Imputation of Orofacial Clefting Data Identifies Novel Risk Loci and Sheds Light on the Genetic Background of Cleft Lip ± Cleft Palate and Cleft Palate Only.

Abstract Nonsyndromic cleft lip with or without cleft palate (nsCL/P) is among the most common human birth defects with multifactorial etiology. Here, we present results from a genome-wide imputation study of nsCL/P in which, after adding replication cohort data, four novel risk loci for nsCL/P are identified (at chromosomal regions 2p21, 14q22, 15q24 and 19p13). On a systematic level, we show that the association signalswithin this high-density datasetare enriched in functionally-relevant genomic regions that are active in both human neural crest cells (hNCC) and mouse embryonic craniofacial tissue. This enrichment is also detectable in hNCC regions primed for later activity. Using GCTA analyses, we suggest that 30% of the estimated variance in risk for nsCL/P in the European population can be attributed to common variants, with 25.5% contributed to by the 24 risk loci known to date. For each of these, we identify credible SNPs using a Bayesian refinementapproach, with two loci harbouring only one probable causal variant. Finally, we demonstrate that there is no polygenic component of nsCL/P detectable that is shared with nonsyndromic cleft palate only (nsCPO). Our data suggest that, while common variants are strongly contributing to risk for nsCL/P, they do not seem to be involved in nsCPO which might be more often caused by rare deleterious variants. Our study generates novel insights into both nsCL/P and nsCPO etiology and provides a systematic framework for research into craniofacial development and malformation

Meta-analysis Reveals Genome-Wide Significance at 15q13 for Nonsyndromic Clefting of Both the Lip and the Palate, and Functional Analyses Implicate GREM1 As a Plausible Causative Gene

Nonsyndromic orofacial clefts are common birth defects with multifactorial etiology. The most common type is cleft lip, which occurs with or without cleft palate (nsCLP and nsCLO, respectively). Although genetic components play an important role in nsCLP, the genetic factors that predispose to palate involvement are largely unknown. In this study, we carried out a meta-analysis on genetic and clinical data from three large cohorts and identified strong association between a region on chromosome 15q13 and nsCLP (P = 8.13×10−14 for rs1258763; relative risk (RR): 1.46, 95% confidence interval (CI): 1.32–1.61)) but not nsCLO (P = 0.27; RR: 1.09 (0.94–1.27)). The 5 kb region of strongest association maps downstream of Gremlin-1 (GREM1), which encodes a secreted antagonist of the BMP4 pathway. We show during mouse embryogenesis, Grem1 is expressed in the developing lip and soft palate but not in the hard palate. This is consistent with genotype-phenotype correlations between rs1258763 and a specific nsCLP subphenotype, since a more than two-fold increase in risk was observed in patients displaying clefts of both the lip and soft palate but who had an intact hard palate (RR: 3.76, CI: 1.47–9.61, Pdiff<0.05). While we did not find lip or palate defects in Grem1-deficient mice, wild type embryonic palatal shelves developed divergent shapes when cultured in the presence of ectopic Grem1 protein (P = 0.0014). The present study identified a non-coding region at 15q13 as the second, genome-wide significant locus specific for nsCLP, after 13q31. Moreover, our data suggest that the closely located GREM1 gene contributes to a rare clinical nsCLP entity. This entity specifically involves abnormalities of the lip and soft palate, which develop at different time-points and in separate anatomical regions.Clefts of the lip and palate are common birth defects, and require long-term multidisciplinary management. Their etiology involves genetic factors and environmental influences and/or a combination of both, however, these interactions are poorly defined. Moreover, although clefts of the lip may or may not involve the palate, the determinants predisposing to specific subphenotypes are largely unknown. Here we demonstrate that variations in the non-coding region near the GREM1 gene show a highly significant association with a particular phenotype in which cleft lip and cleft palate co-occ

Frühmobilisation auf der Intensivstation : sind robotergestützte Systeme die Zukunft?

'''Hintergrund:''' Bei etwa 43% aller Überlebenden der Intensivmedizin wird ein erworbenes Syndrom an Muskelschwäche beobachtet, welches Überleben und Lebensqualität vermindert. Da kausale Therapieoptionen bisher fehlen, stehen die Vermeidung der bekannten Risikofaktoren und Frühmobilisation im Vordergrund. Robotische Unterstützungssysteme werden vermehrt in der Mobilisation erprobt. '''Ziel der Arbeit:''' In diesem Übersichtsartikel wird die aktuelle Evidenz von Frühmobilisation von kritisch Kranken zusammengefasst und der Stellenwert robotischer Assistenzsysteme für Mobilisation diskutiert. '''Ergebnisse:''' Mobilisation sollte auf der Intensivstation nachMöglichkeit früh begonnen werden. Hierunter wird der Beginn in den ersten 72 h nach der Aufnahme auf die Intensivstation verstanden. Physiotherapeutische Interventionen während des Intensivaufenthalts zeigen positive Effekte auf die Lebensqualität von PatientInnen, auf die Dauer von invasiver Beatmung, Intensivaufenthalt und Delir. Strukturierte Behandlungsprotokolle führen zu mehr aktiver Mobilisation, höherer Mobilität und häufigerer funktioneller Unabhängigkeit bei Entlassung aus dem Krankenhaus. Nach Schlaganfällen erhöhen zusätzliche robotergestützte Therapieeinheiten insbesondere bei stärker eingeschränkten PatientInnen die Rate an Rückkehrern zum selbstständigen Gehen, scheinen sicher und verbesserten in kleinen Studien Muskelkraft und Lebensqualität. '''Schlussfolgerung:''' Frühmobilisation verbessert das Outcome von kritisch Erkrankten. Robotische Systeme unterstützen das Gangtraining nach einem Schlaganfall und werden auf der Intensivstation in ersten Studien zu Vertikalisierung und Frühmobilisation untersucht