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Research shows that certain antihypertensives taken during midlife confer Alzheimer's disease (AD) related benefits in later life. We conducted a clinical trial to evaluate the extent to which the angiotensin converting enzyme inhibitor (ACE-I), ramipril, affects AD biomarkers including cerebrospinal fluid (CSF) amyloid-β (Aβ) levels and ACE activity, arterial function, and cognition in participants with a parental history of AD. This four month randomized, double-blind, placebo-controlled, pilot clinical trial evaluated the effects of ramipril, a blood-brain-barrier crossing ACE-I, in cognitively healthy individuals with mild, or Stage I hypertension. Fourteen participants were stratified by gender and apolipoprotein E ε4 (APOE ε4) status and randomized to receive 5 mg of ramipril or matching placebo daily. Participants were assessed at baseline and month 4 on measures of CSF Aβ(1-42) and ACE activity, arterial function, and cognition. Participants were middle-aged (mean 54 y) and highly educated (mean 15.4 y), and included 50% men and 50% APOE ε4 carriers. While results did not show a treatment effect on CSF Aβ(1-42) (p = 0.836), data revealed that ramipril can inhibit CSF ACE activity (p = 0.009) and improve blood pressure, however, there were no differences between groups in arterial function or cognition. In this study, ramipril therapy inhibited CSF ACE activity and improved blood pressure, but did not influence CSF Aβ1-42. While larger trials are needed to confirm our CSF Aβ results, it is possible that prior research reporting benefits of ACE-I during midlife may be attributed to alternative mechanisms including improvements in cerebral blood flow or the prevention of angiotensin II-mediated inhibition of acetylcholine. [ABSTRACT FROM AUTHOR]

Reconstructions of the past climate from proxy records involve a wide range of uncertainties at every step of the process. These uncertainties and the subsequent error bar in the reconstruction of a paleoclimatic variable need to be understood and quantified in order to properly interpret the reconstructed variability and to perform meaningful comparisons with climate model outputs. Classic proxy calibration-validation techniques are not well-suited for identifying the causes of reconstruction errors, estimating their relative contribution, or understanding how errors accumulate from a multitude of sources. In this study, we focus on high resolution proxy records based on calcium carbonate geochemistry of sessile organisms such as mollusks, corals, or sclerosponges, and propose an approach based on Monte Carlo simulations with simple numerical surrogate proxies. A freely available algorithm (MoCo, http://www.isem.cnrs.fr/spip.php?rubrique472) is provided for estimating systematic and standard errors of mean temperature, seasonality and variance reconstructed from marine accretionary archive geochemistry. This algorithm is then used for sensitivity experiments in a case study to characterize and quantitatively evaluate the sensitivity of systematic and standard errors to sampling randomness, stochastic uncertainty sources and systematic proxy limitations. The results of the experiments yield an illustrative example of the range of variations that climate reconstruction errors may undergo, and bring to light their complexity. One of the main improvements of this method is the identification and estimation of systematic bias that would not otherwise be detected. It thus offers the possibility of correcting the proxy-based climate from these biases for a more accurate reconstruction. Beyond the findings of error sources for coral and mollusk-based reconstructions, our study demonstrates that numerical simulations based on Monte Carlo analyses are a simple and powerful approach to improve the proxy calibration process. A thorough understanding of the proxy record errors is essential for the interpretation of paleoclimate records from proxies derived from accretionary skeleton geochemistry. The error estimates provided by MoCo are much more comprehensive and therefore closer to reality than error estimates provided by typical calibration studies. [ABSTRACT FROM AUTHOR]