Clinical Association of White Matter Hyperintensities Localization in a Mexican Family with Spastic Paraparesis Carrying the PSEN1 A431E Mutation

Presenilin 1 gene (PSEN1) mutations are the most common cause of familial Alzheimer’s disease (FAD). One of the most abundant FAD mutations, PSEN1 A431E, has been reported to be associated with spastic paraparesis in about half of its carriers, but the determining mechanisms of this phenotype are still unknown. In our study we characterized three A431E mutation carriers, one symptomatic and two asymptomatic, from a Mexican family with a history of spastic paraparesis in all of its affected members. At cognitive assessment and MRI, the symptomatic subject showed an atypical non-amnestic mild cognitive impairment with visuospatial deficits, olfactory dysfunction and significant parieto-occipital brain atrophy. Furthermore, we found several periventricular white matter hyperintensities whose progression pattern and localization correlated with their motor impairment, cognitive profile, and non-motor symptoms. Together, our data suggests that in this family the A431E mutation leads to a divergent neurological disorder in which cognitive deterioration was clinically exceeded by motor impairment and that it involves early glial and vascular pathological changes

Overexploitation and water quality in the Crevillente aquifer (Alicante, SE Spain)

The Crevillente aquifer is a karstic aquifer, situated in Alicante province in the SE of Spain. The aquifer basically comprises a series of Jurassic limestones and dolomites, belonging to the Betic Cordillera. Intense exploitation of the aquifer started in the early 1960s. Exploitation was initially concentrated in two sectors of the Sierra de Crevillente and, years later, extended to a third sector. As a consequence of abstractions that were much greater than recharge into the system, a continual drop in the water level persisted for several decades. These abstractions have occasionally caused local dewatering over depths of more than 300 m. From a hydrogeological point of view, the aquifer dewatering in one of the sectors was accompanied by increased mineralization and a fall in quality of the groundwater, and several boreholes had to be abandoned. In recent years, the degree to which the aquifer is overexploited has fallen considerably, and it appears to have entered a new hydrodynamic stage. New hydrogeochemical characterisations have been carried out, which indicate that the aquifer water is relatively strongly mineralised due, fundamentally, to the dissolution of evaporite rocks. On the other hand, deterioration in water quality as a consequence of the degree of overabstraction can also be confirmedDepto. de Geodinámica, Estratigrafía y PaleontologíaFac. de Ciencias GeológicasTRUEGeneralitat ValencianaUNESCOpu

Mesoscopic structure conditions the emergence of cooperation on social networks

We study the evolutionary Prisoner's Dilemma on two social networks obtained from actual relational data. We find very different cooperation levels on each of them that can not be easily understood in terms of global statistical properties of both networks. We claim that the result can be understood at the mesoscopic scale, by studying the community structure of the networks. We explain the dependence of the cooperation level on the temptation parameter in terms of the internal structure of the communities and their interconnections. We then test our results on community-structured, specifically designed artificial networks, finding perfect agreement with the observations in the real networks. Our results support the conclusion that studies of evolutionary games on model networks and their interpretation in terms of global properties may not be sufficient to study specific, real social systems. In addition, the community perspective may be helpful to interpret the origin and behavior of existing networks as well as to design structures that show resilient cooperative behavior.Comment: Largely improved version, includes an artificial network model that fully confirms the explanation of the results in terms of inter- and intra-community structur

Serendipitous detection of an overdensity of Herschel-SPIRE 250 micron sources south of MRC1138-26

We report the serendipitous detection of a significant overdensity of Herschel-SPIRE 250 micron sources in the vicinity of MRC1138-26. We use an adaptive kernel density estimate to quantify the significance, including a comparison with other fields. The overdensity has a size of ~3.5-4' and stands out at ~5sigma with respect to the background estimate. No features with similar significance were found in four extragalactic control fields: GOODS-North, Lockman, COSMOS and UDS. The chance of having a similar overdensity in a field with the same number but randomly distributed sources is less than 2%. The clump is also visible as a low surface brightness feature in the Planck 857 GHz map. We detect 76 sources at 250 micron (with a signal-to-noise ratio greater than 3), in a region of 4' radius; 43 of those are above a flux density limit of 20 mJy. This is a factor of 3.6 in excess over the average in the four control fields, considering only the sources above 20 mJy. We also find an excess in the number counts of sources with 250 micron flux densities between 30 and 40 mJy, compared to deep extragalactic blank-field number counts. Assuming a fixed dust temperature (30 K) and emissivity (beta=1.5) a crude, blackbody-derived redshift distribution, zBB, of the detected sources is significantly different from the distributions in the control fields and exhibits a significant peak at zBB ~ 1.5, although the actual peak redshift is highly degenerate with the temperature. We tentatively suggest, based on zBB and the similar S250/S350 colours of the sources within the peak, that a significant fraction of the sources in the clump may be at a similar redshift. Since the overdensity lies ~7' south of the z=2.16 Spiderweb protocluster MRC1138-26, an intriguing possibility (that is presently unverifiable given the data in hand) is that it lies within the same large-scale structure.(abridged)Comment: 10 pages, 8 figures, accepted for publication in MNRA

The action of obestatin in skeletal muscle repair: stem cell expansion, muscle growth, and microenvironment remodeling

The development of therapeutic strategies for skeletal muscle diseases, such as physical injuries and myopathies, depends on the knowledge of regulatory signals that control the myogenic process. The obestatin/GPR39 system operates as an autocrine signal in the regulation of skeletal myogenesis. Using a mouse model of skeletal muscle regeneration after injury and several cellular strategies, we explored the potential use of obestatin as a therapeutic agent for the treatment of trauma-induced muscle injuries. Our results evidenced that the overexpression of the preproghrelin, and thus obestatin, and GPR39 in skeletal muscle increased regeneration after muscle injury. More importantly, the intramuscular injection of obestatin significantly enhanced muscle regeneration by simulating satellite stem cell expansion as well as myofiber hypertrophy through a kinase hierarchy. Added to the myogenic action, the obestatin administration resulted in an increased expression of VEGF/VEGFR2 and the consequent microvascularization, with no effect on collagen deposition in skeletal muscle. Furthermore, the potential inhibition of myostatin during obestatin treatment might contribute to its myogenic action improving muscle growth and regeneration. Taken together, our data demonstrate successful improvement of muscle regeneration, indicating obestatin is a potential therapeutic agent for skeletal muscle injury and would benefit other myopathies related to muscle regeneration

Phases I–III Clinical Trials Using Adult Stem Cells

First randomized clinical trials have demonstrated that stem cell therapy can improve cardiac recovery after the acute phase of myocardial ischemia and in patients with chronic ischemic heart disease. Nevertheless, some trials have shown that conflicting results and uncertainties remain in the case of mechanisms of action and possible ways to improve clinical impact of stem cells in cardiac repair. In this paper we will examine the evidence available, analyze the main phase I and II randomized clinical trials and their limitations, discuss the key points in the design of future trials, and depict new directions of research in this fascinating field

Automatic pre-alignment of multimodality rat brain images using principal axes transformation

Abstract of: AMI Annual Conference 2006, March 25-29The use of small animal studies of different modalities isnowadays widespread, since functional studies like positron emission tomography (PET) or single photon emission computed tomography (SPECT) are better analyzed when mapped to the underlying anatomical structure coming from magnetic resonance imaging (MRI) or computed tomography (CT). The different positioning of the animals in the scanners results in the need for automated image registration methods. One important drawback of the existing algorithms is their limited capture range: if case of large initial misregistration (large translations and rotations) the optimization may not converge to the right solution, and the images do not become correctly coregistered. To avoid this problem we propose the use of a pre-alignment step based on the principal axes transformation.Publicad

Cell Expansion-Dependent Inflammatory and Metabolic Profile of Human Bone Marrow Mesenchymal Stem Cells

Stem cell therapy has emerged as a promising new area in regenerative medicine allowing the recovery of viable tissues. Among the many sources of adult stem cells, bone marrow-derived are easy to expand in culture via plastic adherence and their multipotentiality for differentiation make them ideal for clinical applications. Interestingly, several studies have indicated that MSCs expansion in vitro may be limited mainly due to cell aging related to the number of cell divisions in culture. We have determined that MSCs exhibit a progressive decline across successive passages in the expression of stem cell markers, in plasticity and in the inflammatory response, presenting low immunogenicity. We have exposed human MSCs after several passages to TLRs ligands and analyzed their inflammatory response. These cells responded to pro-inflammatory stimuli (i.e., NOS-2 expression) and to anti-inflammatory cytokines (i.e., HO1 and Arg1) until two expansions, rapidly declining upon subculture. Moreover, in the first passages, MSCs were capable to release IL1β, IL6 and IL8, as well as to produce active MMPs allowing them to migrate. Interestingly enough, after two passages, anaerobic glycolysis was enhanced releasing high levels of lactate to the extracellular medium. All these results may have important implications for the safety and efficacy of MSCs-based cell therapies