Liver X Receptor Activation with an Intranasal Polymer Therapeutic Prevents Cognitive Decline without Altering Lipid Levels

The progressive accumulation of amyloid-beta (Aβ) in specific areas of the brain is a common prelude to late-onset of Alzheimer's disease (AD). Although activation of liver X receptors (LXR) with agonists decreases Aβ levels and ameliorates contextual memory deficit, concomitant hypercholesterolemia/hypertriglyceridemia limits their clinical application. DMHCA (N,N-dimethyl-3β-hydroxycholenamide) is an LXR partial agonist that, despite inducing the expression of apolipoprotein E (main responsible of Aβ drainage from the brain) without increasing cholesterol/triglyceride levels, shows nil activity in vivo because of a low solubility and inability to cross the blood brain barrier. Herein, we describe a polymer therapeutic for the delivery of DMHCA. The covalent incorporation of DMHCA into a PEG-dendritic scaffold via carboxylate esters produces an amphiphilic copolymer that efficiently self-assembles into nanometric micelles that exert a biological effect in primary cultures of the central nervous system (CNS) and experimental animals using the intranasal route. After CNS biodistribution and effective doses of DMHCA micelles were determined in nontransgenic mice, a transgenic AD-like mouse model of cerebral amyloidosis was treated with the micelles for 21 days. The benefits of the treatment included prevention of memory deterioration and a significant reduction of hippocampal Aβ oligomers without affecting plasma lipid levels. These results represent a proof of principle for further clinical developments of DMHCA delivery systems.Fil: Navas Guimaraes, Maria Eugenia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Juan; Argentina. Universidad Catolica de Cuyo. Facultad de Ciencias Medicas. Instituto de Investigacion En Ciencias Biomedicas.; ArgentinaFil: Lopez Blanco, Roi. Universidad de Santiago de Compostela; EspañaFil: Correa, Juan. Universidad de Santiago de Compostela; EspañaFil: Fernandez Villamarin, Marcos. Universidad de Santiago de Compostela; EspañaFil: Bistue Millon, Maria Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Juan; Argentina. Universidad Catolica de Cuyo. Facultad de Ciencias Medicas. Instituto de Investigacion En Ciencias Biomedicas.; ArgentinaFil: Martino Adami, Pamela Victoria. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Morelli, Laura. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Kumar, Vijay. University of Colorado; Estados UnidosFil: Wempe, Michael F.. University of Colorado; Estados UnidosFil: Cuello, A. C.. McGill University; CanadáFil: Fernandez Megia, Eduardo. Universidad de Santiago de Compostela; EspañaFil: Bruno, Martin. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Juan; Argentina. Universidad Catolica de Cuyo. Facultad de Ciencias Medicas. Instituto de Investigacion En Ciencias Biomedicas.; Argentin

Measurement of the (90,91,92,93,94,96)Zr(n,gamma) and (139)La(n,gamma) cross sections at n_TOF

Open AccessNeutron capture cross sections of Zr and La isotopes have important implications in the field of nuclear astrophysics as well as in the nuclear technology. In particular the Zr isotopes play a key role for the determination of the neutron density in the He burning zone of the Red Giant star, while the (139)La is important to monitor the s-process abundances from Ba up to Ph. Zr is also largely used as structural materials of traditional and advanced nuclear reactors. The nuclear resonance parameters and the cross section of (90,91,92,93,94,96)Zr and (139)La have been measured at the n_TOF facility at CERN. Based on these data the capture resonance strength and the Maxwellian-averaged cross section were calculated

Measurements of high-energy neutron-induced fission of (nat)Pb and (209)Bi

This is an Open Access article distributed under the terms of the Creative Commons Attribution-Noncommercial License 3.0, which permits unrestricted use, distribution, and reproduction in any noncommercial medium, provided the original work is properly citedThe CERN Neutron Time-Of-Flight (n_TOF) facility is well suited to measure low cross sections as those of neutron-induced fission in subactinides. The cross section ratios of (nat)Pb and (209)Bi relative to (235)U and (238)U were measured using PPAC detectors and a fragment coincidence method that allows us to identify the fission events. The present experiment provides first results for neutron-induced fission up to 1 GeV. Good agreement is found with previous experimental data below 200 MeV. The comparison with proton-induced fission indicates that the limiting regime where neutron-induced and proton-induced fission reach equal cross sections is close to 1 GeV

Measurement of the neutron capture cross section of the s-only isotope 204Pb from 1 eV to 440 keV

The neutron capture cross section of 204Pb has been measured at the CERN n_TOF installation with high resolution in the energy range from 1 eV to 440 keV. An R-matrix analysis of the resolved resonance region, between 1 eV and 100 keV, was carried out using the SAMMY code. In the interval between 100 keV and 440 keV we report the average capture cross section. The background in the entire neutron energy range could be reliably determined from the measurement of a 208Pb sample. Other systematic effects in this measurement could be investigated and precisely corrected by means of detailed Monte Carlo simulations. We obtain a Maxwellian average capture cross section for 204Pb at kT=30 keV of 79(3) mb, in agreement with previous experiments. However our cross section at kT=5 keV is about 35% larger than the values reported so far. The implications of the new cross section for the s-process abundance contributions in the Pb/Bi region are discussed.Comment: 8 pages, 3 figures, article submitted to Phys. Rev.

New measurement of neutron capture resonances of 209Bi

The neutron capture cross section of Bi209 has been measured at the CERN n TOF facility by employing the pulse-height-weighting technique. Improvements over previous measurements are mainly because of an optimized detection system, which led to a practically negligible neutron sensitivity. Additional experimental sources of systematic error, such as the electronic threshold in the detectors, summing of gamma-rays, internal electron conversion, and the isomeric state in bismuth, have been taken into account. Gamma-ray absorption effects inside the sample have been corrected by employing a nonpolynomial weighting function. Because Bi209 is the last stable isotope in the reaction path of the stellar s-process, the Maxwellian averaged capture cross section is important for the recycling of the reaction flow by alpha-decays. In the relevant stellar range of thermal energies between kT=5 and 8 keV our new capture rate is about 16% higher than the presently accepted value used for nucleosynthesis calculations. At this low temperature an important part of the heavy Pb-Bi isotopes are supposed to be synthesized by the s-process in the He shells of low mass, thermally pulsing asymptotic giant branch stars. With the improved set of cross sections we obtain an s-process fraction of 19(3)% of the solar bismuth abundance, resulting in an r-process residual of 81(3)%. The present (n,gamma) cross-section measurement is also of relevance for the design of accelerator driven systems based on a liquid metal Pb/Bi spallation target.Comment: 10 pages, 5figures, recently published in Phys. Rev.

Measurement of the radiative neutron capture cross section of 206Pb and its astrophysical implications

The (n, gamma) cross section of 206Pb has been measured at the CERN n_TOF facility with high resolution in the energy range from 1 eV to 600 keV by using two optimized C6D6 detectors. In the investigated energy interval about 130 resonances could be observed, from which 61 had enough statistics to be reliably analyzed via the R-matrix analysis code SAMMY. Experimental uncertainties were minimized, in particular with respect to (i) angular distribution effects of the prompt capture gamma-rays, and to (ii) the TOF-dependent background due to sample-scattered neutrons. Other background components were addressed by background measurements with an enriched 208Pb sample. The effect of the lower energy cutoff in the pulse height spectra of the C6D6 detectors was carefully corrected via Monte Carlo simulations. Compared to previous 206Pb values, the Maxwellian averaged capture cross sections derived from these data are about 20% and 9% lower at thermal energies of 5 keV and 30 keV, respectively. These new results have a direct impact on the s-process abundance of 206Pb, which represents an important test for the interpretation of the cosmic clock based on the decay of 238U.Comment: 11 pages, 8 figures, paper to be submitted to Phys. Rev.

High-accuracy determination of the U 238 / U 235 fission cross section ratio up to ≈1 GeV at n-TOF at CERN

Published by the American Physical Society under the terms of the Creative Commons Attribution 3.0 License. Further distribution of this work must maintain attribution to the author(s) and the published article’s title, journal citation, and DOIThe U238 to U235 fission cross section ratio has been determined at n-TOF up to ≈1 GeV, with two different detection systems, in different geometrical configurations. A total of four datasets has been collected and compared. They are all consistent to each other within the relative systematic uncertainty of 3-4%. The data collected at n-TOF have been suitably combined to yield a unique fission cross section ratio as a function of neutron energy. The result confirms current evaluations up to 200 MeV. Good agreement is also observed with theoretical calculations based on the INCL++/Gemini++ combination up to the highest measured energy. The n-TOF results may help solve a long-standing discrepancy between the two most important experimental datasets available so far above 20 MeV, while extending the neutron energy range for the first time up to ≈1 GeV.Peer reviewedFinal Published versio

Resonance capture cross section of 207Pb

The radiative neutron capture cross section of 207Pb has been measured at the CERN neutron time of flight installation n_TOF using the pulse height weighting technique in the resolved energy region. The measurement has been performed with an optimized setup of two C6D6 scintillation detectors, which allowed us to reduce scattered neutron backgrounds down to a negligible level. Resonance parameters and radiative kernels have been determined for 16 resonances by means of an R-matrix analysis in the neutron energy range from 3 keV to 320 keV. Good agreement with previous measurements was found at low neutron energies, whereas substantial discrepancies appear beyond 45 keV. With the present results, we obtain an s-process contribution of 77(8)% to the solar abundance of 207Pb. This corresponds to an r-process component of 23(8)%, which is important for deriving the U/Th ages of metal poor halo stars.Comment: 7 pages, 3 figures, to be published in Phys. Rev.

Towards the high-accuracy determination of the 238U fission cross section at the threshold region at CERN - N-TOF

The 238U fission cross section is an international standard beyond 2 MeV where the fission plateau starts. However, due to its importance in fission reactors, this cross-section should be very accurately known also in the threshold region below 2 MeV. The 238U fission cross section has been measured relative to the 235U fission cross section at CERN - n-TOF with different detection systems. These datasets have been collected and suitably combined to increase the counting statistics in the threshold region from about 300 keV up to 3 MeV. The results are compared with other experimental data, evaluated libraries, and the IAEA standards

Economic evaluation of pharmacogenomic-guided antiplatelet treatment in Spanish patients suffering from acute coronary syndrome participating in the U-PGx PREPARE study

BackgroundCardiovascular diseases and especially Acute Coronary Syndrome (ACS) constitute a major health issue impacting millions of patients worldwide. Being a leading cause of death and hospital admissions in many European countries including Spain, it accounts for enormous amounts of healthcare expenditures for its management. Clopidogrel is one of the oldest antiplatelet medications used as standard of care in ACS.MethodsIn this study, we performed an economic evaluation study to estimate whether a genome-guided clopidogrel treatment is cost-effective compared to conventional one in a large cohort of 243 individuals of Spanish origin suffering from ACS and treated with clopidogrel. Data were derived from the U-PGx PREPARE clinical trial. Effectiveness was measured as survival of individuals while study data on safety and efficacy, as well as on resource utilization associated with each adverse drug reaction were used to measure costs to treat these adverse drug reactions. A generalized linear regression model was used to estimate cost differences for both study groups.ResultsBased on our findings, PGx-guided treatment group is cost-effective. PGx-guided treatment demonstrated to have 50% less hospital admissions, reduced emergency visits and almost 13% less ADRs compared to the non-PGx approach with mean QALY 1.07 (95% CI, 1.04-1.10) versus 1.06 (95% CI, 1.03-1.09) for the control group, while life years for both groups were 1.24 (95% CI, 1.20-1.26) and 1.23 (95% CI, 1.19-1.26), respectively. The mean total cost of PGx-guided treatment was 50% less expensive than conventional therapy with clopidogrel [euro883 (95% UI, euro316-euro1582), compared to euro1,755 (95% UI, euro765-euro2949)].ConclusionThese findings suggest that PGx-guided clopidogrel treatment represents a cost-effective option for patients suffering from ACS in the Spanish healthcare setting.Personalised Therapeutic