Obesity and Longer Term Risks of Dementia in 65-74 Year Olds

Background: overweight or obesity at ages <65 years associates with increased dementia incidence, but at ≥65 years estimates are paradoxical. Weight loss before dementia diagnosis, plus smoking and diseases causing weight loss may confound associations. Objective: to estimate weight loss before dementia diagnosis, plus short and longer-term body mass index associations with incident dementia in 65-74 year olds within primary care populations in England. Methods: we studied dementia diagnosis free subjects: 257,523 non-smokers without baseline cancer, heart failure or multi-morbidity (group A) plus 161,927 with these confounders (group B), followed ≤14.9 years. Competing hazard models accounted for mortality. Results: in group A, 9,774 were diagnosed with dementia and in those with repeat weight measures, 54% lost ≥2.5 kg during 10 years pre-diagnosis. During <10 years obesity (≥30.0 kg/m2) or overweight (25.0 to <30.0) were inversely associated with incident dementia (versus 22.5 to <25.0). However, from 10 to 14.9 years, obesity was associated with increased dementia incidence (hazard ratio [HR] 1.17; 95% CI: 1.03-1.32). Overweight protective associations disappeared in longer-term analyses (HR, 1.01; 95% CI: 0.90-1.13). In group B, (n = 6,070 with incident dementia), obesity was associated with lower dementia risks in the short and longer-term. Conclusions: in 65-74 year olds (free of smoking, cancer, heart failure or multi-morbidity at baseline) obesity associates with higher longer-term incidence of dementia. Paradoxical associations were present short-term and in those with likely confounders. Reports of protective effects of obesity or overweight on dementia risk in older groups may reflect biases, especially weight loss before dementia diagnosis.This article is freely available via Open Access. Click on the Publisher URL to access it via the publisher's site.Supported by the National Institute for Health Research School for Public Health Research (Ageing Well Programme) and the Intramural Research Program of the National Institutes of Health National Institute on Aging.published version, accepted version (12 month embargo), submitted versio

Optimally combining dynamical decoupling and quantum error correction

We show how dynamical decoupling (DD) and quantum error correction (QEC) can be optimally combined in the setting of fault tolerant quantum computing. To this end we identify the optimal generator set of DD sequences designed to protect quantum information encoded into stabilizer subspace or subsystem codes. This generator set, comprising the stabilizers and logical operators of the code, minimizes a natural cost function associated with the length of DD sequences. We prove that with the optimal generator set the restrictive local-bath assumption used in earlier work on hybrid DD-QEC schemes, can be significantly relaxed, thus bringing hybrid DD-QEC schemes, and their potentially considerable advantages, closer to realization.Comment: 6 pages, 1 figur

Epstein-Barr virus proteins EBNA3A and EBNA3C together induce expression of the oncogenic microRNA cluster miR-221/miR-222 and ablate expression of its target p57KIP2.

We show that two host-encoded primary RNAs (pri-miRs) and the corresponding microRNA (miR) clusters--widely reported to have cell transformation-associated activity--are regulated by EBNA3A and EBNA3C. Utilising a variety of EBV-transformed lymphoblastoid cell lines (LCLs) carrying knockout-, revertant- or conditional-EBV recombinants, it was possible to demonstrate unambiguously that EBNA3A and EBNA3C are both required for transactivation of the oncogenic miR-221/miR-222 cluster that is expressed at high levels in multiple human tumours--including lymphoma/leukemia. ChIP, ChIP-seq, and chromosome conformation capture analyses indicate that this activation results from direct targeting of both EBV proteins to chromatin at the miR-221/miR-222 genomic locus and activation via a long-range interaction between enhancer elements and the transcription start site of a long non-coding pri-miR located 28 kb upstream of the miR sequences. Reduced levels of miR-221/miR-222 produced by inactivation or deletion of EBNA3A or EBNA3C resulted in increased expression of the cyclin-dependent kinase inhibitor p57KIP2, a well-established target of miR-221/miR-222. MiR blocking experiments confirmed that miR-221/miR-222 target p57KIP2 expression in LCLs. In contrast, EBNA3A and EBNA3C are necessary to silence the tumour suppressor cluster miR-143/miR-145, but here ChIP-seq suggests that repression is probably indirect. This miR cluster is frequently down-regulated or deleted in human cancer, however, the targets in B cells are unknown. Together these data indicate that EBNA3A and EBNA3C contribute to B cell transformation by inhibiting multiple tumour suppressor proteins, not only by direct repression of protein-encoding genes, but also by the manipulation of host long non-coding pri-miRs and miRs

Specific staining of human chromosomes in Chinese hamster x man hybrid cell lines demonstrates interphase chromosome territories

In spite of Carl Rabl's (1885) and Theodor Boveri's (1909) early hypothesis that chromosomes occupy discrete territories or domains within the interphase nucleus, evidence in favor pf this hypothesis has been limited and indirect so far in higher plants and animals. The alternative possibility that the chromatin fiber of single chromosomes might be extended throughout the major part of even the whole interphase nucleus has been considered for many years. In the latter case, chromosomes would only exist as discrete chromatin bodies during mitosis but not during interphase. Both possibilities are compatible with Boveri's well established paradigm of chromosome individuality. Here we show that an active human X chromosome contained as the only human chromosome in a Chinese hamster x man hybrid cell line can be visualized both in metaphse plates and in interphase nuclei after in situ hybridization with either 3H- or biotin-labeled human genomic DNA. We demonstrate that this chromosome is organized as a distinct chromatin body throughout interphase. In addition, evidence for the territorial organization of human chromosomes is also presented for another hybrid cell line containing several autosomes and the human X chromosome. These findings are discussed in the context of our present knowledge of the organization and topography of interphase chromosomes. General applications of a strategy aimed at specific staining of individual chromosomes in experimental and clinical cytogenetics are briefly considered

Central adiposity and the overweight risk paradox in aging: follow-up of 130,473 UK Biobank participants

This is the final version of the article. Available from American Society for Nutrition via the DOI in this record.Background: For older groups, being overweight [body mass index (BMI; in kg/m(2)): 25 to <30] is reportedly associated with a lower or similar risk of mortality than being normal weight (BMI: 18.5 to <25). However, this "risk paradox" is partly explained by smoking and disease-associated weight loss. This paradox may also arise from BMI failing to measure fat redistribution to a centralized position in later life.Objective: This study aimed to estimate associations between combined measurements of BMI and waist-to-hip ratio (WHR) with mortality and incident coronary artery disease (CAD).Design: This study followed 130,473 UK Biobank participants aged 60-69 y (baseline 2006-2010) for ≤8.3 y (n = 2974 deaths). Current smokers and individuals with recent or disease-associated (e.g., from dementia, heart failure, or cancer) weight loss were excluded, yielding a "healthier agers" group. Survival models were adjusted for age, sex, alcohol intake, smoking history, and educational attainment. Population and sex-specific lower and higher WHR tertiles were <0.91 and ≥0.96 for men and <0.79 and ≥0.85 for women, respectively.Results: Ignoring WHR, the risk of mortality for overweight subjects was similar to that for normal-weight subjects (HR: 1.09; 95% CI: 0.99, 1.19; P = 0.066). However, among normal-weight subjects, mortality increased for those with a higher WHR (HR: 1.33; 95% CI: 1.08, 1.65) compared with a lower WHR. Being overweight with a higher WHR was associated with substantial excess mortality (HR: 1.41; 95% CI: 1.25, 1.61) and greatly increased CAD incidence (sub-HR: 1.64; 95% CI: 1.39, 1.93) compared with being normal weight with a lower WHR. There was no interaction between physical activity and BMI plus WHR groups with respect to mortality.Conclusions: For healthier agers (i.e., nonsmokers without disease-associated weight loss), having central adiposity and a BMI corresponding to normal weight or overweight is associated with substantial excess mortality. The claimed BMI-defined overweight risk paradox may result in part from failing to account for central adiposity, rather than reflecting a protective physiologic effect of higher body-fat content in later life.AB reported grants from the UK National Institute for Health Research (NIHR) School for Public Health Research (Ageing Well Programme) during the conduct of the study and was an employee of Pfizer Italia until November 2012.Supported by UK Medical Research Council award MR/M023095/1 to DM, the National Institute for Health Research School for Public Health Research Ageing Well Programme (partnership), and the Intramural Research Program of the NIH National Institute on Aging

Central adiposity and the overweight risk paradox in aging: follow-up of 130,473 UK Biobank participants

This is the final version of the article. Available from American Society for Nutrition via the DOI in this record.Background: For older groups, being overweight [body mass index (BMI; in kg/m(2)): 25 to <30] is reportedly associated with a lower or similar risk of mortality than being normal weight (BMI: 18.5 to <25). However, this "risk paradox" is partly explained by smoking and disease-associated weight loss. This paradox may also arise from BMI failing to measure fat redistribution to a centralized position in later life.Objective: This study aimed to estimate associations between combined measurements of BMI and waist-to-hip ratio (WHR) with mortality and incident coronary artery disease (CAD).Design: This study followed 130,473 UK Biobank participants aged 60-69 y (baseline 2006-2010) for ≤8.3 y (n = 2974 deaths). Current smokers and individuals with recent or disease-associated (e.g., from dementia, heart failure, or cancer) weight loss were excluded, yielding a "healthier agers" group. Survival models were adjusted for age, sex, alcohol intake, smoking history, and educational attainment. Population and sex-specific lower and higher WHR tertiles were <0.91 and ≥0.96 for men and <0.79 and ≥0.85 for women, respectively.Results: Ignoring WHR, the risk of mortality for overweight subjects was similar to that for normal-weight subjects (HR: 1.09; 95% CI: 0.99, 1.19; P = 0.066). However, among normal-weight subjects, mortality increased for those with a higher WHR (HR: 1.33; 95% CI: 1.08, 1.65) compared with a lower WHR. Being overweight with a higher WHR was associated with substantial excess mortality (HR: 1.41; 95% CI: 1.25, 1.61) and greatly increased CAD incidence (sub-HR: 1.64; 95% CI: 1.39, 1.93) compared with being normal weight with a lower WHR. There was no interaction between physical activity and BMI plus WHR groups with respect to mortality.Conclusions: For healthier agers (i.e., nonsmokers without disease-associated weight loss), having central adiposity and a BMI corresponding to normal weight or overweight is associated with substantial excess mortality. The claimed BMI-defined overweight risk paradox may result in part from failing to account for central adiposity, rather than reflecting a protective physiologic effect of higher body-fat content in later life.AB reported grants from the UK National Institute for Health Research (NIHR) School for Public Health Research (Ageing Well Programme) during the conduct of the study and was an employee of Pfizer Italia until November 2012.Supported by UK Medical Research Council award MR/M023095/1 to DM, the National Institute for Health Research School for Public Health Research Ageing Well Programme (partnership), and the Intramural Research Program of the NIH National Institute on Aging

Energy dependence of kaon production in central Pb+Pb collisions

Recent results from the NA49 experiment on the energy dependence of charged kaon production in central Pb+Pb collisions are presented. First results from the new data at 80 AGeV beam energy are compared with those from lower and higher energies. A difference in the energy dependence of the / and / ratios is observed. The / ratio shows a non-monotonic behaviour with a maximum near 40 AGeV.Comment: 8 pages, 7 figures, proceedings of talk at SQM2001, Frankfurt, Germany, to appear in J. Phys.

Long-time Low-latency Quantum Memory by Dynamical Decoupling

Quantum memory is a central component for quantum information processing devices, and will be required to provide high-fidelity storage of arbitrary states, long storage times and small access latencies. Despite growing interest in applying physical-layer error-suppression strategies to boost fidelities, it has not previously been possible to meet such competing demands with a single approach. Here we use an experimentally validated theoretical framework to identify periodic repetition of a high-order dynamical decoupling sequence as a systematic strategy to meet these challenges. We provide analytic bounds-validated by numerical calculations-on the characteristics of the relevant control sequences and show that a "stroboscopic saturation" of coherence, or coherence plateau, can be engineered, even in the presence of experimental imperfection. This permits high-fidelity storage for times that can be exceptionally long, meaning that our device-independent results should prove instrumental in producing practically useful quantum technologies.Comment: abstract and authors list fixe

Sex chromosome positions in human interphase nuclei as studied by in situ hybridization with chromosome specific DNA probes

Two cloned repetitive DNA probes, pXBR and CY1, which bind preferentially to specific regions of the human X and Y chromosome, respectively, were used to study the distribution of the sex chromosomes in human lymphocyte nuclei by in situ hybridization experiments. Our data indicate a large variability of the distances between the sex chromosomes in male and female interphase nuclei. However, the mean distance observed between the X and Y chromosome was significantly smaller than the mean distance observed between the two X-chromosomes. The distribution of distances determined experimentally is compared with three model distributions of distances, and the question of a non-random distribution of sex chromosomes is discussed. Mathematical details of these model distributions are provided in an Appendix to this paper. In the case of a human translocation chromosome (XqterXp22.2::Yq11Y qter) contained in the Chinese hamster x human hybrid cell line 445 x 393, the binding sites of pXBR and CY1 were found close to each other in most interphase nuclei. These data demonstrate the potential use of chromosome-specific repetitive DNA probes to study the problem of interphase chromosome topography