Development of mavoglurant and its potential for the treatment of fragile X syndrome.

Introduction: Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability. With no curative treatment available, current therapeutic approaches are aimed at symptom management. FXS is caused by silencing the FMR1 gene, which encodes FMRP; as loss of FMRP leads to the development of symptoms associated with FXS. Areas covered: In this evaluation, the authors examine the role of the metabotropic glutamate receptor 5 (mGluR5) in the pathophysiology of FXS, and its suitability as a target for rescuing the disease state. Furthermore, the authors review the evidence from preclinical studies of pharmacological interventions targeting mGluR5 in FXS. Lastly, the authors assess the findings from clinical studies in FXS, in particular the use of the Aberrant Behavior Checklist-Community Edition (ABC-C) and the recently developed ABC-C for FXS scale, as clinical endpoints to assess disease modification in this patient population. Expert opinion: There is cautious optimism for the successful treatment of the core behavioral and cognitive symptoms of FXS based on preclinical data in animal models and early studies in humans. However, the association between mGluR5-heightened responsiveness and the clinical phenotype in humans remains to be demonstrated. Many questions regarding the optimal treatment and outcome measures of FXS remain unanswered.

Increased activation in Broca's area after cognitive remediation in schizophrenia.

Functional magnetic resonance imaging (fMRI) was used to measure changes in cerebral activity in patients with schizophrenia after participation in the Cognitive Remediation Program for Schizophrenia and other related disorders (RECOS). As RECOS therapists make use of problem-solving and verbal mediation techniques, known to be beneficial in the rehabilitation of dysexecutive syndromes, we expected an increased activation of frontal areas after remediation. Executive functioning and cerebral activation during a covert verbal fluency task were measured in eight patients with schizophrenia before (T1) and after (T2) 14 weeks of RECOS therapy. The same measures were recorded in eight patients with schizophrenia who did not participate in RECOS at the same intervals of time (TAU group). Increased activation in Broca's area, as well as improvements in performance of executive/frontal tasks, was observed after cognitive training. Metacognitive techniques of verbalization are hypothesized to be the main factor underlying the brain changes observed in the present study.

A Theory of Wage Setting Behavior

Concerns for fairness, workers' morale and reciprocity infuence firms' wage setting policy. In this paper we formalize a theory of wage setting behavior in a simple and tractable model that explicitly considers these behavioral aspects. A worker is assumed to have reference-dependent preferences and displays loss aversion when evaluating the fairness of a wage contract. The theory establishes a wage-effort relationship that captures the worker's reference-dependent reciprocity, which in turn in uences the firm's optimal wage policy. The paper makes two key contributions: it identifies loss aversion as an explanation for a worker's asymmetric reciprocity; and it provides realistic and generalized microfoundation for downward wage rigidity. We further illustrate the implications of our theory for both wage setting and hiring behavior. Downward wage rigidity generates several implications for the outcome of the initial employment contract. The worker's reference wage, his extent of negative reciprocity and the firms expectations are key drivers of the propositions derived.

Subjective cognitive decline in patients with mild cognitive impairment and healthy older adults: association with personality traits.

AIM: In normal aging, subjective cognitive decline (SCD) might reflect personality traits or affective states rather than objective cognitive decline. However, little is known on the correlates of SCD in mild cognitive impairment (MCI). The present study investigates SCD in MCI patients and healthy older adults, and explores the association of SCD with personality traits, affective states, behavioral and psychological symptoms (BPS), and episodic memory in patients with MCI as compared with healthy older adults. METHODS: A total of 55 patients with MCI and 84 healthy older adults were recruited. Standard instruments were used to evaluate SCD, episodic memory, BPS and affective states. Premorbid and current personality traits were assessed by proxies using the NEO Personality Inventory Revised. RESULTS: Patients with MCI generally reported SCD more often than healthy older adults. SCD was positively associated with depressive symptoms in both groups. With regard to personality, no significant relationship was found in the healthy older group, whereas agreeableness was significantly negatively related to SCD in the MCI group. No significant association was found between SCD and episodic memory. CONCLUSIONS: SCD is more prevalent in patients with MCI than in the healthy elderly, but it does not reflect an objective cognitive impairment. SCD rather echoes depressive symptoms in both patients with MCI and healthy subjects. The negative association of SCD with agreeableness observed in patients with MCI could indicate that MCI patients scoring high on the agreeableness trait would not report SCD in order to prevent their relatives worrying about their increasing cognitive difficulties.

Comparison of the reproductive behavior between isolated Peckia chrysostoma (Wiedemann, 1830) and Adiscochaeta ingens (Walker, 1849) (Diptera: Sarcophagidae) females reared in laboratory

In both species, maintained under laboratory environmental conditions, anautogeny was comproved and all females that had free access to proteic source were fertiles. We obtained the following average values for Peckiachrysostoma: 59.7 ± 15.6 and 81.8 ± 15.4 days of longevity in the respective cases of free access and no access to proteic source, 21.4 ± 4.3 days of pre-larviposition period and 35.2 ± 16.5 days of larviposition period, 5.3 ± 1.8 larvipositions female with 7.0 ± 1.1 days of periodicity, 35.7 ± 6.1 larvae per larviposition leading to a total number of 183.8 ± 69.2 viable larvae per female and 94.8% ± 5.3% of productivity. The mean number of ovarioles per female was 56.4 ± 9.8, resulting in a reproductive potential of 63.3%. For Adiscochaeta ingens, the obtained average values were: 41.3 ± 6.3 and 52 ± 13.1 days of longevity in the respective cases of free access and no access to proteic source, 15.3 ± 1.7 days of pre-larviposition period and 21.5 ± 7.5 days of larviposition period, 3 ± 0.7 larvipositions per female with 10.4 ± 0.8 days of periodicity, 30.3 ± 8.2 larvae per larviposition leading to a total number of 78.5 ± 21.7 viable larvae per female and 90.1% ± 16% of productivity. The mean number of ovarioles per female was 54.6 ± 5.2, resulting in a reproductive potential of 55.5%. Within applied parameters, the values obtained for P. chrysostoma demonstrate its superior productivity in comparison with A. ingens

Cognitive and Emotional Deficits Associated with Minor and Serious Delinquency in High-Risk Adolescents

This study aims at evaluating how minor and serious delinquency relates to cognitive and emotional functioning in high-risk adolescents, taking problematic substance use into account. In 80 high-risk adolescent males (13-19 years), the frequency of minor and serious offences committed over the last year was predicted, in multiple regression analyses, from problematic substance use, intellectual efficiency, trait impulsivity, alexithymia (inability to express feelings in words), and cognitive coping strategies. Both minor and serious delinquency were more frequent in adolescents with more problematic substance use and higher intellectual efficacy. Minor delinquency was further related to a tendency to act out when experiencing negative emotions, and difficulties in focusing energy on instrumental action when under stress; while serious delinquency was predominantly and strongly related to rigid and dichotomous thinking. The results underline the heterogeneous nature of delinquency, minor offences being primarily associated with emotional regulation deficits, while major offences are related with a lack of cognitive flexibility.

Generating controlled image sets in cognitive neuroscience research.

The investigation of perceptual and cognitive functions with non-invasive brain imaging methods critically depends on the careful selection of stimuli for use in experiments. For example, it must be verified that any observed effects follow from the parameter of interest (e.g. semantic category) rather than other low-level physical features (e.g. luminance, or spectral properties). Otherwise, interpretation of results is confounded. Often, researchers circumvent this issue by including additional control conditions or tasks, both of which are flawed and also prolong experiments. Here, we present some new approaches for controlling classes of stimuli intended for use in cognitive neuroscience, however these methods can be readily extrapolated to other applications and stimulus modalities. Our approach is comprised of two levels. The first level aims at equalizing individual stimuli in terms of their mean luminance. Each data point in the stimulus is adjusted to a standardized value based on a standard value across the stimulus battery. The second level analyzes two populations of stimuli along their spectral properties (i.e. spatial frequency) using a dissimilarity metric that equals the root mean square of the distance between two populations of objects as a function of spatial frequency along x- and y-dimensions of the image. Randomized permutations are used to obtain a minimal value between the populations to minimize, in a completely data-driven manner, the spectral differences between image sets. While another paper in this issue applies these methods in the case of acoustic stimuli (Aeschlimann et al., Brain Topogr 2008), we illustrate this approach here in detail for complex visual stimuli.

Cognitive and emotional effects of carotid stenosis.

PRINCIPLES: Patients with carotid artery stenosis (CAS) are at risk of ipsilateral stroke and chronic compromise of cerebral blood flow. It is under debate whether the hypo-perfusion or embolism in CAS is directly related to cognitive impairment. Alternatively, CAS may be a marker for underlying risk factors, which themselves influence cognition. We aimed to determine cognitive performance level and the emotional state of patients with CAS. We hypo-thesised that patients with high grade stenosis, bilateral stenosis, symptomatic patients and/or those with relevant risk factors would suffer impairment of their cognitive performance and emotional state. METHODS: A total of 68 patients with CAS of ≥70% were included in a prospective exploratory study design. All patients underwent structured assessment of executive functions, language, verbal and visual memory, motor speed, anxiety and depression. RESULTS: Significantly more patients with CAS showed cognitive impairments (executive functions, word production, verbal and visual memory, motor speed) and anxiety than expected in a normative sample. Bilateral and symptomatic stenosis was associated with slower processing speed. Cognitive performance and anxiety level were not influenced by the side and the degree of stenosis or the presence of collaterals. Factors associated with less co-gnitive impairment included higher education level, female gender, ambidexterity and treated hypercholesterolemia. CONCLUSIONS: Cognitive impairment and increased level of anxiety are frequent in patients with carotid stenosis. The lack of a correlation between cognitive functioning and degree of stenosis or the presence of collaterals, challenges the view that CAS per se leads to cognitive impairment.

Vigilance behavior of Pyrenean chamois (Rupicapra pyrenaica pyrenaica): Effect of sex and position in the herd

The Pyrenean chamois (Rupicapra pyrenaica pyrenaica) is a mountain-dwelling ungulate with an extensive presence in open areas. Optimal group size results from the trade off between advantages (a reduction in the risk of predation) and disadvantages (competition between members of the herd) of group living. In addition, advantages and disadvantages of group living may vary depending on the position of each individual within the herd. Our objective was to study the effect of central vs. peripheral position in the herd on feeding and vigilance behavior in male and female Pyrenean chamois and to ascertain if a group size effect existed. We used focal animal sampling and recorded social interactions when a focal animal was involved. With males, vigilance rate was higher in the central part of the group than at the periphery, probably due to a higher density of animals in the central part of the herd and a higher probability of being disturbed by conspecifics. With females, vigilance rate did not differ according to position in the herd. Females spent more time feeding than males, and males showed a higher frequency of the vigilance behavior than females. We did not observe a clear relationship between group size and vigilance behavior. The differences in vigilance behavior might be due to social interactions.

Adult abundance, biting behavior and parity of Anopheles aquasalis, Curry 1932 in two malarious areas of Sucre State, Venezuela

The principal vector of malaria in eastern Venezuela, Anopheles aquasalis, is exophagic and exophilic. Control using indoor insecticide house sprays has failed to lower the number of malaria cases. Therefore, studies were initiated in two villages of the eastern coastal state of Sucre to better understand this vector's biology and develop a more integrated control program. An. aquasalis was found to have a crepuscular biting behavior with a major peak at dusk and a minor peak at dawn. Mosquitos were collected more outdoors than indoors. Forty-seven percent of the biting took place before people went to bed (22:30 hr) and 69% of the mosquitos biting during this time period bite outdoors. Outdoor biting could be the reason why indoor spraying alone did not lower malaria cases. Seasonal abundance was greater in the rainy season compared to the dry season. Seasonal parous rates were high (78.3%-100%) and similar indoors and outdoors and between dry and wet season in Santa F e. In Guayana, the seasonal parity was lower (34.6%-42.2%) than Santa F e with indoor parity slightly higher than outdoors. Malaria cases were higher in Santa F e, but adult mosquito density was much lower than in Guayana. This difference could have been due to higher parity in Santa F e compared to Guayana. The greater distance to the nearest breeding site and presence of alternative hosts in Guayana can not be discounted as factors which contributed to the difference in malaria transmission between locations. We concluded that knowledge on seasonal occurrence, biting activity, resting behavior and breeding site location can be used to design a new control strategy for this vector.

Behavior study of pipes after forming, coating and bending

A study of the main types of coatings and its processes that modern industry commonly apply to prevent to the corrosion due to the environmental effects to energetic market pipelines have been done. Extracting main time and temperature range values, coating heat treatment recreation have been applied to x65 pipelines steel grade samples obtained from a pipe which was formed using UOE forming process. Experimental tensile tests and Charpy V‐Notch Impact test have been carried out for a deeply knowledge of the influence on the steel once this recreations are applied. The Yield Strength and toughness have been improved despite lower values in rupture strain and ductile‐brittle temperature transition have been obtained. Finite Element Method have been applied to simulate the entirely pipe cold bending process to predict the mechanical properties and behaviour of the pipe made from x65 steel grade under different conditions.

Effect of Niclosamide (Bayluscide WP 70 (R)), Anacardium occidentale hexane extract and Euphorbia splendens latex on behavior of Biomphalaria glabrata (Say, 1818), under laboratory conditions

The repellent effect of the molluscicides Niclosamide (Bayluscide WP 70 (R)), Anacardium occidentale and the latex of Euphorbia splendens on Biomphalaria glabrata was observed through the investigation of the occurrence of escape behavior among molluscs that were exposed to dosages lower than the LD 50. The total number of individuals out of water among the surviving snails in the control group provided a "Natural Escape Index". The comparison between this total and the total number of surviving snails in each group exposed to the different dosages of the molluscicides after 24 hr provided the "Molluscicide Escape Index" and the detection of a "Repellency Range" to these snails. The escape indexes for Niclosamide, A. occidentale and E. splendens were 10, 6.22 and 6.44 respectively. Repellency occurred at the following concentration ranges: 0.01, 0.02 and 0.03 ppm Bayluscide, 0.1, 0.2 and 0.3 ppm A. occidentale and 0.05, 0.10, 0.15 and 0.20 ppm E. splendens. The Natural Escape Index obtained in the control group was zero.

Behavior of endogenous tumor-associated macrophages assessed in vivo using a functionalized nanoparticle.

Tumor-associated macrophages (TAMs) invade the tumor stroma in many cancers, yet their role is incompletely understood. To visualize and better understand these critical cells in tumor progression, we screened a portfolio of rationally selected, injectable agents to image endogenous TAMs ubiquitously in three different cancer models (colon carcinoma, lung adenocarcinoma, and soft tissue sarcoma). AMTA680, a functionally derivatized magneto-fluorescent nanoparticle, labeled a subset of myeloid cells with an "M2" macrophage phenotype, whereas other neighboring cells, including tumor cells and a variety of other leukocytes, remained unlabeled. We further show that AMTA680-labeled endogenous TAMs are not altered and can be tracked noninvasively at different resolutions and using various imaging modalities, e.g., fluorescence molecular tomography, magnetic resonance imaging, and multiphoton and confocal intravital microscopy. Quantitative assessment of TAM distribution and activity in vivo identified that these cells cluster in delimited foci within tumors, show relatively low motility, and extend cytoplasmic protrusions for prolonged physical interactions with neighboring tumor cells. Noninvasive imaging can also be used to monitor TAM-depleting regimen quantitatively. Thus, AMTA680 or related cell-targeting agents represent appropriate injectable vehicles for in vivo analysis of the tumor microenvironment.