Die Darstellung der Seitenbänder des Hufgelenkes und ihrer Erkrankungen mit Hilfe der Magnetresonanztomographie am stehenden Pferd

Die Darstellung der Seitenbänder des Hufgelenkes und ihrer Erkrankungen mit Hilfe der Magnetresonanztomographie am stehenden Pferd Mit Einführung des Hallmarq Equine Limb Scanner® wurde es möglich, die distalen Gliedmaßenabschnitte des Pferdes und speziell den Huf einer magnetresonanztomographischen Untersuchung am stehend sedierten Tier zu unterziehen. Die Diagnose der Erkrankung der Kollateralbänder des Hufgelenkes wird damit deutlich einfacher möglich, falls der Niederfeldtomograph hierfür geeignet ist. Zur Bewertung der Eignung des Equine Limb Scanner wurden im Zeitraum von 2005 bis 2009 aus eintausend an der Pferdeklinik Bargteheide mittels des Hallmarq Equine Limb Scanner® 0,27 T-Systems im Stehen untersuchten Pferden diejenigen 69 Patienten ausgewählt, welche ausschließlich eine Erkrankung im Bereich der Kollateralbänder des Hufgelenkes aufwiesen. Die Untersuchung erfolgte damit bei gleichzeitiger physiologischer Zug- und Druckbelastung des zu untersuchenden Gliedmaßenabschnittes. Die Beurteilung der Kollateralbänder und ihrer Erkrankungen wurden anhand eines transversalen und frontalen Fast Spin Echo T2 gewichtet durchgeführt. Um den Ursprungsbereich des Kollateralbandes am Kronbein und den Ansatzbereich am Hufbein zu bewerten wurden zusätzlich Gradientenechos T1 und T2* gewichtet, sowie die STIR Sequenz genutzt. Die Verwendung des Fast Spin Echos T2w mit einer Echozeit von TE=84 ms sowie eine fachgerechte Positionierung des Hufes im Magneten diente zum Ausschluss eines möglichen Magic Angle Effect. Das Kollateralband wurde in drei definierte Zonen (Ursprung, Korpus, Insertion) eingeteilt, um die genaue Lokalisation der Läsion zu beschreiben. Dabei konnte beobachtet werden, dass der Kollateralbandursprung (36%) am häufigsten betroffen ist, gefolgt von Schäden in allen drei Zonen (20%) sowie Ursprung und Korpus (20%), Insertion (16%), und Schäden nur am Korpus (3%) und Korpus und Insertion (3%), Ursprung und Insertion (2%). Bei der klinischen Untersuchung fiel auf, dass bei fast allen Patienten die Lahmheit sowohl auf dem harten als auch auf dem weichen Zirkel jeweils auf der inneren Hand am deutlichsten zu erkennen war. Das Phänomen der schlechten Abgrenzung des Kollateralbandes zu seiner Umgebung (poorly defined borders) wurde im transversalen und frontalen Fast Spin Echo T2w beurteilt. Hierbei konnte festgestellt werden, dass diese Veränderung hauptsächlich im Ursprungsbereich vorkommt. Bei 70% der Patienten mit einem lateralen Kollateralbandschaden im Ursprungsbereich am Kronbein und bei 59% der Patienten mit einem medialen Kollateralbandschaden im Ursprungsbereich am Kronbein konnte dies beobachtet werden. Zur Feststellung einer knöchernen Beteiligung von Kron- und/oder Hufbein wurden zusätzlich Gradientenechos T1 und T2*w sowie die STIR Sequenz hinzugezogen. Dabei zeigte sich, dass eine Beteilung des Knochens vorwiegend im Bereich der medialen Insertion (53%) und weniger lateral (27%) vorkommt. Im Ursprungsbereich ist diese lateral in 16% der Fälle und medial in 3% der Fälle vorzufinden. Die Durchmesser des medialen und lateralen Kollateralbandes im Ursprungs-, Korpus-, und Insertionsbereich wurden im Bild eines transversalen Fast Spin Echo T2w ermittelt. Dazu wurden zusätzlich Referenzwerte von 23 klinisch und magnetresonanztomographisch gesunden Patienten angefertigt. Es wurde festgestellt, dass die Mittelwerte der Flächen der medialen Kollateralbänder in allen drei Zonen bei erkrankten Patienten statistisch signifikant größer waren als bei gesunden Pferden (Ursprung p=0,0297, Korpus p=0,00285 und Insertion p=0,0001603). Die Mittelwerte der Flächen der lateralen Kollateralbänder unterschieden sich bei gesunden und kranken Patienten im Ursprungs-, und Korpusbereich nicht signifikant (Ursprung p=0,4372, Korpus p=0,6258), im Bereich der lateralen Insertion konnte ein deutlicher aber statistisch nicht signifikanter Unterschied (p=0,0753) beobachtet werden bei einer Irrtumswahrscheinlichkeit von α=0,05. Die Ergebnisse dieser Arbeit untermauern die Wichtigkeit moderner bildgebender Verfahren zur Ergänzung und Vervollständigung der klinischen Untersuchung, der Diagnosefindung, der differentialdiagnostischen Abgrenzung, der Therapieplanung und prognostischer Aussagen. Insbesondere im Hufbereich liefert die Magnetresonanztomographie wichtige Informationen zur Erkennung der erkrankten Struktur. Sie bietet eine differenzierte Abgrenzung einer erkrankten Struktur, in diesem Fall der Seitenbänder, die bisher häufig dem Begriff Hufrollensyndrom zugeordnet wurde und mit herkömmlichen bildgebenden Verfahren nicht oder nur teilweise dargestellt werden konnte. Die Untersuchung mit dem Hallmarq Equine Limb Scanner® Niederfeldtomographen am stehend sedierten Pferd ist hierfür nach vorliegenden Ergebnissen hervorragend geeignet

Higher frequencies of BCRP+ cardiac resident cells in ischaemic human myocardium

Aims Several cardiac resident progenitor cell types have been reported for the adult mammalian heart. Here we characterize their frequencies and distribution pattern in non-ischaemic human myocardial tissue and after ischaemic events. Methods and results We obtained 55 biopsy samples from human atria and ventricles and used immunohistological analysis to investigate two cardiac cell types, characterized by the expression of breast cancer resistance protein (BCRP)/ABCG2 [for side population (SP) cells] or c-kit. Highest frequencies of BCRP+ cells were detected in the ischaemic right atria with a median of 5.40% (range: 2.48-11.1%) vs. 4.40% (1.79-7.75%) in the non-ischaemic right atria (P = 0.47). Significantly higher amounts were identified in ischaemic compared with non-ischaemic ventricles, viz. 5.44% (3.24-9.30%) vs. 0.74% (0-5.23%) (P = 0.016). Few numbers of BCRP+ cells co-expressed the cardiac markers titin, sarcomeric α-actinin, or Nkx2.5; no co-expression of BCRP and progenitor cell marker Sca-1 or pluripotency markers Oct-3/4, SSEA-3, and SSEA-4 was detected. C-kit+ cells displayed higher frequencies in ischaemic (ratio: 1:25 000 ± 2500 of cell counts) vs. non-ischaemic myocardium (1:105 000 ± 43 000). Breast cancer resistance protein+/c-kit+ cells were not identified. Following in vitro differentiation, BCRP+ cells isolated from human heart biopsy samples (n = 6) showed expression of cardiac troponin T and α-myosin heavy-chain, but no full differentiation into functional beating cardiomyocytes was observed. Conclusion We were able to demonstrate that BCRP+/CD31− cells are more abundant in the heart than their c-kit+ counterparts. In the non-ischaemic hearts, they are preferentially located in the atria. Following ischaemia, their numbers are elevated significantly. Our data might provide a valuable snapshot at potential progenitor cells after acute ischaemia in vivo, and mapping of these easily accessible cells may influence future cell therapeutic strategie

Novel Antibody Drug Conjugates Targeting Tumor-Associated Receptor Tyrosine Kinase ROR2 by Functional Screening of Fully Human Antibody Libraries Using Transpo-mAb Display on Progenitor B Cells

Receptor tyrosine kinase-like orphan receptor 2 (ROR2) has been identified as a highly relevant tumor-associated antigen in a variety of cancer indications of high unmet medical need, including renal cell carcinoma and osteosarcoma, making it an attractive target for targeted cancer therapy. Here, we describe the de novo discovery of fully human ROR2-specific antibodies and potent antibody drug conjugates (ADCs) derived thereof by combining antibody discovery from immune libraries of human immunoglobulin transgenic animals using the Transpo-mAb mammalian cell-based IgG display platform with functional screening for internalizing antibodies using a secondary ADC assay. The discovery strategy entailed immunization of transgenic mice with the cancer antigen ROR2, harboring transgenic IgH and IgL chain gene loci with limited number of fully human V, D, and J gene segments. This was followed by recovering antibody repertoires from the immunized animals, expressing and screening them as full-length human IgG libraries by transposon-mediated display in progenitor B lymphocytes (“Transpo-mAb Display”) for ROR2 binding. Individual cellular “Transpo-mAb” clones isolated by single cell sorting and capable of expressing membrane-bound as well as secreted human IgG were directly screened during antibody discovery, not only for high affinity binding to human ROR2, but also functionally as ADCs using a cytotoxicity assay with a secondary anti-human IgG-toxin-conjugate. Using this strategy, we identified and validated 12 fully human, monoclonal anti-human ROR2 antibodies with nanomolar affinities that are highly potent as ADCs and could be promising candidates for the therapy of human cancer. The screening for functional and internalizing antibodies during the early phase of antibody discovery demonstrates the utility of the mammalian cell-based Transpo-mAb Display platform to select for functional binders and as a powerful tool to improve the efficiency for the development of therapeutically relevant ADCs

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

Prevalence and incidence of iron deficiency in European community-dwelling older adults : An observational analysis of the DO-HEALTH trial

Background and aim Iron deficiency is associated with increased morbidity and mortality in older adults. However, data on its prevalence and incidence among older adults is limited. The aim of this study was to investigate the prevalence and incidence of iron deficiency in European community-dwelling older adults aged ≥ 70 years. Methods Secondary analysis of the DO-HEALTH trial, a 3-year clinical trial including 2157 community-dwelling adults aged ≥ 70 years from Austria, France, Germany, Portugal and Switzerland. Iron deficiency was defined as soluble transferrin receptor (sTfR) > 28.1 nmol/L. Prevalence and incidence rate (IR) of iron deficiency per 100 person-years were examined overall and stratified by sex, age group, and country. Sensitivity analysis for three commonly used definitions of iron deficiency (ferritin  1.5) were also performed. Results Out of 2157 participants, 2141 had sTfR measured at baseline (mean age 74.9 years; 61.5% women). The prevalence of iron deficiency at baseline was 26.8%, and did not differ by sex, but by age (35.6% in age group ≥ 80, 29.3% in age group 75–79, 23.2% in age group 70–74); P  1.5. Occurrences of iron deficiency were observed with IR per 100 person-years of 9.2 (95% CI 8.3–10.1) and did not significantly differ by sex or age group. The highest IR per 100 person-years was observed in Austria (20.8, 95% CI 16.1–26.9), the lowest in Germany (6.1, 95% CI 4.7–8.0). Regarding the other definitions of iron deficiency, the IR per 100 person-years was 4.5 (95% CI 4.0–4.9) for ferritin  1.5. Conclusions Iron deficiency is frequent among relatively healthy European older adults, with people aged ≥ 80 years and residence in Austria and Portugal associated with the highest risk

Insights into the design and interpretation of iCLIP experiments

Abstract Background Ultraviolet (UV) crosslinking and immunoprecipitation (CLIP) identifies the sites on RNAs that are in direct contact with RNA-binding proteins (RBPs). Several variants of CLIP exist, which require different computational approaches for analysis. This variety of approaches can create challenges for a novice user and can hamper insights from multi-study comparisons. Here, we produce data with multiple variants of CLIP and evaluate the data with various computational methods to better understand their suitability. Results We perform experiments for PTBP1 and eIF4A3 using individual-nucleotide resolution CLIP (iCLIP), employing either UV-C or photoactivatable 4-thiouridine (4SU) combined with UV-A crosslinking and compare the results with published data. As previously noted, the positions of complementary DNA (cDNA)-starts depend on cDNA length in several iCLIP experiments and we now find that this is caused by constrained cDNA-ends, which can result from the sequence and structure constraints of RNA fragmentation. These constraints are overcome when fragmentation by RNase I is efficient and when a broad cDNA size range is obtained. Our study also shows that if RNase does not efficiently cut within the binding sites, the original CLIP method is less capable of identifying the longer binding sites of RBPs. In contrast, we show that a broad size range of cDNAs in iCLIP allows the cDNA-starts to efficiently delineate the complete RNA-binding sites. Conclusions We demonstrate the advantage of iCLIP and related methods that can amplify cDNAs that truncate at crosslink sites and we show that computational analyses based on cDNAs-starts are appropriate for such methods

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements

Mitochondrial physiology

As the knowledge base and importance of mitochondrial physiology to evolution, health and disease expands, the necessity for harmonizing the terminology concerning mitochondrial respiratory states and rates has become increasingly apparent. The chemiosmotic theory establishes the mechanism of energy transformation and coupling in oxidative phosphorylation. The unifying concept of the protonmotive force provides the framework for developing a consistent theoretical foundation of mitochondrial physiology and bioenergetics. We follow the latest SI guidelines and those of the International Union of Pure and Applied Chemistry (IUPAC) on terminology in physical chemistry, extended by considerations of open systems and thermodynamics of irreversible processes. The concept-driven constructive terminology incorporates the meaning of each quantity and aligns concepts and symbols with the nomenclature of classical bioenergetics. We endeavour to provide a balanced view of mitochondrial respiratory control and a critical discussion on reporting data of mitochondrial respiration in terms of metabolic flows and fluxes. Uniform standards for evaluation of respiratory states and rates will ultimately contribute to reproducibility between laboratories and thus support the development of data repositories of mitochondrial respiratory function in species, tissues, and cells. Clarity of concept and consistency of nomenclature facilitate effective transdisciplinary communication, education, and ultimately further discovery

Mitochondrial physiology

As the knowledge base and importance of mitochondrial physiology to evolution, health and disease expands, the necessity for harmonizing the terminology concerning mitochondrial respiratory states and rates has become increasingly apparent. The chemiosmotic theory establishes the mechanism of energy transformation and coupling in oxidative phosphorylation. The unifying concept of the protonmotive force provides the framework for developing a consistent theoretical foundation of mitochondrial physiology and bioenergetics. We follow the latest SI guidelines and those of the International Union of Pure and Applied Chemistry (IUPAC) on terminology in physical chemistry, extended by considerations of open systems and thermodynamics of irreversible processes. The concept-driven constructive terminology incorporates the meaning of each quantity and aligns concepts and symbols with the nomenclature of classical bioenergetics. We endeavour to provide a balanced view of mitochondrial respiratory control and a critical discussion on reporting data of mitochondrial respiration in terms of metabolic flows and fluxes. Uniform standards for evaluation of respiratory states and rates will ultimately contribute to reproducibility between laboratories and thus support the development of data repositories of mitochondrial respiratory function in species, tissues, and cells. Clarity of concept and consistency of nomenclature facilitate effective transdisciplinary communication, education, and ultimately further discovery