Der Zusammenhang von Bindungssicherheit und einer Oxytocinrezeptor-Genvariation mit neuralen Korrelaten sozialer Kognition und Hirnmorphometrie

Die Entwicklung des menschlichen Gehirns sowie soziokognitiver und -emotionaler Fähigkeiten wird nicht nur von genetischen Faktoren, sondern auch von frühen Fürsorge­erfahrungen beeinflusst. Die Bindungs­theorie liefert ein Konzept für das Verständnis der soziokognitiven und -emotionalen Entwicklung des Menschen als Folge früher sozialer Fürsorgeerfahrungen und biologischer Veran­lagungen⁠. Individuelle Bindungs­stile entwickeln sich im Laufe des Lebens zu einer relativ stabilen Persönlich­keits­eigenschaft, die soziale Kognitionen, soziales Verhalten und den Umgang mit belast­en­den Lebensereignissen (wie z.B. emotionalen Verlusterfahrungen) beein­flusst. Auf physiologischer Ebene ist das menschliche Bindungs­system mit dem Oxytocin­system verknüpft, das allgemein eine bedeutsame Funktion für soziales Verhalten und soziale Kognitionen hat⁠. Das Oxytocinsystem wird durch frühe Eltern-Kind-Inter­aktionen in seiner Entwicklung geprägt. In humangenetischen Studien war der Gen­polymorphismus rs53576 des Oxytocin­rezeptors (OXTR) mit Unterschieden in der Sensitivität für soziale Reize ⁠assoziiert und interagierte mit frühen sozialen Lebens­erfahrungen auf die Ausprägung sozioemotionaler Persönlichkeits­eigenschaften⁠. Fragestellung: In dieser Arbeit sollte untersucht werden, wie neurale Korrelate der Mentalisierung und die Hirnmorphometrie a) mit der kindlichen Bindungssicherheit unter Berücksichtigung des OXTR-Genpolymorphismus rs53576 und b) mit dem Bindungsstil im Erwachsenenalter zusammenhängen. Methoden: In einer Stichprobe von gesunden Student(inn)en wurden die neuralen Korrelate der Mentalisierung unter Anwendung der funktionellen Magnet­resonanz­tomographie (MRT) während der Bearbeitung einer sozial interaktiven Theory-of-Mind-Aufgabe (ToM, Gefangenen­dilemma, n= 164) erhoben. Die Hirn­morpho­metrie wurde mithilfe der strukturellen MRT und dem Verfahren der voxelbasierten Morphometrie (VBM, n=196) als Volumen der grauen Substanz bestimmt. Des Weiteren wurden Fragebögen eingesetzt, um die kindliche Bindungssicherheit (CAS, „Hazan-Shaver“-Skala), den Bindungsstil im Erwachsenenalter („Relationship Scales Questionnaire“, Subskalen „ängstlicher Bindungsstil“ (ANX) und „vermeidender Bindungsstil“ (AV)), die Alexithymie im Erwachsenen­alter („Toronto Alexithymia Scale 20“) und die Anzahl emotionaler Verlust­erfahrungen (AL, „List of Threatening Experiences Questionnaire”, VBM: n=192) zu erfassen. Die OXTR-Genvariation rs53576 (G/A) wurde durch Genotypisierung der DNA aus Blut­proben bestimmt (ToM: n=163, VBM: n=195). Ergebnisse: Signifikante Interaktionseffekte von rs53576 und CAS (d.h. eine GxU-Interaktion) zeigten sich für ANX, Alexithymie, Hirnstruktur und -funktion: Strukturelle GxU-Inter­aktions­effekte wurden in einem bilateralen fronto-parietalen und links­temporalen Netz­werk (ein­schließlich Hippo­kampus und Amygdala) beobachtet. Funktionelle GxU-Inter­aktions­effekte fanden sich in einem rechts­frontalen und bilateralen parieto-temporo-okzipitalen ToM-assoziierten Netz­werk. GG-Homozygote waren im Vergleich zu A-Allel-Trägern empfänglicher für CAS in Bezug auf das Volumen grauer Substanz, ANX und Alexithymie. Einige der beobachteten GxU-Interaktionseffekte waren sexuell dimorph. Strukturelle und funktio­nelle GxU-Interaktionseffekte überlappten zum Teil regional und waren, wie exploratorische Regressions­analysen zeigten, unter­einander und mit der Ausprägung von ANX und Alexithymie assoziiert. Des Weiteren wurde bei GG-Homozygoten ein signifikant höheres Volumen der grauen Substanz im Temporalpol und Hippokampus beobachtet. Die Bindungsstile des Erwachsenenalters AV und ANX unterschieden sich signifikant in ihrem Zusammenhang mit ToM-assoziierten neuralen Aktivierungen (u.a. in den bilateralen inferioren Frontalgyri (IFG), dem rechten mittleren Cingulum und der Amygdala) und dem Volumen der grauen Substanz im Pars opercularis des linken IFG. Diskussion: Interaktionseffekte von CAS und rs53576 wurden insbesondere für das Volumen und die Aktivierung von Hirnregionen beobachtet, die in soziale Kognitionen wie ToM und das Spiegelneuronensystem involviert sind. Des Weiteren zeigten sich strukturelle GxU-Interaktions­effekte und genetische Haupteffekte in Hirnarealen mit Funktionen für die Gedächtnisbildung. Genetische Effekte auf das Gedächtnis und/oder epigenetische Mechanismen könnten den beobachteten GxU-Interaktionseffekten auf Hirnstruktur, -funktion und Persönlichkeitseigenschaften zugrunde liegen. Die Bindungsstile ANX und AV waren signifikant unterschiedlich mit ToM-assoziierten neuralen Aktivierungen und mit dem Volumen von Hirnregionen assoziiert, die in die Emotions­regulation involviert sind. Die Ergebnisse dieser Arbeit tragen zu einem besseren Verständnis der biologischen Aspekte von Bindung bei. Sie liefern weitere Hinweise, wie sich die neuro­biologischen Grundlagen der sozialen Kognition im Zusammenspiel von Bindungs­sicherheit und Genetik möglicherweise entwickeln

Recombinant Measles Viruses Defective for RNA Editing and V Protein Synthesis Are Viable in Cultured Cells

AbstractThe measles virus (MV) phosphoprotein (P) gene encodes three proteins, P, C, and V. The V protein is synthesized by pseudo-templated transcription, also designated as RNA editing: during P gene transcription one G residue is inserted at a defined position in about 50% of the mRNAs. To study the importance of sequence elements for the nontemplated G insertion, we generated recombinant MVs in which six different mutations were introduced within the region where editing occurs (3′ UUUUUCCC, template strand). These viruses were then analyzed for their ability to edit their P mRNA and to produce V protein. Single U to C changes within the U stretch abolished editing. Extending the template by three C residues at the site of G insertion resulted in a less precise editing phenotype and overproduction of V. None of these mutants were impaired in their multiplication behavior when analyzed in cultured cells. However, the syncytia of a recombinant MV overproducing V protein were in general smaller and lysed 1 to 2 days later than usual

The Vampire Study: Significant elevation of faecal calprotectin in healthy volunteers after 300 ml blood ingestion mimicking upper gastrointestinal bleeding

Background Faecal calprotectin correlates with histological and clinical activity in inflammatory bowel disease. Gastrointestinal bleeding might also increase faecal calprotectin levels, erroneously implying intestinal inflammation; however, this possibility has not been systematically assessed. Methods Sixteen healthy volunteers without gastrointestinal disease and normal faecal calprotectin baseline values ingested their own blood twice, either by drinking or via nasogastric tube. Quantities of 100 ml and 300 ml blood were ingested in a randomised order, with a 28-day wash-out period. Faecal calprotectin, faecal occult blood test, and the occurrence of melaena were assessed. Faecal calprotectin ≥ 50 µg/g was considered elevated. Results Melaena was reported by all healthy volunteers after 300 ml and by 11/15 healthy volunteers (71%) after 100 ml blood ingestion. One day after ingestion of 300 ml blood, 8/16 faecal calprotectin tests were positive compared to 1/16 at baseline ( = 0.016). Faecal calprotectin levels above > 200 µg/g were rarely observed. There was a trend for faecal calprotectin test positivity also after ingestion of 100 ml. Conclusion Ingestion of blood resulted in an increase in faecal calprotectin-positive tests. Gastrointestinal bleeding should be considered as a potential cause of mild faecal calprotectin elevation > 50 µg/g; however, increased faecal calprotectin above > 250-300 µg/g, the established cut-off for relevant intestinal inflammation in patients with inflammatory bowel disease, is rare

Management of upper airway edema caused by hereditary angioedema

Hereditary angioedema is a rare disorder with a genetic background involving mutations in the genes encoding C1-INH and of factor XII. Its etiology is unknown in a proportion of cases. Recurrent edema formation may involve the subcutis and the submucosa - the latter can produce obstruction in the upper airways and thereby lead to life-threatening asphyxia. This is the reason for the high, 30-to 50-per-cent mortality of undiagnosed or improperly managed cases. Airway obstruction can be prevented through early diagnosis, meaningful patient information, timely recognition of initial symptoms, state-of-the-art emergency therapy, and close monitoring of the patient. Prophylaxis can substantially mitigate the risk of upper airway edema and also improve the patients' quality of life. Notwithstanding the foregoing, any form of upper airway edema should be regarded as a potentially life-threatening condition. None of the currently available prophylactic modalities is capable of preventing UAE with absolute certainty

The German National Registry of Primary Immunodeficiencies (2012-2017)

Introduction: The German PID-NET registry was founded in 2009, serving as the first national registry of patients with primary immunodeficiencies (PID) in Germany. It is part of the European Society for Immunodeficiencies (ESID) registry. The primary purpose of the registry is to gather data on the epidemiology, diagnostic delay, diagnosis, and treatment of PIDs. Methods: Clinical and laboratory data was collected from 2,453 patients from 36 German PID centres in an online registry. Data was analysed with the software Stata® and Excel. Results: The minimum prevalence of PID in Germany is 2.72 per 100,000 inhabitants. Among patients aged 1–25, there was a clear predominance of males. The median age of living patients ranged between 7 and 40 years, depending on the respective PID. Predominantly antibody disorders were the most prevalent group with 57% of all 2,453 PID patients (including 728 CVID patients). A gene defect was identified in 36% of patients. Familial cases were observed in 21% of patients. The age of onset for presenting symptoms ranged from birth to late adulthood (range 0–88 years). Presenting symptoms comprised infections (74%) and immune dysregulation (22%). Ninety-three patients were diagnosed without prior clinical symptoms. Regarding the general and clinical diagnostic delay, no PID had undergone a slight decrease within the last decade. However, both, SCID and hyper IgE- syndrome showed a substantial improvement in shortening the time between onset of symptoms and genetic diagnosis. Regarding treatment, 49% of all patients received immunoglobulin G (IgG) substitution (70%—subcutaneous; 29%—intravenous; 1%—unknown). Three-hundred patients underwent at least one hematopoietic stem cell transplantation (HSCT). Five patients had gene therapy. Conclusion: The German PID-NET registry is a precious tool for physicians, researchers, the pharmaceutical industry, politicians, and ultimately the patients, for whom the outcomes will eventually lead to a more timely diagnosis and better treatment

Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors

Background Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. Methods We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. Results Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. Conclusions Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.Peer reviewe

MUSiC : a model-unspecific search for new physics in proton-proton collisions at root s=13TeV

Results of the Model Unspecific Search in CMS (MUSiC), using proton-proton collision data recorded at the LHC at a centre-of-mass energy of 13 TeV, corresponding to an integrated luminosity of 35.9 fb(-1), are presented. The MUSiC analysis searches for anomalies that could be signatures of physics beyond the standard model. The analysis is based on the comparison of observed data with the standard model prediction, as determined from simulation, in several hundred final states and multiple kinematic distributions. Events containing at least one electron or muon are classified based on their final state topology, and an automated search algorithm surveys the observed data for deviations from the prediction. The sensitivity of the search is validated using multiple methods. No significant deviations from the predictions have been observed. For a wide range of final state topologies, agreement is found between the data and the standard model simulation. This analysis complements dedicated search analyses by significantly expanding the range of final states covered using a model independent approach with the largest data set to date to probe phase space regions beyond the reach of previous general searches.Peer reviewe

Measurement of prompt open-charm production cross sections in proton-proton collisions at root s=13 TeV

The production cross sections for prompt open-charm mesons in proton-proton collisions at a center-of-mass energy of 13TeV are reported. The measurement is performed using a data sample collected by the CMS experiment corresponding to an integrated luminosity of 29 nb(-1). The differential production cross sections of the D*(+/-), D-+/-, and D-0 ((D) over bar (0)) mesons are presented in ranges of transverse momentum and pseudorapidity 4 < p(T) < 100 GeV and vertical bar eta vertical bar < 2.1, respectively. The results are compared to several theoretical calculations and to previous measurements.Peer reviewe