A blood based 12-miRNA signature of Alzheimer disease patients

Background: Alzheimer disease (AD) is the most common form of dementia but the identification of reliable, early and non-invasive biomarkers remains a major challenge. We present a novel miRNA-based signature for detecting AD from blood samples. Results: We apply next-generation sequencing to miRNAs from blood samples of 48 AD patients and 22 unaffected controls, yielding a total of 140 unique mature miRNAs with significantly changed expression levels. Of these, 82 have higher and 58 have lower abundance in AD patient samples. We selected a panel of 12 miRNAs for an RT-qPCR analysis on a larger cohort of 202 samples, comprising not only AD patients and healthy controls but also patients with other CNS illnesses. These included mild cognitive impairment, which is assumed to represent a transitional period before the development of AD, as well as multiple sclerosis, Parkinson disease, major depression, bipolar disorder and schizophrenia. miRNA target enrichment analysis of the selected 12 miRNAs indicates an involvement of miRNAs in nervous system development, neuron projection, neuron projection development and neuron projection morphogenesis. Using this 12-miRNA signature, we differentiate between AD and controls with an accuracy of 93%, a specificity of 95% and a sensitivity of 92%. The differentiation of AD from other neurological diseases is possible with accuracies between 74% and 78%. The differentiation of the other CNS disorders from controls yields even higher accuracies. Conclusions: The data indicate that deregulated miRNAs in blood might be used as biomarkers in the diagnosis of AD or other neurological diseases

The non-synonymous SNP, R1150W, in SCN9A is not associated with chronic widespread pain susceptibility

Acknowledgements The authors wish to thank all of the primary care practices and participants in the EPIFUND study, the EPIFUND study team and Arthritis Research UK lab staff for carrying out the genotyping. The authors thank the men who participated in the seven countries and the research/nursing staff in the seven centres of the EMAS study used in the current analysis: C Pott (Manchester), E Wouters (Leuven), M del Mar Fernandez (Santiago de Compostela), M Jedrzejowska (Lodz), H-M Tabo (Tartu) and A Heredi (Szeged) for their data collection, and C Moseley (Manchester) for data entry and project coordination. DV and SB are senior clinical investigators of the Fund for Scientific Research-Flanders, Belgium (F W O-Vlaanderen). SB is holder of the Leuven University Chair in Gerontology and Geriatrics. The researchers thank the Framingham study participants and personnel. This work was supported by Arthritis Research UK, Chesterfield, UK. The European Male Ageing Study (EMAS) is funded by the Commission of the European Communities Fifth Framework Programme ‘Quality of life and management of living resources’ grant QLK6-CT-2001-00258. Genotyping of the Dyne Steel DNA Bank for Ageing and Cognition cohort was supported by the BBSRC and the study was supported by AgeUK. The Framingham study was supported by grants from the National Heart, Lung, and Blood Institute (NHLBI contract N01-HC-25195) and NIH AR47785 and AG18393.Peer reviewedPublisher PD

Active vitamin D (1,25-dihydroxyvitamin D) and bone health in middle-aged and elderly men: the European male aging study (EMAS)

<p>Context: There is little information on the potential impact of serum 1,25-dihydroxyvitamin D [1,25(OH)2D] on bone health including turnover.</p> <p>Objective: The objective of the study was to determine the influence of 1,25(OH)2D and 25-hydroxyvitamin D [25(OH)D] on bone health in middle-aged and older European men.</p> <p>Design, Setting, and Participants: Men aged 40–79 years were recruited from population registers in 8 European centers. Subjects completed questionnaires that included questions concerning lifestyle and were invited to attend for quantitative ultrasound (QUS) of the heel, assessment of height and weight, and a fasting blood sample from which 1,25(OH)2D, 25(OH)D, and PTH were measured. 1,25(OH)2D was measured using liquid chromatography tandem mass spectrometry. Bone markers serum N-terminal propeptide of type 1 procollagen (P1NP) and crosslinks (β-cTX) were also measured. Dual-energy x-ray absorptiometry (DXA) of the hip and lumbar spine was performed in 2 centers.</p> <p>Main Outcome Measure(s): QUS of the heel, bone markers P1NP and β-cTX, and DXA of the hip and lumbar spine were measured.</p> <p>Results: A total of 2783 men, mean age 60.0 years (SD 11.0) were included in the analysis. After adjustment for age and center, 1,25(OH)2D was positively associated with 25(OH)D but not with PTH. 25(OH)D was negatively associated with PTH. After adjustment for age, center, height, weight, lifestyle factors, and season, 1,25(OH)2D was associated negatively with QUS and DXA parameters and associated positively with β-cTX. 1,25(OH)2D was not correlated with P1NP. 25(OH)D was positively associated with the QUS and DXA parameters but not related to either bone turnover marker. Subjects with both high 1,25(OH)2D (upper tertile) and low 25(OH)D (lower tertile) had the lowest QUS and DXA parameters and the highest β-cTX levels.</p> <p>Conclusions: Serum 1,25(OH)2D is associated with higher bone turnover and poorer bone health despite being positively related to 25(OH)D. A combination of high 1,25(OH)2D and low 25(OH)D is associated with the poorest bone health.</p&gt

Active vitamin D (1,25-dihydroxyvitamin D) and bone health in middle-aged and elderly men: the European male aging study (EMAS)

<p>Context: There is little information on the potential impact of serum 1,25-dihydroxyvitamin D [1,25(OH)2D] on bone health including turnover.</p> <p>Objective: The objective of the study was to determine the influence of 1,25(OH)2D and 25-hydroxyvitamin D [25(OH)D] on bone health in middle-aged and older European men.</p> <p>Design, Setting, and Participants: Men aged 40–79 years were recruited from population registers in 8 European centers. Subjects completed questionnaires that included questions concerning lifestyle and were invited to attend for quantitative ultrasound (QUS) of the heel, assessment of height and weight, and a fasting blood sample from which 1,25(OH)2D, 25(OH)D, and PTH were measured. 1,25(OH)2D was measured using liquid chromatography tandem mass spectrometry. Bone markers serum N-terminal propeptide of type 1 procollagen (P1NP) and crosslinks (β-cTX) were also measured. Dual-energy x-ray absorptiometry (DXA) of the hip and lumbar spine was performed in 2 centers.</p> <p>Main Outcome Measure(s): QUS of the heel, bone markers P1NP and β-cTX, and DXA of the hip and lumbar spine were measured.</p> <p>Results: A total of 2783 men, mean age 60.0 years (SD 11.0) were included in the analysis. After adjustment for age and center, 1,25(OH)2D was positively associated with 25(OH)D but not with PTH. 25(OH)D was negatively associated with PTH. After adjustment for age, center, height, weight, lifestyle factors, and season, 1,25(OH)2D was associated negatively with QUS and DXA parameters and associated positively with β-cTX. 1,25(OH)2D was not correlated with P1NP. 25(OH)D was positively associated with the QUS and DXA parameters but not related to either bone turnover marker. Subjects with both high 1,25(OH)2D (upper tertile) and low 25(OH)D (lower tertile) had the lowest QUS and DXA parameters and the highest β-cTX levels.</p> <p>Conclusions: Serum 1,25(OH)2D is associated with higher bone turnover and poorer bone health despite being positively related to 25(OH)D. A combination of high 1,25(OH)2D and low 25(OH)D is associated with the poorest bone health.</p&gt

Efficacy of the 1-year (13-cycle) segesterone acetate and ethinylestradiol contraceptive vaginal system : results of two multicentre, open-label, single-arm, phase 3 trials

A ring-shaped, contraceptive vaginal system designed to last 1 year (13 cycles) delivers an average of 0.15 mg segesterone acetate and 0.013 mg ethinylestradiol per day. We evaluated the efficacy of this contraceptive vaginal system and return to menses or pregnancy after use. In two identically designed, multicentre, open-label, single-arm, phase 3 trials (one at 15 US academic and community sites and one at 12 US and international academic and community sites), participants followed a 21-days-in, 7-days-out segesterone acetate and ethinylestradiol contraceptive vaginal system schedule for up to 13 cycles. Participants were healthy, sexually active, non-pregnant, non-sterilised women aged 18-40 years. Women were cautioned that any removals during the 21 days of cyclic use should not exceed 2 h, and used daily paper diaries to record vaginal system use. Consistent with regulatory requirements for contraceptives, we calculated the Pearl Index for women aged 35 years and younger, excluding adjunctive contraception cycles, as the primary efficacy outcome measure. We also did intention-to-treat Kaplan-Meier life table analyses and followed up women who did not use hormonal contraceptives or desired pregnancy after study completion for 6 months for return to menses or pregnancy. The trials are registered with ClinicalTrials.gov, numbers NCT00455156 and NCT00263341. Between Dec 19, 2006, and Oct 9, 2009, at the 15 US sites, and between Nov 1, 2006, and July 2, 2009, at the 12 US and international sites we enrolled 2278 women. Our overall efficacy analysis included 2265 participants (1130 in the US study and 1135 in the international study) and 1303 (57.5%) participants completed up to 13 cycles. The Pearl Index for the primary efficacy group was 2.98 (95% CI 2.13-4.06) per 100 woman-years, and was well within the range indicative of efficacy for a contraceptive under a woman's control. The Kaplan-Meier analysis revealed the contraceptive vaginal system was 97.5% effective, which provided further evidence of efficacy. Pregnancy occurrence was similar across cycles. All 290 follow-up participants reported return to menses or became pregnant (24 [63%] of 38 women who desired pregnancy) within 6 months. Interpretation The segesterone acetate and ethinylestradiol contraceptive vaginal system is an effective contraceptive for 13 consecutive cycles of use. This new product adds to the contraceptive method mix and the 1-year duration of use means that women do not need to return to the clinic or pharmacy for refills every few months78e1054e1064We thank The Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health (NICHD), the US Agency for International Development (USAID), and WHO for funding the phase 3 studies. We also acknowledge all participating study investigators (appendix p 1) and coordinators at the 27 clinical sites for conduct of the two phase 3 clinical trials and the over 2200 women participants from eight countries. We further acknowledge the medical writing assistance of Kathleen Ohleth (Precise Publications; Bedminster. NJ, USA) supported by TherapeuticsMD (Boca Raton, FL, USA). The NICHD (contract no HHSN27500403372) funded and conducted the US study and USAID (grant no GPO-A-00-04-00019-00) funded the international study, which was conducted by the Population Council. WHO Department of Reproductive Health and Research funded two international study sites. Medical writing support for manuscript submission and resubmission was supported by TherapeuticsMD. The authors acknowledge the major contribution of Daniel R Mishell Jr (deceased), from the Department of Obstetrics and Gynecology, University of Southern California, Keck School of Medicine (Los Angeles, CA, USA) who invented the concept of the vaginal system to deliver contraceptive steroids, did many of the clinical studies for the segesterone acetate and ethinylestradiol contraceptive vaginal system, and was a principle investigator for the 300 B phase 3 study analysed in this Article while a member of the International Committee for Contraceptive Research (ICCR) of the Population Council. The authors also gratefully acknowledge the contribution of Horacio B Croxatto, from the University of Chile (Santiago, Chile), who established the clinical centre in Chile, participated in all pivotal clinical studies for this ring, and provided guidance for the full development of this new contraceptive while a member of the ICC

The ESR1 (6q25) locus is associated with calcaneal ultrasound parameters and radial volumetric bone mineral density in European men

<p><b>Purpose:</b> Genome-wide association studies (GWAS) have identified 6q25, which incorporates the oestrogen receptor alpha gene (ESR1), as a quantitative trait locus for areal bone mineral density (BMD(a)) of the hip and lumbar spine. The aim of this study was to determine the influence of this locus on other bone health outcomes; calcaneal ultrasound (QUS) parameters, radial peripheral quantitative computed tomography (pQCT) parameters and markers of bone turnover in a population sample of European men.</p> <p><b>Methods:</b> Eight single nucleotide polymorphisms (SNP) in the 6q25 locus were genotyped in men aged 40-79 years from 7 European countries, participating in the European Male Ageing Study (EMAS). The associations between SNPs and measured bone parameters were tested under an additive genetic model adjusting for centre using linear regression.</p> <p><b>Results:</b> 2468 men, mean (SD) aged 59.9 (11.1) years had QUS measurements performed and bone turnover marker levels measured. A subset of 628 men had DXA and pQCT measurements. Multiple independent SNPs showed significant associations with BMD using all three measurement techniques. Most notably, rs1999805 was associated with a 0.10 SD (95%CI 0.05, 0.16; p = 0.0001) lower estimated BMD at the calcaneus, a 0.14 SD (95%CI 0.05, 0.24; p = 0.004) lower total hip BMD(a), a 0.12 SD (95%CI 0.02, 0.23; p = 0.026) lower lumbar spine BMD(a) and a 0.18 SD (95%CI 0.06, 0.29; p = 0.003) lower trabecular BMD at the distal radius for each copy of the minor allele. There was no association with serum levels of bone turnover markers and a single SNP which was associated with cortical density was also associated with cortical BMC and thickness.</p> <p><b>Conclusions:</b> Our data replicate previous associations found between SNPs in the 6q25 locus and BMD(a) at the hip and extend these data to include associations with calcaneal ultrasound parameters and radial volumetric BMD.</p&gt

The androgen receptor gene CAG repeat in relation to 4-year changes in androgen-sensitive endpoints in community-dwelling older European men

Context: The Androgen Receptor (AR) gene exon 1 CAG repeat length has been proposed to be a determinant of between-individual variations in androgen action in target tissues, which might regulate phenotypic differences of human ageing. However, findings on its phenotypic effects are inconclusive.Objective: To assess whether the AR CAG repeat length is associated with longitudinal changes in endpoints which are influenced by testosterone (T) levels in middle-aged and elderly European men.Design: Multinational European observational prospective cohort studyParticipants: 1887 men (mean±sd age: 63±11 years; median follow-up: 4.3 years) from centres of 8 European countries comprised the analysis sample after exclusion of those with diagnosed diseases of the hypothalamic-pituitary-testicular (HPT) axis.Main outcome measures: Longitudinal associations between the AR CAG repeat and changes in androgen-sensitive endpoints (ASEs) and medical conditions were assessed using regression analysis adjusting for age and centre. The AR CAG repeat length was treated both as a continuous and categorical (6-20; 21-23; 24-39 repeats) predictor. Additional analysis investigated whether results were independent of baseline T or oestradiol (E2) levels.Results: The AR CAG repeat, when used as a continuous or categorical predictor, was not associated with longitudinal changes in ASEs or medical conditions after adjustments. These results were independent of T and E2 levels.Conclusion: Within a 4-year timeframe, variations in the AR CAG repeat do not contribute to the rate of phenotypic ageing, over and above, that, which might be associated with the age-related decline in T levels