Appetitively motivated tasks in the IntelliCage reveal a higher motivational cost of spatial learning in male than female mice

The IntelliCage (IC) permits the assessment of the behavior and learning abilities of mice in a social home cage context. To overcome water deprivation as an aversive driver of learning, we developed protocols in which spatial learning is motivated appetitively by the preference of mice for sweetened over plain water. While plain water is available at all times, only correct task responses give access to sweetened water rewards. Under these conditions, C57BL/6J mice successfully mastered a corner preference task with the reversal and also learned a more difficult time-place task with reversal. However, the rate of responding to sweetened water decreased strongly with increasing task difficulty, indicating that learning challenges and reduced success in obtaining rewards decreased the motivation of the animals to seek sweetened water. While C57BL/6J mice of both sexes showed similar initial taste preferences and learned similarly well in simple learning tasks, the rate of responding to sweetened water and performance dropped more rapidly in male than in female mice in response to increasing learning challenges. Taken together, our data indicate that male mice can have a disadvantage relative to females in mastering difficult, appetitively motivated learning tasks, likely due to sex differences in value-based decision-making

Detection rate of FNA cytology in medullary thyroid carcinoma. a meta-analysis

Background: The early detection of medullary thyroid carcinoma (MTC) can improve patient prognosis, because histological stage and patient age at diagnosis are highly relevant prognostic factors. As a consequence, delay in the diagnosis and/or incomplete surgical treatment should correlate with a poorer prognosis for patients. Few papers have evaluated the specific capability of fine-needle aspiration cytology (FNAC) to detect MTC, and small series have been reported. This study conducts a meta-analysis of published data on the diagnostic performance of FNAC in MTC to provide more robust estimates. Research Design and Methods: A comprehensive computer literature search of the PubMed/MEDLINE, Embase and Scopus databases was conducted by searching for the terms 'medullary thyroid' AND 'cytology', 'FNA', 'FNAB', 'FNAC', 'fine needle' or 'fine-needle'. The search was updated until 21 March 2014, and no language restrictions were used. Results: Fifteen relevant studies and 641 MTC lesions that had undergone FNAC were included. The detection rate (DR) of FNAC in patients with MTC (diagnosed as 'MTC' or 'suspicious for MTC') on a per lesion-based analysis ranged from 12·5% to 88·2%, with a pooled estimate of 56·4% (95% CI: 52·6-60·1%). The included studies were statistically heterogeneous in their estimates of DR (I-square >50%). Egger's regression intercept for DR pooling was 0·03 (95% CI: -3·1 to 3·2, P = 0·9). The study that reported the largest MTC series had a DR of 45%. Data on immunohistochemistry for calcitonin in diagnosing MTC were inconsistent for the meta-analysis. Conclusions: The presented meta-analysis demonstrates that FNAC is able to detect approximately one-half of MTC lesions. These findings suggest that other techniques may be needed in combination with FNAC to diagnose MTC and avoid false negative results. © 2014 John Wiley & Sons Ltd

Diagnostic delay does not influence survival of pancreatic cancer patients

Background: Most pancreatic ductal adenocarcinoma patients present with advanced disease. Whether it is possible to increase survival by earlier diagnosis is unclear. Objective: The purpose of this study was to investigate the association between presenting complaints and risk factors for pancreatic cancer with diagnostic delay, stage and survival. Methods: This was a single-centre retrospective cohort study. Consecutive patients were interviewed and data on demographics, medical history, risk factors and complaints leading to pancreatic ductal adenocarcinoma diagnosis and disease stage were recorded. Diagnostic delay was considered as time between first complaint and diagnosis. Patients received appropriate treatments and their outcome was recorded in a dedicated database. The Chi-square test for comparison of categorical variables and the Mann–Whitney test for continuous variables were employed with Bonferroni corrections. Correlation between continuous variables was evaluated by means of the Spearman correlation coefficient. Survival analysis was performed with the Kaplan–Meier method and a log-rank test. Results: The median diagnostic delay for 477 pancreatic ductal adenocarcinoma patients was two months (interquartile range 1–5), being significantly shorter for patients presenting with jaundice compared with those with pain, weight loss, diabetes (p < 0.001). The global rate of metastatic disease at diagnosis was 40%, being only 22% in those presenting with jaundice. The median diagnostic delay, however, was not significantly different among disease stages but was significantly longer in patients with a body mass index>25 kg/m2. The median survival time was seven months. Factors associated with worse survival at the multivariable analysis were older age (hazard ratio 1.02 per year), metastatic disease (hazard ratio 2.12) and pain as presenting complaint (hazard ratio 1.32), while diagnostic delay was not. Conclusion: While some complaints are associated with a shorter diagnostic delay and less advanced disease stage, we could not demonstrate that delay is associated with survival, possibly suggesting that prevention rather than early recognition is important to tackle pancreatic cancer lethality

Refinement of IntelliCage protocols for complex cognitive tasks through replacement of drinking restrictions by incentive-disincentive paradigms

The IntelliCage allows automated testing of cognitive abilities of mice in a social home cage environment without handling by human experimenters. Restricted water access in combination with protocols in which only correct responses give access to water is a reliable learning motivator for hippocampus-dependent tasks assessing spatial memory and executive function. However, water restriction may negatively impact on animal welfare, especially in poor learners. To better comply with the 3R principles, we previously tested protocols in which water was freely available but additional access to sweetened water could be obtained by learning a task rule. While this purely appetitive motivation worked for simple tasks, too many mice lost interest in the sweet reward during more difficult hippocampus-dependent tasks. In the present study, we tested a battery of increasingly difficult spatial tasks in which water was still available without learning the task rule, but rendered less attractive either by adding bitter tasting quinine or by increasing the amount of work to obtain it. As in previous protocols, learning of the task rule provided access to water sweetened with saccharin. The two approaches of dual motivation were tested in two cohorts of female C57BL/6 N mice. Compared to purely appetitive motivation, both novel protocols strongly improved task engagement and increased task performance. Importantly, neither of the added disincentives had an adverse impact on liquid consumption, health status or body weight of the animals. Our results show that it is possible to refine test protocols in the IntelliCage so that they challenge cognitive functions without restricting access to water

Structural and connectivity parameters reveal spared connectivity in young patients with non-progressive compared to slow-progressive cerebellar ataxia

INTRODUCTION: Within Pediatric Cerebellar Ataxias (PCAs), patients with non-progressive ataxia (NonP) surprisingly show postural motor behavior comparable to that of healthy controls, differently to slow-progressive ataxia patients (SlowP). This difference may depend on the building of compensatory strategies of the intact areas in NonP brain network. METHODS: Eleven PCAs patients were recruited: five with NonP and six with SlowP. We assessed volumetric and axonal bundles alterations with a multimodal approach to investigate whether eventual spared connectivity between basal ganglia and cerebellum explains the different postural motor behavior of NonP and SlowP patients. RESULTS: Cerebellar lobules were smaller in SlowP patients. NonP patients showed a lower number of streamlines in the cerebello-thalamo-cortical tracts but a generalized higher integrity of white matter tracts connecting the cortex and the basal ganglia with the cerebellum. DISCUSSION: This work reveals that the axonal bundles connecting the cerebellum with basal ganglia and cortex demonstrate a higher integrity in NonP patients. This evidence highlights the importance of the cerebellum-basal ganglia connectivity to explain the different postural motor behavior of NonP and SlowP patients and support the possible compensatory role of basal ganglia in patients with stable cerebellar malformation

Verificación de las Curvas de Paschen y la Ley de Peek en microionizadores por descarga luminiscente

En este trabajo analizamos el sistema de ionización por descarga luminiscente para su utilización como fuente de iones en un equipo de identificación de compuestos químicos tipo IMS. Se realizaron modelos de descarga corona implementados con tecnología MEMS (Sistemas Micro-electro Mecánicos). Se propone que en la escala micrométrica es posible mejorar rendimientos, confiabilidad y demandas operativas. Así se redujo la tensión de la fuente de alimentación a menos de 1kV.Centro de Técnicas Analógico-Digitale

Effective connectivity reveals strategy differences in an expert calculator

Mathematical reasoning is a core component of cognition and the study of experts defines the upper limits of human cognitive abilities, which is why we are fascinated by peak performers, such as chess masters and mental calculators. Here, we investigated the neural bases of calendrical skills, i.e. the ability to rapidly identify the weekday of a particular date, in a gifted mental calculator who does not fall in the autistic spectrum, using functional MRI. Graph-based mapping of effective connectivity, but not univariate analysis, revealed distinct anatomical location of “cortical hubs” supporting the processing of well-practiced close dates and less-practiced remote dates: the former engaged predominantly occipital and medial temporal areas, whereas the latter were associated mainly with prefrontal, orbitofrontal and anterior cingulate connectivity. These results point to the effect of extensive practice on the development of expertise and long term working memory, and demonstrate the role of frontal networks in supporting performance on less practiced calculations, which incur additional processing demands. Through the example of calendrical skills, our results demonstrate that the ability to perform complex calculations is initially supported by extensive attentional and strategic resources, which, as expertise develops, are gradually replaced by access to long term working memory for familiar material

Cognitive Syndromes and C9orf72 Mutation Are Not Related to Cerebellar Degeneration in Amyotrophic Lateral Sclerosis

Objective: The notion that cerebellar pathology may contribute to cognitive impairment in ALS, especially in patients with C9orf72 repeated expansion, has been inconsistently reported. This study aimed exploring the relationship between cerebellar involvement, cognitive impairment and C9orf72 repeated expansion of patients with ALS. Methods: Quantitative in vivo assessment of cerebellar lobules has been investigated in 66 non-demented patients with ALS and 28 healthy controls (HCs). Pathologic C9orf72 repeated expansion was found in 13 patients. Mild cognitive and/or behavioral impairment was diagnosed in 22 C9orf72 negative ALS patients. Measures of cortical volume (CV} and cortical thickness (CT) of cerebellar lobules of all participants were used for Principal Component Analysis (PCA) to identify clusters of lobular measures highly correlated with each other. PCA outcomes were used for between group comparisons and correlation analyses with neuropsychological and clinical features. Results: Disease severity measured with ALS functional rating scale and index of disease progression rate significantly correlated with CV reduction of the second PCA cluster loading CV measures of anterior lobules. In all patients, cognitive impairment, measured with verbal fluency, was related to CV reduction of the third cluster comprising posterior lobules. No specific cortical thinning or volume reduction of cerebellar clustering patterns could be detected in ALS subgroups. Conclusion: Our data show that specific patterns of subregional cerebellar involvement are associated with physical disability or cognitive impairment in ALS, in line with the topographic organization of the cerebellum. However, there was no specific correlation between cerebellar degeneration and cognitive syndromes or C9orf72 mutations

Medical Informatics Platform (MIP): A Pilot Study Across Clinical Italian Cohorts

Introduction: With the shift of research focus to personalized medicine in Alzheimer's Dementia (AD), there is an urgent need for tools that are capable of quantifying a patient's risk using diagnostic biomarkers. The Medical Informatics Platform (MIP) is a distributed e-infrastructure federating large amounts of data coupled with machine-learning (ML) algorithms and statistical models to define the biological signature of the disease. The present study assessed (i) the accuracy of two ML algorithms, i.e., supervised Gradient Boosting (GB) and semi-unsupervised 3C strategy (Categorize, Cluster, Classify—CCC) implemented in the MIP and (ii) their contribution over the standard diagnostic workup. / Methods: We examined individuals coming from the MIP installed across 3 Italian memory clinics, including subjects with Normal Cognition (CN, n = 432), Mild Cognitive Impairment (MCI, n = 456), and AD (n = 451). The GB classifier was applied to best discriminate the three diagnostic classes in 1,339 subjects, and the CCC strategy was used to refine the classical disease categories. Four dementia experts provided their diagnostic confidence (DC) of MCI conversion on an independent cohort of 38 patients. DC was based on clinical, neuropsychological, CSF, and structural MRI information and again with addition of the outcome from the MIP tools. / Results: The GB algorithm provided a classification accuracy of 85% in a nested 10-fold cross-validation for CN vs. MCI vs. AD discrimination. Accuracy increased to 95% in the holdout validation, with the omission of each Italian clinical cohort out in turn. CCC identified five homogeneous clusters of subjects and 36 biomarkers that represented the disease fingerprint. In the DC assessment, CCC defined six clusters in the MCI population used to train the algorithm and 29 biomarkers to improve patients staging. GB and CCC showed a significant impact, evaluated as +5.99% of increment on physicians' DC. The influence of MIP on DC was rated from “slight” to “significant” in 80% of the cases. / Discussion: GB provided fair results in classification of CN, MCI, and AD. CCC identified homogeneous and promising classes of subjects via its semi-unsupervised approach. We measured the effect of the MIP on the physician's DC. Our results pave the way for the establishment of a new paradigm for ML discrimination of patients who will or will not convert to AD, a clinical priority for neurology