Untersuchung des Gerinnungssystems im Rahmen eines simulierten Langstreckenfluges

Gegenstand der vorliegenden Studie war die Frage, in wie weit Bedingungen eines Langstreckenfluges eine Aktivierung des Gerinnungssystems beeinflussen. Dazu wurden 70 Probanden, davon je 25 Probanden mit einer bekannten APC-Resistenz ohne Thromboseanamnese, 20 Probanden mit APC-Resistenz und einer Thrombose in der Anamnese sowie eine gesunden Kontrollgruppe zu 25 Probanden, in einer nicht signifikant unterschiedlichen Altersverteilung von 18-25 Jahren, 25-40 Jahren, 40-60 Jahren und 60-70 Jahren, im Verlauf eines simulierten Langstreckenfluges von insgesamt 12 Stunden bei einer Unterdruckbedingung von bis zu 0,8 bar untersucht. Die Geschlechteraufteilung innerhalb der Gruppen war nahezu homogen und nicht signifikant unterschiedlich. Zur Flugsimulation wurde der Luftdruck innerhalb von 30 Minuten auf 0,87 bar gesenkt, entsprechend eines Kabinendruckes von etwa 1300 m, nach 7,5 Stunden auf 0,8 bar bzw. eines Kabinendruckes von 2000 m reduziert um nach Ablauf von 3,5 Stunden innerhalb von 30 Minuten wieder auf 1 bar erhöht zu werden. Diese Druckänderungen entsprechen einem Langstreckenflug bei dem nach ca. 7-8 Stunden die Flughöhe von 10 000 Meter auf ca. 12 000 Meter ansteigt. Ursache hierfür ist der Gewichtsverlust nach Verbrauch des Treibstoffes. Nach 48 Stunden fanden sich die Probanden zur Nachuntersuchung ein. Die Studie fand am Zentrum für Sauerstoffüberdrucktherapie-, Tauch- und Höhenmedizin an der Orthopädischen Universitätsklinik Frankfurt am Main Friedrichsheim statt. Neben BMI-Werten und allgemeinem Blutbild wurden folgende primäre Bewertungsparameter bestimmt: 1. PAI-Aktivität nach dem Prinzip der Inaktivierung vorgelegter Urokinase (Methode OWOA G15 C0532 (1094) H 2), 2. D-Dimeren-Konzentration nach dem Prinzip der Agglutinierung von Polystyrolteilchen über einen monoklonalen Antikörper (DD5) in Gegenwart von D-Dimeren gemäß der Labormethode OQWW G11 C0533 (675) W 2, 3. Prothrombinfragment F1-F2 über Kaninchen-Antikörper gegenüber Human-F1-F2 nach ELISA Enzygnost 1-2 (Boehringer Mannheim) 4. von-Willebrand-Faktor mittels vWF:Ag ELISA-Test (Rabbit Anti-Human von Willebrand Factor P0226 von Dako A/S, Glostrup, Dänemark sowie Peroxidase-Conjugated Rabbit Anti-Human von Willebrand Factor A 0082). Gemessen wurde nach 2, 6, 9, 12 und 48 Stunden. Die statistische Bewertung erfolgte mittel ANOVA, Chi-Quadrat-Test sowie Wilcoxon-Test. Ein Patient wurde nach 36 Stunden aufgrund des Verdachts einer TVT und anschließender Lungenembolie stationär behandelt. Dieser Patient gehörte zur Gruppe der APC Resistenz mit heterozygoter Ausprägung des Gendefekts, mit über einige Jahre rezidivierenden Thrombophlebitiden. Das Ergebnis zeigte insgesamt keine signifikante Aktivierung des Blutgerinnungssystems infolge des Langstreckenfluges, unabhängig von der betrachteten Risikogruppe. Die PAI-Aktivität sinkt bei allen Probanden, allerdings unsignifikant, im Verlauf der ersten 6 Stunden und steigt anschließend nur geringfügig wieder an. Die D-Dimeren-Konzentration bleibt im Mittel nahezu unverändert. Der Gehalt des Prothrombinfragments F1-F2 steigt im Verlauf von 48 Stunden nicht signifikant an. Der von-Willebrand-Faktor schwankt im zeitlichen Ablauf, die Änderungen haben ebenfalls keine Signifikanz. Höheres Alter kann nur tendenziell als Risikofaktor bestätigt werden, Geschlechtszugehörigkeit zeigte sich hier als nicht signifikant risikoerhöhend. Der Patient mit der postexpositionellen Thromboembolie zeigt ein etwas abweichendes Verhalten: in den ersten 9 Stunden stark sinkende, danach leicht ansteigende aber unter Ausgangsniveau bleibende PAI-Werte. Die D-Dimere-Werte steigen kontinuierlich stark an bis zu 48 Stunden. Die F1-F2-Konzentration steigt um fast 50% nach 2-Stunden, sinkt von da an kontinuierlich bis auf 48 Stunden. Die vw-Antigen-Faktoren steigen nach 48 Stunden an. Abgesehen von dem Embolie-Patienten konnten in dieser Studie keine signifikanten Korrelationen zwischen Langstreckenflügen und erhöhter Blutgerinnungsaktivität ermittelt werden.The present study regards the possible influence of long flights on certain blood coagulation factors, what concerns the ecs-syndrome. For this, 70 subjects were investigated: 25 APC-resistent patients without former thrombosis, 20 APC-resistent patients with certain former thrombosis and a 25-person healthy control group. The subjects were divided in groups differing in age from 18-25, 25-40. 40-60 to 60-70 years old. Division of women and men was not significantly different. A long flight was simulated for a period of 12 hours, first reducing air pressure in a pressurized cabin to 0,87 bar within the first 30 minutes, corresponding to a flight height of 1300 m. 7,5 hours later the pressure was reduced again to 0,8 bar, that is 2000 m height and additionally raised up to 1 bar after the next 3,5 hours within a changing period of 30 minutes. The investigation took place in the 'Zentrum für Sauerstoffüberdrucktherapie-, Tauch- und Höhenmedizin', 'Orthopädische Universitätsklinik Frankfurt am Main Friedrichsheim'. We measured BMI, blood count and special coagulation factors every 2, 6, 9, 12 and 48 hours. PAI-activity by inactivation of Urokinase (method OWOA G15 C0532 (1094) H 2) concentration of D-dimeres by agglutination of polystyrole by monoclonal antibody (method OQWW G11 C0533 (675) W 2) F1-F2 by rabbit-antibody compared to human F1-F2 with ELISA Enzygnost 1-2 (Boehringer Mannheim) vW-factors by vWF:Ag ELISA-Test (Rabbit Anti-Human von Willebrand Factor P0226, Dako A/S, Glostrup, Dänemark, and Peroxidase-Conjugated Rabbit Anti-Human von Willebrand Factor A 0082) Statistics were done by ANOVA, Chi-Quadrat-Test and Wilcoxon-Test. One patient suffered a pulmonary embolism after 36 hours of testing. He belonged to the group of APC-resistance with former TVT. Results: What concerns PAI-activity, all subjects showed slightly decrease during the first 6 hours and little increase the next hours. The concentration of D-dimeres didn't change much, the same result show the fragments F1-F2. The values of vW-Antigen-factors alternate with time, variations not significant. Differences are seen regarding the patient with the pulmonary embolism. PAI-activity decreases within the first 9 hours significantly, then raises again slightly. Concentration of D-dimeres rises continuously up to 48 hours. F1-F2-concentration increases by nearly 50% after 2 hours and then decreases until the end of the study at 48 hours. This fact indicates an enhanced blood coagulation. vW-factors of this patient increase after 48 hours. Besides the pulmonary embolism-patient, in this investigation there is no hint to a significant correlation of blood coagulation and long flights

Performance study of a 3 x 1 x 1 m(3) dual phase liquid Argon Time Projection Chamber exposed to cosmic rays

This work would not have been possible without the support of the Swiss National Science Foundation, Switzerland; CEA and CNRS/IN2P3, France; KEK and the JSPS program, Japan; Ministerio de Ciencia e Innovacion in Spain under grants FPA2016-77347-C2, SEV-2016-0588 and MdM-2015-0509, Comunidad de Madrid, the CERCA program of the Generalitat de Catalunya and the fellowship (LCF/BQ/DI18/11660043) from "La Caixa" Foundation (ID 100010434); the Programme PNCDI III, CERN-RO, under Contract 2/2020, Romania; the U.S. Department of Energy under Grant No. DE-SC0011686. This project has received funding from the European Union's Horizon 2020 Research and Innovation program under Grant Agreement no. 654168. The authors are also grateful to the French government operated by the National Research Agency (ANR) for the LABEX Enigmass, LABEX Lyon Institute of Origins (ANR-10-LABX-0066) of the Universite de Lyon for its financial support within the program "Investissements d'Avenir" (ANR-11-IDEX-0007).We report the results of the analyses of the cosmic ray data collected with a 4 tonne (3x1x1 m(3)) active mass (volume) Liquid Argon Time-Projection Chamber (TPC) operated in a dual-phase mode. We present a detailed study of the TPC's response, its main detector parameters and performance. The results are important for the understanding and further developments of the dual-phase technology, thanks to the verification of key aspects, such as the extraction of electrons from liquid to gas and their amplification through the entire one square metre readout plain, gain stability, purity and charge sharing between readout views.Swiss National Science Foundation (SNSF)French Atomic Energy CommissionCentre National de la Recherche Scientifique (CNRS)High Energy Accelerator Research Organization (KEK)Ministry of Education, Culture, Sports, Science and Technology, Japan (MEXT)Japan Society for the Promotion of ScienceSpanish Government FPA2016-77347-C2 SEV-2016-0588MdM-2015-0509Comunidad de MadridCERCA program of the Generalitat de CatalunyaLa Caixa Foundation LCF/BQ/DI18/11660043 100010434Programme PNCDI III, RomaniaCERN-RO, Romania 2/2020United States Department of Energy (DOE) SC0011686European Commission 654168Universite de Lyon ANR-10-LABX-0066 ANR-11-IDEX-000

Search for electron antineutrino appearance in a long-baseline muon antineutrino beam

Electron antineutrino appearance is measured by the T2K experiment in an accelerator-produced antineutrino beam, using additional neutrino beam operation to constrain parameters of the Pontecorvo-Maki-Nakagawa-Sakata (PMNS) mixing matrix. T2K observes 15 candidate electron antineutrino events with a background expectation of 9.3 events. Including information from the kinematic distribution of observed events, the hypothesis of no electron antineutrino appearance is disfavored with a significance of 2.40σ and no discrepancy between data and PMNS predictions is found. A complementary analysis that introduces an additional free parameter which allows non-PMNS values of electron neutrino and antineutrino appearance also finds no discrepancy between data and PMNS predictions

Scintillator ageing of the T2K near detectors from 2010 to 2021

The T2K experiment widely uses plastic scintillator as a target for neutrino interactions and an active medium for the measurement of charged particles produced in neutrino interactions at its near detector complex. Over 10 years of operation the measured light yield recorded by the scintillator based subsystems has been observed to degrade by 0.9–2.2% per year. Extrapolation of the degradation rate through to 2040 indicates the recorded light yield should remain above the lower threshold used by the current reconstruction algorithms for all subsystems. This will allow the near detectors to continue contributing to important physics measurements during the T2K-II and Hyper-Kamiokande eras. Additionally, work to disentangle the degradation of the plastic scintillator and wavelength shifting fibres shows that the reduction in light yield can be attributed to the ageing of the plastic scintillator. The long component of the attenuation length of the wavelength shifting fibres was observed to degrade by 1.3–5.4% per year, while the short component of the attenuation length did not show any conclusive degradation

Excretion of 19-norandrosterone after consumption of boar meat

The consumption of the offal of noncastrated pigs can lead to the excretion of 19-norandrosterone (NorA) in urine of humans. In doping control, GC/C/IRMS is the method of choice to differentiate between an endogenous or exogenous origin of urinary NorA. In some cases, after the consumption of wild boar offal, the delta C-13 values of urinary NorA fulfill the criteria of an adverse analytical finding due to differing food sources of boar and consumer. However, consumption of wild boar's offal is not very common in Germany, and thus, the occurrence of such an analytical finding is unlikely. In contrast, the commerce with wild boar meat has increased in Germany within the last years. Up to 20,000 tons of wild boar meat are annually consumed. In order to probe for the probability of the occurrence of urinary NorA after consumption of wild boar meat, human urine samples were tested following the ingestion of commercially available game. In approximately half of the urine samples, traces of NorA were detected postadministration of 200 to 400 g boar meat. The highest urinary concentration was 2.9 ng/ml, and significant amounts were detected up to 9 h after the meal. delta C-13 values ranged from -18.5 parts per thousand to -23.5 parts per thousand, which would have led to at least two adverse analytical findings if the samples were collected in an antidoping context. IRMS analysis on German boar tissue samples showed that delta C-13 values for wild boar's steroids are unpredictable and may vary seasonally

Investigations on the in vivo metabolism of 5 alpha-androst-2-en-17-one

Rationale The anabolic steroid 5 alpha-androst-2-en-17-one (2EN) is sold as a prohormone and has been investigated regarding its potential as a steroidal aromatase inhibitor. The administration of 2EN was detected in a doping control sample in 2015, and investigations into its metabolism allowed for the identification and characterization of three urinary metabolites. Unfortunately, the utility of the main metabolite 2 beta,3 alpha-dihydroxy-5 alpha-androstan-17-one for doping control purposes was hampered under routine doping control conditions due to chromatographic issues, thus warranting further studies on the metabolism of the prohibited substance. Methods The metabolism of 2EN was reinvestigated after oral administration of twofold-deuterated 2EN employing hydrogen isotope ratio mass spectrometry (IRMS) in combination with high-accuracy/high-resolution mass spectrometry. After a single dose of 50 mg of doubly labeled 2EN, urine samples were collected for 9 days. All samples were processed using routine doping control methods for IRMS analysis, and all detected metabolites were further characterized by mass spectrometry-based investigations. Results More than 15 different metabolites still containing the deuterium label were detected after administration. The presence of steroids exhibiting a 5 beta-configuration was unexpected as the administered 2EN features a 5 alpha-configured pharmacophore. Further investigations corroborated a significant impact of the administered 2EN on etiocholanolone and 5 beta-androstanediol. Seven metabolites of 2EN not present as endogenous compounds were identified as potential candidates for routine doping controls and could be detected for up to 9 days after administration. Conclusions The new metabolites identified in this study enable the detection of the misuse of 2EN for up to 9 days. The conversion of a 5 alpha-steroid to urinary metabolites with 5 beta-configuration has not been reported so far and should be further investigated

Sensitive detection of testosterone and testosterone prohormone administrations based on urinary concentrations and carbon isotope ratios of androsterone and etiocholanolone

The testing strategy for the detection of testosterone (T) or T-prohormones is based on the longitudinal evaluation of urinary steroid concentrations accompanied by subsequent isotope ratio mass spectrometry (IRMS)-based confirmation of samples showing atypical concentrations or concentration ratios. In recent years, the IRMS methodology focussed more and more on T itself and on the metabolites of T, 5 alpha- and 5 beta-androstanediol. These target analytes showed the best sensitivity and retrospectivity, but their use has occasionally been challenging due to their comparably low urinary concentrations. Conversely, the carbon isotope ratios (CIR) of the main urinary metabolites of T, androsterone (A) and etiocholanolone (EITO), can readily be measured even from low urine volumes; those however, commonly offer a lower sensitivity and shorter retrospectivity in uncovering T misuse. Within this study, the CIRs of A and ETIO were combined with their urinary concentrations, resulting in a single parameter referred to as 'difference from weighted mean' (DWM). Both glucuronidated and sulfated steroids were investigated, encompassing a reference population (n = 110), longitudinal studies on three individuals, influence of ethanol in two individuals, and re-analysis of several administration studies including T, dihydrotestosterone, androstenedione, epiandrosterone, dehydroepiandrosterone, and T-gel. Especially DWM calculated for the sulfoconjugated steroids significantly prolonged the detection time of steroid hormone administrations when individual reference ranges were applied. Administration studies employing T encompassing CIR common for Europe (-23.8 parts per thousand and -24.4 parts per thousand) were investigated and, even though for a significantly shorter time period and less pronounced, DWM could demonstrate the exogenous source of T metabolites