Designing prevention programmes to reduce incidence of dementia: prospective cohort study of modifiable risk factors

Objective To estimate the percentage reduction in incidence of dementia that would be obtained if specific risk factors were eliminated

Search for new resonant states in 10C and 11C and their impact on the cosmological lithium problem

The observed primordial 7Li abundance in metal-poor halo stars is found to be lower than its Big-Bang nucleosynthesis (BBN) calculated value by a factor of approximately three. Some recent works suggested the possibility that this discrepancy originates from missing resonant reactions which would destroy the 7Be, parent of 7Li. The most promising candidate resonances which were found include a possibly missed 1- or 2- narrow state around 15 MeV in the compound nucleus 10C formed by 7Be+3He and a state close to 7.8 MeV in the compound nucleus 11C formed by 7Be+4He. In this work, we studied the high excitation energy region of 10C and the low excitation energy region in 11C via the reactions 10B(3He,t)10C and 11B(3He,t)11C, respectively, at the incident energy of 35 MeV. Our results for 10C do not support 7Be+3He as a possible solution for the 7Li problem. Concerning 11C results, the data show no new resonances in the excitation energy region of interest and this excludes 7Be+4He reaction channel as an explanation for the 7Li deficit.Comment: Accepted for publication in Phys. Rev. C (Rapid Communication

Search for resonant states in 10C and 11C and their impact on the primordial 7Li abundance

The cosmological 7Li problem arises from the significant discrepancy of about a factor 3 between the predicted primordial 7Li abundance and the observed one. The main process for the production of 7Li during Big-Bang nucleosynthesis is the decay of 7Be. Many key nuclear reactions involved in the production and destruction of 7Be were investigated in attempt to explain the 7Li deficit but none of them led to successful conclusions. However, some authors suggested recently the possibility that the destruction of 7Be by 3He and 4He may reconcile the predictions and observations if missing resonant states in the compound nuclei 10C and 11C exist. Hence, a search of these missing resonant states in 10C and 11C was investigated at the Orsay Tandem-Alto facility through 10B(3He,t)10C and 11B(3He,t)11C charge-exchange reactions respectively. After a short overview of the cosmological 7Li problem from a nuclear physics point of view, a description of the Orsay experiment will be given as well as the obtained results and their impact on the 7Li problem

ATM regulates proteasome-dependent subnuclear localization of TRF1, which is important for telomere maintenance

Ataxia telangiectasia mutated (ATM), a PI-3 kinase essential for maintaining genomic stability, has been shown to regulate TRF1, a negative mediator of telomerase-dependent telomere extension. However, little is known about ATM-mediated TRF1 phosphorylation site(s) in vivo. Here, we report that ATM phosphorylates S367 of TRF1 and that this phosphorylation renders TRF1 free of chromatin. We show that phosphorylated (pS367)TRF1 forms distinct non-telomeric subnuclear foci and that these foci occur predominantly in S and G2 phases, implying that their formation is cell cycle regulated. We show that phosphorylated (pS367)TRF1-containing foci are sensitive to proteasome inhibition. We find that a phosphomimic mutation of S367D abrogates TRF1 binding to telomeric DNA and renders TRF1 susceptible to protein degradation. In addition, we demonstrate that overexpressed TRF1-S367D accumulates in the subnuclear domains containing phosphorylated (pS367)TRF1 and that these subnuclear domains overlap with nuclear proteasome centers. Taken together, these results suggest that phosphorylated (pS367)TRF1-containing foci may represent nuclear sites for TRF1 proteolysis. Furthermore, we show that TRF1 carrying the S367D mutation is unable to inhibit telomerase-dependent telomere lengthening or to suppress the formation of telomere doublets and telomere loss in TRF1-depleted cells, suggesting that S367 phosphorylation by ATM is important for the regulation of telomere length and stability

Use of CNS medications and cognitive decline in the aged: a longitudinal population-based study

<p>Abstract</p> <p>Background</p> <p>Previous studies have found associations between the use of central nervous system medication and the risk of cognitive decline in the aged. Our aim was to assess whether the use of a single central nervous system (CNS) medication and, on the other hand, the combined use of multiple CNS medications over time are related to the risk of cognitive decline in an older (≥ 65 yrs) population that is cognitively intact at baseline.</p> <p>Methods</p> <p>We conducted a longitudinal population-based study of cognitively intact older adults. The participants were 65 years old or older and had Mini-Mental State Examination (MMSE) sum scores of 24 points or higher. The study included a 7.6-year follow-up. The use of benzodiazepines and related drugs (BZDs), antipsychotics (APs), antidepressants (ADs), opioids (Ops), anticholinergics (AChs) and antiepileptics (AEs) was determined at baseline and after a 7.6-years of the follow-up period. Cognitive functioning was used as an outcome variable measured with MMSE at baseline and at the mean follow-up of 7.6 years. Control variables were adjusted with analyses of covariance.</p> <p>Results</p> <p>After adjusting for control variables, the use of Ops and the concomitant use of Ops and BZDs as well as the use of Ops and any CNS medication were associated with cognitive decline. The use of AChs was associated with decline in cognitive functioning only in men.</p> <p>Conclusions</p> <p>Of all the CNS medications analyzed in this study, the use of Ops may have the greatest effect on cognitive functioning in the ageing population. Due to small sample sizes these findings cannot be generalized to the unselected ageing population. More studies are needed concerning the long-term use of CNS medications, especially their concomitant use, and their potential cognitive effects.</p

Study of the 26Al(n,p)26Mg and 26Al(n,α)23Na reactions using the 27Al(p,p')27Al inelastic scattering reaction

26Al was the first cosmic radioactivity ever detected in the galaxy as well as one of the first extinct radioactivity observed in refractory phases of meteorites. Its nucleosynthesis in massive stars is still uncertain mainly due to the lack of nuclear information concerning the 26Al(n,p)26Mg and 26 Al(n,α)23Na reactions. We report on a single and coincidence measurement of the 27Al(p,p')27Al(p)26Mg and 27Al(p,p')27Al(α)23Na reactions performed at the Orsay TANDEM facility aiming at the spectroscopy study of 27Al above the neutron threshold. Fourteen states are observed for the first time within 350 keV above the 26Al+n threshold

Psychotropic drugs and the risk of fractures in old age: a prospective population-based study

<p>Abstract</p> <p>Background</p> <p>There is evidence that the use of any psychotropic and the concomitant use of two or more benzodiazepines are related to an increased risk of fractures in old age. However, also controversial results exist. The aim was to describe associations between the use of a psychotropic drug, or the concomitant use of two or more of these drugs and the risk of fractures in a population aged 65 years or over.</p> <p>Methods</p> <p>This study was a part of a prospective longitudinal population-based study carried out in the municipality of Lieto, South-Western Finland. The objective was to describe gender-specific associations between the use of one psychotropic drug [benzodiazepine (BZD), antipsychotic (AP) or antidepressant (AD)] or the concomitant use of two or more psychotropic drugs and the risk of fractures in a population 65 years or over. Subjects were participants in the first wave of the Lieto study in 1990-1991, and they were followed up until the end of 1996. Information about fractures confirmed with radiology reports in 1,177 subjects (482 men and 695 women) during the follow-up was collected from medical records. Two follow-up periods (three and six years) were used, and previously found risk factors of fractures were adjusted as confounding factors separately for men and women. The Poisson regression model was used in the analyses.</p> <p>Results</p> <p>The concomitant use of two or more BZDs and the concomitant use of two or more APs were related to an increased risk of fractures during both follow-up periods after adjusting for confounding factors in men. No similar associations were found in women.</p> <p>Conclusions</p> <p>The concomitant use of several BZDs and that of several APs are associated with an increase in the risk of fractures in older men. Our findings show only risk relations. We cannot draw the conclusion that these drug combinations are causes of fractures.</p

Application of machine learning methods to histone methylation ChIP-Seq data reveals H4R3me2 globally represses gene expression

<p>Abstract</p> <p>Background</p> <p>In the last decade, biochemical studies have revealed that epigenetic modifications including histone modifications, histone variants and DNA methylation form a complex network that regulate the state of chromatin and processes that depend on it including transcription and DNA replication. Currently, a large number of these epigenetic modifications are being mapped in a variety of cell lines at different stages of development using high throughput sequencing by members of the ENCODE consortium, the NIH Roadmap Epigenomics Program and the Human Epigenome Project. An extremely promising and underexplored area of research is the application of machine learning methods, which are designed to construct predictive network models, to these large-scale epigenomic data sets.</p> <p>Results</p> <p>Using a ChIP-Seq data set of 20 histone lysine and arginine methylations and histone variant H2A.Z in human CD4⁺T-cells, we built predictive models of gene expression as a function of histone modification/variant levels using Multilinear (ML) Regression and Multivariate Adaptive Regression Splines (MARS). Along with extensive crosstalk among the 20 histone methylations, we found H4R3me2 was the most and second most globally repressive histone methylation among the 20 studied in the ML and MARS models, respectively. In support of our finding, a number of experimental studies show that PRMT5-catalyzed symmetric dimethylation of H4R3 is associated with repression of gene expression. This includes a recent study, which demonstrated that H4R3me2 is required for DNMT3A-mediated DNA methylation--a known global repressor of gene expression.</p> <p>Conclusion</p> <p>In stark contrast to univariate analysis of the relationship between H4R3me2 and gene expression levels, our study showed that the regulatory role of some modifications like H4R3me2 is masked by confounding variables, but can be elucidated by multivariate/systems-level approaches.</p

The Individual Blood Cell Telomere Attrition Rate Is Telomere Length Dependent

Age-associated telomere shortening is a well documented feature of peripheral blood cells in human population studies, but it is not known to what extent these data can be transferred to the individual level. Telomere length (TL) in two blood samples taken at ∼10 years interval from 959 individuals was investigated using real-time PCR. TL was also measured in 13 families from a multigenerational cohort. As expected, we found an age-related decline in TL over time (r = –0.164, P<0.001, n = 959). However, approximately one-third of the individuals exhibited a stable or increased TL over a decade. The individual telomere attrition rate was inversely correlated with initial TL at a highly significant level (r = –0.752, P<0.001), indicating that the attrition rate was most pronounced in individuals with long telomeres at baseline. In accordance, the age-associated telomere attrition rate was more prominent in families with members displaying longer telomeres at a young age (r = –0.691, P<0.001). Abnormal blood TL has been reported at diagnosis of various malignancies, but in the present study there was no association between individual telomere attrition rate or prediagnostic TL and later tumor development. The collected data strongly suggest a TL maintenance mechanism acting in vivo, providing protection of short telomeres as previously demonstrated in vitro. Our findings might challenge the hypothesis that individual TL can predict possible life span or later tumor development

Hormone Treatment, Estrogen Receptor Polymorphisms and Mortality: A Prospective Cohort Study

International audienceBACKGROUND: The association between hormone treatment (HT) and mortality remains controversial. This study aimed to determine whether the risk of mortality associated with HT use varies depending on the specific characteristics of treatment and genetic variability in terms of the estrogen receptor. METHODOLOGY/PRINCIPAL FINDINGS: A prospective, population-based study of 5135 women aged 65 years and older who were recruited from three cities in France and followed over six years. Detailed information related to HT use was obtained and five estrogen receptor polymorphisms were genotyped. The total follow-up was 25,436 person-years and during this time 352 women died. Cancer (36.4%) and cardiovascular disease (19.3%) were the major causes of death. Cox proportional hazards models adjusted for age, education, centre, living situation, comorbidity, depression, physical and mental incapacities, indicated no significant association between HT and mortality, regardless of the type or duration of treatment, or the age at initiation. However, the association between HT and all-cause or cancer-related mortality varied across women, with significant interactions identified with three estrogen receptor polymorphisms (p-values = 0.004 to 0.03) in adjusted analyses. Women carrying the C allele of ESR1 rs2234693 had a decreased risk of all-cause mortality with HT (HR: 0.42, 95% CI: 0.18-0.97), while in stark contrast, those homozygous for the T allele had a significantly increased risk of cancer-related mortality (HR: 3.18, 95% CI: 1.23-8.20). The findings were similar for ESR1 rs9340799 and ESR2 rs1271572. CONCLUSIONS/SIGNIFICANCE: The risk of mortality was not associated with HT duration, type or age at initiation. It was however not equal across all women, with some women appearing genetically more vulnerable to the effects of HT in terms of their estrogen receptor genotype. These findings, if confirmed in another independent study, may help explain the differential susceptibility of women to the beneficial or adverse effects of HT