Selective visual attention involves dynamic interplay between attentional control systems and sensory brain structures. We used event-related functional magnetic resonance imaging (fMRI) during a ...cued spatial-attention task to dissociate brain activity related to attentional control from that related to selective processing of target stimuli. Distinct networks were engaged by attention-directing cues versus subsequent targets. Superior frontal, inferior parietal and superior temporal cortex were selectively activated by cues, indicating that these structures are part of a network for voluntary attentional control. This control biased activity in multiple visual cortical areas, resulting in selective sensory processing of relevant visual targets.
In the wake of the A/California/7/2009 H1N1 influenza pandemic vaccination campaigns in 2009-2010, an increased incidence of the chronic sleep-wake disorder narcolepsy was detected in children and ...adolescents in several European countries. Over the last decade, in-depth epidemiological and immunological studies have been conducted to investigate this association, which have advanced our understanding of the events underpinning the observed risk. Narcolepsy with cataplexy (defined as type-1 narcolepsy, NT1) is characterized by an irreversible and chronic deficiency of hypocretin peptides in the hypothalamus. The multifactorial etiology is thought to include genetic predisposition, head trauma, environmental triggers, and/or infections (including influenza virus infections), and an increased risk was observed following administration of the A/California/7/2009 H1N1 vaccine
Pandemrix
(GSK). An autoimmune origin of NT1 is broadly assumed. This is based on its strong association with a predisposing allele (the human leucocyte antigen DQB1*0602) carried by the large majority of NT1 patients, and on links with other immune-related genetic markers affecting the risk of NT1. Presently, hypotheses on the underlying potential immunological mechanisms center on molecular mimicry between hypocretin and peptides within the A/California/7/2009 H1N1 virus antigen. This molecular mimicry may instigate a cross-reactive autoimmune response targeting hypocretin-producing neurons. Local CD4
+
T-cell responses recognizing peptides from hypocretin are thought to play a central role in the response. In this model, cross-reactive DQB1*0602-restricted T cells from the periphery would be activated to cross the blood-brain barrier by rare, and possibly pathogen-instigated, inflammatory processes in the brain. Current hypotheses suggest that activation and expansion of cross-reactive T-cells by H1N1/09 influenza infection could have been amplified following the administration of the adjuvanted vaccine, giving rise to a “two-hit” hypothesis. The collective
in silico
,
in vitro
, and preclinical
in vivo
data from recent and ongoing research have progressively refined the hypothetical model of sequential immunological events, and filled multiple knowledge gaps. Though no definitive conclusions can be drawn, the mechanistical model plausibly explains the increased risk of NT1 observed following the 2009-2010 H1N1 pandemic and subsequent vaccination campaign, as outlined in this review.
Most functional imaging studies of memory retrieval investigate memory for standardized laboratory stimuli. However, naturally acquired autobiographical memories differ from memories of standardized ...stimuli in important ways. Neuroimaging studies of natural memories may reveal distinctive patterns of brain activation and may have particular value in assessing clinical disorders of memory. This study used functional magnetic resonance imaging to investigate brain activation during successful retrieval of autobiographical memories elicited by name-cued recall of family members and friends. The caudal part of the left posterior cingulate cortex was the most strongly activated region and was significantly activated in all eight subjects studied. Most subjects also showed significant activation of the left anterior orbitomedial, anterior middle frontal, precuneus, cuneus, and posterior inferior parietal cortices, and the right posterior cingulate and motor cortices.
Our findings are consistent with prior studies showing posterior cingulate cortex activation during autobiographical memory retrieval. This region is also consistently activated during retrieval of standardized memory stimuli when experimental designs emphasizing successful retrieval are employed. Our results support the hypothesis that the posterior cingulate cortex plays an important role in successful memory retrieval. The posterior cingulate cortex has strong reciprocal connections with entorhinal and parahippocampal cortices. Studies of early Alzheimer’s disease, temporal lobectomy, and hypoxic amnesia show that hypometabolism of the posterior cingulate cortex is an early and prominent indicator of pathology in these patients. Our findings suggest that autobiographical memory retrieval tasks could be used to probe the functional status of the posterior cingulate cortex in patients with early Alzheimer’s disease or at risk for that condition.
Introduction
Treatment-resistant schizophrenia (TRS) represents a major clinical issue, characterized by worse psychopathological outcome, a more disrupted neurobiological substrate and higher ...healthcare costs. Cognitive impairment is a core feature of schizophrenia, strongly associated with patients’ functional outcome. Different studies showed that TRS patients exhibit poorer neurocognitive performance, particularly on verbal domains. To date Cognitive Remediation Therapy (CRT) represents the best available tool for treating cognitive deficits in schizophrenia. However, CRT outcomes are highly heterogeneous and significant treatment predictors are still lacking.
Objectives
To investigate possible differences of CRT outcome among patients with schizophrenia, stratified according to antipsychotic response (TRSs vs. first-line responders - FLRs).
Methods
150 patients with schizophrenia, (95 FLRs, 55 TRSs) were assessed for neurocognition with BACS and WCST at baseline and after CRT. General Linear Models (GLMs) were performed to investigate possible differences between groups on basal cognition and CRT outcome (Cohen’s d Effect Size).
Results
At baseline, GLMs showed significant differences in Verbal Memory (F=4,66; p=0,03) and WCST–executive functions (F=5,59; p=0,02), both worse in TRS group. Effecr Sizes of CRT outcome resulted significantly different in domains of Verbal Memory (F=4,68; p=0,03) and WCST–executive functions (F=4,62; p=0,03), with greater improvements among TRS patients.
Conclusions
This is the first study to indicate treatment-resistance as a possible predictor of CRT outcome in schizophrenia. Moreover, we observed that CRT resulted able to fill the cognitive gap between treatment groups. Thus, these results further highlight the importance of early cognitive interventions in order to reduce the neuropsychological and functional burden associated with the disease, especially for TRS patients.
Disclosure
No significant relationships.
Induced pluripotent stem cells (iPSC) offer a unique opportunity for developmental studies, disease modeling and regenerative medicine approaches in humans. The aim of our study was to create an in ...vitro 'patient-specific cell-based system' that could facilitate the screening of new therapeutic molecules for the treatment of catecholaminergic polymorphic ventricular tachycardia (CPVT), an inherited form of fatal arrhythmia. Here, we report the development of a cardiac model of CPVT through the generation of iPSC from a CPVT patient carrying a heterozygous mutation in the cardiac ryanodine receptor gene (RyR2) and their subsequent differentiation into cardiomyocytes (CMs). Whole-cell patch-clamp and intracellular electrical recordings of spontaneously beating cells revealed the presence of delayed afterdepolarizations (DADs) in CPVT-CMs, both in resting conditions and after β-adrenergic stimulation, resembling the cardiac phenotype of the patients. Furthermore, treatment with KN-93 (2-N-(2-hydroxyethyl)-N-(4methoxybenzenesulfonyl)amino-N-(4-chlorocinnamyl)-N-methylbenzylamine), an antiarrhythmic drug that inhibits Ca(2+)/calmodulin-dependent serine-threonine protein kinase II (CaMKII), drastically reduced the presence of DADs in CVPT-CMs, rescuing the arrhythmic phenotype induced by catecholaminergic stress. In addition, intracellular calcium transient measurements on 3D beating clusters by fast resolution optical mapping showed that CPVT clusters developed multiple calcium transients, whereas in the wild-type clusters, only single initiations were detected. Such instability is aggravated in the presence of isoproterenol and is attenuated by KN-93. As seen in our RyR2 knock-in CPVT mice, the antiarrhythmic effect of KN-93 is confirmed in these human iPSC-derived cardiac cells, supporting the role of this in vitro system for drug screening and optimization of clinical treatment strategies.
To address the need for asthma self-management in pediatrics, the authors present the feasibility of a mobile health (mHealth) platform built on their prior work in an asthmatic adult and child. ...Real-time asthma attack risk was assessed through physiological and environmental sensors. Data were sent to a cloud via a smartwatch application (app) using Health Insurance Portability and Accountability Act (HIPAA)-compliant cryptography and combined with online source data. A risk level (high, medium or low) was determined using a random forest classifier and then sent to the app to be visualized as animated dragon graphics for easy interpretation by children. The feasibility of the system was first tested on an adult with moderate asthma, then usability was examined on a child with mild asthma over several weeks. It was found during feasibility testing that the system is able to assess asthma risk with 80.10 ± 14.13% accuracy. During usability testing, it was able to continuously collect sensor data, and the child was able to wear, easily understand and enjoy the use of the system. If tested in more individuals, this system may lead to an effective self-management program that can reduce hospitalization in those who suffer from asthma.
Neurocognitive and social cognitive impairments represent important treatment targets in schizophrenia, as they are significant predictors of functional outcome. Different rehabilitative ...interventions have recently been developed, addressing both cognitive and psychosocial domains. Although promising, results are still heterogeneous and predictors of treatment outcome are not yet identified. In this study we evaluated the efficacy of two newly developed social cognitive interventions, respectively based on the use of videotaped material and comic strips, combined with domain-specific Cognitive Remediation Therapy (CRT). We also analysed possible predictors of training outcome, including basal neurocognitive performance, the degree of cognitive improvement after CRT and psychopathological variables.
Seventy-five patients with schizophrenia treated with CRT, were randomly assigned to: social cognitive training (SCT) group, Theory of Mind Intervention (ToMI) group, and active control group (ACG).
ANOVAs showed that SCT and ToMI groups improved significantly in ToM measures, whereas the ACG did not. We reported no influences of neuropsychological measures and improvement after CRT on changes in ToM. Both paranoid and non-paranoid subjects improved significantly after ToMI and SCT, without differences between groups, despite the better performance in basal ToM found among paranoid patients. In the ACG only non-paranoid patients showed an improvement in non-verbal ToM.
Results showed that both ToMI and SCT are effective in improving ToM in schizophrenia with no influence of neuropsychological domains. Our data also suggest that paranoid symptoms may discriminate between different types of ToM difficulties in schizophrenia.
The human commensal Staphylococcus aureus (SA) is a leading cause of skin/soft tissue and surgical-site infections, and bacteremia. Functional antibodies and T-cell-mediated immunity, particularly ...Th1/Th17 responses, are thought to mediate protection. Vaccine development may be hindered by modulation of vaccine-induced T cells by pathogen-activated immunoregulatory responses, e.g., via IL-10.
We screened SA proteins for CD4
+
T-cell-activating and IL-10/IL-17-inducing capacities using healthy donor-derived PBMCs. Responses were characterized (Th1/Th17/Th22/immunosuppressive IL-10-producing cells) using intracellular cytokine staining and flow cytometry. Phenotypic plasticity of Th1/Th17 cells was evaluated under pro- or anti-inflammatory conditions using modulatory cytokines. The impact of vaccination on SA-specific memory responses was assessed using samples from a clinical trial evaluating AS03-adjuvanted and non-adjuvanted multicomponent (CPS5/CPS8/α-toxin/ClfA) vaccines (NCT01160172).
The donors exhibited SA-specific memory T-cell responses, indicative of pre-existing immunity to SA. We identified effective activators of Th1 responses (EbhA/IsaA/SdrE/MntC/Aaa/α-toxin), and Th17 and Th1/Th17 responses (EbhA/IsaA/SdrE and, to a lesser extent, α-toxin), but not of Th22 responses or IL-10 production. MRPII, IsdA, and ClfA were inefficient CD4
+
T-cell activators in our assays. IL-10, likely produced by innate immune cells, influenced mainly Th1 cells by suppressing IFN-γ production. The memory CD4
+
T-cells observed after long-term stimulation with α-toxin and ClfA indicated that vaccination with these proteins had induced expansion of pre-existing Th1 but not Th17 responses, without apparent adjuvant effect, confirming the trial data. The Th1/Th17-driving proteins (EbhA/IsaA/SdrE) shared low IL-10-promoting abilities and restricted phenotypic plasticity under pro- and anti-inflammatory conditions.
Given the complex immunopathology and multiple virulence factors, identification of Th1/Th17-driving antigens, adjuvants and administration routes, and delineation of the role of memory responses, may advance vaccine development.
The purpose of this study was to examine the reproducibility of functional MR imaging (fMRI) activation (volume and laterality) within both inferior frontal and temporoparietal regions of interest ...for both receptive and expressive language tasks.
Ten healthy volunteers participated in fMRI experiments for 6 language tasks: verb generation, confrontation naming, semantic decision making, visual sentence comprehension, auditory sentence comprehension, and story listening. Each subject was scanned during 2 separate sessions separated by a minimum of 4 weeks. Laterality of activation was defined by laterality indices (LIs), which were calculated by 2 methods: one method based on the measured volume of activation and the other method based on the F statistic of the activation. Reproducibility was calculated by using concurrence ratios for the volume of activation (R(overlap), R(volume)) and test-retest correlation for LIs.
All tasks generated reproducible LIs within at least one of the regions of interest, but verb generation produced the highest test-retest correlations (r = 0.99) within both regions of interest. Verb generation was associated with the highest average concurrence ratios within the inferior frontal region of interest (R(overlap) = 45.2; R(volume) = 70.9). In general, the concurrence ratios were lower within the temporoparietal region of interest compared with the inferior frontal region of interest. LIs calculated with F statistics were more reproducible than the LIs calculated by activation volume.
fMRI is able to provide reproducible LIs in both inferior frontal and temporoparietal regions for assessing hemispheric dominance in language processing. The volume of activation, especially within the temporoparietal regions, is less reproducible than the laterality of activation, so the former should be used with caution.
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