How to keep the brain awake? The complex molecular pharmacogenetics of wake promotion.

Wake-promoting drugs are widely used to treat excessive daytime sleepiness. The neuronal pathways involved in wake promotion are multiple and often not well characterized. We tested d-amphetamine, modafinil, and YKP10A, a novel wake-promoting compound, in three inbred strains of mice. The wake duration induced by YKP10A and d-amphetamine depended similarly on genotype, whereas opposite strain differences were observed after modafinil. Electroencephalogram (EEG) analysis during drug-induced wakefulness revealed a transient approximately 2 Hz slowing of theta oscillations and an increase in beta-2 (20-35 Hz) activity only after YKP10A. Gamma activity (35-60 Hz) was induced by all drugs in a drug- and genotype-dependent manner. Brain transcriptome and clustering analyses indicated that the three drugs have both common and specific molecular signatures. The correlation between specific EEG and gene-expression signatures suggests that the neuronal pathways activated to stay awake vary among drugs and genetic background.

Impact of Prophylactic Cranial Irradiation Timing on Brain Relapse Rates in Patients With Stage IIIB Non-Small-Cell Lung Carcinoma Treated With Two Different Chemoradiotherapy Regimens.

PURPOSE: To retrospectively assess the influence of prophylactic cranial irradiation (PCI) timing on brain relapse rates in patients treated with two different chemoradiotherapy (CRT) regimens for Stage IIIB non-small-cell lung cancer (NSCLC). METHODS AND MATERIALS: A cohort of 134 patients, with Stage IIIB NSCLC in recursive partitioning analysis Group 1, was treated with PCI (30 Gy at 2 Gy/fr) following one of two CRT regimens. Regimen 1 (n = 58) consisted of three cycles of induction chemotherapy (ICT) followed by concurrent CRT (C-CRT). Regimen 2 (n = 76) consisted of immediate C-CRT during thoracic radiotherapy. RESULTS: At a median follow-up of 27.6 months (range, 7.2-40.4), 65 patients were alive. Median, progression-free, and brain metastasis-free survival (BMFS) times for the whole study cohort were 23.4, 15.4, and 23.0 months, respectively. Median survival time and the 3-year survival rate for regimens 1 and 2 were 19.3 vs. 26.1 months (p = 0.001) and 14.4% vs. 34.4% (p < .001), respectively. Median time from the initiation of primary treatment to PCI was 123.2 (range, 97-161) and 63.4 (range, 55-74) days for regimens 1 and 2, respectively (p < 0.001). Overall, 11 (8.2%) patients developed brain metastasis (BM) during the follow-up period: 8 (13.8%) in regimen 1 and 3 (3.9%) in regimen 2 (p = 0.03). Only 3 (2.2%) patients developed BM at the site of first failure, and for 2 of them, it was also the sole site of recurrence. Median BMFS for regimens 1 and 2 were 17.4 (13.5-21.3) vs. 26.0 (22.9-29.1 months), respectively (p < 0.001). CONCLUSION: These results suggest that in Stage IIIB NSCLC patients treated with PCI, lower BM incidence and longer survival rates result from immediate C-CRT rather than ITC-first regimens. This indicates the benefit of earlier PCI use without delay because of induction protocols.

Glucose control after severe brain injury.

PURPOSE OF REVIEW: A substantial body of evidence supports the use of intensive insulin therapy in general critical care practice, particularly in surgical intensive care unit patients. The impact of intensive insulin therapy on the outcome of critically ill neurological patients, however, is still controversial. While avoidance of hyperglycemia is recommended in neurointensive care, no recommendations exist regarding the optimal target for systemic glucose control after severe brain injury. RECENT FINDINGS: An increase in brain metabolic demand leading to a deficiency in cerebral extracellular glucose has been observed in critically ill neurological patients and correlates with poor outcome. In this setting, a reduction of systemic glucose below 6 mmol/l with exogenous insulin has been found to exacerbate brain metabolic distress. Recent studies have confirmed these findings while showing intensive insulin therapy to have no substantial benefit on the outcome of critically ill neurological patients. SUMMARY: Questions persist regarding the optimal target for glucose control after severe brain injury. Further studies are needed to analyze the impact of intensive insulin therapy on brain glucose metabolism and outcome of critically ill neurological patients. According to the available evidence, a less restrictive target for systemic glucose control (6-10 mmol/l) may be more appropriate.

Variability of ascending aorta diameter measurements as assessed with electrocardiography-gated multidetector computerized tomography and computer assisted diagnosis software.

Recently, morphometric measurements of the ascending aorta have been done with ECG-gated multidector computerized tomography (MDCT) to help the development of future novel transcatheter therapies (TCT); nevertheless, the variability of such measurements remains unknown. Thirty patients referred for ECG-gated CT thoracic angiography were evaluated. Continuous reformations of the ascending aorta, perpendicular to the centerline, were obtained automatically with a commercially available computer aided diagnosis (CAD). Then measurements of the maximal diameter were done with the CAD and manually by two observers (separately). Measurements were repeated one month later. The Bland-Altman method, Spearman coefficients, and a Wilcoxon signed-rank test were used to evaluate the variability, the correlation, and the differences between observers. The interobserver variability for maximal diameter between the two observers was up to 1.2 mm with limits of agreement [-1.5, +0.9] mm; whereas the intraobserver limits were [-1.2, +1.0] mm for the first observer and [-0.8, +0.8] mm for the second observer. The intraobserver CAD variability was 0.8 mm. The correlation was good between observers and the CAD (0.980-0.986); however, significant differences do exist (P<0.001). The maximum variability observed was 1.2 mm and should be considered in reports of measurements of the ascending aorta. The CAD is as reproducible as an experienced reader.

Role of surgery in the management of brain arteriovenous malformations: prospective cohort study.

BACKGROUND AND PURPOSE: Management of brain arteriovenous malformation (bAVM) is controversial. We have analyzed the largest surgical bAVM cohort for outcome. METHODS: Both operated and nonoperated cases were included for analysis. A total of 779 patients with bAVMs were consecutively enrolled between 1989 and 2014. Initial management recommendations were recorded before commencement of treatment. Surgical outcome was prospectively recorded and outcomes assigned at the last follow-up visit using modified Rankin Scale. First, a sensitivity analyses was performed to select a subset of the entire cohort for which the results of surgery could be generalized. Second, from this subset, variables were analyzed for risk of deficit or near miss (intraoperative hemorrhage requiring blood transfusion of ≥2.5 L, hemorrhage in resection bed requiring reoperation, and hemorrhage associated with either digital subtraction angiography or embolization). RESULTS: A total of 7.7% of patients with Spetzler-Ponce classes A and B bAVM had an adverse outcome from surgery leading to a modified Rankin Scale >1. Sensitivity analyses that demonstrated outcome results were not subject to selection bias for Spetzler-Ponce classes A and B bAVMs. Risk factors for adverse outcomes from surgery for these bAVMs include size, presence of deep venous drainage, and eloquent location. Preoperative embolization did not affect the risk of perioperative hemorrhage. CONCLUSIONS: Most of the ruptured and unruptured low and middle-grade bAVMs (Spetzler-Ponce A and B) can be surgically treated with a low risk of permanent morbidity and a high likelihood of preventing future hemorrhage. Our results do not apply to Spetzler-Ponce C bAVMs.

The prognostic value of health-related quality-of-life data in predicting survival in glioblastoma cancer patients: results from an international randomised phase III EORTC Brain Tumour and Radiation Oncology Groups, and NCIC Clinical Trials Group study.

This is one of the few studies that have explored the value of baseline symptoms and health-related quality of life (HRQOL) in predicting survival in brain cancer patients. Baseline HRQOL scores (from the EORTC QLQ-C30 and the Brain Cancer Module (BN 20)) were examined in 490 newly diagnosed glioblastoma cancer patients for the relationship with overall survival by using Cox proportional hazards regression models. Refined techniques as the bootstrap re-sampling procedure and the computation of C-indexes and R(2)-coefficients were used to try and validate the model. Classical analysis controlled for major clinical prognostic factors selected cognitive functioning (P=0.0001), global health status (P=0.0055) and social functioning (P<0.0001) as statistically significant prognostic factors of survival. However, several issues question the validity of these findings. C-indexes and R(2)-coefficients, which are measures of the predictive ability of the models, did not exhibit major improvements when adding selected or all HRQOL scores to clinical factors. While classical techniques lead to positive results, more refined analyses suggest that baseline HRQOL scores add relatively little to clinical factors to predict survival. These results may have implications for future use of HRQOL as a prognostic factor in cancer patients.

Lésions cérébrales du prématuré et techniques d'imagerie à visée pronostique du développement neurocognitif [Cerebral brain injury in preterm infants and the role of neuroimaging in predicting neurodevelopmental outcomes].

Due to advances in neonatal intensive care over the last decades, the pattern of brain injury seen in very preterm infants has evolved in more subtle lesions that are still essential to diagnose in regard to neurodevelopmental outcome. While cranial ultrasound is still used at the bedside, magnetic resonance imaging (MRI) is becoming increasingly used in this population for the assessment of brain maturation and white and grey matter lesions. Therefore, MRI provides a better prognostic value for the neurodevelopmental outcome of these preterms. Furthermore, the development of new MRI techniques, such as diffusion tensor imaging, resting state functional connectivity and magnetic resonance spectroscopy, may further increase the prognostic value, helping to counsel parents and allocate early intervention services.

Multimodal evaluation for medical image segmentation

This paper is a joint effort between five institutionsthat introduces several novel similarity measures andcombines them to carry out a multimodal segmentationevaluation. The new similarity measures proposed arebased on the location and the intensity values of themisclassified voxels as well as on the connectivity andthe boundaries of the segmented data. We showexperimentally that the combination of these measuresimprove the quality of the evaluation. The study that weshow here has been carried out using four differentsegmentation methods from four different labs applied toa MRI simulated dataset of the brain. We claim that ournew measures improve the robustness of the evaluation andprovides better understanding about the differencebetween segmentation methods.

Electronic voting system for computer supported collaborative learning

The EVS4CSCL project starts in the context of a Computer Supported Collaborative Learning environment (CSCL). Previous UOC projects created a CSCL generic platform (CLPL) to facilitate the development of CSCL applications. A discussion forum (DF) was the first application developed over the framework. This discussion forum was different from other products on the marketplace because of its focus on the learning process. The DF carried out the specification and elaboration phases from the discussion learning process but there was a lack in the consensus phase. The consensus phase in a learning environment is not something to be achieved but tested. Common tests are done by Electronic Voting System (EVS) tools, but consensus test is not an assessment test. We are not evaluating our students by their answers but by their discussion activity. Our educational EVS would be used as a discussion catalyst proposing a discussion about the results after an initial query or it would be used after a discussion period in order to manifest how the discussion changed the students mind (consensus). It should be also used by the teacher as a quick way to know where the student needs some reinforcement. That is important in a distance-learning environment where there is no direct contact between the teacher and the student and it is difficult to detect the learning lacks. In an educational environment, assessment it is a must and the EVS will provide direct assessment by peer usefulness evaluation, teacher marks on every query created and indirect assessment from statistics regarding the user activity.

Biofilm formation at the solid-liquid and air-liquid interfaces by Acinetobacter species.

BACKGROUND The members of the genus Acinetobacter are Gram-negative cocobacilli that are frequently found in the environment but also in the hospital setting where they have been associated with outbreaks of nosocomial infections. Among them, Acinetobacter baumannii has emerged as the most common pathogenic species involved in hospital-acquired infections. One reason for this emergence may be its persistence in the hospital wards, in particular in the intensive care unit; this persistence could be partially explained by the capacity of these microorganisms to form biofilm. Therefore, our main objective was to study the prevalence of the two main types of biofilm formed by the most relevant Acinetobacter species, comparing biofilm formation between the different species. FINDINGS Biofilm formation at the air-liquid and solid-liquid interfaces was investigated in different Acinetobacter spp. and it appeared to be generally more important at 25°C than at 37°C. The biofilm formation at the solid-liquid interface by the members of the ACB-complex was at least 3 times higher than the other species (80-91% versus 5-24%). In addition, only the isolates belonging to this complex were able to form biofilm at the air-liquid interface; between 9% and 36% of the tested isolates formed this type of pellicle. Finally, within the ACB-complex, the biofilm formed at the air-liquid interface was almost 4 times higher for A. baumannii and Acinetobacter G13TU than for Acinetobacter G3 (36%, 27% & 9% respectively). CONCLUSIONS Overall, this study has shown the capacity of the Acinetobacter spp to form two different types of biofilm: solid-liquid and air-liquid interfaces. This ability was generally higher at 25°C which might contribute to their persistence in the inanimate hospital environment. Our work has also demonstrated for the first time the ability of the members of the ACB-complex to form biofilm at the air-liquid interface, a feature that was not observed in other Acinetobacter species.

Effective diagnosis of Alzheimer's disease by means of large margin-based methodology.

BACKGROUND Functional brain images such as Single-Photon Emission Computed Tomography (SPECT) and Positron Emission Tomography (PET) have been widely used to guide the clinicians in the Alzheimer's Disease (AD) diagnosis. However, the subjectivity involved in their evaluation has favoured the development of Computer Aided Diagnosis (CAD) Systems. METHODS It is proposed a novel combination of feature extraction techniques to improve the diagnosis of AD. Firstly, Regions of Interest (ROIs) are selected by means of a t-test carried out on 3D Normalised Mean Square Error (NMSE) features restricted to be located within a predefined brain activation mask. In order to address the small sample-size problem, the dimension of the feature space was further reduced by: Large Margin Nearest Neighbours using a rectangular matrix (LMNN-RECT), Principal Component Analysis (PCA) or Partial Least Squares (PLS) (the two latter also analysed with a LMNN transformation). Regarding the classifiers, kernel Support Vector Machines (SVMs) and LMNN using Euclidean, Mahalanobis and Energy-based metrics were compared. RESULTS Several experiments were conducted in order to evaluate the proposed LMNN-based feature extraction algorithms and its benefits as: i) linear transformation of the PLS or PCA reduced data, ii) feature reduction technique, and iii) classifier (with Euclidean, Mahalanobis or Energy-based methodology). The system was evaluated by means of k-fold cross-validation yielding accuracy, sensitivity and specificity values of 92.78%, 91.07% and 95.12% (for SPECT) and 90.67%, 88% and 93.33% (for PET), respectively, when a NMSE-PLS-LMNN feature extraction method was used in combination with a SVM classifier, thus outperforming recently reported baseline methods. CONCLUSIONS All the proposed methods turned out to be a valid solution for the presented problem. One of the advances is the robustness of the LMNN algorithm that not only provides higher separation rate between the classes but it also makes (in combination with NMSE and PLS) this rate variation more stable. In addition, their generalization ability is another advance since several experiments were performed on two image modalities (SPECT and PET).

Effectiveness of holistic neuropsychological rehabilitation for Spanish population with acquired brain injury measured using Rasch analysis.

INTRODUCTION The Rasch model is increasingly used in the field of rehabilitation because it improves the accuracy of measurements of patient status and their changes after therapy. OBJECTIVE To determine the long-term effectiveness of a holistic neuropsychological rehabilitation program for Spanish outpatients with acquired brain injury (ABI) using Rasch analysis. METHODS Eighteen patients (ten with long evolution - patients who started the program > 6 months after ABI- and eight with short evolution) and their relatives attended the program for 6 months. Patients' and relatives' answers to the European Brain Injury Questionnaire and the Frontal Systems Behavior Scale at 3 time points (pre-intervention. post-intervention and 12 month follow-up) were transformed into linear measures called logits. RESULTS The linear measures revealed significant improvements with large effects at the follow-up assessment on cognitive and executive functioning, social and emotional self-regulation, apathy and mood. At follow-up, the short evolution group achieved greater improvements in mood and cognitive functioning than the long evolution patients. CONCLUSIONS The program showed long-term effectiveness for most of the variables, and it was more effective for mood and cognitive functioning when patients were treated early. Relatives played a key role in the effectiveness of the rehabilitation program.

Gender and weight shape brain dynamics during food viewing.

Hemodynamic imaging results have associated both gender and body weight to variation in brain responses to food-related information. However, the spatio-temporal brain dynamics of gender-related and weight-wise modulations in food discrimination still remain to be elucidated. We analyzed visual evoked potentials (VEPs) while normal-weighted men (n = 12) and women (n = 12) categorized photographs of energy-dense foods and non-food kitchen utensils. VEP analyses showed that food categorization is influenced by gender as early as 170 ms after image onset. Moreover, the female VEP pattern to food categorization co-varied with participants' body weight. Estimations of the neural generator activity over the time interval of VEP modulations (i.e. by means of a distributed linear inverse solution [LAURA]) revealed alterations in prefrontal and temporo-parietal source activity as a function of image category and participants' gender. However, only neural source activity for female responses during food viewing was negatively correlated with body-mass index (BMI) over the respective time interval. Women showed decreased neural source activity particularly in ventral prefrontal brain regions when viewing food, but not non-food objects, while no such associations were apparent in male responses to food and non-food viewing. Our study thus indicates that gender influences are already apparent during initial stages of food-related object categorization, with small variations in body weight modulating electrophysiological responses especially in women and in brain areas implicated in food reward valuation and intake control. These findings extend recent reports on prefrontal reward and control circuit responsiveness to food cues and the potential role of this reactivity pattern in the susceptibility to weight gain.

Computer-assisted cup placement techniques in total hip arthroplasty improve accuracy of placement.

Malposition of the acetabular component during hip arthroplasty increases the occurrence of impingement, reduces range of motion, and increases the risk of dislocation and long-term wear. To prevent malpositioned hip implants, an increasing number of computer-assisted orthopaedic systems have been described, but their accuracy is not well established. The purpose of this study was to determine the reproducibility and accuracy of conventional versus computer-assisted techniques for positioning the acetabular component in total hip arthroplasty. Using a lateral approach, 150 cups were placed by 10 surgeons in 10 identical plastic pelvis models (freehand, with a mechanical guide, using computer assistance). Conditions for cup implantations were made to mimic the operating room situation. Preoperative planning was done from a computed tomography scan. The accuracy of cup abduction and anteversion was assessed with an electromagnetic system. Freehand placement revealed a mean accuracy of cup anteversion and abduction of 10 degrees and 3.5 degrees, respectively (maximum error, 35 degrees). With the cup positioner, these angles measured 8 degrees and 4 degrees (maximum error, 29.8 degrees), respectively, and using computer assistance, 1.5 degrees and 2.5 degrees degrees (maximum error, 8 degrees), respectively. Computer-assisted cup placement was an accurate and reproducible technique for total hip arthroplasty. It was more accurate than traditional methods of cup positioning.