Tyr682 in the Aβ-precursor protein intracellular domain regulates synaptic connectivity, cholinergic function, and cognitive performance.

Processing of Aβ-precursor protein (APP) plays an important role in Alzheimer's disease (AD) pathogenesis. The APP intracellular domain contains residues important in regulating APP function and processing, in particular the 682YENPTY687 motif. To dissect the functions of this sequence in vivo, we created an APP knock-in allele mutating Y682 to Gly (APP(YG/YG) mice). This mutation alters the processing of APP and TrkA signaling and leads to postnatal lethality and neuromuscular synapse defects when expressed on an APP-like protein 2 KO background. This evidence prompted us to characterize further the APP(YG/YG) mice. Here, we show that APP(YG/YG) mice develop aging-dependent decline in cognitive and neuromuscular functions, a progressive reduction in dendritic spines, cholinergic tone, and TrkA levels in brain regions governing cognitive and motor functions. These data are consistent with our previous findings linking NGF and APP signaling and suggest a causal relationship between altered synaptic connectivity, cholinergic tone depression and TrkA signaling deficit, and cognitive and neuromuscular decline in APP(YG/YG) mice. The profound deficits caused by the Y682 mutation underscore the biological importance of APP and indicate that APP(YG/YG) are a valuable mouse model to study APP functions in physiological and pathological processes

The emerging structure of the Extended Evolutionary Synthesis: where does Evo-Devo fit in?

The Extended Evolutionary Synthesis (EES) debate is gaining ground in contemporary evolutionary biology. In parallel, a number of philosophical standpoints have emerged in an attempt to clarify what exactly is represented by the EES. For Massimo Pigliucci, we are in the wake of the newest instantiation of a persisting Kuhnian paradigm; in contrast, Telmo Pievani has contended that the transition to an EES could be best represented as a progressive reformation of a prior Lakatosian scientific research program, with the extension of its Neo-Darwinian core and the addition of a brand-new protective belt of assumptions and auxiliary hypotheses. Here, we argue that those philosophical vantage points are not the only ways to interpret what current proposals to ‘extend’ the Modern Synthesis-derived ‘standard evolutionary theory’ (SET) entail in terms of theoretical change in evolutionary biology. We specifically propose the image of the emergent EES as a vast network of models and interweaved representations that, instantiated in diverse practices, are connected and related in multiple ways. Under that assumption, the EES could be articulated around a paraconsistent network of evolutionary theories (including some elements of the SET), as well as models, practices and representation systems of contemporary evolutionary biology, with edges and nodes that change their position and centrality as a consequence of the co-construction and stabilization of facts and historical discussions revolving around the epistemic goals of this area of the life sciences. We then critically examine the purported structure of the EES—published by Laland and collaborators in 2015—in light of our own network-based proposal. Finally, we consider which epistemic units of Evo-Devo are present or still missing from the EES, in preparation for further analyses of the topic of explanatory integration in this conceptual framework

Transtornos mentais comuns entre estudantes de medicina da Universidade Federal de Sergipe: estudo transversal

Objetivo: Estimar a prevalência de transtorno mental comum e fatores associados entre estudantes de Medicina da Universidade Federal de Sergipe. Método: Estudo transversal com 473 dos 512 matriculados em 2006, aplicando o Self Reporting Questionnaire-20 e um questionário estruturado sobre características sociodemográficas, processo ensino-aprendizagem e vivências psicoemocionais. Os calouros foram excluídos após comparação inicial com os alunos do 2° ao 12° períodos. Análise estatística por regressão logística múltipla, após estatística descritiva e cálculo das ORs simples e ajustadas. Resultados: A prevalência de transtorno mental comum geral foi de 40% (n = 473), mas com a retirada dos calouros, aumentou para 42,5% (n = 433) entre os alunos do 2° ao 12° semestre, sendo maior entre aqueles que não acreditavam ter adquirido habilidades para se tornarem bons médicos (OR = 2,82), que se sentiam pouco confortáveis com as atividades do curso (OR = 3,75), que se consideravam emocionalmente tensos (OR = 2,14), nos que não se consideravam felizes (OR = 2,85), nos que achavam que o curso era menos do que esperavam (OR = 1,64) e nos que tiveram diagnóstico prévio de transtorno mental feito por psiquiatra (OR = 3,78). Conclusão: Os resultados sugerem a necessidade de mudanças no processo ensino-aprendizagem, bem como estruturação de programas para cuidar da saúde mental dos estudantes. _________________________________________________________________________________________ ABSTRACT: Objective: Estimate the prevalence of common mental disorder and its associated factors among medical students of the Universidade Federal de Sergipe. Method: A cross-sectional study was carried out, applying Self Reporting Questionnaire-20 to 473 students from the 512 medical students enrolled in 2006 and compared with compared with a structured questionnaire by the authors containing information on the socio-demographic characteristics, the teaching–learning process and the psycho-emotional experiences of the students. Freshmen were excluded after initial comparison with the students already exposed to the medical course. Statistical analysis by multiple logistic regression after calculating simple and adjusted odds ratio (OR). Results: The general prevalence of common mental disorder was 40% (n = 473); after exclusion of the freshmen it increased to 42.5% among students from the 2nd to the 12th semester.It was higher among those who did not have faith in their acquisition of the skills needed to become a good doctor (OR = 2.82), who felt less comfortable about course activities (OR = 3.75), who considered themselves emotionally stressed (OR = 2.14), among those who did not consider themselves happy (OR = 2.85), who believed that the course did not match their expectations (OR = 1.64) and those who had a prior diagnosis of mental disorder by a psychiatrist (OR = 3.78). Conclusion: The results suggest the necessity of changes to the teaching-learning process and the establishment of a preventive mental health program for medical students

Neuroinflammation, Mast Cells, and Glia: Dangerous Liaisons

The perspective of neuroinflammation as an epiphenomenon following neuron damage is being replaced by the awareness of glia and their importance in neural functions and disorders. Systemic inflammation generates signals that communicate with the brain and leads to changes in metabolism and behavior, with microglia assuming a pro-inflammatory phenotype. Identification of potential peripheral-to-central cellular links is thus a critical step in designing effective therapeutics. Mast cells may fulfill such a role. These resident immune cells are found close to and within peripheral nerves and in brain parenchyma/meninges, where they exercise a key role in orchestrating the inflammatory process from initiation through chronic activation. Mast cells and glia engage in crosstalk that contributes to accelerate disease progression; such interactions become exaggerated with aging and increased cell sensitivity to stress. Emerging evidence for oligodendrocytes, independent of myelin and support of axonal integrity, points to their having strong immune functions, innate immune receptor expression, and production/response to chemokines and cytokines that modulate immune responses in the central nervous system while engaging in crosstalk with microglia and astrocytes. In this review, we summarize the findings related to our understanding of the biology and cellular signaling mechanisms of neuroinflammation, with emphasis on mast cell-glia interactions

Assessment of the direct effects of DDAH I on tumour angiogenesis in vivo

Nitric oxide (NO) has been strongly implicated in glioma progression and angiogenesis. The endogenous inhibitors of NO synthesis, asymmetric dimethylarginine (ADMA) and N-monomethyl-l-arginine (l-NMMA), are metabolized by dimethylarginine dimethylaminohydrolase (DDAH), and hence, DDAH is an intracellular factor that regulates NO. However, DDAH may also have an NO-independent action. We aimed to investigate whether DDAH I has any direct role in tumour vascular development and growth independent of its NO-mediated effects, in order to establish the future potential of DDAH inhibition as an anti-angiogenic treatment strategy. A clone of rat C6 glioma cells deficient in NO production expressing a pTet Off regulatable element was identified and engineered to overexpress DDAH I in the absence of doxycycline. Xenografts derived from these cells were propagated in the presence or absence of doxycycline and susceptibility magnetic resonance imaging used to assess functional vasculature in vivo. Pathological correlates of tumour vascular density, maturation and function were also sought. In the absence of doxycycline, tumours exhibited high DDAH I expression and activity, which was suppressed in its presence. However, overexpression of DDAH I had no measurable effect on tumour growth, vessel density, function or maturation. These data suggest that in C6 gliomas DDAH has no NO-independent effects on tumour growth and angiogenesis, and that the therapeutic potential of targeting DDAH in gliomas should only be considered in the context of NO regulation

Dosimetric evaluation of Acuros XB Advanced Dose Calculation algorithm in heterogeneous media

<p>Abstract</p> <p>Background</p> <p>A study was realised to evaluate and determine relative figures of merit of a new algorithm for photon dose calculation when applied to inhomogeneous media.</p> <p>Methods</p> <p>The new Acuros XB algorithm implemented in the Varian Eclipse treatment planning system was compared against a Monte Carlo method (VMC++), and the Analytical Anisotropic Algorithm (AAA). The study was carried out in virtual phantoms characterized by simple geometrical structures. An insert of different material and density was included in a phantom built of skeletal-muscle and HU = 0 (setting "A"): Normal Lung (lung, 0.198 g/cm³); Light Lung (lung, 0.035 g/cm³); Bone (bone, 1.798 g/cm³); another phantom (setting "B") was built of adipose material and including thin layers of bone (1.85 g/cm³), adipose (0.92 g/cm³), cartilage (1.4745 g/cm³), air (0.0012 g/cm³). Investigations were performed for 6 and 15 MV photon beams, and for a large (13 × 13 cm²) and a small (2.8 × 13 cm²) field.</p> <p>Results</p> <p>Results are provided in terms of depth dose curves, transverse profiles and Gamma analysis (3 mm/3% and 2 mm/2% distance to agreement/dose difference criteria) in planes parallel to the beam central axis; Monte Carlo simulations were assumed as reference. Acuros XB gave an average gamma agreement, with a 3 mm/3% criteria, of 100%, 86% and 100% for Normal Lung, Light Lung and Bone settings, respectively, and dose to medium calculations. The same figures were 86%, 11% and 100% for AAA, where only dose rescaled to water calculations are possible.</p> <p>Conclusions</p> <p>In conclusion, Acuros XB algorithm provides a valid and accurate alternative to Monte Carlo calculations for heterogeneity management.</p

ADHD symptomatology in eating disorders : a secondary psychopathological measure of severity?

Background: Attention-deficit/hyperactivity disorder (ADHD) has commonly been described in psychiatric disorders. Although several studies have found positive associations between abnormal eating patterns during childhood and ADHD, there is a lack of studies on ADHD and Eating Disorders (ED). The aims of this exploratory study were 1) to assess the ADHD symptoms level in ED and to ascertain whether there are differences among ED subtypes; 2) to analyze whether the presence of ADHD symptoms is associated with more severe eating disorder symptoms and greater general psychopathology; and 3) to assess whether the ADHD symptoms level is associated with specific temperament and character traits. Methods: 191 female ED patients were included. Assessment was carried out with the EDI-2, ASRS-v1.1, the SCL-90-R and the TCI-R. Results: The ADHD symptoms level was similar in bulimia, eating disorder not otherwise specified and binge eating subtypes, and lower in anorexic patients. Obsessiveness and Hostility were significantly positively associated with ADHD symptoms. A path model showed that ADHD was associated with high Novelty Seeking and low Self-Directedness, whereas ED severity was influenced by ADHD severity and low Self-Directedness. Conclusions: Bingeing/purging ED subtypes have a high ADHD symptoms level, also related with more severe eating, general and personality psychopathology

Study on psychoeducation enhancing results of adherence in patients with schizophrenia (SPERA-S): study protocol for a randomized controlled trial.

BACKGROUND: Poor adherence to pharmacotherapy negatively affects the course and the outcome of schizophreniaspectrum psychoses, enhancing the risk of relapse. Falloon and coworkers developed a Psychoeducation Program aimed at improving communication and problem-solving abilities in patients and their families. This study set out to evaluate changes in adherence to pharmacotherapy in patients diagnosed with schizophrenia-spectrum psychoses, by comparing one group exposed to the Falloon Psychoeducation Program (FPP) with another group exposed to family supportive therapy with generic information on the disorders. METHODS: 340 patients diagnosed with schizophrenia and related disorders according to standardized criteria from 10 participating units distributed throughout the Italian National Health System (NHS), will be enrolled with 1:1 allocation by the method of blocks of randomized permutations. Patients will be reassessed at 6, 12 and 18 months after start of treatment (duration: 6 months).The primary objective is to evaluate changes in adherence to pharmacotherapy after psychoeducation. Adherence will be assessed at three-month intervals by measuring blood levels of the primary prescribed drug using high pressure liquid chromatography, and via the Medication Adherence Questionnaire and a modified version of the Adherence Interview. Secondary objectives are changes in the frequency of relapse and readmission, as the main indicator of the course of the disorder.Enrolled patients will be allocated to the FPP (yes/no) randomly, 1:1, in a procedure controlled by the coordinating unit; codes will be masked until the conclusion of the protocol (or the occurrence of a severe negative event). The raters will be blind to treatment allocation and will be tested for blinding after treatment completion. Intention-to-treat will be applied in considering the primary and secondary outcomes. Multiple imputations will be applied to integrate the missing data. The study started recruitment in February 2013; the total duration of the study is 27 months. DISCUSSION: If the psychoeducation program proves effective in improving adherence to pharmacotherapy and in reducing relapse and readmissions, its application could be proposed as a standard adjunctive psychosocial treatment within the Italian NHS

The Liver Plays a Major Role in Clearance and Destruction of Blood Trypomastigotes in Trypanosoma cruzi Chronically Infected Mice

Intravenous challenge with Trypanosoma cruzi can be used to investigate the process and consequences of blood parasite clearance in experimental Chagas disease. One hour after intravenous challenge of chronically infected mice with 5×106 trypomastigotes, the liver constituted a major site of parasite accumulation, as revealed by PCR. Intact parasites and/or parasite remnants were visualized at this time point scattered in the liver parenchyma. Moreover, at this time, many of liver-cleared parasites were viable, as estimated by the frequency of positive cultures, which considerably diminished after 48 h. Following clearance, the number of infiltrating cells in the hepatic tissue notably increased: initially (at 24 h) as diffuse infiltrates affecting the whole parenchyma, and at 48 h, in the form of large focal infiltrates in both the parenchyma and perivascular spaces. Phenotypic characterization of liver-infiltrating cells 24 h after challenge revealed an increase in Mac1+, CD8+ and CD4+ cells, followed by natural killer (NK) cells. As evidence that liver-infiltrating CD4+ and CD8+ cells were activated, increased frequencies of CD69+CD8+, CD69+CD4+ and CD25+CD122+CD4+ cells were observed at 24 and 48 h after challenge, and of CD25−CD122+CD4+ cells at 48 h. The major role of CD4+ cells in liver protection was suggested by data showing a very high frequency of interferon (IFN)-γ-producing CD4+ cells 24 h after challenge. In contrast, liver CD8+ cells produced little IFN-γ, even though they showed an enhanced potential for secreting this cytokine, as revealed by in vitro T cell receptor (TCR) stimulation. Confirming the effectiveness of the liver immune response in blood parasite control during the chronic phase of infection, no live parasites were detected in this organ 7 days after challenge