Declining brain activity in cognitively normal apolipoprotein E ɛ4 heterozygotes: A foundation for using positron emission tomography to efficiently test treatments to prevent Alzheimer's disease

Cross-sectional positron emission tomography (PET) studies find that cognitively normal carriers of the apolipoprotein E (APOE) ɛ4 allele, a common Alzheimer's susceptibility gene, have abnormally low measurements of the cerebral metabolic rate for glucose (CMRgl) in the same regions as patients with Alzheimer's dementia. In this article, we characterize longitudinal CMRgl declines in cognitively normal ɛ4 heterozygotes, estimate the power of PET to test the efficacy of treatments to attenuate these declines in 2 years, and consider how this paradigm could be used to efficiently test the potential of candidate therapies for the prevention of Alzheimer's disease. We studied 10 cognitively normal ɛ4 heterozygotes and 15 ɛ4 noncarriers 50–63 years of age with a reported family history of Alzheimer's dementia before and after an interval of approximately 2 years. The ɛ4 heterozygotes had significant CMRgl declines in the vicinity of temporal, posterior cingulate, and prefrontal cortex, basal forebrain, parahippocampal gyrus, and thalamus, and these declines were significantly greater than those in the ɛ4 noncarriers. In testing candidate primary prevention therapies, we estimate that between 50 and 115 cognitively normal ɛ4 heterozygotes are needed per active and placebo treatment group to detect a 25% attenuation in these CMRgl declines with 80% power and P = 0.005 in 2 years. Assuming these CMRgl declines are related to the predisposition to Alzheimer's dementia, this study provides a paradigm for testing the potential of treatments to prevent the disorder without having to study thousands of research subjects or wait many years to determine whether or when treated individuals develop symptoms.

Greetings: 50 years of Atomic Bomb Casualty Commission–Radiation Effects Research Foundation studies

The Atomic Bomb Casualty Commission was established in Hiroshima in 1947 and in Nagasaki in 1948 under the auspices of the U.S. National Academy of Sciences to initiate a long-term and comprehensive epidemiological and genetic study of the atomic bomb survivors. It was replaced in 1975 by the Radiation Effects Research Foundation which is a nonprofit Japanese foundation binationally managed and supported with equal funding by the governments of Japan and the United States. Thanks to the cooperation of the survivors and the contributions of a multitude of scientists, these studies flourish to this day in what must be the most successful long-term research collaboration between the two countries. Although these studies are necessarily limited to the effects of acute, whole-body, mixed gamma-neutron radiation from the atom bombs, their comprehensiveness and duration make them the most definitive descriptions of the late effects of radiation in humans. For this reason, the entire world relies heavily on these data to set radiation standards. As vital as the study results are, they still represent primarily the effects of radiation on older survivors. Another decade or two should correct this deficiency and allow us to measure definitively the human risk of heritable mutation from radiation. We look to the worldwide radiation and risk community as well as to the survivors who have contributed so much to what has been done already to accomplish this goal.

Confiabilidade aplicada ao problema de interação estaca-solo.

Este trabalho busca aplicar técnicas de confiabilidade ao problema de grupo de estacas utilizadas como fundação de estruturas correntes. Para isso, lança-se mão de um modelo tridimensional de interação estaca-solo onde estão presentes o Método dos Elementos de Contorno (MEC) e o método dos Elementos Finitos (MEF) que atuam de forma acoplada. O MEC, com as soluções fundamentais de Mindlin (meio semi-infinito, homogêneo, isotrópico e elástico-linear é utiliza), é utilizado para modelar o solo. Já o MEF é utilizado para modelar as estacas. Definido o modelo de funcionamento estrutural das estacas, parte-se para a aplicação de métodos trazidos da confiabilidade estrutural para avaliação da adequabilidade em relação aos estados limite de serviço e estados limites últimos. Os métodos de confiabilidade utilizados foram o Método de Monte Carlo, o método FOSM (First-Order Second-Moment) e o método FORM (First-Order Reliability Method).

Revisiting the effect of foundation embedment on elastic settlement: A new approach

The effect of foundation embedment on settlement calculation is a widely researched topic in which there is no scientific consensus regarding the magnitude of settlement reduction. In this paper, a non-linear three dimensional Finite Element analysis has been performed with the aim of evaluating the aforementioned effect. For this purpose, 1800 models were run considering different variables, such as the depth and dimensions of the foundation and the Young’s modulus and Poisson’s ratio of the soil. The settlements from models with foundations at surface level and at depth were then compared and the relationship between them established. The statistical analysis of this data allowed two new expressions, with a mean maximum error of 1.80%, for the embedment influence factor of a foundation to be proposed and these to be compared with commonly used corrections. The proposed equations were validated by comparing the settlements calculated with the proposed influence factors and the true settlements measured in several real foundations. From the comprehensive study of all modelled cases, an improved approach, when compared to those proposed by other authors, for the calculation of the true elastic settlements of an embedded foundation is proposed.

Steel Pedestrian Bridge to Protect a Unique Tree

This paper describes the “Variation Guggenheim 3: Mirador de la palmera” project, situated in Daya Vieja (Alicante-Spain). This structure is inspired by the Guggenheim museum of New York and is designed to protect a land-mark palm-tree from wind loads. This six – trunk palm tree was declared monument by the Valencian government in 2012. The structure that now protect it appears to fly around de palm tree creating a helicoidally skywalk made of steel, while retrofitting the lateral trunks of the tree to protect them from collapse. An 18 m. long straight beam starts on the top of this helix, and stretches towards a lookout point that offers a view of the whole village and its surroundings. The reduction of the visual impact of the structure on the tree was a major aim for the project design. The structural elements are as slender as possible to avoid the visual obstruction of tree. They are painted white, while the walkway steel corrugated plate is painted green in order to highlight its neat shape among the blur created by the apparent mess of bars of the supporting structure. The two main piles of this pedestrian bridge were designed in steel and geometrically resemble trees. A Ground Penetrating Radar analysis was performed to detect the palm root location and to decide the best foundation system. Slender cast in-situ steel-concrete micropiles along with a concrete pile-cap, raised some centimeters above the ground level, were used to reduce the damage to the roots. The projected pile-cap is a slender, continuous, circular ring; which geometry resembles a concrete bench. This structure has been a finalist in the Architecture Awards for the 2010-2014 best construction projects, held by the Diputación de Alicante.

Member State BITS after the Treaty of Lisbon: solid foundation or first victims of EU investment policy? Research Paper in Law, 02/2012

[Introduction.] This paper discusses the uncertain future of Member State BITs with third countries in the light of the developing EU investment policy. The question will be examined on the basis of the proposed Regulation establishing transitional arrangements for bilateral investment agreements between Member States and third countries presented by the Commission on 7 July 20101 and the European Parliament’s Position adopted at first reading on 10 May 2011.2 The proposed Regulation and the Commission Communication of the same day are meant to be the “first steps in the development of an EU international investment policy”.3 The first chapters present the legal framework relevant for this question and its evolution to better understand the particular challenges of this transition process. The second chapter examines the relationship of EU law and investment law, with a brief introduction of the notion of investment law and the scope of the EU’s new investment competence. The third chapter outlines the legal framework for the continuation and termination of treaties under international and EU law. The fourth chapter concerns BITs, first covering the particular nature of BITs and then the CJEU’s judgments in the BIT Cases of 2009. The fifth chapter consists of a step by step analysis of the different provisions of the proposed Regulation.