The effect of a single dose of escitalopram on sensorimotor networks.

Serving as a pilot study of poststroke pharmacotherapy, the present investigation was intended to establish the effect of a single dose of escitalopram on motor task performance in normal volunteers. Ten healthy volunteers of median age 63 years including four females performed a well-studied tactile manipulation task in two fMRI sessions using a double-blind cross-over design. The sessions began approximately three hours after ingestion of 20 mg escitalopram or placebo presented in pseudorandom order. The fMRI image sequences were submitted to principal component analysis (PCA). Based on volume correlations of task-related principal components with the mean component images derived in our previous study, we established the reproducibility of two networks of sensorimotor activity proposed there. The network reflecting motor control (cerebral pattern I) appeared invariably in placebo and verum conditions. In contrast, the other network, attributed to diminished motor control due to distracting mental processing (cerebral pattern II), emerged less regularly and exhibited more variability. Second-level PCAs of both conditions confirmed the findings of the initial analysis. Specifically, it validated the dominant and invariable expression of cerebral pattern I after application of a single dose of escitalopram. Dynamic causal modeling confirmed enhanced motor output as a result of a significantly increased connectivity between primary motor cortex and dorsal premotor cortex. This pilot study suggests the promise of stimulation by a specific serotonin reuptake inhibitor in regard to recovery and preservation of motor control after stroke

The phenotypic spectrum of DYT24 due to ANO3 mutations.

Genes causing primary dystonia are rare. Recently, pathogenic mutations in the anoctamin 3 gene (ANO3) have been identified to cause autosomal dominant craniocervical dystonia and have been assigned to the dystonia locus dystonia-24 (DYT24). Here, we expand on the phenotypic spectrum of DYT24 and provide demonstrative videos. Moreover, tremor recordings were performed, and back-averaged electroencephalography, sensory evoked potentials, and C-reflex studies were carried out in two individuals who carried two different mutations in ANO3. Ten patients from three families are described. The age at onset ranged from early childhood to the forties. Cervical dystonia was the most common site of onset followed by laryngeal dystonia. The characteristic feature in all affected individuals was the presence of tremor, which contrasts DYT24 from the typical DYT6 phenotype. Tremor was the sole initial manifestation in some individuals with ANO3 mutations, leading to misdiagnosis as essential tremor. Electrophysiology in two patients with two different mutations showed co-contraction of antagonist muscles, confirming dystonia, and a 6-Hz arm tremor at rest, which increased in amplitude during action. In one of the studied patients, clinically superimposed myoclonus was observed. The duration of the myoclonus was in the range of 250 msec at about 3 Hz, which is more consistent with subcortical myoclonus. In summary, ANO3 causes a varied phenotype of young-onset or adult-onset craniocervical dystonia with tremor and/or myoclonic jerks. Patients with familial cervical dystonia who also have myoclonus-dystonia as well as patients with prominent tremor and mild dystonia should be tested for ANO3 mutations. © 2014 International Parkinson and Movement Disorder Society

Induction and Exhaustion of Lymphocytic Choriomeningitis Virus–specific Cytotoxic T Lymphocytes Visualized Using Soluble Tetrameric Major Histocompatibility Complex Class I–Peptide Complexes

This study describes the construction of soluble major histocompatibility complexes consisting of the mouse class I molecule, H-2Db, chemically biotinylated β2 microglobulin and a peptide epitope derived from the glycoprotein (GP; amino acids 33–41) of lymphocytic choriomeningitis virus (LCMV). Tetrameric class I complexes, which were produced by mixing the class I complexes with phycoerythrin-labeled neutravidin, permitted direct analysis of virus-specific cytotoxic T lymphocytes (CTLs) by flow cytometry. This technique was validated by (a) staining CD8+ cells in the spleens of transgenic mice that express a T cell receptor (TCR) specific for H-2Db in association with peptide GP33–41, and (b) by staining virus-specific CTLs in the cerebrospinal fluid of C57BL/6 (B6) mice that had been infected intracranially with LCMV-DOCILE. Staining of spleen cells isolated from B6 mice revealed that up to 40% of CD8+ T cells were GP33 tetramer+ during the initial phase of LCMV infection. In contrast, GP33 tetramers did not stain CD8+ T cells isolated from the spleens of B6 mice that had been infected 2 mo previously with LCMV above the background levels found in naive mice. The fate of virus-specific CTLs was analyzed during the acute phase of infection in mice challenged both intracranially and intravenously with a high or low dose of LCMV-DOCILE. The results of the study show that the outcome of infection by LCMV is determined by antigen load alone. Furthermore, the data indicate that deletion of virus-specific CTLs in the presence of excessive antigen is preceded by TCR downregulation and is dependent upon perforin

Robustness assessment of the ‘cooperation under resource pressure’ (CURP) model: Insights on resource availability and sharing practices among hunter-gatherers

A well-known challenge in archaeological research is the exploration of the social mechanisms that hunter-gatherers may have implemented throughout history to deal with changes in resource availability. The agent-based model (ABM) ‘cooperation under resource pressure’ (CURP) was conceived to explore food stress episodes in societies lacking a food preservation technology. It was particularly aimed at understanding how cooperative behaviours in the form of food sharing practices emerge, increase and may become the prevailing strategy in relation to changes in resource availability and expectancy of reciprocity. CURP’s main outcome is the identification of three regimes of behaviour depending on the stress level. In this work, the model’s robustness to the original selection mechanism (random tournament) is assessed, as different dynamics can lead to different persistent regimes. For that purpose, three other selection mechanisms are implemented and evaluated, to identify the prevailing states of the system. Results show that the three regimes are robust irrespective of the analysed dynamics. We consequently examine in more detail the long-term archaeological implications that these results may have.Spanish Ministry of Economy and Competitiveness (former Ministry of Science and Innovation): SimulPast Project (CSD2010- 00034 CONSOLIDER-INGENIO 2010), HAR2009-06996 and CULM Project (HAR2016- 77672-P); from the Argentine National Scientific and Technical Research Council (CONICET): Project PIP-0706; from the Wenner-Gren Foundation for Anthropological Research: Project GR7846; from the project H2020 FET OPEN RIA IBSEN/662725 and from the European Social Fund as one of the authors is the recipient of a predoctoral grant from the Department of Education of Junta de Castilla y León (Spain)

The association between prealbumin, all‐cause mortality and response to nutritional treatment in patients at nutritional risk. Secondary analysis of a randomized‐controlled trial

IntroductionDue to the shorter half-life as compared with albumin, serum prealbumin concentrations have been proposed to be useful nutritional biomarkers for the assessment of patients at nutritional risk. In a post-hoc analysis of patients at nutritional risk from a randomized-controlled nutritional trial, we therefore tested the hypothesis that (a) prealbumin is associated with higher all-cause 180-day mortality rates and that (b) individualized nutritional support compared to usual care nutrition more effectively improves survival at 30 days in patients with low prealbumin levels compared to patients with normal prealbumin levels.MethodsWe performed a pre-specified cohort study in patients included in the pragmatic, Swiss, multicenter, randomized-controlled EFFORT trial comparing the effects of individualized nutritional support with usual care. We studied low prealbumin concentrations (<0.17 g/l) in a subgroup of 517 patients from one participating centre.ResultsA total of 306 (59.2%) patients (mean age 71.9 years, 53.6% men) had low admission prealbumin levels (<0.17 g/L). There was a significant association between low prealbumin levels and mortality at 180-days [115/306 (37.6%) vs. 47/211 (22.3%), fully adjusted hazard ratio (HR) 1.59, 95%CI 1.11 to 2.28, p=0.011]. Prealbumin levels significantly improved the prognostic value of the Nutritional Risk Screening total score regarding mortality prediction at short- and long-term. The difference in mortality between patients receiving individualized nutritional support and usual care nutrition was similar for patients with low prealbumin levels compared with patients with normal prealbumin levels [HR 0.90 (95%CI 0.51 to 1.59) vs. HR 0.88 (95%CI 0.35 to 2.23)] with no evidence for interaction (p=0.823).ConclusionAmong medical inpatients at nutritional risk, low admission prealbumin levels correlated with different nutritional markers and higher mortality risk; but patients with low or high prealbumin levels had a similar benefit from nutritional support. Further studies should identify nutritional markers that help further personalize nutritional interventions.Trial RegistrationClinicalTrials.gov Identifier: NCT0251747

Resistance of MLL–AFF1-positive acute lymphoblastic leukemia to tumor necrosis factor-alpha is mediated by S100A6 upregulation

Mixed-lineage leukemia (MLL)–AFF1 (MLL–AF4)-positive acute lymphoblastic leukemia (ALL) is associated with poor prognosis, even after allogeneic hematopoietic stem cell transplantation (allo-HSCT). The resistance to graft-versus-leukemia (GVL) effects may be responsible for the poor effect of allo-HSCT on MLL–AFF1-positive ALL. Cytotoxic effector mechanisms mediated by tumor necrosis factor-alpha (TNF-α) was reported to contribute to the GVL effect. We showed that MLL–AFF1-positive ALL cell lines are resistant to TNF-α. To examine the mechanism of resistance to TNF-α of MLL–AFF1-positive leukemia, we focused on S100A6 as a possible factor. Upregulation of S100A6 expression and inhibition of the p53–caspase 8–caspase 3 pathway were observed only in MLL–AFF1-positive ALL cell lines in the presence of TNF-α. The effect of S100A6 on resistance to TNF-α by inhibition of the p53–caspase 8–caspase 3 pathway of MLL–AFF1-positive ALL cell lines were also confirmed by analysis using small interfering RNA against S100A6. This pathway was also confirmed in previously established MLL–AFF1 transgenic mice. These results suggest that MLL–AFF1-positive ALL escapes from TNF-α-mediated apoptosis by upregulation of S100A6 expression, followed by interfering with p53–caspase 8–caspase 3 pathway. These results suggest that S100A6 may be a promising therapeutic target for MLL–AFF1-positive ALL in combination with allo-HSCT