Results of the MAJORANA DEMONSTRATOR's Search for Double-Beta Decay of 76Ge to Excited States of 76Se

The MAJORANA DEMONSTRATOR is searching for double-beta decay of 76Ge to excited states (E.S.) in 76Se using a modular array of high purity Germanium detectors. 76Ge can decay into three E.S.s of 76Se. The E.S. decays have a clear event signature consisting of a ββ-decay with the prompt emission of one or two γ-rays, resulting in with high probability in a multi-site event. The granularity of the DEMONSTRATOR detector array enables powerful discrimination of this event signature from backgrounds. Using 21.3 kg-y of isotopic exposure, the DEMONSTRATOR has set world leading limits for each E.S. decay, with 90% CL lower half-life limits in the range of (0.56 2.1) ⋅ 1024 y. In particular, for the 2v transition to the first 0+ E.S. of 76Se, a lower half-life limit of 0.68 ⋅ 1024 at 90% CL was achieved

Glycogen Synthase Kinase (GSK) 3β phosphorylates and protects nuclear myosin 1c from proteasome-mediated degradation to activate rDNA transcription in early G1 cells

Nuclear myosin 1c (NM1) mediates RNA polymerase I (pol I) transcription activation and cell cycle progression by facilitating PCAF-mediated H3K9 acetylation, but the molecular mechanism by which NM1 is regulated remains unclear. Here, we report that at early G1 the glycogen synthase kinase (GSK) 3β phosphorylates and stabilizes NM1, allowing for NM1 association with the chromatin. Genomic analysis by ChIP-Seq showed that this mechanism occurs on the rDNA as active GSK3β selectively occupies the gene. ChIP assays and transmission electron microscopy in GSK3β-/- mouse embryonic fibroblasts indicated that at G1 rRNA synthesis is suppressed due to decreased H3K9 acetylation leading to a chromatin state incompatible with transcription. We found that GSK3β directly phosphorylates the endogenous NM1 on a single serine residue (Ser-1020) located within the NM1 C-terminus. In G1 this phosphorylation event stabilizes NM1 and prevents NM1 polyubiquitination by the E3 ligase UBR5 and proteasome-mediated degradation. We conclude that GSK3β-mediated phosphorylation of NM1 is required for pol I transcription activation

ADC Nonlinearity Correction for the Majorana Demonstrator

Imperfections in analog-to-digital conversion (ADC) cannot be ignored when signal digitization requirements demand both wide dynamic range and high resolution, as is the case for the Majorana Demonstrator 76Ge neutrinoless double-beta decay search. Enabling the experiment's high-resolution spectral analysis and efficient pulse shape discrimination required careful measurement and correction of ADC nonlinearities. A simple measurement protocol was developed that did not require sophisticated equipment or lengthy data-taking campaigns. A slope-dependent hysteresis was observed and characterized. A correction applied to digitized waveforms prior to signal processing reduced the differential and integral nonlinearities by an order of magnitude, eliminating these as dominant contributions to the systematic energy uncertainty at the double-beta decay Q value

Can AMP induce sputum eosinophils, even in subjects with complete asthma remission?

<p>Abstract</p> <p>Background</p> <p>The definition of <b>"</b>clinical asthma remission" is based on absence of symptoms and use of medication. However, in the majority of these subjects airway inflammation is still present when measured. In the present study we investigated whether "complete asthma remission", additionally defined by the absence of bronchial hyperresponsiveness (BHR) and the presence of a normal lung function, is associated with the absence of airway inflammation.</p> <p>Methods</p> <p>Patients with a former diagnosis of asthma and a positive histamine provocation test were re-examined to identify subjects with complete asthma remission (no asthma symptoms or medication, PC₂₀histamine > 32 mg/ml, FEV₁> 90% predicted). Patients with PC₂₀histamine ≤ 32 mg/ml were defined as current asthmatics and were divided in two groups, i.e. asthmatics with and without BHR to adenosine 5'monophoshate (AMP). Sputum induction was performed 1 week before and 1 hour after AMP provocation. Sputum induction and AMP provocation were previously shown to be sensitive markers of airway inflammation.</p> <p>Results</p> <p>Seven patients met criteria for complete asthma remission. Twenty-three were current asthmatics, including twelve without hyperresponsiveness to AMP. Subjects with complete asthma remission showed no AMP-induced sputum eosinophilia (median (range) 0.2 (0 - 4.6)% at baseline and 0.2 (0 - 2.6)% after AMP). After AMP, current asthmatics had a significant increase in sputum eosinophils (0.5 (0 - 26.0)% at baseline and 2.6 (0 - 32.0) % after AMP), as had the subgroup of current asthmatics without hyperresponsiveness to AMP (0.2 (0 - 1.8)% at baseline and 1.3 (0 - 6.3)% after AMP).</p> <p>Conclusions</p> <p>Subjects with complete asthma remission, in contrast to subjects with current asthma, do not respond with eosinophilic inflammation in sputum after AMP provocations. These data lend support to the usefulness of the definition of complete asthma remission.</p

Image informatics strategies for deciphering neuronal network connectivity

Brain function relies on an intricate network of highly dynamic neuronal connections that rewires dramatically under the impulse of various external cues and pathological conditions. Among the neuronal structures that show morphologi- cal plasticity are neurites, synapses, dendritic spines and even nuclei. This structural remodelling is directly connected with functional changes such as intercellular com- munication and the associated calcium-bursting behaviour. In vitro cultured neu- ronal networks are valuable models for studying these morpho-functional changes. Owing to the automation and standardisation of both image acquisition and image analysis, it has become possible to extract statistically relevant readout from such networks. Here, we focus on the current state-of-the-art in image informatics that enables quantitative microscopic interrogation of neuronal networks. We describe the major correlates of neuronal connectivity and present workflows for analysing them. Finally, we provide an outlook on the challenges that remain to be addressed, and discuss how imaging algorithms can be extended beyond in vitro imaging studies

Gross genomic damage measured by DNA image cytometry independently predicts gastric cancer patient survival

BACKGROUND: DNA aneuploidy reflects gross genomic changes. It can be measured by flow cytometry (FCM-DNA) or image cytometry (ICM-DNA). In gastric cancer, the prevalence of DNA aneuploidy has been reported to range from 27 to 100%, with conflicting associations with clinicopathological variables. The aim of our study was to compare the DNA ploidy status measured using FCM-DNA and ICM-DNA in gastric cancer and to evaluate its association with clinicopathological variables. METHODS: Cell nuclei were isolated from 221 formalin-fixed, paraffin-embedded gastric cancer samples. DNA ploidy was assessed using FCM-DNA and ICM-DNA. RESULTS: A total of 178 (80.5%) gastric cancer samples were classified as DNA aneuploid using FCM-DNA, compared with 172 (77.8%) gastric cancer samples when using ICM-DNA. Results obtained from both methods were concordant in 183 (82.8%) cases (kappa = 0.48). Patients with ICM-DNA diploid gastric cancer survived significantly longer than those with ICM-DNA aneuploid gastric cancer (log rank 10.1, P = 0.001). For FCM-DNA data, this difference did not reach statistical significance. The multivariate Cox model showed that ICM-DNA ploidy status predicted patient survival independently of tumour-node-metastasis status. CONCLUSION: ICM-DNA ploidy status is an independent predictor of survival in gastric cancer patients and may therefore be a more clinically relevant read out of gross genomic damage than FCM-DNA. British Journal of Cancer (2009) 101, 1011-1018. doi:10.1038/sj.bjc.6605266 www.bjcancer.com (C) 2009 Cancer Research U

Het Rijksvaccinatieprogramma in Nederland. Ontwikkelingen in 2006

In 2006 several changes were made in the Dutch National Immunisation Programme (NIP): Hepatitis B vaccination at birth was added for children born to mothers positive for hepatitis B surface antigen; a new vaccine for diphtheria, tetanus, pertussis (a-cellular), poliomyelitis and Haemophilus influenzae (DTaP-IPV/Hib) was introduced; vaccination against pneumococcal disease was added at two, three, four and eleven months; risk groups for hepatitis B receive a combined vaccine for DTaP-IPV/Hib and HBV at the same ages; DT-IPV and aP at the age of four years were combined in one vaccine; and new MMR vaccines were introduced. As new information became available in 2006, the desirability to introduce vaccinations in the NIP for the following diseases could be (re)considered: hepatitis B (universal vaccination), rotavirus, varicella and human papillomavirus. For respiratory syncytial virus and meningococcal serogroup B disease no candidate vaccines are available yet. Extension of the programme with available vaccines for hepatitis A, influenza and tuberculosis is not (yet) recommended. The NIP in the Netherlands is effective and safe. However, continued monitoring of the effectiveness and safety of the NIP is important as changes are made regularly. Maintaining high vaccine uptake is vital to prevent (re)emergence of diseases. Furthermore, the programme should be regularly reviewed as new vaccines become available.In 2006 traden verschillende veranderingen op in het Rijksvaccinatieprogramma (RVP) in Nederland: kinderen die geboren worden uit moeders die chronisch geinfecteerd zijn met hepatitis B krijgen vlak na de geboorte een hepatitis B vaccinatie; er is een ander vaccin geintroduceerd voor difterie, kinkhoest (a-cellulair), tetanus, poliomyelitis en Haemophilus influenzae (DaKTP/Hib); vaccinatie tegen pneumokokken is toegevoegd op de leeftijd van 2, drie, vier en elf maanden; risicogroepen voor hepatitis B krijgen op diezelfde leeftijden een combinatievaccin voor DaKTP/Hib en hepatitis B; DTP en aK zijn gecombineerd in een vaccin op vierjarige leeftijd; en er zijn nieuwe BMR vaccins geintroduceerd. Op basis van informatie die in 2006 beschikbaar is gekomen wordt geadviseerd de introductie van vaccinaties voor de volgende ziekten te overwegen: hepatitis B (universele vaccinatie), rotavirus, waterpokken en humaan papillomavirus. Voor respiratoir syncytieel virus en meningokokken B zijn nog geen kandidaatvaccins beschikbaar en uitbreiding van het RVP met beschikbare vaccins voor hepatitis A, influenza en tuberculose wordt nog niet aanbevolen. Het RVP is effectief en veilig, maar voortdurende bewaking hiervan is groot belang, omdat er regelmatig veranderingen optreden. Handhaven van de hoge vaccinatiegraad is essentieel om terugkeer van ziekten te voorkomen. Verder moet regelmatig bekeken worden of het RVP aangepast moet worden aangezien er steeds nieuwe vaccins beschikbaar komen

Time-dependent failure in load-bearing polymers: a potential hazard in structural applications of polylactides

With their excellent biocompatibility and relatively high mechanical strength, polylactides are attractive candidates for application in load-bearing, resorbable implants. Pre-clinical studies provided a proof of principle for polylactide cages as temporary constructs to facilitate spinal fusion, and several cages already made it to the market. However, also failures have been reported: clinical studies reported considerable amounts of subsidence with lumbar spinal fusion cages, and in an in vivo goat study, polylactide spinal cages failed after only three months of implantation, although mechanical testing had predicted sufficient strength for at least eight months. The failures appear to be related to the long-term performance of polylactides under static loading conditions, a phenomenon which is common to all glassy polymers and finds its origin in stress-activated molecular mobility leading to plastic flow. This paper reviews the mechanical properties and deformation kinetics of amorphous polylactides. Compression tests were performed with various strain rates, and static stress experiments were done to determine time-to failure. Pure PLLA appeared to have a higher yield strength than its co-polymers with d-lactide, but the kinetic behaviour of the polymers was the same: an excellent short-term strength at higher loading rates, but lifetime under static stress is rather poor. As spinal implants need to maintain mechanical integrity for a period of at least six months, this has serious implications for the clinical application of amorphous polylactides in load bearing situations. It is recommended that standards for mechanical testing of implants made of polymers be revised in order to consider this typical time-dependent behaviour

Distinct effects of rectum delineation methods in 3D-confromal vs. IMRT treatment planning of prostate cancer

BACKGROUND: The dose distribution to the rectum, delineated as solid organ, rectal wall and rectal surface, in 3D conformal (3D-CRT) and intensity-modulated radiotherapy treatment (IMRT) planning for localized prostate cancer was evaluated. MATERIALS AND METHODS: In a retrospective planning study 3-field, 4-field and IMRT treatment plans were analyzed for ten patients with localized prostate cancer. The dose to the rectum was evaluated based on dose-volume histograms of 1) the entire rectal volume (DVH) 2) manually delineated rectal wall (DWH) 3) rectal wall with 3 mm wall thickness (DWH(3)) 4) and the rectal surface (DSH). The influence of the rectal filling and of the seminal vesicles' anatomy on these dose parameters was investigated. A literature review of the dose-volume relationship for late rectal toxicity was conducted. RESULTS: In 3D-CRT (3-field and 4-field) the dose parameters differed most in the mid-dose region: the DWH showed significantly lower doses to the rectum (8.7% ± 4.2%) compared to the DWH(3 )and the DSH. In IMRT the differences between dose parameters were larger in comparison with 3D-CRT. Differences were statistically significant between DVH and all other dose parameters and between DWH and DSH. Mean doses were increased by 23.6% ± 8.7% in the DSH compared to the DVH in the mid-dose region. Furthermore, both the rectal filling and the anatomy of the seminal vesicles influenced the relationship between the dose parameters: a significant correlation of the difference between DVH and DWH and the rectal volume was seen in IMRT treatment. DISCUSSION: The method of delineating the rectum significantly influenced the dose representation in the dose-volume histogram. This effect was pronounced in IMRT treatment planning compared to 3D-CRT. For integration of dose-volume parameters from the literature into clinical practice these results have to be considered

Assessment of data quality in a multi-centre cross-sectional study of participation and quality of life of children with cerebral palsy

BACKGROUND: SPARCLE is a cross-sectional survey in nine European regions, examining the relationship of the environment of children with cerebral palsy to their participation and quality of life. The objective of this report is to assess data quality, in particular heterogeneity between regions, family and item non-response and potential for bias. METHODS: 1,174 children aged 8–12 years were selected from eight population-based registers of children with cerebral palsy; one further centre recruited 75 children from multiple sources. Families were visited by trained researchers who administered psychometric questionnaires. Logistic regression was used to assess factors related to family non-response and self-completion of questionnaires by children. RESULTS: 431/1,174 (37%) families identified from registers did not respond: 146 (12%) were not traced; of the 1,028 traced families, 250 (24%) declined to participate and 35 (3%) were not approached. Families whose disabled children could walk unaided were more likely to decline to participate. 818 children entered the study of which 500 (61%) self-reported their quality of life; children with low IQ, seizures or inability to walk were less likely to self-report. There was substantial heterogeneity between regions in response rates and socio-demographic characteristics of families but not in age or gender of children. Item non-response was 2% for children and ranged from 0.4% to 5% for questionnaires completed by parents. CONCLUSION: While the proportion of untraced families was higher than in similar surveys, the refusal rate was comparable. To reduce bias, all analyses should allow for region, walking ability, age and socio-demographic characteristics. The 75 children in the region without a population based register are unlikely to introduce bias