Sonographic characterization of the prenatal development of the elephant

Deckblatt-Impressum Inhaltsverzeichnis Abbildungsverzeichnis Abkürzungen Tabellenverzeichnis Einleitung Material und Methoden Ergebnisse Diskussion Zusammenfassung Summary Literaturverzeichnis Danksagung SelbständigkeitserklärungDie Trächtigkeit des Elefanten ist mit durchschnittlich 660 Tagen (Meyer et al. , 2004) die längste Trächtigkeit im Tierreich überhaupt. Hieraus ergibt sich die Frage, welche Vorgänge sich während der pränatalen Entwicklung abspielen. In der Vergangenheit basierten Untersuchungen zur pränatalen Entwicklung des Elefanten fast ausschließlich auf toten Elefantenföten, die während der culling - Aktionen (kontrollierter Abschuss zur lokalen Populationskontrolle) in den Jahren 1964 - 1995 in Südafrika geborgen wurden. Beobachtungen bezüglich Implantation, Plazentation, Entwicklung der extraembryonalen Organe und fötalem Wachstum konnten daher nicht in den zeitlichen Verlauf der Trächtigkeit eingeordnet werden. Eine grobe Alterseinschätzung der Föten anhand ihrer Masse erfolgte nach den Formeln von Huggett & Widdas (1951) und Craig (1984). Die Etablierung der transrektalen Sonographie beim Elefanten durch Hildebrandt et al. (1998) ermöglicht heute eine longitudinale Überwachung der Trächtigkeit in vivo. In der vorliegenden Arbeit wurden 19 trächtige Elefanten (9 Afrikanische und 10 Asiatische Elefanten) mit bekanntem Ovulationszeitpunkt sonographisch untersucht. Das Alter der Trächtigkeit bzw. das embryonale und fötale Alter konnte so zu jedem Zeitpunkt exakt bestimmt werden. Weiterhin wurden biometrische Daten (Scheitel - Steiß - Länge und Masse) von 22 formalinfixierten Afrikanischen Elefantenföten und Daten von 3 abortierten Föten zur Beschreibung des pränatalen Wachstums einbezogen. Transrektale Sonographie war im ersten Drittel der Trächtigkeit (bis Tag 240 p.o) möglich. Wichtige Ereignisse wie Implantation, Plazentation und Organogenese wurden erstmals am lebenden Fötus dargestellt. Die Embryonalperiode betrug im Vergleich zur Gesamtträchtigkeit nur etwa ein Sechstel. Die verlängerte Fötalperiode lässt sich vermutlich auf eine ausgeprägte Hirnreifung in utero zurückführen. Anhand von Ultraschallmessungen an Föten bekannten Alters in utero wurden Wachstumskurven erstellt. Die mathematische Beschreibung dieser Kurven führte zur Entwicklung neuer Formeln zur pränatalen Altersbestimmung. Um die neu entwickelten Formeln mit den bisher verwendeten Formeln nach Huggett & Widdas (1951) und Craig (1984) zu vergleichen, wurden das bekannte Alter der sonographisch untersuchten Föten mit dem auf Basis ihrer Masse berechneten Alter der formalinfixierten Föten verglichen. Hieraus ergab sich, dass das wahre Alter der Föten nach Huggett & Widdas um bis zu 20 Tage unterschätzt wurde. Die Formel nach Craig hingegen überschätzte das fötale Alter um 25 bis 65 Tage. Um den Verlauf des Wachstums über die gesamte Länge der Trächtigkeit zu beschreiben, wurden die Wachstumsmodelle nach Gompertz (1825) und von Bertalanffy (1960) an die Scheitel- Steiss - Längen Messungen der Elefanten angepasst.Elephants have the longest pregnancy of all mammals, with an average gestation of around 660 days (Meyer et al. , 2004). The processes involved in prenatal development are therefore of special interest. In the past, research on the prenatal development of the elephant relied mainly on foetal specimens collected during culling actions in South Africa, which took place in the period between 1964 - 1995. Observations concerning implantation, placentation, development of the extraembryonic organs and foetal growth could not be correlated to foetal age. Foetal age was estimated on the basis of foetal weight according to the formulas of Huggett & Widdas (1951) and Craig (1984). With the establishment of transrectal ultrasonography by Hildebrandt et al. (1998), the longitudinal monitoring of elephant pregnancies in vivo is now possible. In this study, the pregnancies of 19 elephants (9 African and 10 Asian elephants) with known date of ovulation were assessed by ultrasound. Gestational age could be exactly calculated at all times. Furthermore, biometrical measurements (crown - rump - length and mass) of 22 preserved African elephant specimens and data of 3 aborted fetuses were included to describe prenatal growth. Transrectal sonography was feasible in the first third of pregnancy (until day 240 p.o). For the first time, important events such as implantation, placentation and organogenesis could be depicted in the living foetus. The embryonic period comprised only approximately one sixth of the entire gestation. The foetal period is supposedly elongated due to extensive cerebral maturation in utero. Growth graphs were developed on the basis of sonographic measurements of foetuses of known age in utero. The mathematical description of these graphs resulted in the development of new formulas for foetal age determination. To compare the newly developed formulas with those according to Huggett & Widdas (1951) and Craig (1984), the known foetal age of the sonographically assessed foetuses was compared with the age of the preserved specimens, which was calculated on the basis of foetal mass. The comparison showed that the formula of Huggett & Widdas underestimated true foetal age by 20 days. In contrast, the formula of Craig overestimated foetal age by up to 65 days. To describe prenatal growth over the whole length of pregnancy, the growth models according to Gompertz (1825) and von Bertalanffy (1960) have been adapted to crown - rump - measurments of foetal elephants

The Long Gestation of the Small Naked Mole-Rat (Heterocephalus glaber RÜPPELL, 1842) Studied with Ultrasound Biomicroscopy and 3D-Ultrasonography

The naked mole-rat (Heterocephalus glaber) is one of the two known mammalian species that live in a eusocial population structure. Here we investigate the exceptionally long gestation period of 70 days observed in the mole-rat queen. The course of seven successful pregnancies in two individuals was recorded in a colony of captive naked mole-rats using ultrasound biomicroscopy (UBM) and 3D-ultrasonography. We establish a catalogue of basic reference ultrasound data for this species by describing the ultrasonographic appearance of reproductive organs, calculating growth curves to predict gestational age and defining ultrasonographic milestones to characterize pregnancy stages. Mean litter size was 10.9±2.7, of which 7.2±1.5 survived the weaning period. Mean interbirth interval was 128.8±63.0 days. The reproductive success in our colony did not differ from previously published data. In the queen the active corpora lutea had an anechoic, fluid filled centre. Using UBM, pregnancy could be detected 53 days before parturition. The period of embryonic development is assumed to last until 30 days before parturition. Embryonic resorptions were detected frequently in the queen, indicating that this might be an ordinary event in this species. We discuss the extraordinary long gestation period of this small rodent and postulate that the long gestation is beneficial to both the eusocial structure and longevity. An increased litter size, twice as large as for other rodents of similar size, seemingly compensates for the doubling of pregnancy length. We demonstrate that the lifetime reproductive effort of a naked mole-rat queen is equivalent to the mass of offspring that would be produced if all of the females of a colony would be reproducing

Microvascular changes following exposure to iodinated contrast media in vitro. A qualitative comparison to serum creatinine concentrations in post-cardiac catheterization patients

Introduction Contrast-associated acute kidney injury (CA-AKI) is characterized as a loss of renal function following radiological contrast media administration. While all contrast media induce variable changes in microvascular endothelial cells in vitro, only few studies report clinical significance of their findings. A comprehensive assessment of the effect of iodinated contrast media on the renal function in vitro and in vivo is essential. The aim of our study was to morphometrically quantify the effect of two different contrast media (Iobitridol and Iodixanol) on vascular endothelial capillaries in vitro and to analyze their effect on the renal function of patients who underwent cardiac catheterization including the intra-arterial administration of contrast media, by measuring serum creatinine concentration (SCr), a byproduct of muscle metabolism, primarily excreted by the kidneys. Our hypothesis suggests that conducting a qualitative comparison of both outcomes will enable identification of differences and similarities between in vitro and in vivo exposure. Material and methods In vitro, co-cultures of human dermal fibroblasts and human dermal microvascular endothelial cells forming capillary beds were exposed to a mixture of phosphate buffered saline and either Iobitridol, Iodixanol, or one of their supplements EDTA or Trometamol for 1.5 or 5 min. Negative control co-cultures were exposed exclusively to phosphate buffered saline. Co-cultures were either directly fixed or underwent a regeneration time of 1, 3 or 7 days. An artificial intelligence software was trained for detection of labeled endothelial capillaries (CD31) on light microscope images and measurements of morphometric parameters. In vivo, we retrospectively analyzed data from patients who underwent intra-arterial administration of contrast media and for whom SCr values were available pre- and post-contrast exposition (1, 3, and 7 days following procedure). Temporal development of SCr and incidence of CA-AKI were assessed. Both exposure types were qualitatively compared. Results In vitro, Iobitridol, Iodixanol and EDTA induced a strong decrease of two morphometric parameters after 3 days of regeneration. In vivo, a significant increase of SCr and incidence of CA-AKI was observed 3 days following procedure in the post-contrast media patients. No difference was observed between groups. Discussion Two of the morphometric parameters were inversely proportional to the SCr of the patients. If the endothelial damages observed in vitro occur in vivo, it may result in renal hypoxia, inducing a loss of kidney function clinically translated into an increase of SCr. Further development of our in vitro model could allow closer replication of the internal structure of a kidney and bridge the gap between in vitro studies and their clinical findings

Bi-allelic mutation in SEC16B alters collagen trafficking and increases ER stress

Osteogenesis imperfecta (OI) is a genetically and clinically heterogeneous disorder characterized by bone fragility and reduced bone mass generally caused by defects in type I collagen structure or defects in proteins interacting with collagen processing. We identified a homozygous missense mutation in SEC16B in a child with vertebral fractures, leg bowing, short stature, muscular hypotonia, and bone densitometric and histomorphometric features in keeping with OI with distinct ultrastructural features. In line with the putative function of SEC16B as a regulator of trafficking between the ER and the Golgi complex, we showed that patient fibroblasts accumulated type I procollagen in the ER and exhibited a general trafficking defect at the level of the ER. Consequently, patient fibroblasts exhibited ER stress, enhanced autophagosome formation, and higher levels of apoptosis. Transfection of wild-type SEC16B into patient cells rescued the collagen trafficking. Mechanistically, we show that the defect is a consequence of reduced SEC16B expression, rather than due to alterations in protein function. These data suggest SEC16B as a recessive candidate gene for OI

Comparison of CATs, CURB-65 and PMEWS as Triage Tools in Pandemic Influenza Admissions to UK Hospitals: Case Control Analysis Using Retrospective Data

Triage tools have an important role in pandemics to identify those most likely to benefit from higher levels of care. We compared Community Assessment Tools (CATs), the CURB-65 score, and the Pandemic Medical Early Warning Score (PMEWS); to predict higher levels of care (high dependency - Level 2 or intensive care - Level 3) and/or death in patients at or shortly after admission to hospital with A/H1N1 2009 pandemic influenza. This was a case-control analysis using retrospectively collected data from the FLU-CIN cohort (1040 adults, 480 children) with PCR-confirmed A/H1N1 2009 influenza. Area under receiver operator curves (AUROC), sensitivity, specificity, positive predictive values and negative predictive values were calculated. CATs best predicted Level 2/3 admissions in both adults [AUROC (95% CI): CATs 0.77 (0.73, 0.80); CURB-65 0.68 (0.64, 0.72); PMEWS 0.68 (0.64, 0.73), p<0.001] and children [AUROC: CATs 0.74 (0.68, 0.80); CURB-65 0.52 (0.46, 0.59); PMEWS 0.69 (0.62, 0.75), p<0.001]. CURB-65 and CATs were similar in predicting death in adults with both performing better than PMEWS; and CATs best predicted death in children. CATs were the best predictor of Level 2/3 care and/or death for both adults and children. CATs are potentially useful triage tools for predicting need for higher levels of care and/or mortality in patients of all ages

Clinical manifestations and immunomodulatory treatment experiences in psychiatric patients with suspected autoimmune encephalitis: a case series of 91 patients from Germany

Autoimmune encephalitis (AE) can rarely manifest as a predominantly psychiatric syndrome without overt neurological symptoms. This study’s aim was to characterize psychiatric patients with AE; therefore, anonymized data on patients with suspected AE with predominantly or isolated psychiatric syndromes were retrospectively collected. Patients with readily detectable neurological symptoms suggestive of AE (e.g., epileptic seizures) were excluded. Patients were classified as “probable psychiatric AE (pAE),” if well-characterized neuronal IgG autoantibodies were detected or “possible pAE” (e.g., with detection of nonclassical neuronal autoantibodies or compatible cerebrospinal fluid (CSF) changes). Of the 91 patients included, 21 (23%) fulfilled our criteria for probable (autoantibody-defined) pAE and 70 (77%) those for possible pAE. Among patients with probable pAE, 90% had anti-NMDA receptor (NMDA-R) autoantibodies. Overall, most patients suffered from paranoid-hallucinatory syndromes (53%). Patients with probable pAE suffered more often from disorientation (p < 0.001) and impaired memory (p = 0.001) than patients with possible pAE. Immunotherapies were performed in 69% of all cases, mostly with high-dose corticosteroids. Altogether, 93% of the patients with probable pAE and 80% of patients with possible pAE reportedly benefited from immunotherapies (p = 0.251). In summary, this explorative, cross-sectional evaluation confirms that autoantibody-associated AE syndromes can predominantly manifest as psychiatric syndromes, especially in anti-NMDA-R encephalitis. However, in three out of four patients, diagnosis of possible pAE was based on nonspecific findings (e.g., slight CSF pleocytosis), and well-characterized neuronal autoantibodies were absent. As such, the spectrum of psychiatric syndromes potentially responding to immunotherapies seems not to be limited to currently known autoantibody-associated AE. Further trials are needed

The Steady State Great Ape? Long Term Isotopic Records Reveal the Effects of Season, Social Rank and Reproductive Status on Bonobo Feeding Behavior

Dietary ecology of extant great apes is known to respond to environmental conditions such as climate and food availability, but also to vary depending on social status and life history characteristics. Bonobos (Pan paniscus) live under comparatively steady ecological conditions in the evergreen rainforests of the Congo Basin. Bonobos are an ideal species for investigating influences of sociodemographic and physiological factors, such as female reproductive status, on diet. We investigate the long term dietary pattern in wild but fully habituated bonobos by stable isotope analysis in hair and integrating a variety of long-term sociodemographic information obtained through observations. We analyzed carbon and nitrogen stable isotopes in 432 hair sections obtained from 101 non-invasively collected hair samples. These samples represented the dietary behavior of 23 adult bonobos from 2008 through 2010. By including isotope and crude protein data from plants we could establish an isotope baseline and interpret the results of several general linear mixed models using the predictors climate, sex, social rank, reproductive state of females, adult age and age of infants. We found that low canopy foliage is a useful isotopic tracer for tropical rainforest settings, and consumption of terrestrial herbs best explains the temporal isotope patterns we found in carbon isotope values of bonobo hair. Only the diet of male bonobos was affected by social rank, with lower nitrogen isotope values in low-ranking young males. Female isotope values mainly differed between different stages of reproduction (cycling, pregnancy, lactation). These isotopic differences appear to be related to changes in dietary preference during pregnancy (high protein diet) and lactation (high energy diet), which allow to compensate for different nutritional needs during maternal investment

A comprehensive assessment of somatic mutation detection in cancer using whole-genome sequencing.

As whole-genome sequencing for cancer genome analysis becomes a clinical tool, a full understanding of the variables affecting sequencing analysis output is required. Here using tumour-normal sample pairs from two different types of cancer, chronic lymphocytic leukaemia and medulloblastoma, we conduct a benchmarking exercise within the context of the International Cancer Genome Consortium. We compare sequencing methods, analysis pipelines and validation methods. We show that using PCR-free methods and increasing sequencing depth to ∼ 100 × shows benefits, as long as the tumour:control coverage ratio remains balanced. We observe widely varying mutation call rates and low concordance among analysis pipelines, reflecting the artefact-prone nature of the raw data and lack of standards for dealing with the artefacts. However, we show that, using the benchmark mutation set we have created, many issues are in fact easy to remedy and have an immediate positive impact on mutation detection accuracy.We thank the DKFZ Genomics and Proteomics Core Facility and the OICR Genome Technologies Platform for provision of sequencing services. Financial support was provided by the consortium projects READNA under grant agreement FP7 Health-F4-2008-201418, ESGI under grant agreement 262055, GEUVADIS under grant agreement 261123 of the European Commission Framework Programme 7, ICGC-CLL through the Spanish Ministry of Science and Innovation (MICINN), the Instituto de Salud Carlos III (ISCIII) and the Generalitat de Catalunya. Additional financial support was provided by the PedBrain Tumor Project contributing to the International Cancer Genome Consortium, funded by German Cancer Aid (109252) and by the German Federal Ministry of Education and Research (BMBF, grants #01KU1201A, MedSys #0315416C and NGFNplus #01GS0883; the Ontario Institute for Cancer Research to PCB and JDM through funding provided by the Government of Ontario, Ministry of Research and Innovation; Genome Canada; the Canada Foundation for Innovation and Prostate Cancer Canada with funding from the Movember Foundation (PCB). PCB was also supported by a Terry Fox Research Institute New Investigator Award, a CIHR New Investigator Award and a Genome Canada Large-Scale Applied Project Contract. The Synergie Lyon Cancer platform has received support from the French National Institute of Cancer (INCa) and from the ABS4NGS ANR project (ANR-11-BINF-0001-06). The ICGC RIKEN study was supported partially by RIKEN President’s Fund 2011, and the supercomputing resource for the RIKEN study was provided by the Human Genome Center, University of Tokyo. MDE, LB, AGL and CLA were supported by Cancer Research UK, the University of Cambridge and Hutchison-Whampoa Limited. SD is supported by the Torres Quevedo subprogram (MI CINN) under grant agreement PTQ-12-05391. EH is supported by the Research Council of Norway under grant agreements 221580 and 218241 and by the Norwegian Cancer Society under grant agreement 71220-PR-2006-0433. Very special thanks go to Jennifer Jennings for administrating the activity of the ICGC Verification Working Group and Anna Borrell for administrative support.This is the final version of the article. It first appeared from Nature Publishing Group via http://dx.doi.org/10.1038/ncomms1000

Overview of the first Wendelstein 7-X long pulse campaign with fully water-cooled plasma facing components

After a long device enhancement phase, scientific operation resumed in 2022. The main new device components are the water cooling of all plasma facing components and the new water-cooled high heat flux divertor units. Water cooling allowed for the first long-pulse operation campaign. A maximum discharge length of 8 min was achieved with a total heating energy of 1.3 GJ. Safe divertor operation was demonstrated in attached and detached mode. Stable detachment is readily achieved in some magnetic configurations but requires impurity seeding in configurations with small magnetic pitch angle within the edge islands. Progress was made in the characterization of transport mechanisms across edge magnetic islands: Measurement of the potential distribution and flow pattern reveals that the islands are associated with a strong poloidal drift, which leads to rapid convection of energy and particles from the last closed flux surface into the scrape-off layer. Using the upgraded plasma heating systems, advanced heating scenarios were developed, which provide improved energy confinement comparable to the scenario, in which the record triple product for stellarators was achieved in the previous operation campaign. However, a magnetic configuration-dependent critical heating power limit of the electron cyclotron resonance heating was observed. Exceeding the respective power limit leads to a degradation of the confinement

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts