Trilateral retinoblastoma: neuroimaging characteristics and value of routine brain screening on admission.

Trilateral retinoblastoma (TRb) is a rare disease associating intraocular retinoblastoma with intracranial primitive neuroectodermal tumor. Treatment is difficult and prognosis is poor. This multicenter study evaluates clinical findings and MR imaging characteristics of associated intracranial tumors in Rb patients. Clinical data of 17 patients (16 TRb and 1 quadrilateral Rb patients) included time intervals between Rb and TRb diagnosis and presence of baseline brain-imaging (BBI). Two reviewers reviewed all images individually and one reviewer per center evaluated their images. Consensus was reached during a joint scoring session. Studies were reviewed for tumor location, size and imaging characteristics (signal intensity (SI) on T1- and T2-weighted images, enhancement pattern and cystic appearance). Of 18 intracranial tumors, 78 % were located in the pineal gland and 22 % suprasellar. All tumors showed well-defined borders with mostly heterogenous enhancement (72 %) and isointense SI on T1- (78 %) and T2-weighted images (72 %) compared to gray matter. The majority of pineal TRbs showed a cystic component (57 %). TRb detected synchronously with the intraocular tumors on BBI (n = 7) were significantly smaller (P = 0.02), and mainly asymptomatic than TRb detected later on (n = 10). Overall, 5-year-survival of TRb patients detected on BBI was 67 % (95 % CI 29-100 %) compared to 11 % (95 % CI 0-32 %) for the group with delayed diagnosis. TRb mainly develops in the pineal gland and frequently presents with a cystic appearance that could be misinterpreted as benign pineal cysts. Routine BBI in all newly diagnosed Rb patients can detect TRb at a subclinical stage.

High b-value Diffusion-weighted Imaging: A Sensitive Method to Reveal White Matter Changes in Schizophrenia

Background: b-value is the parameter characterizing the intensity of the diffusion weighting during image acquisition. Data acquisition is usually performed with low b value (b~1000 s/mm2). Evidence shows that high b-values (b>2000 s/mm2) are more sensitive to the slow diffusion compartment (SDC) and maybe more sensitive in detecting white matter (WM) anomalies in schizophrenia.Methods: 12 male patients with schizophrenia (mean age 35 +/-3 years) and 16 healthy male controls matched for age were scanned with a low b-value (1000 s/mm2) and a high b-value (4000 s/mm2) protocol. Apparent diffusion coefficient (ADC) is a measure of the average diffusion distance of water molecules per time unit (mm2/s). ADC maps were generated for all individuals. 8 region of interests (frontal and parietal region bilaterally, centrum semi-ovale bilaterally and anterior and posterior corpus callosum) were manually traced blind to diagnosis.Results: ADC measures acquired with high b-value imaging were more sensitive in detecting differences between schizophrenia patients and healthy controls than low b-value imaging with a gain in significance by a factor of 20- 100 times despite the lower image Signal-to-noise ratio (SNR). Increased ADC was identified in patient's WM (p=0.00015) with major contributions from left and right centrum semi-ovale and to a lesser extent right parietal region.Conclusions: Our results may be related to the sensitivity of high b-value imaging to the SDC believed to reflect mainly the intra-axonal and myelin bound water pool. High b-value imaging might be more sensitive and specific to WM anomalies in schizophrenia than low b-value imaging

cDNA cloning and mapping of a novel islet-brain/JNK-interacting protein.

IB1/JIP-1 is a scaffold protein that regulates the c-Jun NH(2)-terminal kinase (JNK) signaling pathway, which is activated by environmental stresses and/or by treatment with proinflammatory cytokines including IL-1beta and TNF-alpha. The JNKs play an essential role in many biological processes, including the maturation and differentiation of immune cells and the apoptosis of cell targets of the immune system. IB1 is expressed predominantly in brain and pancreatic beta-cells where it protects cells from proapoptotic programs. Recently, a mutation in the amino-terminus of IB1 was associated with diabetes. A novel isoform, IB2, was cloned and characterized. Overall, both IB1 and IB2 proteins share a very similar organization, with a JNK-binding domain, a Src homology 3 domain, a phosphotyrosine-interacting domain, and polyacidic and polyproline stretches located at similar positions. The IB2 gene (HGMW-approved symbol MAPK8IP2) maps to human chromosome 22q13 and contains 10 coding exons. Northern and RT-PCR analyses indicate that IB2 is expressed in brain and in pancreatic cells, including insulin-secreting cells. IB2 interacts with both JNK and the JNK-kinase MKK7. In addition, ectopic expression of the JNK-binding domain of IB2 decreases IL-1beta-induced pancreatic beta-cell death. These data establish IB2 as a novel scaffold protein that regulates the JNK signaling pathway in brain and pancreatic beta-cells and indicate that IB2 represents a novel candidate gene for diabetes.

Clinical trial substantiates the predictive value of O-6-methylguanine-DNA methyltransferase promoter methylation in glioblastoma patients treated with temozolomide.

PURPOSE: In the setting of a prospective clinical trial, we determined the predictive value of the methylation status of the O-6-methylguanine-DNA methyltransferase (MGMT) promoter for outcome in glioblastoma patients treated with the alkylating agent temozolomide. Expression of this excision repair enzyme has been associated with resistance to alkylating chemotherapy. EXPERIMENTAL DESIGN: The methylation status of MGMT in the tumor biopsies was evaluated in 38 patients undergoing resection for newly diagnosed glioblastoma and enrolled in a Phase II trial testing concomitant and adjuvant temozolomide and radiation. The epigenetic silencing of the MGMT gene was determined using methylation-specific PCR. RESULTS: Inactivation of the MGMT gene by promoter methylation was associated with longer survival (P = 0.0051; Log-rank test). At 18 months, survival was 62% (16 of 26) for patients testing positive for a methylated MGMT promoter but reached only 8% (1 of 12) in absence of methylation (P = 0.002; Fisher's exact test). In the presence of other clinically relevant factors, methylation of the MGMT promoter remains the only significant predictor (P = 0.017; Cox regression). CONCLUSIONS: This prospective clinical trial identifies MGMT-methylation status as an independent predictor for glioblastoma patients treated with a methylating agent. The association of the epigenetic inactivation of the DNA repair gene MGMT with better outcome in this homogenous cohort may have important implications for the design of future trials and supports efforts to deplete MGMT by O-6-benzylguanine, a noncytotoxic substrate of this enzyme.

Creating a list of low-value health care activities in Swiss primary care.

Trisomy 21 is the most frequent genetic cause of cognitive impairment. To assess the perturbations of gene expression in trisomy 21, and to eliminate the noise of genomic variability, we studied the transcriptome of fetal fibroblasts from a pair of monozygotic twins discordant for trisomy 21. Here we show that the differential expression between the twins is organized in domains along all chromosomes that are either upregulated or downregulated. These gene expression dysregulation domains (GEDDs) can be defined by the expression level of their gene content, and are well conserved in induced pluripotent stem cells derived from the twins' fibroblasts. Comparison of the transcriptome of the Ts65Dn mouse model of Down's syndrome and normal littermate mouse fibroblasts also showed GEDDs along the mouse chromosomes that were syntenic in human. The GEDDs correlate with the lamina-associated (LADs) and replication domains of mammalian cells. The overall position of LADs was not altered in trisomic cells; however, the H3K4me3 profile of the trisomic fibroblasts was modified and accurately followed the GEDD pattern. These results indicate that the nuclear compartments of trisomic cells undergo modifications of the chromatin environment influencing the overall transcriptome, and that GEDDs may therefore contribute to some trisomy 21 phenotypes.

Predictive value of readiness, importance, and confidence in ability to change drinking and smoking.

BACKGROUND: Visual analog scales (VAS) are sometimes used to assess change constructs that are often considered critical for change. Aims of Study: 1.) To determine the association of readiness to change, importance of changing and confidence in ability to change alcohol and tobacco use at baseline with the risk for drinking (more than 21 drinks per week/6 drinks or more on a single occasion more than once per month) and smoking (one or more cigarettes per day) six months later. 2.) To determine the association of readiness, importance and confidence with alcohol (number of drinks/week, number of binge drinking episodes/month) and tobacco (number of cigarettes/day) use at six months. METHODS: This is a secondary analysis of data from a multi-substance brief intervention randomized trial. A sample of 461 Swiss young men was analyzed as a prospective cohort. Participants were assessed at baseline and six months later on alcohol and tobacco use, and at baseline on readiness to change, importance of changing and confidence in ability to change constructs, using visual analog scales ranging from 1-10 for drinking and smoking behaviors. Regression models controlling for receipt of brief intervention were employed for each change construct. The lowest level (1-4) of each scale was the reference group that was compared to the medium (5-7) and high (8-10) levels. RESULTS: Among the 377 subjects reporting unhealthy alcohol use at baseline, mean (SD) readiness, importance and confidence to change drinking scores were 3.9 (3.0), 2.7 (2.2) and 7.2 (3.0), respectively. At follow-up, 108 (29%) reported no unhealthy alcohol use. Readiness was not associated with being risk-free at follow-up, but high importance (OR 2.94; 1.15, 7.50) and high confidence (OR 2.88; 1.46, 5.68) were. Among the 255 smokers at baseline, mean readiness, importance and confidence to change smoking scores were 4.6 (2.6), 5.3 (2.6) and 5.9 (2.7), respectively. At follow-up, 13% (33) reported no longer smoking. Neither readiness nor importance was associated with being a non-smoker, whereas high confidence (OR 3.29; 1.12, 9.62) was. CONCLUSIONS: High confidence in ability to change was associated with favorable outcomes for both drinking and smoking, whereas high importance was associated only with a favorable drinking outcome. This study points to the value of confidence as an important predictor of successful change for both drinking and smoking, and shows the value of importance in predicting successful changes in alcohol use. TRIAL REGISTRATION NUMBER: ISRCTN78822107.

Improved multiple-locus variable-number tandem-repeat assay for Staphylococcus aureus genotyping, providing a highly informative technique together with strong phylogenetic value.

We describe an improved multiple-locus variable-number tandem-repeat (VNTR) analysis (MLVA) scheme for genotyping Staphylococcus aureus. We compare its performance to those of multilocus sequence typing (MLST) and spa typing in a survey of 309 strains. This collection includes 87 epidemic methicillin-resistant S. aureus (MRSA) strains of the Harmony collection, 75 clinical strains representing the major MLST clonal complexes (CCs) (50 methicillin-sensitive S. aureus [MSSA] and 25 MRSA), 135 nasal carriage strains (133 MSSA and 2 MRSA), and 13 published S. aureus genome sequences. The results show excellent concordance between the techniques' results and demonstrate that the discriminatory power of MLVA is higher than those of both MLST and spa typing. Two hundred forty-two genotypes are discriminated with 14 VNTR loci (diversity index, 0.9965; 95% confidence interval, 0.9947 to 0.9984). Using a cutoff value of 45%, 21 clusters are observed, corresponding to the CCs previously defined by MLST. The variability of the different tandem repeats allows epidemiological studies, as well as follow-up of the evolution of CCs and the identification of potential ancestors. The 14 loci can conveniently be analyzed in two steps, based upon a first-line simplified assay comprising a subset of 10 loci (panel 1) and a second subset of 4 loci (panel 2) that provides higher resolution when needed. In conclusion, the MLVA scheme proposed here, in combination with available on-line genotyping databases (including http://mlva.u-psud.fr/), multiplexing, and automatic sizing, can provide a basis for almost-real-time large-scale population monitoring of S. aureus.

Evaluating effects of spectral training data distribution on continuous field mapping performance

Continuous field mapping has to address two conflicting remote sensing requirements when collecting training data. On one hand, continuous field mapping trains fractional land cover and thus favours mixed training pixels. On the other hand, the spectral signature has to be preferably distinct and thus favours pure training pixels. The aim of this study was to evaluate the sensitivity of training data distribution along fractional and spectral gradients on the resulting mapping performance. We derived four continuous fields (tree, shrubherb, bare, water) from aerial photographs as response variables and processed corresponding spectral signatures from multitemporal Landsat 5 TM data as explanatory variables. Subsequent controlled experiments along fractional cover gradients were then based on generalised linear models. Resulting fractional and spectral distribution differed between single continuous fields, but could be satisfactorily trained and mapped. Pixels with fractional or without respective cover were much more critical than pure full cover pixels. Error distribution of continuous field models was non-uniform with respect to horizontal and vertical spatial distribution of target fields. We conclude that a sampling for continuous field training data should be based on extent and densities in the fractional and spectral, rather than the real spatial space. Consequently, adequate training plots are most probably not systematically distributed in the real spatial space, but cover the gradient and covariate structure of the fractional and spectral space well. (C) 2009 International Society for Photogrammetry and Remote Sensing, Inc. (ISPRS). Published by Elsevier B.V. All rights reserved.

The habenula encodes negative motivational value associated with primary punishment in humans.

Learning what to approach, and what to avoid, involves assigning value to environmental cues that predict positive and negative events. Studies in animals indicate that the lateral habenula encodes the previously learned negative motivational value of stimuli. However, involvement of the habenula in dynamic trial-by-trial aversive learning has not been assessed, and the functional role of this structure in humans remains poorly characterized, in part, due to its small size. Using high-resolution functional neuroimaging and computational modeling of reinforcement learning, we demonstrate positive habenula responses to the dynamically changing values of cues signaling painful electric shocks, which predict behavioral suppression of responses to those cues across individuals. By contrast, negative habenula responses to monetary reward cue values predict behavioral invigoration. Our findings show that the habenula plays a key role in an online aversive learning system and in generating associated motivated behavior in humans.

Value of positron emission tomography in full-thickness chest wall resections for malignancies.

Preoperative imaging for resection of chest wall malignancies is generally performed by computed tomography (CT). We evaluated the role of (18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET) in planning full-thickness chest wall resections for malignancies. We retrospectively included 18 consecutive patients operated from 2004 to 2006 at our institution. Tumor extent was measured by CT and PET, using the two largest perpendicular tumor extensions in the chest wall plane to compute the tumor surface assuming an elliptical shape. Imaging measurements were compared to histopathology assessment of tumor borders. CT assessment consistently overestimated the tumor size as compared to PET (+64% vs. +1%, P<0.001). Moreover, PET was significantly better than CT at defining the size of lesions >24 cm(2) corresponding to a mean diameter >5.5 cm or an ellipse of >4 cm x 7.6 cm (positive predictive value 80% vs. 44% and specificity 93% vs. 64%, respectively). Metabolic PET imaging was superior to CT for defining the extent of chest wall tumors, particularly for tumors with a diameter >5.5 cm. PET can complement CT in planning full-thickness chest wall resection for malignancies, but its true value remains to be determined in larger, prospective studies.

The value of adding mirror therapy for upper limb motor recovery of subacute stroke patients: a randomized controlled trial.

BACKGROUND: Upper limb paresis remains a relevant challenge in stroke rehabilitation. AIM: To evaluate if adding mirror therapy (MT) to conventional therapy (CT) can improve motor recovery of the upper limb in subacute stroke patients. DESIGN: Prospective, single-center, single-blind, randomised, controlled trial. SETTING: Subacute stroke patients referred to a Physical and Rehabilitation Medicine Unit between October 2009 and August 2011. POPULATION: Twenty-six subacute stroke patients (time from stroke <4 weeks) with upper limb paresis (Motricity Index â0/00¤ 77). METHODS: Patients were randomly allocated to the MT (N.=13) or to the CT group (N.=13). Both followed a comprehensive rehabilitative treatment. In addition, MT Group had 30 minutes of MT while the CT group had 30 minutes of sham therapy. Action Research Arm Test (ARAT) was the primary outcome measures. Motricity Index (MI) and the Functional Independence Measure (FIM) were the secondary outcome measures. RESULTS: After one month of treatment patients of both groups showed statistically significant improvements in all the variables measured (P<0.05). Moreover patients of the MT group had greater improvements in the ARAT, MI and FIM values compared to CT group (P<0.01, Glass's Î" Effect Size: 1.18). No relevant adverse event was recorded during the study. CONCLUSION: MT is a promising and easy method to improve motor recovery of the upper limb in subacute stroke patients. CLINICAL REHABILITATION IMPACT: While MT use has been advocated for acute patients with no or negligible motor function, it can be usefully extended to patients who show partial motor recovery. The easiness of implementation, the low cost and the acceptability makes this therapy an useful tool in stroke rehabilitation.