Clinical significance of VEGF-A, -C and -D expression in esophageal malignancies

Vascular endothelial growth factors ( VEGF)- A, - C and - D are members of the proangiogenic VEGF family of glycoproteins. VEGF-A is known to be the most important angiogenic factor under physiological and pathological conditions, while VEGF-C and VEGF-D are implicated in the development and sprouting of lymphatic vessels, so called lymphangiogenesis. Local tumor progression, lymph node metastases and hematogenous tumor spread are important prognostic factors for esophageal carcinoma ( EC), one of the most lethal malignancies throughout the world. We found solid evidence in the literature that VEGF expression contributes to tumor angiogenesis, tumor progression and lymph node metastasis in esophageal squamous cell carcinoma ( SCC), and many authors could show a prognostic value for VEGF-assessment. In adenocarcinoma (AC) of the esophagus angiogenic properties are acquired in early stages, particularly in precancerous lesions like Barrett's dysplasia. However, VEGF expression fails to give prognostic information in AC of the esophagus. VEGF-C and VEGF-D were detected in SCC and dysplastic lesions, but not in normal mucosa of the esophagus. VEGF-C expression might be associated with lymphatic tumor invasion, lymph node metastases and advanced disease in esophageal SCC and AC. Therapeutic interference with VEGF signaling may prove to be a promising way of anti-angiogenic co-treatment in esophageal carcinoma. However, concrete clinical data are still pending

Deception in context: coding nonverbal cues, situational variables and risk of detection

There are many situations in which deception may arise and understanding the behaviors associated with it are compounded by various contexts in which it may occur. This paper sets out a coding protocol for identifying cues to deception and reports on three studies, in which deception was studied in different contexts. The contexts involved manipulating risks (i.e., probability) of being detected and reconnaissance, both of which are related to terrorist activities. Two of the studies examined the impact of changing the risks of deception detection, whilst the third investigated increased cognitive demand of duplex deception tasks including reconnaissance and deception. In all three studies, cues to deception were analyzed in relation to observable body movements and subjective impressions given by participants. In general, the results indicate a pattern of hand movement reduction by deceivers, and suggest the notion that raising the risk of detection influences deceivers? behaviors. Participants in the higher risk condition displayed increased negative affect (found in deceivers) and tension (found in both deceivers and truth-tellers) than those in lower risk conditions

Telomere disruption results in non-random formation of de novo dicentric chromosomes involving acrocentric human chromosomes

Copyright: © 2010 Stimpson et al.Genome rearrangement often produces chromosomes with two centromeres (dicentrics) that are inherently unstable because of bridge formation and breakage during cell division. However, mammalian dicentrics, and particularly those in humans, can be quite stable, usually because one centromere is functionally silenced. Molecular mechanisms of centromere inactivation are poorly understood since there are few systems to experimentally create dicentric human chromosomes. Here, we describe a human cell culture model that enriches for de novo dicentrics. We demonstrate that transient disruption of human telomere structure non-randomly produces dicentric fusions involving acrocentric chromosomes. The induced dicentrics vary in structure near fusion breakpoints and like naturally-occurring dicentrics, exhibit various inter-centromeric distances. Many functional dicentrics persist for months after formation. Even those with distantly spaced centromeres remain functionally dicentric for 20 cell generations. Other dicentrics within the population reflect centromere inactivation. In some cases, centromere inactivation occurs by an apparently epigenetic mechanism. In other dicentrics, the size of the alpha-satellite DNA array associated with CENP-A is reduced compared to the same array before dicentric formation. Extrachromosomal fragments that contained CENP-A often appear in the same cells as dicentrics. Some of these fragments are derived from the same alpha-satellite DNA array as inactivated centromeres. Our results indicate that dicentric human chromosomes undergo alternative fates after formation. Many retain two active centromeres and are stable through multiple cell divisions. Others undergo centromere inactivation. This event occurs within a broad temporal window and can involve deletion of chromatin that marks the locus as a site for CENP-A maintenance/replenishment.This work was supported by the Tumorzentrum Heidelberg/Mannheim grant (D.10026941)and by March of Dimes Research Foundation grant #1-FY06-377 and NIH R01 GM069514

Protocol for a randomised controlled trial of a school based cognitive behaviour therapy (CBT) intervention to prevent depression in high risk adolescents (PROMISE)

<p>Abstract</p> <p>Background</p> <p>Depression in adolescents is a significant problem that impairs everyday functioning and increases the risk of severe mental health disorders in adulthood. Relatively few adolescents with depression are identified and referred for treatment indicating the need to investigate alternative preventive approaches.</p> <p>Study Design</p> <p>A pragmatic cluster randomised controlled trial evaluating the effectiveness of a school based prevention programme on symptoms of depression in "high risk" adolescents (aged 12-16). The unit of allocation is year groups (n = 28) which are assigned to one of three conditions: an active intervention based upon cognitive behaviour therapy, attention control or treatment as usual. Assessments will be undertaken at screening, baseline, 6 months and 12 months. The primary outcome measure is change on the Short Mood and Feeling Questionnaire at 12 months. Secondary outcome measures will assess changes in negative thoughts, self esteem, anxiety, school connectedness, peer attachment, alcohol and substance misuse, bullying and self harm.</p> <p>Discussion</p> <p>As of August 2010, all 28 year groups (n = 5023) had been recruited and the assigned interventions delivered. Final 12 month assessments are scheduled to be completed by March 2011.</p> <p>Trial Registration</p> <p>ISRCTN19083628</p

School-based intervention to improve the mental health of low-income, secondary school students in Santiago, Chile (YPSA): study protocol for a randomized controlled trial

<p>Abstract</p> <p>Background</p> <p>Depression is common and can have devastating effects on the life of adolescents. Psychological interventions are the first-line for treating or preventing depression among adolescents. This proposal aims to evaluate a school-based, universal psychological intervention to reduce depressive symptoms among student's aged 13-14 attending municipal state secondary schools in Santiago, Chile.</p> <p>Study design</p> <p>This is a cluster randomised controlled trial with schools as the main clusters. We compared this intervention with a control group in a study involving 22 schools, 66 classes and approximately 2,600 students. Students in the active schools attended 11 weekly and 3 booster sessions of an intervention based on cognitive-behavioural models. The control schools received their usual but enhanced counselling sessions currently included in their curriculum. Mean depression scores and indicators of levels of functioning were assessed at 3 and 12 months after the completion of the intervention in order to assess the effectiveness of the intervention. Direct and indirect costs were measured in both groups to assess the cost-effectiveness of this intervention.</p> <p>Discussion</p> <p>As far as we are aware this is the first cluster randomised controlled trial of a school intervention for depression among adolescents outside the Western world.</p> <p>Trial Registration</p> <p><a href="http://www.controlled-trials.com/ISRCTN19466209">ISRCTN19466209</a></p

Effects of Ambulant Myofeedback Training and Ergonomic Counselling in Female Computer Workers with Work-Related Neck-Shoulder Complaints: A Randomized Controlled Trial

Objective: To investigate the effects of ambulant myofeedback training including ergonomic counselling (Mfb) and ergonomic counselling alone (EC), on work-related neck-shoulder pain and disability. Methods: Seventy-nine female computer workers reporting neck-shoulder complaints were randomly assigned to Mfb or EC and received four weeks of intervention. Pain intensity in neck, shoulders, and upper back, and pain disability, were measured at baseline, immediately after intervention, and at three and six months follow-up. Results: Pain intensity and disability had significantly decreased immediately after four weeks Mfb or EC, and the effects remained at follow up. No differences were observed between the Mfb and EC group for outcome and subjects in both intervention groups showed comparable chances for improvement in pain intensity and disability. Conclusions: Pain intensity and disability significantly reduced after both interventions and this effect remained at follow-up. No differences were observed between the two intervention groups

Utilisation of an operative difficulty grading scale for laparoscopic cholecystectomy

Background A reliable system for grading operative difficulty of laparoscopic cholecystectomy would standardise description of findings and reporting of outcomes. The aim of this study was to validate a difficulty grading system (Nassar scale), testing its applicability and consistency in two large prospective datasets. Methods Patient and disease-related variables and 30-day outcomes were identified in two prospective cholecystectomy databases: the multi-centre prospective cohort of 8820 patients from the recent CholeS Study and the single-surgeon series containing 4089 patients. Operative data and patient outcomes were correlated with Nassar operative difficultly scale, using Kendall’s tau for dichotomous variables, or Jonckheere–Terpstra tests for continuous variables. A ROC curve analysis was performed, to quantify the predictive accuracy of the scale for each outcome, with continuous outcomes dichotomised, prior to analysis. Results A higher operative difficulty grade was consistently associated with worse outcomes for the patients in both the reference and CholeS cohorts. The median length of stay increased from 0 to 4 days, and the 30-day complication rate from 7.6 to 24.4% as the difficulty grade increased from 1 to 4/5 (both p < 0.001). In the CholeS cohort, a higher difficulty grade was found to be most strongly associated with conversion to open and 30-day mortality (AUROC = 0.903, 0.822, respectively). On multivariable analysis, the Nassar operative difficultly scale was found to be a significant independent predictor of operative duration, conversion to open surgery, 30-day complications and 30-day reintervention (all p < 0.001). Conclusion We have shown that an operative difficulty scale can standardise the description of operative findings by multiple grades of surgeons to facilitate audit, training assessment and research. It provides a tool for reporting operative findings, disease severity and technical difficulty and can be utilised in future research to reliably compare outcomes according to case mix and intra-operative difficulty

Simulation of developmental changes in action potentials with ventricular cell models

During cardiomyocyte development, early embryonic ventricular cells show spontaneous activity that disappears at a later stage. Dramatic changes in action potential are mediated by developmental changes in individual ionic currents. Hence, reconstruction of the individual ionic currents into an integrated mathematical model would lead to a better understanding of cardiomyocyte development. To simulate the action potential of the rodent ventricular cell at three representative developmental stages, quantitative changes in the ionic currents, pumps, exchangers, and sarcoplasmic reticulum (SR) Ca2+ kinetics were represented as relative activities, which were multiplied by conductance or conversion factors for individual ionic systems. The simulated action potential of the early embryonic ventricular cell model exhibited spontaneous activity, which ceased in the simulated action potential of the late embryonic and neonatal ventricular cell models. The simulations with our models were able to reproduce action potentials that were consistent with the reported characteristics of the cells in vitro. The action potential of rodent ventricular cells at different developmental stages can be reproduced with common sets of mathematical equations by multiplying conductance or conversion factors for ionic currents, pumps, exchangers, and SR Ca2+ kinetics by relative activities

Succinic semialdehyde dehydrogenase deficiency: Lessons from mice and men

Succinic semialdehyde dehydrogenase (SSADH) deficiency, a disorder of GABA degradation with subsequent elevations in brain GABA and GHB, is a neurometabolic disorder with intellectual disability, epilepsy, hypotonia, ataxia, sleep disorders, and psychiatric disturbances. Neuroimaging reveals increased T2-weighted MRI signal usually affecting the globus pallidus, cerebellar dentate nucleus, and subthalamic nucleus, and often cerebral and cerebellar atrophy. EEG abnormalities are usually generalized spike-wave, consistent with a predilection for generalized epilepsy. The murine phenotype is characterized by failure-to-thrive, progressive ataxia, and a transition from generalized absence to tonic-clonic to ultimately fatal convulsive status epilepticus. Binding and electrophysiological studies demonstrate use-dependent downregulation of GABA(A) and (B) receptors in the mutant mouse. Translational human studies similarly reveal downregulation of GABAergic activity in patients, utilizing flumazenil-PET and transcranial magnetic stimulation for GABA(A) and (B) activity, respectively. Sleep studies reveal decreased stage REM with prolonged REM latencies and diminished percentage of stage REM. An ad libitum ketogenic diet was reported as effective in the mouse model, with unclear applicability to the human condition. Acute application of SGS–742, a GABA(B) antagonist, leads to improvement in epileptiform activity on electrocorticography. Promising mouse data using compounds available for clinical use, including taurine and SGS–742, form the framework for human trials