Repetition-imitation and aphasia: Neural Basis and treatment

Study 2: a single-case study was developed. Repetition performance was widely assessed in a patient with crossed conduction aphasia and striatal/capsular vascular lesions encompassing the right arcuate fasciculus (AF) and inferior frontal-occipital fasciculus (IFOF), the temporal stem and the white matter underneath the supramarginal gyrus. He showed lexicality effects repeating better words than non-words, but manipulation of other lexical-semantic variables exerted less influence on repetition performance. Imageability and frequency effects, production of meaning-based paraphrases during sentence repetition, or better performance on repeating novel sentences than overlearned clichés were hardly ever observed in this patient. Diffusion tensor imaging disclosed damage to the right long direct segment of the AF and IFOF with relative sparing of the anterior indirect and posterior segments of the AF, together with fully developed left perisylvian white matter pathways. These findings suggest that striatal/capsular lesions extending into the right AF and IFOF in some individuals with right hemisphere language dominance are associated with atypical repetition patterns which might reflect reduced interactions between phonological and lexical-semantic processes. Study 3: A within-patient design, with multiple assessments, was developed with the same patient as in Study 2A. The initial dose of Donepezil (5 mg/day) was titulated up to 10 mg/day and administered alone (without aphasia therapy) during 3 months (Endpoint 1). Then, the drug was combined with a verbal repetition-imitation therapy (Look-Listen and Repeat - LLR) (1 hour/day) during 2 months (Endpoint 2). Language evaluations, diffusion tensor imaging (DTI) and voxel-based morphometry (VBM) were performed at baseline and at both endpoints. Donepezil alone and combined with LLR induced marked improvement in measures of speech production (Correct Information Units/minute during picture description, and repetition of word lists, idiomatic-novel phrases and sentences). Greater benefits were observed after combined therapy and the obtained gains in speech production remained well-above baseline scores even four months after combined therapy interruption. Longitudinal DTI showed structural plasticity in the right frontal aslant tract (FAT) with both interventions and VBM additionally revealed increased grey matter density in cortical areas connected through the FAT. Donepezil alone and combined with LLR improved speech production deficits by inducing structural plastic changes in white matter tracts and grey matter areas spared by the lesion in the injured hemisphere. Conclusions: Cholinergic modulation and intensive verbal repetition-imitation therapy improve speech production deficits in crossed conduction aphasia by inducing right hemisphere structural plasticity. Conclusions: MSRT become a simultaneous training of attention, auditory and visual input processing with the activation of different semantic fields, STM, executive processing, and language production. Treatment with donepezil has a positive effect in communication skills of CA patient. We observe a summative effect between donepezil and MSRT. The improvement associates neuroplasticity changes in neuroimaging.In the past two decades, single-case studies evaluated the effect of massed repetition training to improve speech production and short-term memory deficits in conduction aphasia (CA). Improvements were reported in treated language and memory domains with modest generalisation of gains to spontaneous speech or auditory comprehension. Although these results are encouraging, sentence repetition training has not been compared with distributed speech-language therapy, and no studies have examined the role of pharmacological interventions to enhance gains promoted by these behavioural interventions in CA. To explore repetition and imitation in the context of neural basis and treatment of aphasia, we developed three studies (STUDY 1, 2 & 3). Study 1: The effects of massed sentence repetition therapy (MSRT) were compared to those of distributed speech-language therapy (DSLT) in measures of verbal output, short-term memory and repetition in patients with chronic post-stroke CA receiving treatment with the cholinesterase inhibitor donepezil (DP). Both interventions improved performance in speech production tasks, but better improvements were found with DP-MSRT than with DP-DSLT. Larger treatment effects were found for DP-MSRT in comparison with baselines and DP-DSLT in repetition of word pairs and triplets, and novel and experimental sentences with generalisation of gains to aphasia severity, connected speech and non-treated control sentences

Targeted proteomics in urinary extracellular vesicles identifies biomarkers for diagnosis and prognosis of prostate cancer

Altres ajuts: The study was supported by grants AECC-JB-2013-02 of Asociación Española Contra el Cáncer, 7th Framework Programe, IRSES (PROTBIOFLUID −269285) - Belgium, pre-doctoral fellowship of Vall d'Hebron Research Institute (VHIR) and cofinanced by the European Regional Development Fund(ERDF).Rapid and reliable diagnosis of prostate cancer (PCa) is highly desirable as current used methods lack specificity. In addition, identification of PCa biomarkers that can classify patients into high- and low-risk groups for disease progression at early stage will improve treatment decision-making. Here, we describe a set of protein-combination panels in urinary extracellular vesicles (EVs), defined by targeted proteomics and immunoblotting techniques that improve early non-invasive detection and stratification of PCa patients.We report a two-protein combination in urinary EVs that classifies benign and PCa patients (ADSV-TGM4), and a combination of five proteins able to significantly distinguish between high- and low-grade PCa patients (CD63-GLPK5-SPHM-PSA-PAPP). Proteins composing the panels were validated by immunohistochemistry assays in tissue microarrays (TMAs) confirming a strong link between the urinary EVs proteome and alterations in PCa tissues. Moreover, ADSV and TGM4 abundance yielded a high diagnostic potential in tissue and promising TGM4 prognostic power. These results suggest that the proteins identified in urinary EVs distinguishing high- and low grade PCa are a reflection of histological changes that may be a consequence of their functional involvement in PCa development. In conclusion, our study resulted in the identification of protein-combination panels present in urinary EVs that exhibit high sensitivity and specificity for PCa detection and patient stratification. Moreover, our study highlights the potential of targeted proteomic approaches-such as selected reaction monitoring (SRM)-as diagnostic assay for liquid biopsies via urinary EVs to improve diagnosis and prognosis of suspected PCa patients

Targeted proteomics in urinary extracellular vesicles identifies biomarkers for diagnosis and prognosis of prostate cancer

Rapid and reliable diagnosis of prostate cancer (PCa) is highly desirable as current used methods lack specificity. In addition, identification of PCa biomarkers that can classify patients into high- and low-risk groups for disease progression at early stage will improve treatment decision-making. Here, we describe a set of protein-combination panels in urinary extracellular vesicles (EVs), defined by targeted proteomics and immunoblotting techniques that improve early non-invasive detection and stratification of PCa patients.We report a two-protein combination in urinary EVs that classifies benign and PCa patients (ADSV-TGM4), and a combination of five proteins able to significantly distinguish between high- and low-grade PCa patients (CD63-GLPK5-SPHM-PSA-PAPP). Proteins composing the panels were validated by immunohistochemistry assays in tissue microarrays (TMAs) confirming a strong link between the urinary EVs proteome and alterations in PCa tissues. Moreover, ADSV and TGM4 abundance yielded a high diagnostic potential in tissue and promising TGM4 prognostic power. These results suggest that the proteins identified in urinary EVs distinguishing high- and low grade PCa are a reflection of histological changes that may be a consequence of their functional involvement in PCa development. In conclusion, our study resulted in the identification of protein-combination panels present in urinary EVs that exhibit high sensitivity and specificity for PCa detection and patient stratification. Moreover, our study highlights the potential of targeted proteomic approaches-such as selected reaction monitoring (SRM)-as diagnostic assay for liquid biopsies via urinary EVs to improve diagnosis and prognosis of suspected PCa patients

Aging-related tau astrogliopathy (ARTAG): not only tau phosphorylation in astrocytes

Aging-related tau astrogliopathy (ARTAG) is defined by the presence of two types of tau-bearing astrocytes: thorn-shaped astrocytes (TSAs) and granular/fuzzy astrocytes in the brain of old-aged individuals. The present study is focused on TSAs in rare forms of ARTAG with no neuronal tau pathology or restricted to entorhinal and transentorhinal cortices, to avoid bias from associated tauopathies. TSAs show 4Rtau phosphorylation at several specific sites and abnormal tau conformation, but they lack ubiquitin and they are not immunostained with tau-C3 antibodies which recognize truncated tau at Asp421. Astrocytes in ARTAG have atrophic processes, reduced glial fibrillary acidic protein (GFAP) and increased superoxide dismutase 2 (SOD2) immunoreactivity. Gel electrophoresis and western blotting of sarkosyl-insoluble fractions reveal a pattern of phospho-tau in ARTAG characterized by two bands of 68 and 64 kDa, and several middle bands between 35 and 50 kDa which differ from what is seen in AD. Phosphoproteomics of dissected vulnerable regions identifies an increase of phosphorylation marks in a large number of proteins in ARTAG compared with controls. GFAP, aquaporin 4, several serine-threonine kinases, microtubule associated proteins and other neuronal proteins are among the differentially phosphorylated proteins in ARTAG thus suggesting a hyper-phosphorylation background that affects several molecules, including many kinases and proteins from several cell compartments and various cell types. Finally, present results show for the first time that tau seeding is produced in neurons of the hippocampal complex, astrocytes, oligodendroglia and along fibers of the corpus callosum, fimbria and fornix following inoculation into the hippocampus of wild type mice of sarkosyl-insoluble fractions enriched in hyper-phosphorylated tau from selected ARTAG cases. These findings show astrocytes as crucial players of tau seeding in tauopathies

The OTELO survey: A case study of [O III] lambda 4959,5007 emitters at z=0.83

Context. The OSIRIS Tunable Filter Emission Line Object (OTELO) survey is a very deep, blind exploration of a selected region of the Extended Groth Strip and is designed for finding emission-line sources (ELSs). The survey design, observations, data reduction, astrometry, and photometry, as well as the correlation with ancillary data used to obtain a final catalogue, including photo-z estimates and a preliminary selection of ELS, were described in a previous contribution. Aims. Here, we aim to determine the main properties and luminosity function (LF) of the [O III] ELS sample of OTELO as a scientific demonstration of its capabilities, advantages, and complementarity with respect to other surveys. Methods. The selection and analysis procedures of ELS candidates obtained using tunable filter pseudo-spectra are described. We performed simulations in the parameter space of the survey to obtain emission-line detection probabilities. Relevant characteristics of [O III] emitters and the LF ([O III]), including the main selection biases and uncertainties, are presented. Results. From 541 preliminary emission-line source candidates selected around z = 0.8, a total of 184 sources were confirmed as [O III] emitters. Consistent with simulations, the minimum detectable line flux and equivalent width in this ELS sample are ∼5 × 10−19 erg s−1 cm2 and ∼6 Å, respectively. We are able to constrain the faint-end slope (α = −1.03 ± 0.08) of the observed LF ([O III]) at a mean redshift of z = 0.83. This LF reaches values that are approximately ten times lower than those from other surveys. The vast majority (84%) of the morphologically classified [O III] ELSs are disc-like sources, and 87% of this sample is comprised of galaxies with stellar masses of M⋆ <  1010 M⊙

Characteristics of patients with type 2 diabetes mellitus newly treated with GLP-1 receptor agonists (CHADIG Study): a cross-sectional multicentre study in Spain

Objective: Several glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1Ra) have been made recently available in Spain for type 2 diabetes mellitus (DM2) treatment. There are no published data on the clinical and sociodemographic profile of patients initiating treatment with GLP-1Ra in Spain. Our objective was to understand these patients' characteristics in a real-world clinical practice setting. Design: Cross-sectional observational study. Setting: Spanish specialist outpatient clinics. Participants: 403 adults with DM2 initiating GLP-1Ra treatment were included. Primary and secondary outcome measures: Sociodemographic and DM2-related clinical data, including treatment at and after GLP-1Ra initiation and comorbidities, were collected. Results: Evaluable patients (n=403; 50.9% female) were included ( July 2013 to March 2014) at 24 centres by 53 specialists (47 endocrinology, 6 internal medicine), with the following profile (value±SD): age (58.3±10.4 years), diabetes duration (9.9±7 years), body mass index (BMI; 36.2±5.5) and glycated haemoglobin (HbA1c; 8.4±1.4%); 14% had HbA1c≤7%. Previous antidiabetic treatment: 53.8% only oral antidiabetic drugs (OADs), 5.2% insulin and 40% insulin and OAD; of those receiving OAD, 35% single drug, 38.2% 2 drugs and 24% 3 drugs. Concomitant to GLP-1Ra, 55.3% were only on OAD, 36.2% on insulin and OAD, and 7.2% only on insulin. Of those receiving OAD, the GLP-1Ra was mainly associated with 1 drug (65%) or 2 drugs (31.8%). GLP-1Ra are frequently added to existing antidiabetic drugs, with dipeptidyl peptidase-4 inhibitors being the OAD most frequently switched (45% receiving 1 before starting GLP-1Ra, only 2.7% receiving it concomitantly). Conclusions: In Spain, GLP-1Ra therapy is usually started in combination with OADs or OADs and insulin. These drugs are used in relatively young patients often not reaching therapeutic goals with other treatment combinations, roughly a decade after diagnosis and with a relatively high BMI. The latter could be explaine

Ruxolitinib in refractory acute and chronic graft-versus-host disease : a multicenter survey study

Graft-versus-host disease is the main cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation. First-line treatment is based on the use of high doses of corticosteroids. Unfortunately, second-line treatment for both acute and chronic graft-versus-host disease, remains a challenge. Ruxolitinib has been shown as an effective and safe treatment option for these patients. Seventy-nine patients received ruxolitinib and were evaluated in this retrospective and multicenter study. Twenty-three patients received ruxolitinib for refractory acute graft-versus-host disease after a median of 3 (range 1-5) previous lines of therapy. Overall response rate was 69.5% (16/23) which was obtained after a median of 2 weeks of treatment, and 21.7% (5/23) reached complete remission. Fifty-six patients were evaluated for refractory chronic graft-versus-host disease. The median number of previous lines of therapy was 3 (range 1-10). Overall response rate was 57.1% (32/56) with 3.5% (2/56) obtaining complete remission after a median of 4 weeks. Tapering of corticosteroids was possible in both acute (17/23, 73%) and chronic graft-versus-host disease (32/56, 57.1%) groups. Overall survival was 47% (CI: 23-67%) at 6 months for patients with aGVHD (62 vs 28% in responders vs non-responders) and 81% (CI: 63-89%) at 1 year for patients with cGVHD (83 vs 76% in responders vs non-responders). Ruxolitinib in the real life setting is an effective and safe treatment option for GVHD, with an ORR of 69.5% and 57.1% for refractory acute and chronic graft-versus-host disease, respectively, in heavily pretreated patients

The Fourteenth Data Release of the Sloan Digital Sky Survey: First Spectroscopic Data from the extended Baryon Oscillation Spectroscopic Survey and from the second phase of the Apache Point Observatory Galactic Evolution Experiment

The fourth generation of the Sloan Digital Sky Survey (SDSS-IV) has been in operation since July 2014. This paper describes the second data release from this phase, and the fourteenth from SDSS overall (making this, Data Release Fourteen or DR14). This release makes public data taken by SDSS-IV in its first two years of operation (July 2014-2016). Like all previous SDSS releases, DR14 is cumulative, including the most recent reductions and calibrations of all data taken by SDSS since the first phase began operations in 2000. New in DR14 is the first public release of data from the extended Baryon Oscillation Spectroscopic Survey (eBOSS); the first data from the second phase of the Apache Point Observatory (APO) Galactic Evolution Experiment (APOGEE-2), including stellar parameter estimates from an innovative data driven machine learning algorithm known as "The Cannon"; and almost twice as many data cubes from the Mapping Nearby Galaxies at APO (MaNGA) survey as were in the previous release (N = 2812 in total). This paper describes the location and format of the publicly available data from SDSS-IV surveys. We provide references to the important technical papers describing how these data have been taken (both targeting and observation details) and processed for scientific use. The SDSS website (www.sdss.org) has been updated for this release, and provides links to data downloads, as well as tutorials and examples of data use. SDSS-IV is planning to continue to collect astronomical data until 2020, and will be followed by SDSS-V.Comment: SDSS-IV collaboration alphabetical author data release paper. DR14 happened on 31st July 2017. 19 pages, 5 figures. Accepted by ApJS on 28th Nov 2017 (this is the "post-print" and "post-proofs" version; minor corrections only from v1, and most of errors found in proofs corrected

The genomes of two key bumblebee species with primitive eusocial organization

Background: The shift from solitary to social behavior is one of the major evolutionary transitions. Primitively eusocial bumblebees are uniquely placed to illuminate the evolution of highly eusocial insect societies. Bumblebees are also invaluable natural and agricultural pollinators, and there is widespread concern over recent population declines in some species. High-quality genomic data will inform key aspects of bumblebee biology, including susceptibility to implicated population viability threats. Results: We report the high quality draft genome sequences of Bombus terrestris and Bombus impatiens, two ecologically dominant bumblebees and widely utilized study species. Comparing these new genomes to those of the highly eusocial honeybee Apis mellifera and other Hymenoptera, we identify deeply conserved similarities, as well as novelties key to the biology of these organisms. Some honeybee genome features thought to underpin advanced eusociality are also present in bumblebees, indicating an earlier evolution in the bee lineage. Xenobiotic detoxification and immune genes are similarly depauperate in bumblebees and honeybees, and multiple categories of genes linked to social organization, including development and behavior, show high conservation. Key differences identified include a bias in bumblebee chemoreception towards gustation from olfaction, and striking differences in microRNAs, potentially responsible for gene regulation underlying social and other traits. Conclusions: These two bumblebee genomes provide a foundation for post-genomic research on these key pollinators and insect societies. Overall, gene repertoires suggest that the route to advanced eusociality in bees was mediated by many small changes in many genes and processes, and not by notable expansion or depauperation