White matter integrity as a predictor of response to treatment in first episode psychosis

The integrity of brain white matter connections is central to a patient's ability to respond to pharmacological interventions. This study tested this hypothesis using a specific measure of white matter integrity, and examining its relationship to treatment response using a prospective design in patients within their first episode of psychosis. Diffusion tensor imaging data were acquired in 63 patients with first episode psychosis and 52 healthy control subjects (baseline). Response was assessed after 12 weeks and patients were classified as responders or non-responders according to treatment outcome. At this second time-point, they also underwent a second diffusion tensor imaging scan. Tract-based spatial statistics were used to assess fractional anisotropy as a marker of white matter integrity. At baseline, non-responders showed lower fractional anisotropy than both responders and healthy control subjects (P < 0.05; family-wise error-corrected), mainly in the uncinate, cingulum and corpus callosum, whereas responders were indistinguishable from healthy control subjects. After 12 weeks, there was an increase in fractional anisotropy in both responders and non-responders, positively correlated with antipsychotic exposure. This represents one of the largest, controlled investigations of white matter integrity and response to antipsychotic treatment early in psychosis. These data, together with earlier findings on cortical grey matter, suggest that grey and white matter integrity at the start of treatment is an important moderator of response to antipsychotics. These findings can inform patient stratification to anticipate care needs, and raise the possibility that antipsychotics may restore white matter integrity as part of the therapeutic response

Size constancy in bat biosonar?

Perception and encoding of object size is an important feature of sensory systems. In the visual system object size is encoded by the visual angle (visual aperture) on the retina, but the aperture depends on the distance of the object. As object distance is not unambiguously encoded in the visual system, higher computational mechanisms are needed. This phenomenon is termed "size constancy". It is assumed to reflect an automatic re-scaling of visual aperture with perceived object distance. Recently, it was found that in echolocating bats, the 'sonar aperture', i.e., the range of angles from which sound is reflected from an object back to the bat, is unambiguously perceived and neurally encoded. Moreover, it is well known that object distance is accurately perceived and explicitly encoded in bat sonar. Here, we addressed size constancy in bat biosonar, recruiting virtual-object techniques. Bats of the species Phyllostomus discolor learned to discriminate two simple virtual objects that only differed in sonar aperture. Upon successful discrimination, test trials were randomly interspersed using virtual objects that differed in both aperture and distance. It was tested whether the bats spontaneously assigned absolute width information to these objects by combining distance and aperture. The results showed that while the isolated perceptual cues encoding object width, aperture, and distance were all perceptually well resolved by the bats, the animals did not assign absolute width information to the test objects. This lack of sonar size constancy may result from the bats relying on different modalities to extract size information at different distances. Alternatively, it is conceivable that familiarity with a behaviorally relevant, conspicuous object is required for sonar size constancy, as it has been argued for visual size constancy. Based on the current data, it appears that size constancy is not necessarily an essential feature of sonar perception in bats

The process evaluation of it\u27s your move!, an Australian adolescent community-based obesity prevention project

BackgroundEvidence on interventions for preventing unhealthy weight gain in adolescents is urgently needed. The aim of this paper is to describe the process evaluation for a three-year (2005-2008) project conducted in five secondary schools in the East Geelong/Bellarine region of Victoria, Australia. The project, \u27It\u27s Your Move!\u27 aimed to reduce unhealthy weight gain by promoting healthy eating patterns, regular physical activity, healthy body weight, and body size perception amongst youth; and improve the capacity of families, schools, and community organisations to sustain the promotion of healthy eating and physical activity in the region.MethodsThe project was supported by Deakin University (training and evaluation), a Reference Committee (strategic direction, budgetary approval and monitoring) and a Project Management Committee (project delivery). A workshop of students, teachers and other stakeholders formulated a 10-point action plan, which was then translated into strategies and initiatives specific to each school by the School Project Officers (staff members released from teaching duties one day per week) and trained Student Ambassadors. Baseline surveys informed intervention development. Process data were collected on all intervention activities and these were collated and enumerated, where possible, into a set of mutually exclusive tables to demonstrate the types of strategies and the dose, frequency and reach of intervention activities.ResultsThe action plan included three guiding objectives, four on nutrition, two on physical activity and one on body image. The process evaluation data showed that a mix of intervention strategies were implemented, including social marketing, one-off events, lunch time and curriculum programs, improvements in infrastructure, and healthy school food policies. The majority of the interventions were implemented in schools and focused on capacity building and healthy eating strategies as physical activity practices were seen by the teachers as already meeting students\u27 needs.ConclusionsWhile substantial health-promoting activities were conducted (especially related to healthy eating), there remain further opportunities for secondary schools to use a whole-of-school approach through the school curriculum, environment, policies and ethos to improve healthy eating, physical activity and healthy body perceptions in youth. To achieve this, significant, sustained leadership will be required within the education sector generally and within schools specifically.<br /

Ezrin interacts with the SARS coronavirus spike protein and restrains infection at the entry stage

© 2012 Millet et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Background: Entry of Severe Acute Respiratory Syndrome coronavirus (SARS-CoV) and its envelope fusion with host cell membrane are controlled by a series of complex molecular mechanisms, largely dependent on the viral envelope glycoprotein Spike (S). There are still many unknowns on the implication of cellular factors that regulate the entry process. Methodology/Principal Findings: We performed a yeast two-hybrid screen using as bait the carboxy-terminal endodomain of S, which faces the cytosol during and after opening of the fusion pore at early stages of the virus life cycle. Here we show that the ezrin membrane-actin linker interacts with S endodomain through the F1 lobe of its FERM domain and that both the eight carboxy-terminal amino-acids and a membrane-proximal cysteine cluster of S endodomain are important for this interaction in vitro. Interestingly, we found that ezrin is present at the site of entry of S-pseudotyped lentiviral particles in Vero E6 cells. Targeting ezrin function by small interfering RNA increased S-mediated entry of pseudotyped particles in epithelial cells. Furthermore, deletion of the eight carboxy-terminal amino acids of S enhanced S-pseudotyped particles infection. Expression of the ezrin dominant negative FERM domain enhanced cell susceptibility to infection by SARS-CoV and S pseudotyped particles and potentiated S-dependent membrane fusion. Conclusions/Significance: Ezrin interacts with SARS-CoV S endodomain and limits virus entry and fusion. Our data present a novel mechanism involving a cellular factor in the regulation of S-dependent early events of infection.This work was supported by the Research Grant Council of Hong Kong (RGC#760208)and the RESPARI project of the International Network of Pasteur Institutes

Fast, scalable, Bayesian spike identification for multi-electrode arrays

We present an algorithm to identify individual neural spikes observed on high-density multi-electrode arrays (MEAs). Our method can distinguish large numbers of distinct neural units, even when spikes overlap, and accounts for intrinsic variability of spikes from each unit. As MEAs grow larger, it is important to find spike-identification methods that are scalable, that is, the computational cost of spike fitting should scale well with the number of units observed. Our algorithm accomplishes this goal, and is fast, because it exploits the spatial locality of each unit and the basic biophysics of extracellular signal propagation. Human intervention is minimized and streamlined via a graphical interface. We illustrate our method on data from a mammalian retina preparation and document its performance on simulated data consisting of spikes added to experimentally measured background noise. The algorithm is highly accurate

Oncological considerations of skin-sparing mastectomy

AIM: To review evidence concerning the oncological safety of performing skin-sparing mastectomy (SSM) for invasive breast cancer and ductal carcinoma in situ (DCIS). Furthermore, the evidence concerning RT in relation to SSM and the possibility of nipple preservation was considered. METHODS: Literature review facilitated by Medline and PubMed databases. FINDINGS: Despite the lack of randomised controlled trials, SSM has become an accepted procedure in women undergoing mastectomy and immediate reconstruction for early breast cancer. Compared to non-skin-sparing mastectomy (NSSM), SSM seems to be oncologically safe in patients undergoing mastectomy for invasive tumours smaller than 5 cm, multicentric tumours, DCIS or risk-reduction. However, the technique should be avoided in patients with inflammatory breast cancer or in those with extensive tumour involvement of the skin in view of the high risk of local recurrence. SSM with nipple areola complex (NAC) preservation appears to be oncologically safe, provided the tumour is not close to the nipple and a frozen section protocol for the retro-areolar tissue is followed. Although radiotherapy (RT) does not represent a contraindication to SSM, the latter should be used with caution if postoperative RT is likely, since it detracts from the final cosmetic outcome

Aurora kinase A drives the evolution of resistance to third-generation EGFR inhibitors in lung cancer.

Although targeted therapies often elicit profound initial patient responses, these effects are transient due to residual disease leading to acquired resistance. How tumors transition between drug responsiveness, tolerance and resistance, especially in the absence of preexisting subclones, remains unclear. In epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma cells, we demonstrate that residual disease and acquired resistance in response to EGFR inhibitors requires Aurora kinase A (AURKA) activity. Nongenetic resistance through the activation of AURKA by its coactivator TPX2 emerges in response to chronic EGFR inhibition where it mitigates drug-induced apoptosis. Aurora kinase inhibitors suppress this adaptive survival program, increasing the magnitude and duration of EGFR inhibitor response in preclinical models. Treatment-induced activation of AURKA is associated with resistance to EGFR inhibitors in vitro, in vivo and in most individuals with EGFR-mutant lung adenocarcinoma. These findings delineate a molecular path whereby drug resistance emerges from drug-tolerant cells and unveils a synthetic lethal strategy for enhancing responses to EGFR inhibitors by suppressing AURKA-driven residual disease and acquired resistance

Accuracy of Transperineal Targeted Prostate Biopsies, Visual Estimation and Image Fusion in Men Needing Repeat Biopsy in the PICTURE Trial

PURPOSE: To evaluate detection of clinically significant prostate cancer (csPCa) using MRI-targeted biopsies, and compare visual-estimation to image-fusion targeting, in patients requiring repeat prostate biopsies. MATERIALS AND METHODS: Prospective, ethics-committee approved, registered PICTURE trial enrolling 249 consecutive patients (11th/January/2012-29th/January/2014). Men underwent an mpMRI and were blinded to its results. All underwent transperineal template prostate mapping (TTPM) biopsies. In 200 with a lesion, this was preceded by visual-estimation and image-fusion targeted biopsies. For the primary endpoint, csPCa was defined as Gleason >/=4+3 and/or any grade of cancer length >/=6mm. Other definitions of csPCa were also evaluated. RESULTS: Mean (SD) age was 62.6 (7) years, median (IQR) PSA 7.17ng/ml (5.25, 10.09), mean primary lesion size 0.37cc (SD1.52), with mean 4.3 (SD2.3) targeted cores per lesion (visual-estimation and image-fusion combined) and mean 48.7 (SD12.3) TTPM-biopsy cores. TTPM-biopsies detected 97 (48.5%) cases of csPCa and 85 (42.5%) insignificant cancers. Overall, mpMRI-targeted biopsies detected 81 (40.5%) csPCa and 63 (31.5%) insignificant cancers. Eighteen (9%) with csPCa on MRI-targeted biopsies were benign or clinically insignificant on TTPM-biopsy. Thirty-four (17%) had csPCa detected on TTPM-biopsy but not on MRI-targeted biopsies; approximately half of these were present in non-targeted areas. csPCa was found with visual-estimation and image-fusion in 53/169 (31.3%) and 48/169 (28.4%) (McNemar's test, p=0.5322). Visual-estimation missed 23 (13.6%) csPCa detected by image-fusion; image-fusion missed 18 (10.8%) csPCa that visual-estimation detected. CONCLUSIONS: MRI-targeted biopsies are accurate at detection of csPCa and reducing over-diagnosis of insignificant cancers. To maximise detection both visual-estimation and image-fusion targeted biopsies are required

A Top Dog Tale with Preference Complementarities

The emergence of a winner-take-all (top dog) outcome is generally due to political or institutional constraints or to specific technological features which favour the performance of just one individual. In this paper we provide a different explanation for the occurrence of a top-dog equilibrium in exchange economies. We show that once heterogeneous complementarities (i.e. Scarf’s preferences) are analysed with general endowment distributions, a variety of equilibria different from the well-known symmetric outcome with full utilisation of resources can emerge. Specifically, we show that stable corner equilibria with a winner-take-all (top dog) individual arise that are Pareto optima although the remaining individuals are no better off than with zero consumption and resources can be unused. Because of heterogenous complementarities, market mechanisms are weak and cannot overcome the top dog’s power. Voting mechanisms or taxation policies can reduce the top dog’s privileged position

The Evolution of Bat Vestibular Systems in the Face of Potential Antagonistic Selection Pressures for Flight and Echolocation

PMCID: PMC3634842This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited