The differential effects of ecstasy/polydrug use on executive components: shifting, inhibition, updating and access to semantic memory

Rationale/Objectives Recent theoretical models suggest that the central executive may not be a unified structure. The present study explored the nature of central executive deficits in ecstasy users. Methods In study 1, 27 ecstasy users and 34 non-users were assessed using tasks to tap memory updating (computation span; letter updating) and access to long-term memory (a semantic fluency test and the Chicago Word Fluency Test). In study 2, 51 ecstasy users and 42 non-users completed tasks that assess mental set switching (number/letter and plus/minus) and inhibition (random letter generation). Results MANOVA revealed that ecstasy users performed worse on both tasks used to assess memory updating and on tasks to assess access to long-term memory (C- and S-letter fluency). However, notwithstanding the significant ecstasy group-related effects, indices of cocaine and cannabis use were also significantly correlated with most of the executive measures. Unexpectedly, in study 2, ecstasy users performed significantly better on the inhibition task, producing more letters than non-users. No group differences were observed on the switching tasks. Correlations between indices of ecstasy use and number of letters produced were significant. Conclusions The present study provides further support for ecstasy/polydrug-related deficits in memory updating and in access to long-term memory. The surplus evident on the inhibition task should be treated with some caution, as this was limited to a single measure and has not been supported by our previous work

Differential effects of exogenous and endogenous cueing in multi-stream RSVP: implications for theories of attentional blink

The attentional blink (AB) refers to the finding that performance on the second of two targets (T1 and T2) in a rapid serial visual presentation (RSVP) stream is impaired when the targets are presented within 200–500 ms. To explore the possible interaction between spatial attentional orienting and temporary attentional deficits, this study used central (endogenous) and peripheral (exogenous) cues in a multi-stream RSVP task and compared the endogenous and exogenous cueing effects inside and outside of the AB period. While the endogenous cueing effect was constant in magnitude over time, the exogenous cueing effect was significantly larger inside than outside of the AB period. Theoretical implications of these findings for the interaction between attention mechanisms in spatial and temporal domains are discussed

Central nervous system relapse in patients with breast cancer is associated with advanced stages, with the presence of circulating occult tumor cells and with the HER2/neu status

INTRODUCTION: To evaluate the incidence of central nervous system (CNS) involvement in patients with breast cancer treated with a taxane-based chemotherapy regimen and to determine predictive factors for CNS relapse. METHODS: The medical files of patients with early breast cancer (n = 253) or advanced stage breast cancer (n = 239) as well of those with other solid tumors (n = 336) treated with or without a taxane-based chemotherapy regimen during a 42-month period were reviewed. HER2/neu overexpression was identified by immunohistochemistry, whereas cytokeratin 19 (CK-19) mRNA-positive circulating tumor cells (CTCs) in the peripheral blood were identified by real-time PCR. RESULTS: The incidence of CNS relapse was similar in patients suffering from breast cancer or other solid tumors (10.4% and 11.4%, respectively; P = 0.517). The incidence of CNS relapse was significantly higher in breast cancer patients with advanced disease (P = 0.041), visceral disease and bone disease (P = 0.036), in those who were treated with a taxane-containing regimen (P = 0.024), in those with HER2/neu-overexpressing tumors (P = 0.022) and, finally, in those with detectable CK-19 mRNA-positive CTCs (P = 0.008). Multivariate analysis revealed that the stage of disease (odds ratio, 0.23; 95% confidence interval, 0.007–0.23; P = 0.0001), the HER2/neu status (odds ratio, 29.4; 95% confidence interval, 7.51–101.21; P = 0.0001) and the presence of CK-19 mRNA-positive CTCs (odds ratio, 8.31; 95% confidence interval, 3.97–12.84; P = 0.001) were independent predictive factors for CNS relapse. CONCLUSION: CNS relapses are common among breast cancer patients treated with a taxane-based chemotherapy regimen, patients with HER2/neu-positive tumor and patients with CK-19 mRNA-positive CTCs

Clinical review: Allocating ventilators during large-scale disasters – problems, planning, and process

Catastrophic disasters, particularly a pandemic of influenza, may force difficult allocation decisions when demand for mechanical ventilation greatly exceeds available resources. These situations demand integrated incident management responses on the part of the health care facility and community, including resource management, provider liability protection, community education and information, and health care facility decision-making processes designed to allocate resources as justly as possible. If inadequate resources are available despite optimal incident management, a process that is evidence-based and as objective as possible should be used to allocate ventilators. The process and decision tools should be codified pre-event by the local and regional healthcare entities, public health agencies, and the community. A proposed decision tool uses predictive scoring systems, disease-specific prognostic factors, response to current mechanical ventilation, duration of current and expected therapies, and underlying disease states to guide decisions about which patients will receive mechanical ventilation. Although research in the specifics of the decision tools remains nascent, critical care physicians are urged to work with their health care facilities, public health agencies, and communities to ensure that a just and clinically sound systematic approach to these situations is in place prior to their occurrence

Strategic use of new generation antidepressants for depression: SUN(^_^)D study protocol

<p>Abstract</p> <p>Background</p> <p>After more than half a century of modern psychopharmacology, with billions of dollars spent on antidepressants annually world-wide, we lack good evidence to guide our everyday decisions in conducting antidepressant treatment of patients with major depression. First we did not know which antidepressant to use as first line treatment. Second we do not know which dosage we should be aiming at with that antidepressant. Because more than half of the patients with major depression starting treatment do not remit after adequate trial with the first agent, they will need a second line treatment. Dose escalation, augmentation and switching are the three often recommended second line strategies but we do not know which is better than the others. Moreover, we do not know when to start considering this second line treatment.</p> <p>The recently published multiple-treatments meta-analysis of 12 new generation antidepressants has provided some partial answers to the first question. Starting with these findings, this proposed trial aims to establish the optimum 1st line and 2nd line antidepressant treatment strategy among adult patients with a non-psychotic unipolar major depressive episode.</p> <p>Methods</p> <p>SUN(^_^)D, the Strategic Use of New generation antidepressants for Depression, is an assessor-blinded, parallel-group, multi-centre randomised controlled trial. Step I is a cluster-randomised trial comparing titration up to the minimum vs maximum of the recommended dose range among patients starting with sertraline. The primary outcome is the change in the Patient Health Questionnaire (PHQ)-9 scores administered by a blinded rater via telephone at week 1 through 3. Step II is an individually randomised trial comparing staying on sertraline, augmentation of sertraline with mirtazapine, and switching to mirtazapine among patients who have not remitted on the first line treatment by week 3. The primary outcome is the change in the PHQ-9 scores at week 4 through 9. Step III represents a continuation phase to Steps I and II and aims to establish longer-term effectiveness and acceptability of the above-examined treatment strategies up to week 25. The trial is supported by the Grant-in-Aid by the Ministry of Health, Labour and Welfare, Japan.</p> <p>Discussion</p> <p>SUN(^_^)D promises to be a pragmatic large trial to answer important clinical questions that every clinician treating patients with major depression faces in his/her daily practices concerning its first- and second-line treatments.</p> <p>Trial registration</p> <p>ClinicalTrials.gov: <a href="http://www.clinicaltrials.gov/ct2/show/NCT01109693">NCT01109693</a></p

Modelling Visual Neglect: Computational Insights into Conscious Perception

Background: Visual neglect is an attentional deficit typically resulting from parietal cortex lesion and sometimes frontal lesion. Patients fail to attend to objects and events in the visual hemifield contralateral to their lesion during visual search. Methodology/Principal Finding: The aim of this work was to examine the effects of parietal and frontal lesion in an existing computational model of visual attention and search and simulate visual search behaviour under lesion conditions. We find that unilateral parietal lesion in this model leads to symptoms of visual neglect in simulated search scan paths, including an inhibition of return (IOR) deficit, while frontal lesion leads to milder neglect and to more severe deficits in IOR and perseveration in the scan path. During simulations of search under unilateral parietal lesion, the model’s extrastriate ventral stream area exhibits lower activity for stimuli in the neglected hemifield compared to that for stimuli in the normally perceived hemifield. This could represent a computational correlate of differences observed in neuroimaging for unconscious versus conscious perception following parietal lesion. Conclusions/Significance: Our results lead to the prediction, supported by effective connectivity evidence, that connections between the dorsal and ventral visual streams may be an important factor in the explanation of perceptua

IL-6 Stabilizes Twist and Enhances Tumor Cell Motility in Head and Neck Cancer Cells through Activation of Casein Kinase 2

BACKGROUND: Squamous cell carcinoma of the head and neck (SCCHN) is the seventh most common cancer worldwide. Unfortunately, the survival of patients with SCCHN has not improved in the last 40 years, and thus new targets for therapy are needed. Recently, elevations in serum level of interleukin 6 (IL-6) and expression of Twist in tumor samples were found to be associated with poor clinical outcomes in multiple types of cancer, including SCCHN. Although Twist has been proposed as a master regulator of epithelial-mesenchymal transition and metastasis in cancers, the mechanisms by which Twist levels are regulated post-translationally are not completely understood. Tumor progression is characterized by the involvement of cytokines and growth factors and Twist induction has been connected with a number of these signaling pathways including IL-6. Since many of the effects of IL-6 are mediated through activation of protein phosphorylation cascades, this implies that Twist expression must be under a tight control at the post-translational level in order to respond in a timely manner to external stimuli. METHODOLOGY/PRINCIPAL FINDINGS: Our data show that IL-6 increases Twist expression via a transcription-independent mechanism in many SCCHN cell lines. Further investigation revealed that IL-6 stabilizes Twist in SCCHN cell lines through casein kinase 2 (CK2) phosphorylation of Twist residues S18 and S20, and that this phosphorylation inhibits degradation of Twist. Twist phosphorylation not only increases its stability but also enhances cell motility. Thus, post-translational modulation of Twist contributes to its tumor-promoting properties. CONCLUSIONS/SIGNIFICANCE: Our study shows Twist expression can be regulated at the post-translational level through phosphorylation by CK2, which increases Twist stability in response to IL-6 stimulation. Our findings not only provide novel mechanistic insights into post-translational regulation of Twist but also suggest that CK2 may be a viable therapeutic target in SCCHN

The Role of Motor Learning in Spatial Adaptation near a Tool

Some visual-tactile (bimodal) cells have visual receptive fields (vRFs) that overlap and extend moderately beyond the skin of the hand. Neurophysiological evidence suggests, however, that a vRF will grow to encompass a hand-held tool following active tool use but not after passive holding. Why does active tool use, and not passive holding, lead to spatial adaptation near a tool? We asked whether spatial adaptation could be the result of motor or visual experience with the tool, and we distinguished between these alternatives by isolating motor from visual experience with the tool. Participants learned to use a novel, weighted tool. The active training group received both motor and visual experience with the tool, the passive training group received visual experience with the tool, but no motor experience, and finally, a no-training control group received neither visual nor motor experience using the tool. After training, we used a cueing paradigm to measure how quickly participants detected targets, varying whether the tool was placed near or far from the target display. Only the active training group detected targets more quickly when the tool was placed near, rather than far, from the target display. This effect of tool location was not present for either the passive-training or control groups. These results suggest that motor learning influences how visual space around the tool is represented

1α,25(OH)2-3-Epi-Vitamin D3, a Natural Physiological Metabolite of Vitamin D3: Its Synthesis, Biological Activity and Crystal Structure with Its Receptor

Background: The 1 alpha,25-dihydroxy-3-epi-vitamin-D(3) (1 alpha,25(OH)(2)-3-epi-D(3)), a natural metabolite of the seco-steroid vitamin D(3), exerts its biological activity through binding to its cognate vitamin D nuclear receptor (VDR), a ligand dependent transcription regulator. In vivo action of 1 alpha,25(OH)(2)-3-epi-D(3) is tissue-specific and exhibits lowest calcemic effect compared to that induced by 1 alpha,25(OH)(2)D(3). To further unveil the structural mechanism and structure-activity relationships of 1 alpha,25(OH)(2)-3-epi-D3 and its receptor complex, we characterized some of its in vitro biological properties and solved its crystal structure complexed with human VDR ligand-binding domain (LBD). Methodology/Principal Findings: In the present study, we report the more effective synthesis with fewer steps that provides higher yield of the 3-epimer of the 1 alpha,25(OH)(2)D(3). We solved the crystal structure of its complex with the human VDR-LBD and found that this natural metabolite displays specific adaptation of the ligand-binding pocket, as the 3-epimer maintains the number of hydrogen bonds by an alternative water-mediated interaction to compensate the abolished interaction with Ser278. In addition, the biological activity of the 1 alpha,25(OH)(2)-3-epi-D(3) in primary human keratinocytes and biochemical properties are comparable to 1 alpha,25(OH)(2)D(3). Conclusions/Significance: The physiological role of this pathway as the specific biological action of the 3-epimer remains unclear. However, its high metabolic stability together with its significant biologic activity makes this natural metabolite an interesting ligand for clinical applications. Our new findings contribute to a better understanding at molecular level how natural metabolites of 1 alpha,25(OH)(2)D(3) lead to significant activity in biological systems and we conclude that the C3-epimerization pathway produces an active metabolite with similar biochemical and biological properties to those of the 1 alpha,25(OH)(2)D(3)