Neural generators of sustained activity differ for stimulus-encoding and delay maintenance

The ability to maintain information online beyond sensory stimulation is regarded as a key contribution of working memory to goal-directed behaviour. It is widely accepted that sustained neural activity is a key mechanism of stimulus maintenance, but it is unclear to what extent the neural generators of sustained activity change from stimulus-encoding to maintenance. Using event-related potentials in humans, we show that, in a delayed match-to-sample task, slow shifts over parieto-occipital electrode sites had a different topography and polarity during encoding and delay maintenance of images depicting scenes. This clearly demonstrates that neural generators of sustained activity associated with stimulus-encoding and delay maintenance differed, and that the change between these generators occurred time-locked to the onset of the delay period. We also investigated how monetary reward incentives modulated the amplitude and topography of sustained delay activity and the ability to suppress irrelevant distracting information during the delay. Reward incentives improved maintenance performance and this was correlated with an expansion of the parieto-occipital electrode sites that were entrained into sustained delay activity (rather than improved distractor suppression), suggesting that under the influence of reward, the parieto-occipital regions that contributed to delay maintenance expanded in size.     

Diffusion-weighted MR-imaging for the detection of pulmonary nodules at 1.5 Tesla: intraindividual comparison with multidetector computed tomography

Introduction: To investigate the feasibility of diffusion‐weighted imaging (DWI) MRI for detecting pulmonary nodules at 1.5 Tesla in comparison with standard multidetector computed tomography (MDCT). Methods: Twenty patients with disseminated cancer disease in which MDCT had assured the presence of at least one pulmonary nodule were examined using a respiratory‐gated DWI MR‐sequence. Grey scale inverted source images and coronal maximum intensity projection (MIP) images were consensually analysed by two experienced radiologists. Size and location of any nodule detected were assessed. Additionally, the readers evaluated each hemithorax for the presence of at least one nodule and applied a four‐point conspicuity scale (1‐hemithorax definitely affected; 4‐hemithorax definitely not affected). MDCT data served as reference. Results: At MDCT, a total of 71 pulmonary noduIes was found (size 3–5 mm, n = 16; 6–9 mm, n = 22; ≥10 mm, n = 33). For the DWI MR‐sequence, a sensitivity of 86.4% was calculated for nodules ranging 6–9 mm and 97% for nodules ≥10 mm. In contrast, only 43.8% of lesions ≤5 mm was detected. The separate analysis of each hemithorax for the presence of at least one pulmonary nodule revealed a specificity rate, PPV and NPV of DWI‐MR of 92.3%, 96% and 80%, respectively. Conclusions: The presented study is the first to confirm the diagnostic potential of DWI‐MR in the detection of solid lung nodules. This technique allows for the detection of nodules ≥6 mm with reasonably high sensitivity rates (>86%). The observation of false positive findings decreases the accuracy of this approach compared with MDCT.     

EpCAM-autoantibody levels in the course of disease of ovarian cancer patients

EpCAM is a tumor-associated antigen, which is frequently expressed in ovarian cancer. Recently, autoantibodies against EpCAM have been identified in patients with ovarian cancer. It is not clear whether these autoantibodies are of prognostic importance. We evaluated whether EpCAM-autoantibodies have an impact on the clinical course of patients with ovarian cancer. EpCAM-autoantibodies were determined in sera of 28 healthy voluntary age-matched women and 84 patients with primary epithelial ovarian cancer before and after platinum-based chemotherapy using a recombinant EpCAM-protein for antibody detection by ELISA technique. The median follow-up time was 18 months. Samples exceeding the mean antibody titer of healthy controls plus 2 standard deviations were considered positive. The antibody titer of healthy controls was 0.061 ± 0.015. Using a cut-off value of 0.091, we found 3/84 (4%) patients before and 12/61 (20%) patients with ovarian cancer to be positive for EpCAM-autoantibodies after first-line treatment. Using the paired T-Test, we noted a significant post-therapeutic increase of AABs (P < 0.0001). Notably, AAB-levels after first-line therapy were found to be correlated with the tumor resection status in primary surgery. Analysis of progression-free survival, FIGO stage, grading, age and sensitivity to platinum-based chemotherapy did not reveal significant associations with EpCAM-AAB titers. We observed an increase in AAB-levels during the first-line treatment of patients with ovarian cancer. EpCAM-AAB-levels after first-line treatment appear to correlate with macroscopic tumor residuals after initial surgery.     

Perfluorinated compounds--exposure assessment for the general population in Western countries

Perfluorinated compounds (PFCs) can currently be detected in many environmental media and biota, as well as in humans. Because of their persistence and their potential to accumulate they are of toxicological concern. The present review presents the current knowledge of PFC monitoring data in environmental media relevant for human exposure. In this context, PFC concentrations in indoor and ambient air, house dust, drinking water and food are outlined. Furthermore, we summarize human biomonitoring data of PFC levels in blood, breast milk, and human tissues. An estimate of the overall exposure of the general adult population is provided and compared with tolerable intake values. Using a simplified model, the average (and upper) level of daily exposure including all potential routes amounts to 1.6 ng/kg(body weight) (8.8 ng/kg(body weight)) for PFOS and 2.9 ng/kg(body weight) (12.6 ng/kg(body weight)) for PFOA in adults in the general population. The majority of exposure can be attributed to the oral route, mainly to diet. Overall, the contribution of PFOS and PFOA precursors to total exposure seems to be limited. Besides this background exposure of the general population, a specific additional exposure may occur which causes an increased PFC body burden. This has been observed in populations living near PFC production facilities or in areas with environmental contamination of PFCs. The consumption of highly contaminated fish products may also cause an increase in PFC body burdens.     

Pediatric multiple sclerosis

Diagnosing multiple sclerosis (MS) in a child is challenging because of the limited diagnostic criteria and their overlap with acute disseminated encephalomyelitis. Pediatric-onset MS patients are more likely to be male, have seizures, and have brainstem and cerebellar symptoms than adults, and are less likely to have spinal cord symptoms than adults. They mostly experience a relapsing-remitting course. Their initial brain MRI shows more frequent involvement of the posterior fossa, less well-defined ovoid lesions, and more confluent lesions that decrease over time in patients with prepubertal onset, making early diagnosis even more difficult. Although disability progression is slower than in adults, pediatric onset MS leads to significant disability at a younger age and may be worse in non-white patients (up to 50% in North America). The rareness of pediatric-onset MS has precluded enrollment in clinical trials. Thus, children are receiving off-label adult therapies without clear evidence of their effectiveness and limited knowledge of their tolerability.     

Diabetes abolishes sildenafil-induced cGMP-dependent protein kinase-I expression and cardioprotection

The selective phosphodiesterase type 5 inhibitor sildenafil has been demonstrated to produce cardioprotection; however, diabetes is known to abolish cardioprotective signaling. We tested the hypothesis that sildenafil-induced cGMP-dependent protein kinase-I (PKG-I) expression and cardioprotection are attenuated by diabetes. Barbiturate-anesthetized dogs (n = 38) were instrumented for measurement of hemodynamics and subjected to 60-minute occlusion of the left anterior descending coronary artery and 3-hour reperfusion. Dogs were randomly assigned to receive 0.9% saline (control) or intravenous sildenafil (0.7 or 1.4 mg/kg) in the absence or presence of diabetes (3 weeks after administration of alloxan and streptozotocin). No differences in hemodynamics or coronary collateral blood flow (radioactive microspheres) were observed between groups before and during ischemia and reperfusion, except that infusion of sildenafil produced transient decreases in left ventricle systolic pressure. Sildenafil significantly (P < 0.05) reduced infarct size (16 +/- 2% of the left ventricular area at risk; triphenyltetrazolium staining) as compared to control (31 +/- 39%). Diabetes alone did not alter infarct size (31 +/- 2%) but abolished the protective effect of sildenafil (0.7 mg/kg: 26 +/- 3%; 1.4 mg/kg: 26 +/- 3%). Sildenafil increased PKG-I expression (immunohistochemistry and Western blotting) in the absence but not the presence of diabetes. The results indicate that diabetes abolishes cardioprotection by sildenafil and implicates PKG-I in the signal transduction pathway activated by this drug.     

Effects of altered corticosteroid milieu on rat hippocampal neurochemistry and structure--an in vivo magnetic resonance spectroscopy and imaging study

Altered corticosteroid milieu induces changes in hippocampal volume, neuronal structure, neurochemistry and cognitive function in humans and rodents. This in vivo magnetic resonance spectroscopy (1H MRS) and imaging (MRI) study investigated whether long-term alterations of the corticosteroid milieu cause: (i) metabolic and/or (ii) structural changes of the rat hippocampus. Therefore, hypocortisolism was induced by adrenalectomy (ADX), normocortisolism by ADX with low-dose corticosterone replacement, and hypercortisolism by ADX and high-dose dexamethasone treatment (for 11 weeks, respectively). All groups including a control group (n=23) were studied by in vivo 1H MRS and MR volumetry. Effects of treatment on normalized hippocampal metabolites and volumes were tested for significance using one-factorial multivariate analysis of variance (MANOVA). Hypercortisolemic rats revealed significantly elevated glutamate. Hypocortisolemic rats showed significantly decreased myo-inositol ratio levels, and were associated with significantly reduced normalized hippocampal volumes. Our findings suggest chronic hypercortisolism to be associated with glutamate-mediated excitotoxicity in the absence of volumetric abnormalities. In contrast, hypocortisolism appears to be associated with neurodegenerative processes, altered astrocytic metabolism but preserved neuronal density.     

Decreased tumor surveillance after adoptive T-cell therapy

The effect of cancer immunotherapy on the endogenous immune response against tumors is largely unknown. Therefore, we studied immune responses against murine tumors expressing the glycoprotein (GP) and/or nucleoprotein of lymphocytic choriomeningitis virus (LCMV) with or without adoptive T-cell therapy. In nontreated animals, CTLs specific for different epitopes as well as LCMV-GP-specific antibodies contributed to tumor surveillance. Adoptive immunotherapy with monoclonal CTLs specific for LCMV-gp33 impaired the endogenous tumor-specific antibody and CTL response by targeting antigen cross-presenting cells. As a consequence and in contrast to expectations, immunotherapy enhanced tumor growth. Thus, for certain immunogenic tumors, a reduction of tumor-specific B- and T-cell responses and enhanced tumor growth may be an unwanted consequence of adoptive immunotherapy.