Anomalous self-experiences are related to general cognition deficits in schizophrenia.

Anomalous self-experiences (ASEs) are prevalent in schizophrenia, but its underpinnings are not completely understood. Given the likely complex substrate of the experience of the self, neurocognitive functions requiring coordinate cerebral activity may relate to ASEs. Moreover, cognitive deficits functioning may be involved in the link between self-experience disturbances and some aspects of social dysfunction in schizophrenia. We have assessed ASEs in 41 schizophrenia patients (11 first episodes) using the Inventory of Psychotic-Like Anomalous Self-Experiences (IPASE), and the general cognition using the Brief Assessment of Cognition in Schizophrenia (BACS). Besides, social cognition was assessed using two complementary tools Meyer, Salovey and Caruso Emotional Intelligence Test (MSCEIT) and GEOPTE (Grupo Español para la Optimización del Tratamiento de la Esquizofrenia). The results revealed that Self-awareness/presence and Somatization IPASE scores were inversely explained by motor speed in the BACS; Consciousness IPASE scores were inversely explained by problem solving performance in the BACS. These data reveal a significant relationship between certain domains of general cognition and anomalous self-experiences, that may be useful in further investigation on the substrates of ASEs.

Analysis of KCNH2 and CACNA1C schizophrenia risk genes on EEG functional network modulation during an auditory odd-ball task.

A deficit in task-related functional connectivity modulation from electroencephalogram (EEG) has been described in schizophrenia. The use of measures of neuronal connectivity as an intermediate phenotype may allow identifying genetic factors involved in these deficits, and therefore, establishing underlying pathophysiological mechanisms. Genes involved in neuronal excitability and previously associated with the risk for schizophrenia may be adequate candidates in relation to functional connectivity alterations in schizophrenia. The objective was to study the association of two genes of voltage-gated ion channels (CACNA1C and KCNH2) with the functional modulation of the cortical networks measured with EEG and graph-theory parameter during a cognitive task, both in individuals with schizophrenia and healthy controls. Both CACNA1C (rs1006737) and KCNH2 (rs3800779) were genotyped in 101 controls and 50 schizophrenia patients. Small-world index (SW) was calculated from EEG recorded during an odd-ball task in two different temporal windows (pre-stimulus and response). Modulation was defined as the difference in SW between both windows. Genetic, group and their interaction effects on SW in the pre-stimulus window and in modulation were evaluated using ANOVA. The CACNA1C genotype was not associated with SW properties. KCNH2 was significantly associated with SW modulation. Healthy subjects showed a positive SW modulation irrespective of the KCNH2 genotype, whereas within patients allele-related differences were observed. Patients carrying the KCNH2 risk allele (A) presented a negative SW modulation and non-carriers showed SW modulation similar to the healthy subjects. Our data suggest that KCNH2 genotype contributes to the efficient modulation of brain electrophysiological activity during a cognitive task in schizophrenia patients.

Structural connectivity in schizophrenia and bipolar disorder: Effects of chronicity and antipsychotic treatment.

Previous studies based on graph theory parameters applied to diffusion tensor imaging support an alteration of the global properties of structural connectivity network in schizophrenia. However, the specificity of this alteration and its possible relation with chronicity and treatment have received small attention. We have assessed small-world (SW) and connectivity strength indexes of the structural network built using fractional anisotropy values of the white matter tracts connecting 84 cortical and subcortical regions in 25 chronic and 18 first episode (FE) schizophrenia and 24 bipolar patients and 28 healthy controls. Chronic schizophrenia and bipolar patients showed significantly smaller SW and connectivity strength indexes in comparison with controls and FE patients. SW reduction was driven by increased averaged path-length (PL) values. Illness duration but not treatment doses were negatively associated with connectivity strength, SW and PL in patients. Bipolar patients exposed to antipsychotics did not differ in SW or connectivity strength from bipolar patients without such an exposure. Executive functions and social cognition were related to SW index in the schizophrenia group. Our results support a role for chronicity but not treatment in structural network alterations in major psychoses, which may not differ between schizophrenia and bipolar disorder, and may hamper cognition.

Síndrome opsoclonus-mioclonus secundario a intoxicación por duloxetina / Opsoclonus-myoclonus syndrome secondary to duloxetine poisoning

Introducción: El síndrome opsoclonus-mioclonus es una entidad poco frecuente, de origen autoinmune y que puede aparecer a cualquier edad, siendo mucho más frecuente en la edad pediátrica. Su etiología es muy diversa, frecuentemente paraneoplásica o de origen infeccioso. Los casos secundarios a intoxicación por drogas o medicamentos son infrecuentes. Caso clínico: Mujer de 43 años valorada por Psiquiatría de Enlace por sobreingesta de 80 comprimidos de duloxetina 30mg. Acude a Urgencias por un cuadro de inicio brusco de visión borrosa, temblor generalizado, dificultad para caminar y alucinaciones visuales. Ingresa en Neurología por sospecha de síndrome opsoclonus-mioclonus, recibe tratamiento esteroideo precoz, tras el que se observa mejoría clínica y recuperación temprana. Las pruebas complementarias resultan normales, excepto los niveles de duloxetina, que están muy por encima del rango normal. Discusión: El síndrome opsoclonus-mioclonus es un trastorno del movimiento infrecuente, que requiere una correcta evaluación debido a la posibilidad de estar relacionado con neoplasias subyacentes

Introduction: Opsoclonus-myoclonus syndrome is a rare entity of autoimmune origin, which can appear at any age, being much more common in paediatric patients. Its aetiology is very diverse, often of para-neoplastic or of infectious origin. Cases secondary to poisoning by drugs or other kind of medication are uncommon. Clinical case: A 43 year-old woman was examined by Liaison Psychiatry due to an overdose of 80 tablets of duloxetine 30mg. The patient went to the Emergency Service due to a sudden onset of blurred vision, general tremor, difficulty to walk, and visual hallucinations. She was admitted to the Neurology Department due to a clinical suspicion of opsoclonus-myoclonus syndrome. She received early steroid treatment, after which both clinical improvement and early recovery were observed. Complementary tests were normal except for duloxetine levels, which were found to be well above their normal range. Discussion: Opsoclonus-myoclonus syndrome is an uncommon disorder, which requires a correct diagnostic evaluation and analysis, as it could possibly be related to underlying neoplasms

Monodisperse nanoparticles from self-assembling amphiphilic cyclodextrins: modulable tools for the encapsulation and controlled release of pharmaceuticals.

Selective chemical functionalization of cyclodextrins (CDs) is a readily amenable methodology to produce amphiphilic macromolecules endowed with modulable self-organizing capabilities. Herein, the synthesis of well-defined amphiphilic CD derivatives, with a "skirt-type" architecture, that incorporate long-chain fatty esters at the secondary hydroxyl rim and a variety of chemical functionalities (e. g. iodo, bromo, azido, cysteaminyl or isothiocyanato) at the primary hydroxyls rim is reported. Nanoprecipitation of the new CD facial amphiphiles, or binary mixtures of them, resulted in nanoparticles with average hydrodynamic diameters ranging from 100 to 240 nm that were stable in suspension for several months. The precise size, zeta potential and topology of the nanoparticles are intimately dependent on the functionalization pattern at the CD scaffold. Highly efficient molecular encapsulation capabilities of poorly bioavailable drugs such as diazepam (DZ) were demonstrated for certain derivatives, the drug release profile being dependent on the type of formulation (nanospheres or nanocapsules). The efficiency and versatility of the synthetic strategy, together with the possibility of exploiting the reactivity of the functional groups at the nanoparticle surface, offer excellent opportunities to further manipulate the carrier capabilities of this series of amphiphilic CDs from a bottom-up approach.

Probing carbohydrate-lectin recognition in heterogeneous environments with monodisperse cyclodextrin-based glycoclusters.

A series of ß-cyclodextrin (ßCD)-scaffolded glycoclusters exposing heterogeneous yet perfectly controlled displays of α-mannosyl (α-Man) and ß-lactosyl (ß-Lact) antennas were synthesized to probe the mutual influence of varying densities of the saccharide motifs in the binding properties toward different plant lectins. Enzyme-linked lectin assay (ELLA) data indicated that the presence of ß-Lact residues reinforced binding of α-Man to the mannose-specific lectin concanavalin A (Con A) even though homogeneous ß-Lact clusters are not recognized at all by this lectin, supporting the existence of synergic recognition mechanisms (heterocluster effect). Conversely, the presence of α-Man motifs in the heteroglycoclusters also resulted in a binding-enhancing effect of ß-Lact toward peanut agglutinin (PNA), a lectin strongly binding multivalent lactosides but having no detectable affinity for α-mannopyranosides, for certain architectural arrangements. Two-site, sandwich-type ELLA data corroborated the higher lectin clustering efficiency of heterogeneous glycoclusters compared with homogeneous displays of the putative sugar ligand with identical valency. A turbidity assay was also consistent with the previous observations. Most revealingly, the lectin cross-linking ability of heterogeneous glycoclusters was sensitive to the presence of high concentrations of the non-ligand sugar, strongly suggesting that "mismatching" saccharide motifs may modulate carbohydrate-lectin specific recognition in a lectin-dependent manner when present in highly dense displays together with the "matching" ligand, a situation frequently encountered in biological systems.

Comparative studies on lectin-carbohydrate interactions in low and high density homo- and heteroglycoclusters.

A versatile synthetic procedure to construct series of high- and low-density homo- and heteroglycoclusters is reported. The binding properties of these synthetic multivalent glycoconjugates to concanavalin A (Con A), a model lectin, have been assessed by using a range of competitive and non-competitive binding assays including enzyme-linked lectin assays (ELLA), isothermal titration microcalorimetry (ITC) and surface plasmon resonance (SPR). In all cases, highly dense glycoclusters showed a substantial amplification of the lectin-binding strength in comparison with low-density counterparts. Interestingly, highly-dense glycoligand presentations, regardless of their homo- or heteroglycoligand pattern, furnished similar Con A binding properties, supporting the existence of a synergic effect (heterocluster effect) due to secondary interactions of "non-active" structural motifs in the presence of a certain density of "active" glycoligands.

Polycationic amphiphilic cyclodextrins for gene delivery: synthesis and effect of structural modifications on plasmid DNA complex stability, cytotoxicity, and gene expression.

A molecular-diversity-oriented approach for the preparation of well-defined polycationic amphiphilic cyclodextrins (paCDs) as gene-delivery systems is reported. The synthetic strategy takes advantage of the differential reactivity of primary versus secondary hydroxyl groups on the CD torus to regioselectively decorate each rim with cationic elements and lipophilic tails, respectively. Both the charge density and the hydrophobic-hydrophilic balance can be finely tuned in a highly symmetrical architecture that is reminiscent of both cationic lipids and cationic polymers, the two most prominent types of nonviral gene vectors. The monodisperse nature of paCDs and the modularity of the synthetic scheme are particularly well suited for structure-activity relationship studies. Gel electrophoresis revealed that paCDs self-assemble in the presence of plasmid DNA (pDNA) to provide homogeneous, stable nanoparticles (CDplexes) of 70-150 nm that fully protect pDNA from the environment. The transfection efficiency of the resulting CDplexes has been investigated in vitro on BNL-CL2 and COS-7 cell lines in the absence and presence of serum and found to be intimately dependent on architectural features. Facial amphiphilicity and the presence of a cluster of cationic and hydrogen-bonding centers for cooperative and reversible complexation of the polyanionic DNA chain is crucial to attain high transgene expression levels with very low toxicity profiles. Further enhancement of gene expression, eventually overcoming that of polyplexes from commercial polyethyleneimine (PEI) polymers (22 kDa), is achieved by building up space-oriented dendritic polycationic constructs.

Preorganized macromolecular gene delivery systems: amphiphilic beta-cyclodextrin "click clusters".

Gene delivery systems based on the beta-cyclodextrin scaffold have been synthesized by combining the copper(I)-catalyzed azide-alkyne coupling ("click chemistry") and an efficient acylation method of the secondary hydroxyls; molecular flexibility, charge density and hydrophobic-hydrophilic balance are critical parameters that can be fine-tuned by the click approach.

Rational design of cationic cyclooligosaccharides as efficient gene delivery systems.

Self-assembled cyclodextrin (CD)-DNA nanoparticles (CDplexes) exhibiting transfection efficiencies significantly higher than PEI-based polyplexes have been prepared from homogeneous seven-fold symmetric polyaminothiourea amphiphiles constructed on a beta-cyclodextrin scaffold.

Probing secondary carbohydrate-protein interactions with highly dense cyclodextrin-centered heteroglycoclusters: the heterocluster effect.

Comparison of the lectin-binding properties for highly dense beta-cyclodextrin-centered homo- and heteroglycoclusters with defined architecture provides evidence for the existence of strong synergic effects (heterocluster effect) on carbohydrate-protein recognition events.

Optimizing saccharide-directed molecular delivery to biological receptors: design, synthesis, and biological evaluation of glycodendrimer-cyclodextrin conjugates.

Dendritic beta-cyclodextrin (betaCD) derivatives bearing multivalent mannosyl ligands have been prepared and assessed for their binding efficiency toward the tetrameric plant lectin concanavalin A (Con A) and a mammalian mannose/fucose specific cell surface receptor from macrophages. The synthetic strategy exploits the reactivity between isothiocyanate and amine functionalities for the high-yielding assembly via thioureido links of the various building blocks, including host, spacer, branching, and carbohydrate ligand elements. The methodology has been applied to the preparation of a series of betaCD-polymannoside scaffolds differing in the ligand valency and geometry. This series allowed us to explore: (i) The effects of the glycodendritic architecture on the binding efficiency; (ii) the mutual influence between the cyclodextrin core and the glycodendritic moieties on the molecular inclusion and lectin-binding properties; and (iii) the consequence of inclusion complex formation, using the anticancer drug docetaxel (Taxotère) as a target guest, on biological recognition. Our results confirm the high drug solubilization capability of this new type of betaCD-dendrimer construct and indicate that subtle changes in the architecture of the conjugate may have important consequences on receptor affinity. Interestingly, the host-guest interaction can be monitored to build up supramolecular dynamic glycoclusters with increased lectin affinity. Alternatively, the information obtained from the structure-lectin-binding avidity-inclusion capability studies has been put forward in the design of very efficient molecular transporters for docetaxel based on glycodendritic CD dimers.