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Purpose: Advanced Ewing sarcomas have poor prognosis. They are defined by early relapse (<24 months after diagnosis) and/or by metastasis to multiple bones or bone marrow (BM). We analyzed risk factors, toxicity and survival in advanced Ewing sarcoma patients treated with the MetaEICESS vs. EICESS92 protocols.
Design: Of 44 patients, 18 patients were enrolled into two subsequent MetaEICESS protocols between 1992 and 2014, and compared to outcomes of 26 advanced Ewing sarcoma patients treated with EICESS 1992 between 1992 and 1996. MetaEICESS 1992 consisted of induction chemotherapy, whole body imaging directed radiotherapy to the primary tumor and metastases, tandem high-dose chemotherapy and autologous rescue. In MetaEICESS 2007 this treatment was complemented by allogeneic stem cell transplantation. EICESS 1992 comprised induction chemotherapy, local therapy to the primary tumor only followed by consolidation chemotherapy.
Results: In MetaEICESS 8/18 patients survived in complete remission vs. 2/26 in EICESS 1992 (p<0.05). Survival did not differ between MetaEICESS 2007 and MetaEICESS 1992. Three MetaEICESS patients died of complications, all in MetaEICESS 1992. After exclusion of patients succumbing to treatment related complications (n=3), 7/10 patients survived without BM involvement, in contrast to 0/5 patients with BM involvement. This was confirmed in a multivariate analysis. There was no correlation between BM involvement and the number of metastases at diagnosis.
Conclusion: The MetaEICESS protocols yield long-term disease-free survival in patients with advanced Ewing sarcoma. Allogeneic stem cell transplantation was not associated with increased death of complications. Bone marrow involvement is a risk factor distinct from multiple bone metastases.
Background: There is an urgent need for expanding and enhancing autism spectrum disorder (ASD) samples, in order to better understand causes of ASD.
Methods: In a unique public-private partnership, 13 sites with extensive experience in both the assessment and diagnosis of ASD embarked on an ambitious, 2-year program to collect samples for genetic and phenotypic research and begin analyses on these samples. The program was called The Autism Simplex Collection (TASC). TASC sample collection began in 2008 and was completed in 2010, and included nine sites from North America and four sites from Western Europe, as well as a centralized Data Coordinating Center.
Results: Over 1,700 trios are part of this collection, with DNA from transformed cells now available through the National Institute of Mental Health (NIMH). Autism Diagnostic Interview-Revised (ADI-R) and Autism Diagnostic Observation Schedule-Generic (ADOS-G) measures are available for all probands, as are standardized IQ measures, Vineland Adaptive Behavioral Scales (VABS), the Social Responsiveness Scale (SRS), Peabody Picture Vocabulary Test (PPVT), and physical measures (height, weight, and head circumference). At almost every site, additional phenotypic measures were collected, including the Broad Autism Phenotype Questionnaire (BAPQ) and Repetitive Behavior Scale-Revised (RBS-R), as well as the non-word repetition scale, Communication Checklist (Children's or Adult), and Aberrant Behavior Checklist (ABC). Moreover, for nearly 1,000 trios, the Autism Genome Project Consortium (AGP) has carried out Illumina 1 M SNP genotyping and called copy number variation (CNV) in the samples, with data being made available through the National Institutes of Health (NIH). Whole exome sequencing (WES) has been carried out in over 500 probands, together with ancestry matched controls, and this data is also available through the NIH. Additional WES is being carried out by the Autism Sequencing Consortium (ASC), where the focus is on sequencing complete trios. ASC sequencing for the first 1,000 samples (all from whole-blood DNA) is complete and data will be released in 2014. Data is being made available through NIH databases (database of Genotypes and Phenotypes (dbGaP) and National Database for Autism Research (NDAR)) with DNA released in Dist 11.0. Primary funding for the collection, genotyping, sequencing and distribution of TASC samples was provided by Autism Speaks and the NIH, including the National Institute of Mental Health (NIMH) and the National Human Genetics Research Institute (NHGRI).
Conclusions: TASC represents an important sample set that leverages expert sites. Similar approaches, leveraging expert sites and ongoing studies, represent an important path towards further enhancing available ASD samples.
The N-terminus of the hepatitis B virus (HBV) large surface protein (LHB) differs with respect to genotypes. Compared to the amino terminus of genotype (Gt)D, in GtA, GtB and GtC, an additional identical 11 amino acids (aa) are found, while GtE and GtG share another similar 10 aa. Variants of GtB and GtC affecting this N-terminal part are associated with hepatoma formation. Deletion of these amino-terminal 11 aa in GtA reduces the amount of LHBs and changes subcellular accumulation (GtA-like pattern) to a dispersed distribution (GtD-like pattern). Vice versa, the fusion of the GtA-derived N-terminal 11 aa to GtD causes a GtA-like phenotype. However, insertion of the corresponding GtE-derived 10 aa to GtD has no effect. Deletion of these 11aa decreases filament size while neither the number of released viral genomes nor virion size and infectivity are affected. A negative regulatory element (aa 2–8) and a dominant positive regulatory element (aa 9–11) affecting the amount of LHBs were identified. The fusion of this motif to eGFP revealed that the effect on protein amount and subcellular distribution is not restricted to LHBs. These data identify a novel region in the N-terminus of LHBs affecting the amount and subcellular distribution of LHBs and identify release-promoting and -inhibiting aa residues within this motive.
Attention-deficit/hyperactivity disorder (ADHD) is often accompanied by problems in social behaviour, which are sometimes similar to some symptoms of autism-spectrum disorders (ASD). However, neuronal mechanisms of ASD-like deficits in ADHD have rarely been studied. The processing of biological motion–recently discussed as a marker of social cognition–was found to be disrupted in ASD in several studies. Thus in the present study we tested if biological motion processing is disrupted in ADHD. We used 64-channel EEG and spatio-temporal source analysis to assess event-related potentials associated with human motion processing in 21 children and adolescents with ADHD and 21 matched typically developing controls. On the behavioural level, all subjects were able to differentiate between human and scrambled motion. But in response to both scrambled and biological motion, the N200 amplitude was decreased in subjects with ADHD. After a spatio-temporal dipole analysis, a human motion specific activation was observable in occipital-temporal regions with a reduced and more diffuse activation in ADHD subjects. These results point towards neuronal determined alterations in the processing of biological motion in ADHD.
Simple cells in primary visual cortex were famously found to respond to low-level image components such as edges. Sparse coding and independent component analysis (ICA) emerged as the standard computational models for simple cell coding because they linked their receptive fields to the statistics of visual stimuli. However, a salient feature of image statistics, occlusions of image components, is not considered by these models. Here we ask if occlusions have an effect on the predicted shapes of simple cell receptive fields. We use a comparative approach to answer this question and investigate two models for simple cells: a standard linear model and an occlusive model. For both models we simultaneously estimate optimal receptive fields, sparsity and stimulus noise. The two models are identical except for their component superposition assumption. We find the image encoding and receptive fields predicted by the models to differ significantly. While both models predict many Gabor-like fields, the occlusive model predicts a much sparser encoding and high percentages of ‘globular’ receptive fields. This relatively new center-surround type of simple cell response is observed since reverse correlation is used in experimental studies. While high percentages of ‘globular’ fields can be obtained using specific choices of sparsity and overcompleteness in linear sparse coding, no or only low proportions are reported in the vast majority of studies on linear models (including all ICA models). Likewise, for the here investigated linear model and optimal sparsity, only low proportions of ‘globular’ fields are observed. In comparison, the occlusive model robustly infers high proportions and can match the experimentally observed high proportions of ‘globular’ fields well. Our computational study, therefore, suggests that ‘globular’ fields may be evidence for an optimal encoding of visual occlusions in primary visual cortex.
We study the extrapolation of nuclear shell structure to the region of superheavy nuclei in self-consistent mean-field models—the Skyrme-Hartree-Fock approach and the relativistic mean-field model—using a large number of parametrizations which give similar results for stable nuclei but differ in detail. Results obtained with the folded-Yukawa potential which is widely used in macroscopic-macroscopic models are shown for comparison. We focus on differences in the isospin dependence of the spin-orbit interaction and the effective mass between the models and their influence on single-particle spectra. The predictive power of the mean-field models concerning single-particle spectra is discussed for the examples of 208Pb and the spin-orbit splittings of selected neutron and proton levels in 16O, 132Sn, and 208Pb. While all relativistic models give a reasonable description of spin-orbit splittings, all Skyrme interactions show a wrong trend with mass number. The spin-orbit splitting of heavy nuclei might be overestimated by 40%–80%, which exposes a fundamental deficiency of the current nonrelativistic models. In most cases the occurrence of spherical shell closures is found to be nucleon-number dependent. Spherical doubly magic superheavy nuclei are found at 184298114, 172292120, or 184310126 depending on the parametrization. The Z=114 proton shell closure, which is related to a large spin-orbit splitting of proton 2f states, is predicted only by forces which by far overestimate the proton spin-orbit splitting in 208Pb. The Z=120 and N=172 shell closures predicted by the relativistic models and some Skyrme interactions are found to be related to a central depression of the nuclear density distribution. This effect cannot appear in macroscopic-microscopic models or semiclassical approaches like the extended Thomas-Fermi-Strutinski integral approach which have a limited freedom for the density distribution only. In summary, our findings give a strong argument for 172292120 to be the next spherical doubly magic superheavy nucleus.
We investigate the structure of the potential energy surfaces of the superheavy nuclei 158258Fm100, 156264Hs108, 166278112, 184298114, and 172292120 within the framework of self-consistent nuclear models, i.e., the Skyrme-Hartree-Fock approach and the relativistic mean-field model. We compare results obtained with one representative parametrization of each model which is successful in describing superheavy nuclei. We find systematic changes as compared to the potential energy surfaces of heavy nuclei in the uranium region: there is no sufficiently stable fission isomer any more, the importance of triaxial configurations to lower the first barrier fades away, and asymmetric fission paths compete down to rather small deformation. Comparing the two models, it turns out that the relativistic mean-field model gives generally smaller fission barriers.
Background: In September 2018, Burkholderia cepacia complex (BCC) infections in 3 patients associated with exposure to a mouthwash solution (MWS) were reported to the Robert Koch Institute (RKI). As the product was still on the market and the scale of the outbreak was unclear, a nation-wide investigation was initiated.
Methods: We aimed to investigate BCC infections/colonizations associated with MWS. Hospitals, laboratories, and public health services were informed that BCC isolates should be sent to the RKI. These isolates were typed by pulsed-field gel electrophoresis (PFGE) and whole-genome sequencing (WGS) including development of an ad hoc core genome MLST (cgMLST) scheme.
Results: In total, 36 patients from 6 hospitals met the case definition, the last patient in November 2018. Twenty-nine isolates from 26 of these patients were available for typing. WGS analysis revealed 2 distinct cgMLST clusters. Cluster 1 (Burkholderia arboris) contained isolates from patients and MWS obtained from 4 hospitals and isolates provided by the manufacturer. Patient and MWS isolates from another hospital were assigned to cluster 2 (B. cepacia).
Conclusions: The combined clinical, epidemiological, and microbiological investigation, including whole-genome analysis, allowed for uncovering a supraregional BCC outbreak in health care settings. Strains of B. arboris and B. cepacia were identified as contaminating species of MWS bottles and subsequent colonization and putative infection of patients in several hospitals. Despite a recall of the product by the manufacturer in August 2018, the outbreak lasted until December 2018. Reporting of contaminated medical products and recalls should be optimized to protect patients.
Die Bestimmung von Lipoprotein(a) im Plasma mittels kinetischer Nephelometrie (Beckman Instruments) wurde mit einem immunoradiometrischen Assay (Mercodia) verglichen. Untersucht wurden 182 Proben in frischem Zustand und 18 Proben, die für kurze Zeit bei -25 °C gelagert waren. Die Meßergebnisse zeigen eine gute Übereinstimmung der Median werte (147 mg/1 bzw. 160 mg/1) und eine gute Korrelation bei den frischen und den eingefrorenen Proben (r = 0,971/rs= 0,985 bzw. r = 0,971). Die Variationskoeffizienten der Nephelometrie entsprechen mit 4.2% in der Serie (Intraassay) und 5,5-6,5% von Tag zu Tag (Interassay) den bisherigen Literaturwerten. Entgegen der Empfehlung, nur frisches Probenmaterial für die Nephelometrie einzusetzen, wurde bei einer Probe mit einer hohen Lipoprotein(a) Konzentration (960 mg/1) über 5 Wochen keine bedeutende Abnahme der Meßwerte registriert. Um den Einfluß der Triglyzeridkonzentration auf die Lp(a) Bestimmung zu untersuchen, wurden sechs Plasmaproben mit Triglyzeridwerten > 5,75 mmol/1 ausgewählt und in verschiedenen Verdünnungen mit Triglyzeridkonzentrationen zwischen 3,45-8,05 mmol/1 analysiert. Während 4 Proben keinen Einfluß der Triglyzeridkonzentration zeigten, wurde bei 2 Proben ein geringer Abfall der Lipoprotein(a) Meßwerte mit steigender Triglyzeridkonzentration beobachtet.