Early maladaptive schemas and suicidal risk in inpatients with bipolar disorder

The present study aimed to assess the associations of early maladaptive schemas (EMSs) and clinical factors (hypomanic/manic and depressive symptoms) with suicidal risk (current suicidal ideation and lifetime suicide attempts) in inpatients with bipolar disorder (BD). One hundred inpatients with BD completed the Young Schema Questionnaire-Short Form (YSQ-SF), the Bipolar Depression Rating Scale (BDRS), the Young Mania Rating Scale (YMRS), and the Beck Scale for Suicide Ideation (BSSI). 59 of patients had lifetime suicide attempts and 59 showed high suicidal risk (BSSI>/=6). BD patients with lifetime suicide attempts had higher scores on the entitlement and social isolation schemas, depression, and hypomanic/manic symptoms than those without such attempts. Patients with high suicidal risk had higher levels of depressive and hypomanic/manic symptoms as well as some EMSs than those without high suicidal risk. Logistic regression analyses revealed that hypomanic/manic symptoms as well as the entitlement and defectiveness schemas were significantly associated with current suicidal ideation. Also, the entitlement and social isolation schemas were associated with lifetime suicide attempts. These results suggest that the entitlement, social isolation, and defectiveness schemas may relate to suicidal risk in patients with BD

The non-octarepeat copper binding site of the prion protein is a key regulator of prion conversion

The conversion of the prion protein (PrP(C)) into prions plays a key role in transmissible spongiform encephalopathies. Despite the importance for pathogenesis, the mechanism of prion formation has escaped detailed characterization due to the insoluble nature of prions. PrP(C) interacts with copper through octarepeat and non-octarepeat binding sites. Copper coordination to the non-octarepeat region has garnered interest due to the possibility that this interaction may impact prion conversion. We used X-ray absorption spectroscopy to study copper coordination at pH 5.5 and 7.0 in human PrP(C) constructs, either wild-type (WT) or carrying pathological mutations. We show that mutations and pH cause modifications of copper coordination in the non-octarepeat region. In the WT at pH 5.5, copper is anchored to His96 and His111, while at pH 7 it is coordinated by His111. Pathological point mutations alter the copper coordination at acidic conditions where the metal is anchored to His111. By using in vitro approaches, cell-based and computational techniques, we propose a model whereby PrP(C) coordinating copper with one His in the non-octarepeat region converts to prions at acidic condition. Thus, the non-octarepeat region may act as the long-sought-after prion switch, critical for disease onset and propagation

Exacerbation of experimental autoimmune encephalomyelitis in prion protein (PrPc)-null mice: evidence for a critical role of the central nervous system

<p>Abstract</p> <p>Background</p> <p>The cellular prion protein (PrPc) is a host-encoded glycoprotein whose transconformation into PrP scrapie (PrPSc) initiates prion diseases. The role of PrPc in health is still obscure, but many candidate functions have been attributed to the protein, both in the immune and the nervous systems. Recent data show that experimental autoimmune encephalomyelitis (EAE) is worsened in mice lacking PrPc. Disease exacerbation has been attributed to T cells that would differentiate into more aggressive effectors when deprived of PrPc. However, alternative interpretations such as reduced resistance of neurons to autoimmune insult and exacerbated gliosis leading to neuronal deficits were not considered.</p> <p>Method</p> <p>To better discriminate the contribution of immune cells versus neural cells, reciprocal bone marrow chimeras with differential expression of PrPc in the lymphoid or in the central nervous system (CNS) were generated. Mice were subsequently challenged with MOG_35-55peptide and clinical disease as well as histopathology were compared in both groups. Furthermore, to test directly the T cell hypothesis, we compared the encephalitogenicity of adoptively transferred PrPc-deficient versus PrPc-sufficient, anti-MOG T cells.</p> <p>Results</p> <p>First, EAE exacerbation in PrPc-deficient mice was confirmed. Irradiation exacerbated EAE in all the chimeras and controls, but disease was more severe in mice with a PrPc-deleted CNS and a normal immune system than in the reciprocal construction. Moreover, there was no indication that anti-MOG responses were different in PrPc-sufficient and PrPc-deficient mice. Paradoxically, PrPc-deficient anti-MOG 2D2 T cells were less pathogenic than PrPc-expressing 2D2 T cells.</p> <p>Conclusions</p> <p>In view of the present data, it can be concluded that the origin of EAE exacerbation in PrPc-ablated mice resides in the absence of the prion protein in the CNS. Furthermore, the absence of PrPc on both neural and immune cells does not synergize for disease worsening. These conclusions highlight the critical role of PrPc in maintaining the integrity of the CNS in situations of stress, especially during a neuroinflammatory insult.</p

Functionally Relevant Domains of the Prion Protein Identified In Vivo

The prion consists essentially of PrPSc, a misfolded and aggregated conformer of the cellular protein PrPC. Whereas PrPC deficient mice are clinically healthy, expression of PrPC variants lacking its central domain (PrPΔCD), or of the PrP-related protein Dpl, induces lethal neurodegenerative syndromes which are repressed by full-length PrP. Here we tested the structural basis of these syndromes by grafting the amino terminus of PrPC (residues 1–134), or its central domain (residues 90–134), onto Dpl. Further, we constructed a soluble variant of the neurotoxic PrPΔCD mutant that lacks its glycosyl phosphatidyl inositol (GPI) membrane anchor. Each of these modifications abrogated the pathogenicity of Dpl and PrPΔCD in transgenic mice. The PrP-Dpl chimeric molecules, but not anchorless PrPΔCD, ameliorated the disease of mice expressing truncated PrP variants. We conclude that the amino proximal domain of PrP exerts a neurotrophic effect even when grafted onto a distantly related protein, and that GPI-linked membrane anchoring is necessary for both beneficial and deleterious effects of PrP and its variants

Using C. elegans to decipher the cellular and molecular mechanisms underlying neurodevelopmental disorders

Prova tipográfica (uncorrected proof)Neurodevelopmental disorders such as epilepsy, intellectual disability (ID), and autism spectrum disorders (ASDs) occur in over 2 % of the population, as the result of genetic mutations, environmental factors, or combination of both. In the last years, use of large-scale genomic techniques allowed important advances in the identification of genes/loci associated with these disorders. Nevertheless, following association of novel genes with a given disease, interpretation of findings is often difficult due to lack of information on gene function and effect of a given mutation in the corresponding protein. This brings the need to validate genetic associations from a functional perspective in model systems in a relatively fast but effective manner. In this context, the small nematode, Caenorhabditis elegans, presents a good compromise between the simplicity of cell models and the complexity of rodent nervous systems. In this article, we review the features that make C. elegans a good model for the study of neurodevelopmental diseases. We discuss its nervous system architecture and function as well as the molecular basis of behaviors that seem important in the context of different neurodevelopmental disorders. We review methodologies used to assess memory, learning, and social behavior as well as susceptibility to seizures in this organism. We will also discuss technological progresses applied in C. elegans neurobiology research, such as use of microfluidics and optogenetic tools. Finally, we will present some interesting examples of the functional analysis of genes associated with human neurodevelopmental disorders and how we can move from genes to therapies using this simple model organism.The authors would like to acknowledge Fundação para a Ciência e Tecnologia (FCT) (PTDC/SAU-GMG/112577/2009). AJR and CB are recipients of FCT fellowships: SFRH/BPD/33611/2009 and SFRH/BPD/74452/2010, respectively

Alexithymia influences craving through facets of emotion regulation in alcoholic patients

There is evidence that alexithymia is related to alcohol problems. However, no study has been conducted to show whether emotion regulation (ER) subscales such as reappraisal and suppression mediate the relationship between alexithymia and craving. The aim of this study was to evaluate the effects of ER subscales (i. e., reappraisal and suppression) as mediators on the relationships between alexithymia and subscales of craving (i. e., obsessive and compulsive subscales). A total of 205 alcoholic outpatients completed the Farsi version of the Toronto Alexithymia Scale (FTAS-20), the Emotion Regulation Questionnaire (ERQ), the Obsessive Compulsive Drinking Scale (OCDS), the Alcohol Use Disorders Identification Test (AUDIT), and the Beck Depression Inventory-II (BDI-II). Results revealed that alexithymia indirectly influenced obsessive and compulsive cravings through both paths of ER decreased reappraisal and increased suppression subscales. Also, the relations of alexithymia to obsessive and compulsive cravings through the mediation pathway of decreased reappraisal were stronger than the path of suppression. It was concluded that low reappraisal and high suppression seem to be important in predicting obsessive and compulsive cravings for alcoholics with alexithymia. This suggests that the efforts based on increasing reappraisal and decreasing suppression may be important in reducing craving in alcoholic patients

Difficulties in emotion regulation mediate negative and positive affects and craving in alcoholic patients

The aim of this study was to assess the mediating effects of difficulties in emotion regulation (DER) on the relations of negative and positive affects to craving in alcoholic patients. 205 treatment-seeking alcoholic outpatients were included. DER, positive and negative affects as well as craving were evaluated by the Difficulties in Emotion Regulation Scale (DERS), the Positive/Negative Affect Scales, and the Obsessive Compulsive Drinking Scale (OCDS) respectively. Clinical factors including depression and severity of alcohol dependence were investigated by the Alcohol Use Disorders Identification Test (AUDIT) and the Beck Depression Inventory-II (BDI-II) respectively. Results revealed that both increased negative affect and decreased positive affect indirectly influenced craving through limited access to emotion regulation strategies. It was concluded that limited access to emotion regulation strategies may be important in predicting craving for alcoholics who experience both increased negative affect and decreased positive affect. This suggests that treatment and prevention efforts focused on increasing positive affect, decreasing negative affect and teaching effective regulation strategies may be critical in reducing craving in alcoholic patients. (C) 2017 Elsevier Ltd. All rights reserved

The relationship between alexithymia and symptom dimensions in patients with obsessive-compulsive disorder

The aims of this study were to evaluate alexithymia subscales i.e. difficulty in identifying feelings (DIF), difficulty in describing feelings (DDF) and externallyoriented thinking (EOT) in patients with obsessive-compulsive disorder (OCD) and to clarify the relationships of alexithymia subscales to obsessive-compulsive (OC) symptom dimensions and other clinical variables. One hundred fifteen OCD outpatients and two control groups including 80 normal controls and 100 alcoholic patients participated in this study. The data were collected by the YaleBrown Obsessive Compulsive Scale (Y-BOCS), the ObsessiveCompulsive Inventory-Revised (OCI-R), the Farsi version of the Toronto Alexithymia Scale (FTAS-20) and the Depression Anxiety Stress Scales (DASS-21). 60.7% of OCD patients and 48% of alcoholics were classified as alexithymics. Those with OCD revealed significantly higher scores on alexithymia and its subscales than alcoholics and normal controls. OCD patients with alexithymia showed higher means in YROCS and its subscales as well as the OC dimensions of mental neutralizing and obsessing than non-alexithymics. DIF and EOT were significantly correlated with obsessing and mental neutralizing respectively. DDF and EOT were related to OCD severity. It was concluded that DIF and EOT may be specific to obsessing and mental neutralizing in OCD patients