can depress the immune system and damage the layer of cells in the lungs that protect and cleanse the airways. Further work on the biological and histological impacts of wood smoke will allow us to reveal mechanisms behind the changes observed, as well identifying biomarkers of cell damage by specific CDPM ROCs. For vulnerable populations, such as people with asthma, chronic respiratory disease and those with cardiovascular disease, wood smoke is particularly harmful, even at short exposures it can prove dangerous. Wood smoke interferes with normal lung development in infants and children. It also increases children’s risk of lower respiratory infections such as bronchitis and pneumonia. Prytherch, Z., Job, C., Marshall, H., Oreffo, V., Foster, M. and BéruBé, K.A. (2011) Macro. Bios. 11, 1467–77. This work was supported by HICE (www.hice-vi.eu)

Exposure and harm to combustion-derived particles: Searching for biomarkers

The physicochemical properties of size, surface area and presence of transition metals have been implicated as drivers of the oxidative capacity of CDPM. However, the precise role of reactive organic compounds (ROC) in ambient aerosols, present either in the gas phase or the particle phase or in both phases, have not been fully-investigated for their relevance in the induction of the observed adverse health effects. Oxidation of fatty acids linked to the cell membrane phospholipids leads to many metabolites that have been used as markers of the process. Such metabolites have long been considered to be involved in two possibly inter-related processes: cell/tissue damage and signalling. As one approach to resolve the role played by ROCs, their effects on fatty acid and lipid metabolism in human lung tissues will be studied in detail by using the standard biochemical techniques and lipidomics

Influence of Polymorphism on the Electronic Structure of Ga2O3

The search for new wide band gap materials is intensifying to satisfy the need for more advanced and energy efficient power electronic devices. Ga$_2$O$_3$ has emerged as an alternative to SiC and GaN, sparking a renewed interest in its fundamental properties beyond the main $\beta$-phase. Here, three polymorphs of Ga$_2$O$_3$, $\alpha$, $\beta$ and $\varepsilon$, are investigated using X-ray diffraction, X-ray photoelectron and absorption spectroscopy, and ab initio theoretical approaches to gain insights into their structure - electronic structure relationships. Valence and conduction electronic structure as well as semi-core and core states are probed, providing a complete picture of the influence of local coordination environments on the electronic structure. State-of-the-art electronic structure theory, including all-electron density functional theory and many-body perturbation theory, provide detailed understanding of the spectroscopic results. The calculated spectra provide very accurate descriptions of all experimental spectra and additionally illuminate the origin of observed spectral features. This work provides a strong basis for the exploration of the Ga$_2$O$_3$ polymorphs as materials at the heart of future electronic device generations.Comment: Updated manuscript version after peer revie

Helden in der Schule. Akten der Tagung Kloster Banz 2014

Ausgehend von der Feststellung, dass die Integration mittelalterlicher Texte im Deutschunterricht in der Schulpraxis weitgehend ein Desiderat darstellt, präsentierten Beitragende aus Schule und Wissenschaft bei der Tagung „Helden in der Schule“ im Oktober 2014 ihre Projekte und Ideen zu und Erfahrungen mit der Implementation germanistisch-mediävistischer Inhalte im Deutschunterricht. Dabei reichen die Beiträge von allgemeinen Überlegungen zum Nutzen mittelalterlicher Literatur in der Schule über konkrete Unterrichtsentwürfe bis hin zur Umsetzung in der Waldorfschule und der Integration schulbezogener Lehrveranstaltungen in der Universität. Bei aller Verschiedenheit in den Herangehensweisen wird in allen Beiträgen eindrucksvoll deutlich gemacht, dass mittelalterliche Literatur auch im 21. Jahrhundert überaus lohnend in die Unterrichtspraxis einbezogen werden kann.Since medieval texts are not treated enough in school, lecturers working in school and university presented their projects, ideas and experiences concerning the implementation of German-mediavistic contents in German school lessons during the conference “Heroes in School” in October 2014. The topics concern general reflection about the profitability of medieval literature in school, concrete lesson plans, the implementation in Rudolf Steiner schools, the integration of seminars in university that deal with the work in school etc. All articles demonstrate that the integration of medieval literature in school worth the effort – also in the 21st century

A Cost-Effective ELP-Intein Coupling System for Recombinant Protein Purification from Plant Production Platform

BACKGROUND: Plant bioreactor offers an efficient and economical system for large-scale production of recombinant proteins. However, high cost and difficulty in scaling-up of downstream purification of the target protein, particularly the common involvement of affinity chromatography and protease in the purification process, has hampered its industrial scale application, therefore a cost-effective and easily scale-up purification method is highly desirable for further development of plant bioreactor. METHODOLOGY/PRINCIPAL FINDINGS: To tackle this problem, we investigated the ELP-intein coupling system for purification of recombinant proteins expressed in transgenic plants using a plant lectin (PAL) with anti-tumor bioactivity as example target protein and rice seeds as production platform. Results showed that ELP-intein-PAL (EiP) fusion protein formed novel irregular ER-derived protein bodies in endosperm cells by retention of endogenous prolamins. The fusion protein was partially self-cleaved in vivo, but only self-cleaved PAL protein was detected in total seed protein sample and deposited in protein storage vacuoles (PSV). The in vivo uncleaved EiP protein was accumulated up to 2-4.2% of the total seed protein. The target PAL protein could be purified by the ELP-intein system efficiently without using complicated instruments and expensive chemicals, and the yield of pure PAL protein by the current method was up to 1.1 mg/g total seed protein. CONCLUSION/SIGNIFICANCE: This study successfully demonstrated the purification of an example recombinant protein from rice seeds by the ELP-intein system. The whole purification procedure can be easily scaled up for industrial production, providing the first evidence on applying the ELP-intein coupling system to achieve cost-effective purification of recombinant proteins expressed in plant bioreactors and its possible application in industry

FoxO1, A2M, and TGF-beta 1 : three novel genes predicting depression in gene X environment interactions are identified using cross-species and cross-tissues transcriptomic and miRNomic analyses

To date, gene-environment (GxE) interaction studies in depression have been limited to hypothesis-based candidate genes, since genome-wide (GWAS)-based GxE interaction studies would require enormous datasets with genetics, environmental, and clinical variables. We used a novel, cross-species and cross-tissues "omics" approach to identify genes predicting depression in response to stress in GxE interactions. We integrated the transcriptome and miRNome profiles from the hippocampus of adult rats exposed to prenatal stress (PNS) with transcriptome data obtained from blood mRNA of adult humans exposed to early life trauma, using a stringent statistical analyses pathway. Network analysis of the integrated gene lists identified the Forkhead box protein O1 (FoxO1), Alpha-2-Macroglobulin (A2M), and Transforming Growth Factor Beta 1 (TGF-beta 1) as candidates to be tested for GxE interactions, in two GWAS samples of adults either with a range of childhood traumatic experiences (Grady Study Project, Atlanta, USA) or with separation from parents in childhood only (Helsinki Birth Cohort Study, Finland). After correction for multiple testing, a meta-analysis across both samples confirmed six FoxO1 SNPs showing significant GxE interactions with early life emotional stress in predicting depressive symptoms. Moreover, in vitro experiments in a human hippocampal progenitor cell line confirmed a functional role of FoxO1 in stress responsivity. In secondary analyses, A2M and TGF-beta 1 showed significant GxE interactions with emotional, physical, and sexual abuse in the Grady Study. We therefore provide a successful 'hypothesis-free' approach for the identification and prioritization of candidate genes for GxE interaction studies that can be investigated in GWAS datasets.Peer reviewe