A systematic review of progranulin concentrations in biofluids in over 7,000 people—assessing the pathogenicity of GRN mutations and other influencing factors

Background: Pathogenic heterozygous mutations in the progranulin gene (GRN) are a key cause of frontotemporal dementia (FTD), leading to significantly reduced biofluid concentrations of the progranulin protein (PGRN). This has led to a number of ongoing therapeutic trials aiming to treat this form of FTD by increasing PGRN levels in mutation carriers. However, we currently lack a complete understanding of factors that affect PGRN levels and potential variation in measurement methods. Here, we aimed to address this gap in knowledge by systematically reviewing published literature on biofluid PGRN concentrations. Methods: Published data including biofluid PGRN concentration, age, sex, diagnosis and GRN mutation were collected for 7071 individuals from 75 publications. The majority of analyses (72%) had focused on plasma PGRN concentrations, with many of these (56%) measured with a single assay type (Adipogen) and so the influence of mutation type, age at onset, sex, and diagnosis were investigated in this subset of the data. Results: We established a plasma PGRN concentration cut-off between pathogenic mutation carriers and non-carriers of 74.8 ng/mL using the Adipogen assay based on 3301 individuals, with a CSF concentration cut-off of 3.43 ng/mL. Plasma PGRN concentration varied by GRN mutation type as well as by clinical diagnosis in those without a GRN mutation. Plasma PGRN concentration was significantly higher in women than men in GRN mutation carriers (p = 0.007) with a trend in non-carriers (p = 0.062), and there was a significant but weak positive correlation with age in both GRN mutation carriers and non-carriers. No significant association was seen with weight or with TMEM106B rs1990622 genotype. However, higher plasma PGRN levels were seen in those with the GRN rs5848 CC genotype in both GRN mutation carriers and non-carriers. Conclusions: These results further support the usefulness of PGRN concentration for the identification of the large majority of pathogenic mutations in the GRN gene. Furthermore, these results highlight the importance of considering additional factors, such as mutation type, sex and age when interpreting PGRN concentrations. This will be particularly important as we enter the era of trials for progranulin-associated FTD.</p

Repensar els estudis catalans des de la teoria queer

Catalan Studies are basically focused on national/linguistic identity, but recent debate on Catalan identity triggered by the current pro-independent process in Catalonia, may help reshape this academic field. A more diverse approach to Catalan culture should consider sexuality, which has traditionally been banished from literary analysis as a ‘private’ matter. Here, we discussed how queer theory can reframe Catalan Studies mainly by building a specific LGBT literary tradition, identifying queer episodes and characters in the canon, questioning received meanings, promoting interdisciplinary analysis of Catalan culture and exploring the role of queer subjectivity in history

Toxicity studies of polymer based superparamagnetic iron oxide nanoparticles

Resumen del póster presentado a la: "13th edition of Trends in Nanotechnology International Conference" celebrada en Madrid (España) del 10 al 14 de septiembre de 2012.-- Pdf adjunto con las figuras.Superparamagnetic iron oxide nanoparticles (SPIONs) have been of great interest since the last decades due to their important contributions to nanomedicine. These inorganic nanomaterials can be useful as a diagnostic tool (e.g. magnetic resonance image contrast agent), a therapeutic tool (e.g. hyperthermia), or a theranostic tool. Stable biocompatible suspension of these nanoparticles is mandatory for efficient application, which is achieved by an adequate polymeric coating. Our model consists of iron oxide nanoparticles (ɣ-Fe2O3) embedded within a hydrophobic poly(vinylpyridine) (P4VP) polymer and coated with a hydrophilic polyethylene glycol (PEG). A fraction of coating PEG can also be functionalized for the conjugation of fluorescent dyes (dual reporter nanoparticles), antibodies and drugs Fig1. These nanoparticles are dispersed in phosphate buffer saline (PBS) at pH 7.4 to mimic physiological conditions. The resulting ferrofluids have core diameter (ferric oxide nanoparticles diameter) ranging between 4 to 15 nm, with 10% size dispersion, and hydrodynamic diameter ranging between 50 to 164 nm. Since the in vivo delivery of these nanoparticles for biomedical applications ends at the cell, studies pertaining to the toxicological effect on the cell (cytotoxicity), and nanoparticles cellular uptake and uptake kinetics are of utmost importance. Cytotoxicity studies of the ferrofluids have been carried out on two different cell lines, opossum kidney cells (OK) and vascular smooth muscle cells (VSMS). The activity of the lactate dehydrogenase in culture media was determined as a function of the dose. LC50 has been also calculated. As the nanoparticles uptake by the cell is depending on several factors, this work focused on the effect of the nanoparticle size and cell type on the cellular uptake. Sub cellular tracking studies have been carried out using fluorescent nanoparticles. Results show the localization of the nanoparticles after 24h of incubation with the cells inside the lysosomes Fig 2. By using the pharmacological inhibitor we found that the nanoparticles uptake takes place by clathrin-dependent endocytosis. These nanoparticles are developed for intravenous administration; therefore, studies pertaining to their haematological behaviour are of outmost importance and should be included in the toxicity and compatibility tests to be made in the development of these nanoparticles. We studied the effect of the nanoparticles and their polymers on the blood coagulation process. Results show that P4VPg-PEG-coated SPIONs in PBS act as non-specific circulating anticoagulant agents in vitro. While PEG component does not seem to have any effect on the coagulation process, the coating copolymer P4VP-g-PEG shows strong anticoagulant behaviour indicating that P4VP is at the origin of the effect.Peer reviewe

Viral infections of the central nervous system in Spain: a prospective study.

The aim of the study was to determine the incidence of viruses causing aseptic meningitis, meningoencephalitis, and encephalitis in Spain. This was a prospective study, in collaboration with 17 Spanish hospitals, including 581 cases (CSF from all and sera from 280): meningitis (340), meningoencephalitis (91), encephalitis (76), febrile syndrome (7), other neurological disorders (32), and 35 cases without clinical information. CSF were assayed by PCR for enterovirus (EV), herpesvirus (herpes simplex [HSV], varicella-zoster [VZV], cytomegalovirus [CMV], Epstein-Barr [EBV], and human herpes virus-6 [HHV-6]), mumps (MV), Toscana virus (TOSV), adenovirus (HAdV), lymphocytic choriomeningitis virus (LCMV), West Nile virus (WNV), and rabies. Serology was undertaken when methodology was available. Amongst meningitis cases, 57.1% were characterized; EV was the most frequent (76.8%), followed by VZV (10.3%) and HSV (3.1%; HSV-1: 1.6%; HSV-2: 1.0%, HSV non-typed: 0.5%). Cases due to CMV, EBV, HHV-6, MV, TOSV, HAdV, and LCMV were also detected. For meningoencephalitis, 40.7% of cases were diagnosed, HSV-1 (43.2%) and VZV (27.0%) being the most frequent agents, while cases associated with HSV-2, EV, CMV, MV, and LCMV were also detected. For encephalitis, 27.6% of cases were caused by HSV-1 (71.4%), VZV (19.1%), or EV (9.5%). Other positive neurological syndromes included cerebellitis (EV and HAdV), seizures (HSV), demyelinating disease (HSV-1 and HHV-6), myelopathy (VZV), and polyradiculoneuritis (HSV). No rabies or WNV cases were identified. EVs are the most frequent cause of meningitis, as is HSV for meningoencephalitis and encephalitis. A significant number of cases (42.9% meningitis, 59.3% meningoencephalitis, 72.4% encephalitis) still have no etiological diagnosis.Grant sponsor: Fondo de Investigación Sanitaria, Instituto de Salud Carlos III, Spanish Ministry of Economy and Competitiveness; Grant number: PI07/90154S

Multifunctional nanoplatform for biomedical applications

Resumen del trabajo presentado a la "2nd European Event in Nanoscience & Nanotechnology" celebrado en Bilbao (España) del 23 al 26 de abril de 2013.Working machinery in life is nanometric, thus, it is no wonder tliat the development of adequate nanotools would be very helpful in biomedical science. In this direction, the idea behind this work is to build a nanoplatform that can incorporate, in an easy way, multiple physical and biological functionalities. The core of the platform is an hydrophobic polymer that may be used as a matrix for the encapsulation of inorganic nanoparticles (magnetic, luminescent, radioactive, . . .). This matrix contains a Michael acceptor (or an acceptor) on its surface for functionalization. Organic bioactive molecules are attached to one end of a hydrophilic polymer (Le. PEG) terminated on a Michael acceptor (or a donor), and then they are anchored to the hydrophobic core by Michael addition. This system has the advantages of a clean synthesis (no by-products), mild conditions, and an easy and controlled multifunctionalization. The nanoplatform has been functionalized with radiochemical tracers (In111), luminescent dyes (fluorescein, rhodamine, lanthanide compounds), and magnetic nanoparticles, and therefore it can be a powerful tool in imaging. Besides, it has also been functionalized with a therapeutical drug, an antibody, and an optical thermometer made of lanthanide complexes. Health safety of tlhe system has been tested in cellular and in vivo assays. The nanoplatform is highly stable in biological fluids, shows low cell toxicity, high capacity of cell internalization, excellent hematocompatibility, and anticoagulation properties. It is shown that magnetic properties can be tuned up in the whole superparamagnetic range. Moreover, the system has shown excellent performance in magnetic resonance imaging and liyperthermia.Peer Reviewe