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According to one view, neural oscillations structure information processing in time, determining whether sensory inputs have a strong or weak impact on behavior. Recent work showed that during sequential integration of visual inputs, stimuli that fall in the preferred phase of slow (1-3 Hz), endogenous EEG activity carry greater weight in subsequent judgment. Here, we asked two questions. Firstly, is this phenomenon modality-specific, or is it supramodal? Secondly, does this effect occur at the level of sequential encoding, or only during decision formation? We analyzed scalp EEG recordings from healthy human participants while they compared the approximate number of visual, auditory or somatosensory pulses in two successive intervals (N1 and N2). Despite differences in activity evoked in different domains, a common, slowly-oscillating (~3 Hz) choice-predictive signal was observed in all three modalities with a maximum coincident with pulse onset. Critically, this signal was present during N2 (when a decision was being formed) but absent during N1 (when perceptual information was encoded, but no decision could be made). In other words, rhythmic gain control during sequential processing is a supramodal phenomenon that occurs while information is integrated towards a categorical decision., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Mutations disabling the TP53 tumour suppressor gene represent the most frequent events in human cancer and typically occur through a two-hit mechanism involving a missense mutation in one allele and a 'loss of heterozygosity' deletion encompassing the other. While TP53 missense mutations can also contribute gain-of-function activities that impact tumour progression, it remains unclear whether the deletion event, which frequently includes many genes, impacts tumorigenesis beyond TP53 loss alone. Here we show that somatic heterozygous deletion of mouse chromosome 11B3, a 4-megabase region syntenic to human 17p13.1, produces a greater effect on lymphoma and leukaemia development than Trp53 deletion. Mechanistically, the effect of 11B3 loss on tumorigenesis involves co-deleted genes such as Eif5a and Alox15b (also known as Alox8), the suppression of which cooperates with Trp53 loss to produce more aggressive disease. Our results imply that the selective advantage produced by human chromosome 17p deletion reflects the combined impact of TP53 loss and the reduced dosage of linked tumour suppressor genes.

The tumor suppressors BAP1 and ASXL1 interact to form a polycomb deubiquitinase complex that removes monoubiquitin from histone H2A lysine 119 (H2AK119Ub). However, BAP1 and ASXL1 are mutated in distinct cancer types, consistent with independent roles in regulating epigenetic state and malignant transformation. Here we demonstrate that Bap1 loss in mice results in increased trimethylated histone H3 lysine 27 (H3K27me3), elevated enhancer of zeste 2 polycomb repressive complex 2 subunit (Ezh2) expression, and enhanced repression of polycomb repressive complex 2 (PRC2) targets. These findings contrast with the reduction in H3K27me3 levels seen with Asxl1 loss. Conditional deletion of Bap1 and Ezh2 in vivo abrogates the myeloid progenitor expansion induced by Bap1 loss alone. Loss of BAP1 results in a marked decrease in H4K20 monomethylation (H4K20me1). Consistent with a role for H4K20me1 in the transcriptional regulation of EZH2, expression of SETD8-the H4K20me1 methyltransferase-reduces EZH2 expression and abrogates the proliferation of BAP1-mutant cells. Furthermore, mesothelioma cells that lack BAP1 are sensitive to EZH2 pharmacologic inhibition, suggesting a novel therapeutic approach for BAP1-mutant malignancies.

Racial minorities face a unique "race talk" dilemma in contemporary American society: their racial background is often integral to their identity and how others perceive them, yet talk of race is taboo. This dilemma highlights the conflict between two fundamental social processes: social identity development and social norm adherence. To examine how, and with what costs, this dilemma is resolved, 9-12-year-old Latino, Asian, Black, and White children ( n =108) completed a photo identification task in which acknowledging racial difference is beneficial to performance. Results indicate minority children are just as likely to avoid race as White children, and such avoidance exacted a cost to performance and nonverbal comfort. Results suggest that teachers are particularly important social referents for instilling norms regarding race. Norms that equate colorblindness with socially appropriate behavior appear more broadly influential than previously thought, stifling talk of race even among those for whom it may be most meaningful.

Cohesin complex members have recently been identified as putative tumor suppressors in hematologic and epithelial malignancies. The cohesin complex guides chromosome segregation; however, cohesin mutant leukemias do not show genomic instability. We hypothesized that reduced cohesin function alters chromatin structure and disrupts cis-regulatory architecture of hematopoietic progenitors. We investigated the consequences of Smc3 deletion in normal and malignant hematopoiesis. Biallelic Smc3 loss induced bone marrow aplasia with premature sister chromatid separation and revealed an absolute requirement for cohesin in hematopoietic stem cell (HSC) function. In contrast, Smc3 haploinsufficiency increased self-renewal in vitro and in vivo, including competitive transplantation. Smc3 haploinsufficiency reduced coordinated transcriptional output, including reduced expression of transcription factors and other genes associated with lineage commitment. Smc3 haploinsufficiency cooperated with Flt3-ITD to induce acute leukemia in vivo, with potentiated Stat5 signaling and altered nucleolar topology. These data establish a dose dependency for cohesin in regulating chromatin structure and HSC function., (© 2015 Viny et al.)

When touching and viewing a moving surface our visual and somatosensory systems receive congruent spatiotemporal input. Behavioral studies have shown that motion congruence facilitates interplay between visual and tactile stimuli, but the neural mechanisms underlying this interplay are not well understood. Neural oscillations play a role in motion processing and multisensory integration. They may also be crucial for visuotactile motion processing. In this electroencephalography study, we applied linear beamforming to examine the impact of visuotactile motion congruence on beta and gamma band activity (GBA) in visual and somatosensory cortices. Visual and tactile inputs comprised of gratings that moved either in the same or different directions. Participants performed a target detection task that was unrelated to motion congruence. While there were no effects in the beta band (13-21Hz), the power of GBA (50-80Hz) in visual and somatosensory cortices was larger for congruent compared with incongruent motion stimuli. This suggests enhanced bottom-up multisensory processing when visual and tactile gratings moved in the same direction. Supporting its behavioral relevance, GBA was correlated with shorter reaction times in the target detection task. We conclude that motion congruence plays an important role for the integrative processing of visuotactile stimuli in sensory cortices, as reflected by oscillatory responses in the gamma band., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Although clinically tested JAK inhibitors reduce splenomegaly and systemic symptoms, molecular responses are not observed in most myeloproliferative neoplasm (MPN) patients. We previously demonstrated that MPN cells become persistent to type I JAK inhibitors that bind the active conformation of JAK2. We investigated whether CHZ868, a type II JAK inhibitor, would demonstrate activity in JAK inhibitor persistent cells, murine MPN models, and MPN patient samples. JAK2 and MPL mutant cell lines were sensitive to CHZ868, including type I JAK inhibitor persistent cells. CHZ868 showed significant activity in murine MPN models and induced reductions in mutant allele burden not observed with type I JAK inhibitors. These data demonstrate that type II JAK inhibition is a viable therapeutic approach for MPN patients., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Achievement gaps continue to garner a great deal of attention both in academic and in popular circles. Many students continue to struggle despite broad educational reforms aimed at narrowing these gaps in learning and performance., Aims: In this article, we review a number of social psychological interventions that show promise in reducing gaps in achievement, not by addressing structural barriers to achievement, but by helping students cope with threats to their identity that impair intellectual functioning and motivation. For example, interventions involving meditation, role models, emotional reappraisal, growth mindsets, imagining possible selves, self-affirmations, belongingness and cooperative learning have been shown to ameliorate threats to identity and raise achievement. We describe and evaluate these social psychological interventions., Arguments: Many achievement gaps involve a psychological predicament: a threat to one's social identity or to one's sense of belonging. Students' implicit theories - how they mind the gap - can act as barriers to their success. By helping students cope with these threats, these theory-based interventions represent a genuine advance in the way schools may reduce gaps in achievement., Conclusion: These interventions show how students' educational success depends partly on fluid aspects of context - how tasks are framed, who else is in the room, or what they believe about intelligence. Because of this fluidity, these interventions may not work in all settings. Achievement gaps are ultimately caused by a variety of factors, both objective and subjective that produce inequality. The research reviewed here suggests that even without changes in objective barriers to success, brief psychological interventions can narrow what many see as intractable gaps in academic achievement., (© 2015 The British Psychological Society.)

Protein phosphatase 2A (PP2A) is a serine/threonine phosphatase that is required for normal cell growth and development. PP2A is a potent tumor suppressor, which is inactivated in cancer cells as a result of genetic deletions and mutations. In myeloid leukemias, genes encoding PP2A subunits are generally intact. Instead, PP2A is functionally inhibited by post-translational modifications of its catalytic C subunit, and interactions with negative regulators by its regulatory B and scaffold A subunits. Here, we review the molecular mechanisms of genetic and functional inactivation of PP2A in human cancers, with a particular focus on human acute myeloid leukemias (AML). By analyzing expression of genes encoding PP2A subunits using transcriptome sequencing, we find that PP2A dysregulation in AML is characterized by silencing and overexpression of distinct A scaffold and B regulatory subunits, respectively. We review the mechanisms of functional PP2A activation by drugs such as fingolimod, forskolin, OP449, and perphenazine. This analysis yields two non-mutually exclusive mechanisms for therapeutic PP2A re-activation: (i) allosteric activation of the phosphatase activity, and (ii) stabilization of active holo-enzyme assembly and displacement of negative regulatory factors from A and B subunits. Future studies should allow the development of specific and potent pharmacologic activators of PP2A, and definition of susceptible disease subsets based on specific mechanisms of PP2A dysregulation.

Dopaminergic denervation in Parkinson's disease (PD) leads to motor deficits but also depression, lack of motivation and apathy. These symptoms can be reversed by dopaminergic treatment, which may even lead to an increased hedonic tone in some patients with PD. Here, we tested the effects of dopamine on emotional processing as indexed by changes in local field potential (LFP) activity of the subthalamic nucleus (STN) in 28 PD patients undergoing deep brain stimulation. LFP activity from the STN was recorded after the administration of levodopa (ON group) or after overnight withdrawal of medication (OFF group) during presentation of an emotional picture-viewing task. Neutral and emotionally arousing pleasant and unpleasant stimuli were chosen from the International Affective Picture System. We found a double dissociation of the alpha band response depending on dopamine state and stimulus valence: dopamine enhanced the processing of pleasant stimuli, while activation during unpleasant stimuli was reduced, as indexed by the degree of desynchronization in the alpha frequency band. This pattern was reversed in the OFF state and more pronounced in the subgroup of non-depressed PD patients. Further, we found an early gamma band increase with unpleasant stimuli that occurred when ON but not OFF medication and was correlated with stimulus arousal. The late STN alpha band decrease is thought to represent active processing of sensory information. Our findings support the idea that dopamine enhances approach-related processes during late stimulus evaluation in PD. The early gamma band response may represent local encoding of increased attention, which varies as a function of stimulus arousal., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Retrieval practice of previously studied material can impair subsequent memory for related unpracticed material. An emerging view holds that such retrieval-induced forgetting (RIF) may affect episodic recollection, but not the context-free familiarity of the affected items. Here, a survey of accruing recent findings of RIF in recognition tests shows that the impairment of unpracticed material depends vitally on baseline memory strength. Therein, the absence of RIF under specific conditions, previously taken as evidence for the immunity of familiarity, can be predicted on grounds of exceedingly low baseline levels. Similarly, differential RIF effects on the parameters of dual-process recognition models can be explained by baseline differences, suggesting that RIF might impair any sub-process that substantially contributes to overall recognition accuracy. By contrast, the strengthening of practiced material appears independent of baseline levels and does not predict the magnitude of RIF, in accordance with an inhibitory causation of the forgetting. In summary, the inventory presents RIF in recognition as a subtle proportional impairment, future illumination of which may demand increased attention to baseline memory levels.

Somatic cohesin mutations have been reported in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). To account for the morphologic and cytogenetic diversity of these neoplasms, a well-annotated cohort of 1060 patients with myeloid malignancies including MDS (n = 386), myeloproliferative neoplasms (MPNs) (n = 55), MDS/MPNs (n = 169), and AML (n = 450) were analyzed for cohesin gene mutational status, gene expression, and therapeutic and survival outcomes. Somatic cohesin defects were detected in 12% of patients with myeloid malignancies, whereas low expression of these genes was present in an additional 15% of patients. Mutations of cohesin genes were mutually exclusive and mostly resulted in predicted loss of function. Patients with low cohesin gene expression showed similar expression signatures as those with somatic cohesin mutations. Cross-sectional deep-sequencing analysis for clonal hierarchy demonstrated STAG2, SMC3, and RAD21 mutations to be ancestral in 18%, 18%, and 47% of cases, respectively, and each expanded to clonal dominance concordant with disease transformation. Cohesin mutations were significantly associated with RUNX1, Ras-family oncogenes, and BCOR and ASXL1 mutations and were most prevalent in high-risk MDS and secondary AML. Cohesin defects were associated with poor overall survival (27.2 vs 40 months; P = .023), especially in STAG2 mutant MDS patients surviving >12 months (median survival 35 vs 50 months; P = .017)., (© 2014 by The American Society of Hematology.)

Building on evidence for working memory (WM) coding of vibrotactile frequency information in monkey prefrontal cortex, recent electroencephalography studies found frequency processing in human WM to be reflected by quantitative modulations of prefrontal upper beta activity (20-30 Hz) as a function of the to-be-maintained stimulus attribute. This kind of stimulus-dependent activity has been observed across different sensory modalities, suggesting a generalized role of prefrontal beta during abstract WM processing of quantitative magnitude information. However, until now the available empirical evidence for such quantitative WM representation remains critically limited to the retention of periodic stimulus frequencies. In the present experiment, we used retrospective cueing to examine the quantitative WM processing of stationary (intensity) and temporal (duration) attributes of a previously presented tactile stimulus. We found parametric modulations of prefrontal beta activity during cued WM processing of each type of quantitative information, in a very similar manner as had before been observed only for periodic frequency information. In particular, delayed prefrontal beta modulations systematically reflected the magnitude of the retrospectively selected stimulus attribute and were functionally linked to successful behavioral task performance. Together, these findings converge on a generalized role of stimulus-dependent prefrontal beta-band oscillations during abstract scaling of analog quantity information in human WM., (© The Author 2013. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Neuroimaging studies of working memory (WM) suggest that prefrontal cortex may assist sustained maintenance, but also internal manipulation, of stimulus representations in lower-level areas. A different line of research in the somatosensory domain indicates that neuronal activity in ventrolateral prefrontal cortex (VLPFC) may also represent specific memory contents in itself, however leaving open to what extent top-down control on lower-level areas is exerted, or how internal manipulation processes are implemented. We used functional imaging and connectivity analysis to study static maintenance and internal manipulation of tactile working memory contents after physically identical stimulation conditions, in human subjects. While both tasks recruited similar subareas in the inferior frontal gyrus (IFG) in VLPFC, static maintenance of the tactile information was additionally characterized by increased functional coupling between IFG and primary somatosensory cortex. Independently, during internal manipulation, a quantitative representation of the task-relevant information was evident in IFG itself, even in the absence of physical stimulation. Together, these findings demonstrate the functional diversity of activity within VLPFC according to different working memory demands, and underline the role of IFG as a core region in sensory WM processing., (Copyright © 2013 Wiley Periodicals, Inc.)

Inequalities are everywhere, yet little is known about how children respond to people affected by inequalities. This article explores two responses-minimizing inequalities and favoring those who are advantaged by them. In Studies 1a (N = 37) and 1b (N = 38), 4- and 5-year-olds allocated a resource to a disadvantaged recipient, but judged advantaged recipients more positively. In Studies (N = 38) and (N = 74), a delay occurred between seeing the inequality and allocating resources, or stating a preference, during which time participants forgot who was initially more advantaged. Children then favored advantaged recipients on the preference and resource allocation measures, suggesting an implicit "affective tagging" mechanism drives the tendency to favor the advantaged. In contrast, reducing inequalities through resource allocation appears to require explicit reasoning., (© 2013 The Authors. Child Development © 2013 Society for Research in Child Development, Inc.)

Background: Across Europe, illicit drug-related mortality has not declined despite ever increasing prevention measures. The cause of these deaths has traditionally been associated with overdose. Previous findings have revealed the appearance of non-lethal opioid concentrations, leading us to investigate a further cause of death. The symptoms of heroin intoxication with asphyxia and/or cardiovascular involvement resemble anaphylaxis, and therefore it has been speculated that such deaths might be caused by an allergic reaction. The study´s aims were to investigate levels of allergic mediators in long-term injecting drug users (IDU) compared to healthy controls and to determine if oral opioid substitution therapy (OST) resulted in similar allergic symptoms to those reported by IDU after intravenous (IV) heroin use., Methods: We quantified the concentrations of histamine, diamine oxidase (DAO), tryptase and lipoprotein-associated phospholipase A2 (LpPLA2) at baseline and 1 h after administration of Substitol®retard (482 ± 220 mg) in 56 patients at a withdrawal centre (Austria) and compared them with healthy controls (n = 103). Questionnaires and face-to-face interviews were used to assess allergic symptoms and side effects in IDU. Descriptive statistical analyses of quantitative data were performed by using SPSS., Results: Baseline histamine, tryptase and LpPLA2 were significantly elevated in IDU compared to the healthy control group, while DAO decreased. Blood levels showed no significant change after oral substitution uptake. Self-reported allergic symptoms and side effects after IV heroin use were reported in 55 cases (98.2%), minimal symptoms were documented after OST (12.5%, 7/56)., Conclusions: This study revealed that baseline histamine concentrations were elevated in chronic IDU, although only relatively small changes in tryptase plasma levels occurred. After IV heroin application the reported allergic symptoms were mostly mild and did not lead to clinically relevant side effects. The substitution substance was clearly better tolerated than IV administered heroin. Elevated levels of allergic mediators such as histamine in IDUs may place them at greater risk of severe or fatal anaphylaxis when exposed to heroin; however, this requires further investigation.

The human motion complex hMT+/V5 is activated not only by visual motion, but also by tactile and auditory motion. Whilst direction-selectivity has been found within this complex for visual and auditory stimuli, it is unknown whether hMT+/V5 also contains direction-specific information from the tactile modality. In the current study, we sought to investigate whether hMT+/V5 contains direction-specific information about visual/tactile moving stimuli. Leftward and rightward moving stimuli were presented in the visual and tactile modalities in an event-related fMRI design. Using region-of-interest-based multivariate pattern analysis we could decode the two motion directions for both tactile and visual stimuli in hMT+/V5. The activity patterns of the two modalities differed significantly, indicating that motion direction information from different modalities may be carried by distinct sets of neuronal populations. Our findings show that hMT+/V5 contains specific information about the direction of a moving stimulus in both the tactile and visual modalities, supporting the theory of hMT+/V5 being a multimodal motion area., (© 2013.)

Dyskeratosis congenita (DC) is a rare inherited disorder characterized by bone marrow failure and cancer predisposition. We present a case of a 28-year-old woman with DC who was admitted for hematopoietic stem cell transplantation (HSCT) for aplastic anemia and who developed acute myeloid leukemia with complex genetic karyotype abnormalities including the MLL (11q23) gene, 1q25, and chromosome 8. After transplantation, a monomorphic Epstein-Barr virus (EBV) negative posttransplant-associated lymphoproliferative disorder (PTLD) diffuse large B-cell lymphoma was discovered involving the liver, omental tissue, and peritoneal fluid samples showing additional MLL (11q23) gene abnormalities by fluorescence in situ hybridization. Despite treatment, the patient died of complications associated with transplantation and invasive fungal infection. This case represents the first bona fide documented case of EBV-negative monomorphic PTLD host derived, with MLL gene abnormalities in a patient with DC, and shows another possible mechanism for the development of a therapy-related lymphoid neoplasm after transplantation.

Accumulating empirical evidence suggests a role of Bayesian inference and learning for shaping neural responses in auditory and visual perception. However, its relevance for somatosensory processing is unclear. In the present study we test the hypothesis that cortical somatosensory processing exhibits dynamics that are consistent with Bayesian accounts of brain function. Specifically, we investigate the cortical encoding of Bayesian surprise, a recently proposed marker of Bayesian perceptual learning, using EEG data recorded from 15 subjects. Capitalizing on a somatosensory mismatch roving paradigm, we performed computational single-trial modeling of evoked somatosensory potentials for the entire peri-stimulus time period in source space. By means of Bayesian model selection, we find that, at 140 ms post-stimulus onset, secondary somatosensory cortex represents Bayesian surprise rather than stimulus change, which is the conventional marker of EEG mismatch responses. In contrast, at 250 ms, right inferior frontal cortex indexes stimulus change. Finally, at 360 ms, our analyses indicate additional perceptual learning attributable to medial cingulate cortex. In summary, the present study provides novel evidence for anatomical-temporal/functional segregation in human somatosensory processing that is consistent with the Bayesian brain hypothesis., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Numerous studies in animals and humans have related central aspects of somatosensory working memory function to neural activity in the inferior frontal gyrus (IFG). However, as previous studies have almost exclusively used correlational analyses, the question whether sustained neural activity in the IFG is causally involved in successful maintenance of somatosensory information remains unanswered. We used an online repetitive transcranial magnetic stimulation (rTMS) protocol to disrupt neuronal activity in the IFG while participants were maintaining tactile information throughout the delay for later comparison against a probe stimulus. rTMS impaired participants' performance in the working memory task, but not in a physically matched perceptual control task. Targeting the IFG in either hemisphere led to comparable working memory impairment. Our results show that the neural activity in the IFG plays a causal role in successful maintenance of somatosensory information., (© 2011 The Authors. European Journal of Neuroscience © 2011 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.)

Despite recent advances in uncovering the neural signature of tactile working memory processing in animals and humans, the representation of internally modified somatosensory working memory content has not been studied so far. Here, recording EEG in human participants (n = 25) performing a modified delayed match-to-sample task allowed us to disambiguate internally driven memory processing from encoding-related delay activity. After presentation of two distinct vibrotactile frequencies to different index fingers, a visual cue indicated which of the two previous stimuli had to be maintained in working memory throughout a retention interval for subsequent frequency discrimination against a probe stimulus. During cued stimulus maintenance, α activity (8-13 Hz) over early somatosensory cortices was lateralized according to the cued tactile stimulus, even though the location of the stimuli was task irrelevant. The task-relevant memory content, in contrast, was found to be represented in right prefrontal cortex. The key finding was that the visually presented instructions triggered systematic modulations of prefrontal β-band activity (20-25 Hz), which selectively reflected the to-be-maintained frequency of the cued tactile vibration. The results expand previous evidence for parametric representations of vibrotactile frequency in the prefrontal cortex and corroborate a central role of dynamic β-band synchronization during active processing of an analog stimulus quantity in human working memory. In particular, our findings suggest that such processing supports not only sustained maintenance but also purposeful modification and updating of the task-relevant working memory contents.

Previous research has shown that emotional stimuli are more likely than neutral stimuli to be selected by attention, indicating that the processing of emotional information is prioritized. In this study, we examined whether the emotional significance of stimuli influences visual processing already at the level of transient storage of incoming information in iconic memory, before attentional selection takes place. We used a typical iconic memory task in which the delay of a poststimulus cue, indicating which of several visual stimuli has to be reported, was varied. Performance decreased rapidly with increasing cue delay, reflecting the fast decay of information stored in iconic memory. However, although neutral stimulus information and emotional stimulus information were initially equally likely to enter iconic memory, the subsequent decay of the initially stored information was slowed for threatening stimuli, a result indicating that fear-relevant information has prolonged availability for read-out from iconic memory. This finding provides the first evidence that emotional significance already facilitates stimulus processing at the stage of iconic memory.

Purpose: To evaluate whether tumour therapy for malignant uveal melanoma leads to a shedding of melanoma cells into the systemic circulation., Methods: Ninety-four peripheral blood samples from 81 patients with malignant uveal melanoma were collected before and after different tumour therapies and the number of circulating melanoma cells (CMCs) was investigated (seven patients with enucleation, 49 patients with stereotactic radiotherapy, 19 patients with endoresection of the tumour, 15 patients with ruthenium-brachytherapy and four patients with transpupillary thermotherapy). A cellular approach was used to detect CMCs through an immunocytological assay with tumour cell enrichment by immunomagnetic cell sorting. The number of CMCs was analysed further according to specific patient characteristics, tumour parameters and the development of metastasis., Results: There was no significant difference between the number of CMCs before and after the different therapies (p = 0.78). There was also no significant association between established prognostic parameters of primary uveal melanoma and the detection of CMCs (all p >0.05). The number of CMCs was not related to the development of metastasis in a short median follow-up time of 16 months (p > 0.05)., Conclusion: No changes in CMC values were observed before and after different tumour therapies. In the majority of cases therapy does not lead to a shedding of detectable melanoma cells into the systemic circulation., (© 2009 The Authors. Journal compilation © 2009 Acta Ophthalmol.)

Background: To identify predictive factors for improvement of visual acuity and central retinal thickness by intravitreal bevacizumab for the treatment of macular edema (ME) due to branch retinal vein occlusion (BRVO)., Methods: Two hundred and five eyes from 204 patients with ME secondary to BRVO were retrospectively included at six sites. All eyes received intravitreal bevacizumab therapy (1.25 mg/0.05 ml). The mean follow-up was 36.8 ± 12.7 weeks (range, 18 to 54 weeks). Measurement of ETDRS best-corrected visual acuity (BCVA, in all eyes) and optical coherence tomography (OCT, in 87% of eyes) were performed at baseline and at follow-up examinations every 12 weeks. Using fluorescein angiography, the perfusion status of the macula at baseline could be assessed in 84% of the eyes. The main outcome measures were changes in BCVA and central retinal thickness (CRT). For analysis of predictive factors, the results at 24 weeks were used., Results: The median BCVA was 0.6 LogMAR at baseline and improved to 0.4 LogMAR at 24 and 48 weeks. This visual improvement was associated by a significant reduction in CRT, decreasing from a baseline of 454 μm to 267 μm and 248 μm after 24 and 48 weeks respectively. Eyes with ME and intact (perfused) or interrupted (ischemic) foveal capillary ring showed a 2-line increase of median BCVA [45 eyes (22%) and 128 eyes (62%) respectively]. However, the final median BCVA was significantly worse in eyes with ischemic ME (0.6 versus 0.3 logMAR in perfused ME). Other factors for visual improvement were absence of previous treatments of the ME, age younger than 60 years and low baseline BCVA (≥0.6 logMAR) (2, 3, and 2 median BCVA lines increase respectively). Furthermore, eyes with duration of the ME of less than 12 months responded with a 3-line increase of the median BCVA. Final CRT only showed minor differences between the subgroups. During the entire follow-up, retreatments were performed in 85% of the eyes, with a median number of injections of three (mean 3.2; range, 1 to 10) and a median time-interval between injections of 11.6 weeks (mean 14.6 weeks)., Conclusions: Intravitreal injection of bevacizumab resulted in a significant improvement of BCVA and reduction of ME in BRVO. Baseline BCVA, patient's age, and duration of BRVO were found to be of prognostic relevance for visual improvement. A less favorable outcome of the bevacizumab therapy in eyes with longstanding BRVO would advocate initiation of treatment within 12 months after onset.

Processing of motion and pattern has been extensively studied in the visual domain, but much less in the somatosensory system. Here, we used ultra-high-field functional magnetic resonance imaging (fMRI) at 7 Tesla to investigate the neuronal correlates of tactile motion and pattern processing in humans under tightly controlled stimulation conditions. Different types of dynamic stimuli created the sensation of moving or stationary bar patterns during passive touch. Activity in somatosensory cortex was increased during both motion and pattern processing and modulated by motion directionality in primary and secondary somatosensory cortices (SI and SII) as well as by pattern orientation in the anterior intraparietal sulcus. Furthermore, tactile motion and pattern processing induced activity in the middle temporal cortex (hMT+/V5) and in the inferior parietal cortex (IPC), involving parts of the supramarginal und angular gyri. These responses covaried with subjects' individual perceptual performance, suggesting that hMT+/V5 and IPC contribute to conscious perception of specific tactile stimulus features. In addition, an analysis of effective connectivity using psychophysiological interactions (PPI) revealed increased functional coupling between SI and hMT+/V5 during motion processing, as well as between SI and IPC during pattern processing. This connectivity pattern provides evidence for the direct engagement of these specialized cortical areas in tactile processing during somesthesis.

Interplay between the cerebral hemispheres is vital for coordinating perception and behavior. One influential account holds that the hemispheres engage in rivalry, each inhibiting the other. In the somatosensory domain, a seminal paper claimed to demonstrate such interhemispheric rivalry, reporting improved tactile detection sensitivity on the right hand after transcranial magnetic stimulation (TMS) to the right parietal lobe (Seyal, Ro, & Rafal, 1995). Such improvement in tactile detection ipsilateral to TMS could follow from interhemispheric rivalry, if one assumes that TMS disrupted cortical processing under the coil and thereby released the other hemisphere from inhibition. Here we extended the study by Seyal et al. (1995) to determine the effects of right parietal TMS on tactile processing for either hand, rather than only the ipsilateral hand. We performed two experiments applying TMS in the context of median-nerve stimulation; one experiment required somatosensory detection, the second somatosensory intensity discrimination. We found different TMS effects on detection versus discrimination, but neither set of results followed the prediction from hemispheric rivalry that enhanced performance for one hand should invariably be associated with impaired performance for the other hand, and vice-versa. Our results argue against a strict rivalry interpretation, instead suggesting that parietal TMS can provide a pedestal-like increment in somatosensory response., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Purpose: To determine and compare cyclo-oxygenase-2 (COX-2) expression in photon-radiated and non-radiated malignant uveal melanomas and to analyse the correlation between COX-2 expression and prognosis., Methods: Immunohistochemical staining for COX-2 was performed on 21 uveal melanomas that were endoresected after prior stereotactic radiotherapy with photons and on 22 tumours that were treated by endoresection without prior radiotherapy. COX-2 staining was further analysed in respect to cell type, maximal prominence, time interval between radiotherapy and surgery, apoptotic index (AI), proliferative index (PI) and the development of metastatic disease., Results: There was no difference in COX-2 expression between radiated and non-radiated melanomas (P>0.15). COX-2 staining correlated with neither the tumour prominence (P>0.40) nor the AI or the PI (both P>0.35). Tumours with high COX-2 expression were significantly more likely to develop metastasis (P=0.022)., Conclusion: Radiotherapy with photons does not induce COX-2 expression in malignant melanomas of the uvea. But high COX-2 expression may be a marker for poor prognosis.

When a visual stimulus is quickly followed in time by a second visual stimulus, we are normally unable to perceive it consciously. This study examined how affective states influence this temporal limit of conscious perception. Using a masked visual perception task, we found that the temporal threshold for access to consciousness is decreased in negative mood and increased in positive mood. To identify the brain mechanisms associated with this effect, we analysed brain oscillations. The mood-induced differences in perception performance were associated with differences in ongoing alpha power (around 10 Hz) before stimulus presentation. Additionally, after stimulus presentation, the better performance during negative mood was associated with enhanced global coordination of neuronal activity of theta oscillations (around 5 Hz). Thus, the effect of mood on the speed of conscious perception seems to depend on changes in oscillatory brain activity, rendering the cognitive system more or less sensitive to incoming stimuli.

Prior studies, mostly using intentional learning, suggest that power increases in theta and gamma oscillations and power decreases in alpha and beta oscillations are positively related to later remembering. Using incidental learning, this study investigated whether these brain oscillatory subsequent memory effects can be differentiated by encoding task. One group of subjects studied material performing a semantic (deep) encoding task, whereas the other group studied the same material performing a nonsemantic (shallow) encoding task. Successful encoding in the semantic task was related to power decreases in the alpha (8-12 Hz) and beta (12-20 Hz) frequency band, and a power increase in the gamma band (55-70 Hz). In the shallow task, successful encoding was related to a power decrease in the alpha band and a power increase in the theta frequency band (4-7 Hz). A direct comparison of results between the 2 encoding tasks revealed that semantic subsequent memory effects were specifically reflected by power decreases in the beta (0.5-1.5 s) and the alpha frequency band (0.5-1.0 s), whereas nonsemantic subsequent memory effects were specifically reflected by a power increase in the theta frequency band (0.5-1.0 s).

Retrieval practice on a subset of previously studied material enhances later memory for practiced material but can inhibit memory for related unpracticed material. The present study examines the effects of prior retrieval practice on evoked (ERPs) and induced (oscillatory power) measures of electrophysiological activity underlying recognition of practiced and unpracticed words. Compared to control material, recognition of unpracticed words was characterized by reduced amplitudes of the P2 ERP component and by reduced early (200-400 msec) oscillatory theta power. The reduction in P2 amplitude was associated with decreased evoked theta power but not with decreased theta phase locking (phase-locking index). Recognition of unpracticed material was further accompanied by a reduction in occipital gamma power (>250 msec). In contrast, the beneficial effects of retrieval practice on practiced words were reflected by larger parietal ERP positivity (>500 msec) and by a stronger decrease in oscillatory alpha power in a relatively late time window (>700 msec). The results suggest that the beneficial and detrimental effects of retrieval practice are mediated by different processes. In particular, they suggest that reduced theta (4-7 Hz) and gamma (60-90 Hz) power reflect the specific effects of inhibitory processes on the unpracticed material's memory representation.

Prior work on retrieval-induced forgetting showed that retrieving a subset of formerly studied items can impair item recognition of related, nonretrieved material. Here it was investigated whether retrieval practice can also impair the items' recognition as a member of a studied category. Subjects studied preexperimentally unrelated words that were categorized by their font colors, then practiced retrieving a subset of the words using a word stem completion task. Finally, an episodic category recognition test based on confidence ratings was applied. Receiver operating characteristic analysis of the data demonstrated a reliable impairment in subjects' recognition of the nonretrieved items' category relative to control items. The result indicates that retrieval-induced forgetting is not restricted to item recognition but generalizes to category recognition tasks. Inhibitory as well as noninhibitory explanations of the finding are discussed.

Floral fragrance is responsible for attracting pollinators as well as repelling pathogens and pests. As such, it is of immense biological importance. Molecular dissection of the mechanisms underlying scent production would benefit from the use of model plant systems with big floral organs that generate an array of volatiles and that are amenable to methods of forward and reverse genetics. One candidate is petunia (Petunia hybrida), which has emerged as a convenient model system, and both RNAi and overexpression approaches using transgenes have been harnessed for the study of floral volatiles. Virus-induced gene silencing (VIGS) is characterized by a simple inoculation procedure and rapid results relative to transgenesis. Here, we demonstrate the applicability of the tobacco rattle virus-based VIGS system to studies of floral scent. Suppression of the anthocyanin pathway via chalcone synthase silencing was used as a reporter, allowing easy visual identification of anthocyaninless silenced flowers/tissues with no effect on the level of volatile emissions. Use of tobacco rattle virus constructs containing target genes involved in phenylpropanoid volatile production, fused to the chalcone synthase reporter, allowed simple identification of flowers with suppressed activity of the target genes. The applicability of VIGS was exemplified with genes encoding S-adenosyl-l-methionine:benzoic acid/salicylic acid carboxyl methyltransferase, phenylacetaldehyde synthase, and the myb transcription factor ODORANT1. Because this high-throughput reverse-genetics approach was applicable to both structural and regulatory genes responsible for volatile production, it is expected to be highly instrumental for large-scale scanning and functional characterization of novel scent genes.

Aim: To compare the antiproliferative and cytotoxic properties of bevacizumab (Avastin), pegaptanib (Macugen) and ranibizumab (Lucentis) on human retinal pigment epithelium (ARPE19) cells, rat retinal ganglion cells (RGC5) and pig choroidal endothelial cells (CEC)., Methods: Monolayer cultures of ARPE19, RGC5 and CEC were used. Bevacizumab (0.1-0.3 mg/ml), pegaptanib (0.025-0.08 mg/ml) or ranibizumab (0.04-0.125 mg/ml) diluted in culture medium were added to the cells. Expression of VEGF-receptors (VEGFR1 and VEGFR2) and von Willebrand factor (a marker for endothelial cells) were analysed by immunohistochemistry. CEC cells were stimulated with VEGF. Cellular proliferative activity was monitored by BrdU-incorporation into cellular DNA. For cytotoxicity assays cells were grown to confluence and then cultured in a serum-depleted medium to ensure a static milieu. MTT-test was performed after one day., Results: CEC and ARPE19 cells stained positively for VEGFR1 and VEGFR2. More than 95% of the CEC cells were positive for von Willebrand factor. Ranibizumab reduced CEC cell proliferation by 44.1%, bevacizumab by 38.2% and pegaptanib by 35.1% when the drugs were used at their established clinical doses. The differences, however, between the three drugs in respect to cell growth inhibition were not statistically significant. Only a mild antiproliferative effect of bevacizumab or pegaptanib on ARPE19 cells could be observed. Ranibizumab did not alter ARPE19 cell proliferation. No cytotoxicity on RGC5, CEC and ARPE19 cells could be seen., Conclusions: Bevacizumab, pegaptanib and ranibizumab significantly suppress choroidal endothelial cell proliferation. However, when used at the currently established doses none of the drugs was superior over the others in respect to endothelial cell growth inhibition. The biocompatibility of all three drugs--including the off-label bevacizumab--seems to be excellent when used at the currently recommended intravitreal dose.

Retrieving a subset of previously studied material can impair later recognition of related items. Using the remember-know procedure (Experiment 1) and the receiver operating characteristic procedure (Experiment 2), the authors examined how such retrieval-induced forgetting can be explained in terms of single-process and dual-process accounts of recognition memory. Consistent across the 2 experiments, dual-process analysis suggested that retrieval practice reduces unpracticed items' familiarity but leaves their recollection largely unaffected, a finding that disagrees with prior work that points to recollective deficits in the forgotten items. Assuming that recognition is entirely based on a single source of memorial information, single-process analysis led to an excellent description of the data and suggested that retrieval practice reduces unpracticed items' general memory strength. This suggestion is consistent with prior work on free recall, cued recall, associative recognition, and response latencies and agrees with the inhibitory account of retrieval-induced forgetting. The authors argue that retrieval-induced forgetting in item recognition is caused by a reduction in general memory strength., (2007 APA)

Local adaptation has often been documented in herbivorous insects. The potential for local maladaptation in phytophagous insects, however, has not been widely considered. I performed a two-generation reciprocal cross-transplant experiment with the generalist soft scale insect Saissetia coffeae (Hemiptera: Coccidae) on two common species of host plants in rain forest habitat in Costa Rica. In this system, S. coffeae showed significant local maladaptation at the level of the host species. Lineages originally collected from Witheringia enjoyed a strong advantage over those collected from Lomariopsis when both sets of lineages were placed on Lomariopsis; however, when both sets of lineages were raised on Witheringia, their fitnesses were statistically indistinguishable. While some aspects of the biology of S. coffeae may impair its ability to adapt to local selection pressures, scale insects are often locally adapted on fine spatial scales, and local maladaptation is therefore especially surprising. Other documented cases of local maladaptation in parasites appear to be due to evolution on the part of the host. The possibility that hosts or natural enemies may place local genotypes at a disadvantage, producing a pattern of local maladaptation, is one that deserves more consideration in the context of plant-insect interactions.