146 research outputs found
a retrospective study
Deckblatt \- Impressum
Inhaltsverzeichnis
Abkürzungsverzeichnis
I Einleitung 1
II Literaturübersicht 2
III Eigene Untersuchungen 53
IV Ergebnisse 70
V Diskussion 106
VI Zusammenfassung 127
VII Summary 129
VIII Literaturverzeichnis 131
IX
Anhang
154
Danksagung
SelbständigkeitserklärungDer portosystemische Shunt des Hundes ist eine meist angeborene Gefäßanomalie
des Pfortaderkreislaufes. Er tritt überwiegend bei jungen Hunden auf. Für
reinrassige Hunde besteht eine erhöhte Disposition.
Im Rahmen der vorliegenden Untersuchungen wurden 56 Patienten der Klinik und
Poliklinik für kleine Haustiere der Freien Universität Berlin erfasst, die
zwischen 1981 und 1996 mit der Verdachtsdiagnose eines portosystemischen
Shunts vorgestellt wurden. Davon gehörten 60,7 % zu den kleinen Rassen, 10,7 %
zu den mittleren und 28,6 % zu den großen Rassen. Am häufigsten waren die
Yorkshire-Terrier vertreten. Das durchschnittliche Erkrankungsalter lag bei
1,4 Jahren.
Die Shunts wurden in intrahepatische und extrahepatischen Shunts eingeteilt.
Bei den extrahepatischen Shunts wurde zwischen dem Portokavalen, dem
Portoazygos und dem Portophreniko Shunt unterschieden.
Intrahepatische Shunts wurden bei 17 Hunden überwiegend großer Rassen (30,4 %)
diagnostiziert. Bei 12 Hunden verlief er im linken lateralen Leberlappen
entsprechend einem Ductus venosus, bei einem Hund im mittleren und bei drei
Hunden im rechten lateralen Leberlappen. Extrahepatische Shunts traten bei 39
Hunden überwiegend kleiner Rassen (69,6 %) auf, davon war der Portokavale
Shunt mit 29 Tieren (74,4 %) am stärksten vertreten, gefolgt von sieben Tieren
(17,9 %) mit einem Portoazygos Shunt und drei (7,7 %) mit einem Portophreniko
Shunt.
Allgemeine Symptome manifestierten sich vorwiegend mit Störungen des
Gastrointestinaltraktes mit Vomitus und Diarrhoe oder des Harnapparates mit
Polyurie/Polydipsie. Bei den neurologischen Symptomen dominierten motorische
Unruhe, Apathie und epileptische Anfälle. Bei neun Hunden (16,1 %) traten
ausschließlich allgemeine Symptome auf, sechs Hunde (10,7 %) zeigten nur
neurologische Symptome. Der prozentual größte Teil der Patienten mit 73,2 %
wurde wegen allgemeiner sowie neurologischer Beschwerden vorgestellt.
Die auffälligsten Laborbefunde waren ein sehr hoher Ammoniak-Gehalt im Serum
sowie ein erniedrigter Harnstoff- und Gesamteiweiß-Gehalt.
Im Röntgenbild zeigten 59,2 % der Patienten eine kleine Leber. Mit Hilfe der
Portographie über eine V. jejunalis konnte neben einer genauen Darstellung des
Shuntverlaufs festgestellt werden, in wie weit ein Pfortaderkreislauf
ausgebildet war und/oder ob sich neben dem Shunt zusätzliche Gefäße zeigten.
Bei 26 % der Tiere (n = 13) wurde der Shunt bei der ersten Operation komplett
verschlossen, bei 74 % (n = 38) nur eingeengt. Während anschließender
Operationen konnte noch in weiteren 12 Fällen der Shunt komplett verschlossen
werden, so dass insgesamt 50 % der Shunts verschlossen werden konnten. Der
Grad der Einengung bzw. des Verschlusses wurde unter anderem aufgrund der Höhe
des Portaldrucks und der Darstellbarkeit von Portalgefäßen in der Leber
bemessen.
Intraoperative Komplikationen traten in Form von bereits bestehendem portalen
Hochdruck (n = 6), Blutung durch Verletzung des Shunts (n = 1) oder durch
Verklebungen durch vorausgegangene Operationen auf (n = 1).
Während der Operation bzw. ihres stationären Aufenthaltes wurden 12 Tiere
(21,8 %) euthanasiert oder verstarben.
In einem Zeitraum von sieben Tagen und achteinhalb Jahren konnten 33 Patienten
zu Kontrolluntersuchungen wiederbestellt werden. Ein ungestörtes
Allgemeinbefinden zeigten 19 Tiere. Kurzfristig traten Symptome bei 14 Tieren
auf. Die Laborwerte zeigten deutliche Verbesserung. Bei 54 % regulierten sich
die Ammoniak-Konzentration, 46 % zeigten einen Anstieg der Gesamteiweißwerte
und bei 32 % war ein Anstieg der Harnstoffwerte zu verzeichnen.
Übersichtsaufnahmen des Abdomens zeigten in 14 Fällen eine deutliche Zunahme
des Lebergewebes.
Die chirurgische Versorgung des portosystemischen Shunts mit dem Ziel, den
Shunt zu verschließen, wird von uns als prognostisch günstig eingestuft.
Unsere Ergebnisse belegen, dass in ca. 78 % der Fälle gute Langzeitergebnisse
zu erwarten sind.The portosystemic shunt in dogs is a congenital anomaly of the portal vein
system and occurs particularly often in young dogs. Thoroughbreds have a
predisposition for the condition.
In the following study a total of 56 dogs with suspected portosystemic shunt
were examined in the Clinic for Small Animals of the Free University in
Berlin in the period between 1981 and 1996.
60,7 % belonged to small, 10,7 % to middle and 28,6 % to large breeds.
Yorkshire Terriers were the most common breed. The average age was 1.4 years.
Portosystemic shunts were divided into intrahepatic and extrahepatic shunts.
There were three types of extrahepatic shunt, the portocaval shunt, the
portoazygos shunt and the portophrenico shunt.
Intrahepatic shunts were found in 17 dogs of mostly large breeds (30,4 %). In
12 dogs the shunt was located in the left lateral liver lobe according to the
ductus venosus. In one dog the shunt was found in the medial liver lobe. A
shunt located in the right lateral liver lobe was diagnosed three times.
Extrahepatic shunts were found in 39 dogs of mostly small breeds (69,6 %). 29
(74,4 %) of them had a portocaval shunt, seven (17,9 %) a portoazygos and
three (7,7 %) a portophrenico shunt.
The most common nonspecific clinical signs were gastroenteric signs such as
vomiting and diarrhoea or urinary tract disorders like polyuria/polydipsia.
Neurological abnormalities were primarily aimless wandering, apathy and
seizures. Nine dogs (16,1 %) showed nonspecific symptoms only, six dogs (10,7
%) suffered from neurological disorders. Most of the dogs (73,2 %) showed both
neurological and nonspecific signs.
Biochemical screening tests showed a high serum ammonia level, low urea
concentration and low total protein concentration.
Plain radiographs of 59,2 % of the patients revealed a small liver. With the
radiographic contrast imaging of the portal venous system the shunt was
outlined. The shunt type could be differentiated into intra- or extrahepatic.
Furthermore it was possible to show if there was a portal circulation and if
there were additional vessels.
In 26 % of the patients (n = 13) the shunt was completely ligated in the first
operation, in 74 % (n = 37) it was only attenuated. In further operations it
was possible to close the shunt completely in 12 more dogs. In total, the
shunt was ligated in 50 % of all cases. The degree of attenuation was
measurded using the portal pressure and the visualisation of a portal
circulation.
Surgical complications of shunt ligation included portal hypertension (n = 6),
haemorrhages from the shunt (n = 4) or adhesions because of previous
operations ( n= 1).
During operation or hospitalization 12 dogs (21,8 %) were euthanized or died.
In a period of time stretching from seven days to eight and a half years 33
follow-up checks were made. 19 patients had no symptoms. Only 14 dogs showed
slight symptoms. The laboratory findings improved a lot. In 54 % the ammonia
concentration decreased, in 46 % we noticed an increase in the total protein
concentration and 32 % showed an increase in urea concentration. Plain
radiographs of 14 patients showed an increased hepatic mass.
The surgical management of the portosystemic shunt with the complete ligation
of the shunt could be classified as having positive prognoses. Our results
prove that in 78% of all cases good longterm results can be expected
OCT4/POU5F1 is indispensable for the lineage differentiation of the inner cell mass in bovine embryos
The mammalian blastocyst undergoes two lineage segregations, that is, formation of the trophectoderm and subsequently differentiation of the hypoblast (HB) from the inner cell mass, leaving the epiblast (EPI) as the remaining pluripotent lineage. To clarify the expression patterns of markers specific for these lineages in bovine embryos, we analyzed day 7, 9, and 12 blastocysts completely produced in vivo by staining for OCT4, NANOG, SOX2 (EPI), and GATA6, SOX17 (HB) and identified genes specific for these developmental stages in a global transcriptomics approach. To study the role of OCT4, we generated OCT4-deficient (OCT4 KO) embryos via somatic cell nuclear transfer or in vitro fertilization. OCT4 KO embryos reached the expanded blastocyst stage by day 8 but lost NANOG and SOX17 expression, while SOX2 and GATA6 were unaffected. Blastocysts transferred to recipient cows from day 6 to 9 expanded, but the OCT4 KO phenotype was not rescued by the uterine environment. Exposure of OCT4 KO embryos to exogenous FGF4 or chimeric complementation with OCT4 intact embryos did not restore NANOG or SOX17 in OCT4-deficient cells. Our data show that OCT4 is required cell autonomously for the maintenance of pluripotency of the EPI and differentiation of the HB in bovine embryos
Clinical Relevance of Transjugular Liver Biopsy in Comparison with Percutaneous and Laparoscopic Liver Biopsy
Background. Transjugular liver biopsy (TJLB) is frequently used to obtain liver specimens in high-risk patients. However, TJLB sample size possibly limits their clinical relevance. Methods. 102 patients that underwent TJLB were included. Clinical parameters and outcome of TJLB were analyzed. Control samples consisted of 112 minilaparoscopic liver biopsies (mLLBs) and 100 percutaneous liver biopsies (PLBs). Results. Fewer portal tracts were detected in TJLB (4.3 ± 0.3) in comparison with PLB (11.7 ± 0.5) and mLLB (11.0 ± 0.6). No difference regarding the specification of indeterminate liver disease and staging/grading of chronic hepatitis was observed. In acute liver failure (n = 32), a proportion of hepatocellular necrosis beyond 25% was associated with a higher rate of death or liver transplantation. Conclusions. Despite smaller biopsy samples the impact on the clinical decision process was found to be comparable to PLB and mLLB. TJLB represents a helpful tool to determine hepatocellular necrosis rates in patients with acute liver failure
The SARS-CoV-2 spike protein binds and modulates estrogen receptors
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) protein binds angiotensin-converting enzyme 2 as its primary infection mechanism. Interactions between S and endogenous proteins occur after infection but are not well understood. We profiled binding of S against >9000 human proteins and found an interaction between S and human estrogen receptor alpha (ER alpha). Using bioinformatics, supercomputing, and experimental assays, we identified a highly conserved and functional nuclear receptor coregulator (NRC) LXD-like motif on the S2 sub-unit. In cultured cells, S DNA transfection increased ER alpha cytoplasmic accumulation, and S treatment induced ER-dependent biological effects. Non-invasive imaging in SARS-CoV-2-infected hamsters localized lung pathology with increased ER alpha lung levels. Postmortem lung experiments from infected hamsters and humans confirmed an increase in cytoplasmic ER alpha and its colocalization with S in alveolar macrophages. These findings describe the discovery of a S-ER alpha interaction, imply a role for S as an NRC, and advance knowledge of SARS-CoV-2 biology and coronavirus disease 2019 pathology
Argo data 1999-2019: two million temperature-salinity profiles and subsurface velocity observations from a global array of profiling floats.
© The Author(s), 2020. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Wong, A. P. S., Wijffels, S. E., Riser, S. C., Pouliquen, S., Hosoda, S., Roemmich, D., Gilson, J., Johnson, G. C., Martini, K., Murphy, D. J., Scanderbeg, M., Bhaskar, T. V. S. U., Buck, J. J. H., Merceur, F., Carval, T., Maze, G., Cabanes, C., Andre, X., Poffa, N., Yashayaev, I., Barker, P. M., Guinehut, S., Belbeoch, M., Ignaszewski, M., Baringer, M. O., Schmid, C., Lyman, J. M., McTaggart, K. E., Purkey, S. G., Zilberman, N., Alkire, M. B., Swift, D., Owens, W. B., Jayne, S. R., Hersh, C., Robbins, P., West-Mack, D., Bahr, F., Yoshida, S., Sutton, P. J. H., Cancouet, R., Coatanoan, C., Dobbler, D., Juan, A. G., Gourrion, J., Kolodziejczyk, N., Bernard, V., Bourles, B., Claustre, H., D'Ortenzio, F., Le Reste, S., Le Traon, P., Rannou, J., Saout-Grit, C., Speich, S., Thierry, V., Verbrugge, N., Angel-Benavides, I. M., Klein, B., Notarstefano, G., Poulain, P., Velez-Belchi, P., Suga, T., Ando, K., Iwasaska, N., Kobayashi, T., Masuda, S., Oka, E., Sato, K., Nakamura, T., Sato, K., Takatsuki, Y., Yoshida, T., Cowley, R., Lovell, J. L., Oke, P. R., van Wijk, E. M., Carse, F., Donnelly, M., Gould, W. J., Gowers, K., King, B. A., Loch, S. G., Mowat, M., Turton, J., Rama Rao, E. P., Ravichandran, M., Freeland, H. J., Gaboury, I., Gilbert, D., Greenan, B. J. W., Ouellet, M., Ross, T., Tran, A., Dong, M., Liu, Z., Xu, J., Kang, K., Jo, H., Kim, S., & Park, H. Argo data 1999-2019: two million temperature-salinity profiles and subsurface velocity observations from a global array of profiling floats. Frontiers in Marine Science, 7, (2020): 700, doi:10.3389/fmars.2020.00700.In the past two decades, the Argo Program has collected, processed, and distributed over two million vertical profiles of temperature and salinity from the upper two kilometers of the global ocean. A similar number of subsurface velocity observations near 1,000 dbar have also been collected. This paper recounts the history of the global Argo Program, from its aspiration arising out of the World Ocean Circulation Experiment, to the development and implementation of its instrumentation and telecommunication systems, and the various technical problems encountered. We describe the Argo data system and its quality control procedures, and the gradual changes in the vertical resolution and spatial coverage of Argo data from 1999 to 2019. The accuracies of the float data have been assessed by comparison with high-quality shipboard measurements, and are concluded to be 0.002°C for temperature, 2.4 dbar for pressure, and 0.01 PSS-78 for salinity, after delayed-mode adjustments. Finally, the challenges faced by the vision of an expanding Argo Program beyond 2020 are discussed.AW, SR, and other scientists at the University of Washington (UW) were supported by the US Argo Program through the NOAA Grant NA15OAR4320063 to the Joint Institute for the Study of the Atmosphere and Ocean (JISAO) at the UW. SW and other scientists at the Woods Hole Oceanographic Institution (WHOI) were supported by the US Argo Program through the NOAA Grant NA19OAR4320074 (CINAR/WHOI Argo). The Scripps Institution of Oceanography's role in Argo was supported by the US Argo Program through the NOAA Grant NA15OAR4320071 (CIMEC). Euro-Argo scientists were supported by the Monitoring the Oceans and Climate Change with Argo (MOCCA) project, under the Grant Agreement EASME/EMFF/2015/1.2.1.1/SI2.709624 for the European Commission
Transethnic Genome-Wide Association Study Provides Insights in the Genetic Architecture and Heritability of Long QT Syndrome
BACKGROUND: Long QT syndrome (LQTS) is a rare genetic disorder and a major preventable cause of sudden cardiac death in the young. A causal rare genetic variant with large effect size is identified in up to 80% of probands (genotype positive) and cascade family screening shows incomplete penetrance of genetic variants. Furthermore, a proportion of cases meeting diagnostic criteria for LQTS remain genetically elusive despite genetic testing of established genes (genotype negative). These observations raise the possibility that common genetic variants with small effect size contribute to the clinical picture of LQTS. This study aimed to characterize and quantify the contribution of common genetic variation to LQTS disease susceptibility. METHODS: We conducted genome-wide association studies followed by transethnic meta-analysis in 1656 unrelated patients with LQTS of European or Japanese ancestry and 9890 controls to identify susceptibility single nucleotide polymorphisms. We estimated the common variant heritability of LQTS and tested the genetic correlation between LQTS susceptibility and other cardiac traits. Furthermore, we tested the aggregate effect of the 68 single nucleotide polymorphisms previously associated with the QT-interval in the general population using a polygenic risk score. RESULTS: Genome-wide association analysis identified 3 loci associated with LQTS at genome-wide statistical significance (P<5×10-8) near NOS1AP, KCNQ1, and KLF12, and 1 missense variant in KCNE1(p.Asp85Asn) at the suggestive threshold (P<10-6). Heritability analyses showed that ≈15% of variance in overall LQTS susceptibility was attributable to common genetic variation (h2SNP 0.148; standard error 0.019). LQTS susceptibility showed a strong genome-wide genetic correlation with the QT-interval in the general population (rg=0.40; P=3.2×10-3). The polygenic risk score comprising common variants previously associated with the QT-interval in the general population was greater in LQTS cases compared with controls (P<10-13), and it is notable that, among patients with LQTS, this polygenic risk score was greater in patients who were genotype negative compared with those who were genotype positive (P<0.005). CONCLUSIONS: This work establishes an important role for common genetic variation in susceptibility to LQTS. We demonstrate overlap between genetic control of the QT-interval in the general population and genetic factors contributing to LQTS susceptibility. Using polygenic risk score analyses aggregating common genetic variants that modulate the QT-interval in the general population, we provide evidence for a polygenic architecture in genotype negative LQTS.</p
First measurement of hadronic event shapes in pp collisions at √s = 7 TeV
This is the Pre-Print version of the Article - Copyright @ 2011 ElsevierHadronic event shapes have been measured in proton-proton collisions at sqrt(s)=7 TeV, with a data sample collected with the CMS detector at the LHC. The sample corresponds to an integrated luminosity of 3.2 inverse picobarns. Event-shape distributions, corrected for detector response, are compared with five models of QCD multijet production
Enhancing rare variant interpretation in inherited arrhythmias through quantitative analysis of consortium disease cohorts and population controls.
PURPOSE: Stringent variant interpretation guidelines can lead to high rates of variants of uncertain significance (VUS) for genetically heterogeneous disease like long QT syndrome (LQTS) and Brugada syndrome (BrS). Quantitative and disease-specific customization of American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines can address this false negative rate. METHODS: We compared rare variant frequencies from 1847 LQTS (KCNQ1/KCNH2/SCN5A) and 3335 BrS (SCN5A) cases from the International LQTS/BrS Genetics Consortia to population-specific gnomAD data and developed disease-specific criteria for ACMG/AMP evidence classes-rarity (PM2/BS1 rules) and case enrichment of individual (PS4) and domain-specific (PM1) variants. RESULTS: Rare SCN5A variant prevalence differed between European (20.8%) and Japanese (8.9%) BrS patients (p = 5.7 × 10-18) and diagnosis with spontaneous (28.7%) versus induced (15.8%) Brugada type 1 electrocardiogram (ECG) (p = 1.3 × 10-13). Ion channel transmembrane regions and specific N-terminus (KCNH2) and C-terminus (KCNQ1/KCNH2) domains were characterized by high enrichment of case variants and >95% probability of pathogenicity. Applying the customized rules, 17.4% of European BrS and 74.8% of European LQTS cases had (likely) pathogenic variants, compared with estimated diagnostic yields (case excess over gnomAD) of 19.2%/82.1%, reducing VUS prevalence to close to background rare variant frequency. CONCLUSION: Large case-control data sets enable quantitative implementation of ACMG/AMP guidelines and increased sensitivity for inherited arrhythmia genetic testing
Genome-wide association analyses identify new Brugada syndrome risk loci and highlight a new mechanism of sodium channel regulation in disease susceptibility.
Brugada syndrome (BrS) is a cardiac arrhythmia disorder associated with sudden death in young adults. With the exception of SCN5A, encoding the cardiac sodium channel Na1.5, susceptibility genes remain largely unknown. Here we performed a genome-wide association meta-analysis comprising 2,820 unrelated cases with BrS and 10,001 controls, and identified 21 association signals at 12 loci (10 new). Single nucleotide polymorphism (SNP)-heritability estimates indicate a strong polygenic influence. Polygenic risk score analyses based on the 21 susceptibility variants demonstrate varying cumulative contribution of common risk alleles among different patient subgroups, as well as genetic associations with cardiac electrical traits and disorders in the general population. The predominance of cardiac transcription factor loci indicates that transcriptional regulation is a key feature of BrS pathogenesis. Furthermore, functional studies conducted on MAPRE2, encoding the microtubule plus-end binding protein EB2, point to microtubule-related trafficking effects on Na1.5 expression as a new underlying molecular mechanism. Taken together, these findings broaden our understanding of the genetic architecture of BrS and provide new insights into its molecular underpinnings
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