Evolution of genuine cross-correlation strength of focal onset seizures

To quantify the evolution of genuine zero-lag cross-correlations of focal onset seizures, we apply a recently introduced multivariate measure to broad band and to narrow-band EEG data. For frequency components below 12.5 Hz, the strength of genuine cross-correlations decreases significantly during the seizure and the immediate postseizure period, while higher frequency bands show a tendency of elevated cross-correlations during the same period. We conclude that in terms of genuine zero-lag cross-correlations, the electrical brain activity as assessed by scalp electrodes shows a significant spatial fragmentation, which might promote seizure offset.

Negative regulation of NF-κB by the ING4 tumor suppressor in breast cancer

Nuclear Factor kappa B (NF-κB) is a key mediator of normal immune response but contributes to aggressive cancer cell phenotypes when aberrantly activated. Here we present evidence that the Inhibitor of Growth 4 (ING4) tumor suppressor negatively regulates NF-κB in breast cancer. We surveyed primary breast tumor samples for ING4 protein expression using tissue microarrays and a newly generated antibody. We found that 34% of tumors expressed undetectable to low levels of the ING4 protein (n = 227). Tumors with low ING4 expression were frequently large in size, high grade, and lymph node positive, suggesting that down-regulation of ING4 may contribute to breast cancer progression. In the same tumor set, we found that low ING4 expression correlated with high levels of nuclear phosphorylated p65/RelA (p-p65), an activated form of NF-κB (p = 0.018). Fifty seven percent of ING4-low/p-p65-high tumors were lymph node-positive, indicating a high metastatic tendency of these tumors. Conversely, ectopic expression of ING4 inhibited p65/RelA phosphorylation in T47D and MCF7 breast cancer cells. In addition, ING4 suppressed PMA-induced cell invasion and NF-κB-target gene expression in T47D cells, indicating that ING4 inhibited NF-κB activity in breast cancer cells. Supportive of the ING4 function in the regulation of NF-κB-target gene expression, we found that ING4 expression levels inversely correlated with the expression of NF-κB-target genes in primary breast tumors by analyzing public gene expression datasets. Moreover, low ING4 expression or high expression of the gene signature composed of a subset of ING4-repressed NF-κB-target genes was associated with reduced disease-free survival in breast cancer patients. Taken together, we conclude that ING4 negatively regulates NF-κB in breast cancer. Consequently, down-regulation of ING4 leads to activation of NF-κB, contributing to tumor progression and reduced disease-free patient survival in breast cancer.

Evaluation of smell and taste in patients with Wegener's granulomatosis

Although a reduced olfactory/gustatory function affects patients in all parts of life, this problem has not received much attention in Wegener's granulomatosis (WG). The aim of this study was to assess the smell/taste function of WG patients. Demographic data of 16 WG patients (9 males, 7 females) were obtained. They all subjectively assessed their taste/smell function on visual analogue scale. Olfactory/gustatory functions of the patients were tested with 'Sniffin' Sticks and 'Taste' strips, respectively. The results were then compared with those from sex and age-matched control group (n = 16) and normative data. WG patients subjectively assessed their olfactory (p = 0.03) and gustatory (p = 0.02) function to be lower than control group. All the olfactory scores (odour identification, odour discrimination and threshold) in both genders were significantly below the scores in the control group. WG patients were hyposmic. For taste (total taste score, as well as scores for the qualities sweet, sour, salty and bitter), WG patients did not significantly differ from controls and were normogeusic. However, the gustatory scores showed the tendency of reduction as compared to the control group. In conclusion, WG patients truly suffer from olfactory/taste dysfunction, but this is worse with olfaction. It is, therefore, imperative that physicians should make their patients to be aware of these sensory dysfunctions and educate them on methods to cope with it for better quality of life.

Ligament balancing in TKA: Evaluation of a force-sensing device and the influence of patellar eversion and ligament release

Ligament balancing in total knee arthroplasty may have an important influence on joint stability and prosthesis lifetime. In order to provide quantitative information and assistance during ligament balancing, a device that intraoperatively measures knee joint forces and moments was developed. Its performance and surgical advantages were evaluated on six cadaver specimens mounted on a knee joint loading apparatus allowing unconstrained knee motion as well as compression and varus-valgus loading. Four different experiments were performed on each specimen. (1) Knee joints were axially loaded. Comparison between applied and measured compressive forces demonstrated the accuracy and reliability of in situ measurements (1.8N). (2) Assessment of knee stability based on condyle contact forces or varus-valgus moments were compared to the current surgical method (difference of varus-valgus loads causing condyle lift-off). The force-based approach was equivalent to the surgical method while the moment-based, which is considered optimal, showed a tendency of lateral imbalance. (3) To estimate the importance of keeping the patella in its anatomical position during imbalance assessment, the effect of patellar eversion on the mediolateral distribution of tibiofemoral contact forces was measured. One fourth of the contact force induced by the patellar load was shifted to the lateral compartment. (4) The effect of minor and major medial collateral ligament releases was biomechanically quantified. On average, the medial contact force was reduced by 20% and 46%, respectively. Large variation among specimens reflected the difficulty of ligament release and the need for intraoperative force monitoring. This series of experiments thus demonstrated the device's potential to improve ligament balancing and survivorship of total knee arthroplasty.

Efficacy of New Generation Antidepressants: Differences Seem Illusory

Background: Recently, Cipriani and colleagues examined the relative efficacy of 12 new-generation antidepressants on major depression using network meta-analytic methods. They found that some of these medications outperformed others in patient response to treatment. However, several methodological criticisms have been raised about network meta-analysis and Cipriani’s analysis in particular which creates the concern that the stated superiority of some antidepressants relative to others may be unwarranted. Materials and Methods: A Monte Carlo simulation was conducted which involved replicating Cipriani’s network metaanalysis under the null hypothesis (i.e., no true differences between antidepressants). The following simulation strategy was implemented: (1) 1000 simulations were generated under the null hypothesis (i.e., under the assumption that there were no differences among the 12 antidepressants), (2) each of the 1000 simulations were network meta-analyzed, and (3) the total number of false positive results from the network meta-analyses were calculated. Findings: Greater than 7 times out of 10, the network meta-analysis resulted in one or more comparisons that indicated the superiority of at least one antidepressant when no such true differences among them existed. Interpretation: Based on our simulation study, the results indicated that under identical conditions to those of the 117 RCTs with 236 treatment arms contained in Cipriani et al.’s meta-analysis, one or more false claims about the relative efficacy of antidepressants will be made over 70% of the time. As others have shown as well, there is little evidence in these trials that any antidepressant is more effective than another. The tendency of network meta-analyses to generate false positive results should be considered when conducting multiple comparison analyses.

Impacts of a word-picture training on reading in youth with mixed intellectual disabilities. A waiting-list control group comparison

Individuals with intellectual disabilities (ID) often struggle with learning how to read. Reading difficulties seem to be the most common secondary condition of ID. Only one in five children with mild or moderate ID achieves even minimal literacy skills. However, literacy education for children and adolescents with ID has been largely overlooked by researchers and educators. While there is little research on reading of children with ID, many training studies have been conducted with other populations with reading difficulties. The most common approach of acquiring literacy skills consists of sophisticated programs that train phonological skills and auditory perception. Only few studies investigated the influence of implicit learning on literacy skills. Implicit learning processes seem to be largely independent of age and IQ. Children are sensitive to the statistics of their learning environment. By frequent word reading they acquire implicit knowledge about the frequency of single letters and letter patterns in written words. Additionally, semantic connections not only improve the word understanding, but also facilitate storage of words in memory. Advances in communication technology have introduced new possibilities for remediating literacy skills. Computers can provide training material in attractive ways, for example through animations and immediate feedback .These opportunities can scaffold and support attention processes central to learning. Thus, the aim of this intervention study was to develop and implement a computer based word-picture training, which is based on statistical and semantic learning, and to examine the training effects on reading, spelling and attention in children and adolescents (9-16 years) diagnosed with mental retardation (general IQ  74). Fifty children participated in four to five weekly training sessions of 15-20 minutes over 4 weeks, and completed assessments of attention, reading, spelling, short-term memory and fluid intelligence before and after training. After a first assessment (T1), the entire sample was divided in a training group (group A) and a waiting control group (group B). After 4 weeks of training with group A, a second assessment (T2) was administered with both training groups. Afterwards, group B was trained for 4 weeks, before a last assessment (T3) was carried out in both groups. Overall, the results showed that the word-picture training led to substantial gains on word decoding and attention for both training groups. These effects were preserved six weeks later (group A). There was also a clear tendency of improvement in spelling after training for both groups, although the effect did not reach significance. These findings highlight the fact that an implicit statistical learning training in a playful way by motivating computer programs can not only promote reading development, but also attention in children with intellectual disabilities.

PEG spacers of different length influence the biological profile of bombesin-based radiolabeled antagonists

INTRODUCTION The gastrin-releasing peptide receptor (GRPR) was shown to be expressed with high density on several types of cancers. Radiolabeled peptides for imaging and targeted radionuclide therapy have been developed. In this study, we evaluated the potential of statine-based bombesin antagonists, conjugated to 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) through oligoethyleneglycol spacers, labeled with (177)Lu and we determined the effect of polyethyleneglycol (PEG) spacer length on in vitro and in vivo properties. METHODS The bombesin antagonists were synthesized on solid phase using Fmoc chemistry; the spacers Fmoc-dPEGx-OH (x=2, 4, 6 and 12) and the DOTA(tBu)3 were coupled using a standard procedure. The peptides were labeled with (177)Lu and evaluated in vitro (lipophilicity, serum stability, internalization and binding affinity assays). Biodistribution studies were performed in PC-3 tumor-bearing nude mice. RESULTS The solid-phase synthesis was straightforward with an overall yield ranging from 30% to 35% based on the first Fmoc cleavage. The hydrophilicity increased with spacer length (logD: -1.95 vs -2.22 of PEG2 and PEG12 analogs, respectively). There is a tendency of increased serum stability by increasing the spacer length (T1/2=246±4 and 584±20 for PEG2 and PEG6 analogs, respectively) which seems to reverse with the PEG12 analog. The IC50 values are similar with the only significant difference of the PEG12 analog. The (177)Lu-labeled PEG4 and PEG6 conjugates showed similar pharmacokinetic with high tumor uptake and excellent tumor-to-kidney ratios (7.8 and 9.7 at 4h for the PEG4 and PEG6 derivatives, respectively). The pancreas uptake was relatively high at 1h but it shows fast washout (0.46%±0.02% IA/g and 0.29%±0.08% IA/g already at 4h). CONCLUSION Among all the studied analogs the PEG4 and PEG6 showed significantly better properties. The very high tumor-to-non-target organ ratios, in particular tumor-to-kidney ratios, already at early time point will be important in regard to safety concerning kidney toxicity.

On the reduced sensitivity of the Atlantic overturning to Greenland ice sheet melting in projections: a multi-model assessment

Large uncertainties exist concerning the impact of Greenland ice sheet melting on the Atlantic meridional overturning circulation (AMOC) in the future, partly due to different sensitivity of the AMOC to freshwater input in the North Atlantic among climate models. Here we analyse five projections from different coupled ocean–atmosphere models with an additional 0.1 Sv (1 Sv = 10 6 m3/s) of freshwater released around Greenland between 2050 and 2089. We find on average a further weakening of the AMOC at 26°N of 1.1 ± 0.6 Sv representing a 27 ± 14% supplementary weakening in 2080–2089, as compared to the weakening relative to 2006–2015 due to the effect of the external forcing only. This weakening is lower than what has been found with the same ensemble of models in an identical experimen - tal set-up but under recent historical climate conditions. This lower sensitivity in a warmer world is explained by two main factors. First, a tendency of decoupling is detected between the surface and the deep ocean caused by an increased thermal stratification in the North Atlantic under the effect of global warming. This induces a shoaling of ocean deep ventilation through convection hence ventilating only intermediate levels. The second important effect concerns the so-called Canary Current freshwater leakage; a process by which additionally released fresh water in the North Atlantic leaks along the Canary Current and escapes the convection zones towards the subtropical area. This leakage is increasing in a warming climate, which is a consequence of decreasing gyres asymmetry due to changes in Ekman rumping. We suggest that these modifications are related with the northward shift of the jet stream in a warmer world. For these two reasons the AMOC is less susceptible to freshwater perturbations (near the deep water formation sides) in the North Atlantic as compared to the recent historical climate conditions. Finally, we propose a bilinear model that accounts for the two former processes to give a conceptual explanation about the decreasing AMOC sensitivity due to freshwater input. Within the limit of this bilinear model, we find that 62 ± 8% of the reduction in sensitivity is related with the changes in gyre asymmetry and freshwater leakage and 38 ± 8% is due to the reduction in deep ocean ventilation associated with the increased stratification in the North Atlantic.

Hierarchical self-assembly of the DNA-grafted supramolecular polymers

Conjugation of functional entities with a specific set of optical, mechanical or biological properties to DNA strands allows engineering of sophisticated DNA-containing architectures. Among various hybrid systems, DNA-grafted polymers occupy an important place in modern materials science. In this contribution we present the non-covalent synthesis and properties of DNA-grafted linear supramolecular polymers (SPs), which are assembled in a controllable manner from short chimeric DNA-pyrene oligomers. The synthetic oligomers consist of two parts: a 10 nucleotides long DNA chain and a covalently attached segment of variable number of phosphodiester-linked pyrenes. The temperature-dependent formation of DNA-grafted SPs is described by a nucleation-elongation mechanism. The high tendency of pyrenes to aggregate in water, leads to the rapid formation of SPs. The core of the assemblies consists of stacked pyrenes. They form a 1D platform, to which the DNA chains are attached. Combined spectroscopic and microscopic studies reveal that the major driving forces of the polymerization are π-stacking of pyrenes and hydrophobic interactions, and DNA pairing contributes to a lesser extent. AFM and TEM experiments demonstrate that the 1D SPs appear as elongated ribbons with a length of several hundred nanometers. They exhibit an apparent helical structure with a pitch-to-pitch distance of 50±15 nm. Since DNA pairing is a highly selective process, the ongoing studies are aimed to utilize DNA-grafted SPs for the programmable arrangement of functional entities. For example, the addition of non-modified complementary DNA strands to the DNA-grafted SPs leads to the cooperative formation of higher-order assemblies. Also, our experiments suggest that the fluorescent pyrene core of 1D ribbons serves as an efficient donor platform for energy transfer applications.

Hierarchical self-assembly of the DNA-grafted supramolecular polymers

Conjugation of functional entities with a specific set of optical, mechanical or biological properties to DNA strands allows engineering of sophisticated DNA-containing architectures. Among various hybrid systems, DNA-grafted polymers occupy an important place in modern materials science. In this contribution we present the non-covalent synthesis and properties of DNA-grafted linear supramolecular polymers (SPs), which are assembled in a controllable manner from short chimeric DNA-pyrene oligomers. The synthetic oligomers consist of two parts: a 10 nucleotides long DNA chain and a covalently attached segment of variable number of phosphodiester-linked pyrenes. The temperature-dependent formation of DNA-grafted SPs is described by a nucleation-elongation mechanism. The high tendency of pyrenes to aggregate in water, leads to the rapid formation of SPs. The core of the assemblies consists of stacked pyrenes. They form a 1D platform, to which the DNA chains are attached. Combined spectroscopic and microscopic studies reveal that the major driving forces of the polymerization are π-stacking of pyrenes and hydrophobic interactions, and DNA pairing contributes to a lesser extent. AFM and TEM experiments demonstrate that the 1D SPs appear as elongated ribbons with a length of several hundred nanometers. They exhibit an apparent helical structure with a pitch-to-pitch distance of 50±15 nm. Since DNA pairing is a highly selective process, the ongoing studies are aimed to utilize DNA-grafted SPs for the programmable arrangement of functional entities. For example, the addition of non-modified complementary DNA strands to the DNA-grafted SPs leads to the cooperative formation of higher-order assemblies. Also, our experiments suggest that the fluorescent pyrene core of 1D ribbons serves as an efficient donor platform for energy transfer applications.

Of missing fathers and Big Fish: reconstructive tendencies after postmodernism

Many things have been said about literature after postmodernism, but one point there seems to be some agreement on is that it does not turn its back radically on its postmodernist forerunner, but rather generally continues to heed and value their insights. There seems to be something strikingly non-oedipal about the recent aesthetic shift. It is a project of reconstruction that remains deeply rooted in postmodernist tenets. Such an essentially non-oedipal attitude, I would argue, is central to the nature of the reconstructive shift. This, however, also raises questions about the wider cultural context from which such an aesthetic stance arises. If postmodernism was nurtured by the revolutionary spirits of the late 1960s, reconstruction faces a different world with different strategies. Instead of the postmodernist urge to subvert, expose and undermine, reconstruction yearns towards tentative and fragile intersubjective understanding, towards responsibility and community. Instead of revolt and rebellion it explores reconciliation and compromise. One instance in which this becomes visible in reconstructive narratives is the recurring figure of the lost father. Missing father figures abound in recent novels by authors like Mark Z. Danielewski, Dave Eggers, Yann Mantel, David Mitchell etc. It almost seems like a younger generation is yearning for the fathers which postmodernism has struggled hard to do away with. My paper will focus on one particularly striking example to explore the implications of this development: Daniel Wallace’s novel Big Fish and Tim Burton’s well-known film adaptation of the same. In their negotiation of fact and fiction, of doubt and belief, of freedom and responsibility, all of which converge in a father-son relationship, they serve well to illustrate central characteristics and concerns of recent attempts to leave postmodernism behind.

Denying the foreseeability of an event as a means of self-protection. The Impact of Self-Threatening Outcome Information on the Strength of the Hindsight Bias

The hindsight bias represents the tendency of people to falsely believe that they would have predicted the outcome of an event, once the outcome is known. Two experiments will be presented that show a reduction or even reversal of the hindsight bias when the outcome information is self-threatening for the participants. Participants read a report of an interaction between a man and a woman that ended with different outcomes: The woman was raped vs. the woman was not raped vs. no outcome information was given. Results of the first experiment indicated that especially female participants, who did not accept rape myths, showed a reversed hindsight bias, when they received the rape outcome information. The more threatening the rape outcome had been, the lower was their estimated likelihood of rape. Results of the second experiment confirmed those of the first. Female participants, who did not accept rape myths and perceived themselves highly similar to the victim, showed a strong reversed hindsight bias, when threatened by the rape outcome, whereas female participants, who did believe in rape myth and were not similar to the victim, showed a classical hindsight bias. These effects were interpreted in terms of self-serving or in-group serving functions of the hindsight bias: Participants deny the foreseeability of a self-threatening outcome as a means of self-protection even if they are not personally affected by the negative information, but a member of their group.

Exculpating victims and the reversal of hindsight bias

This experiment examines the role of the hindsight bias and of motivational forces such as the motive to believe in a just world as possible causes of the derogation of victims effect in the context of rape. The hindsight bias is the tendency of people to falsely believe that they would have predicted the outcome of an event once the outcome is known. Participants read descriptions of an interaction between a man and a woman that ended with one of four possible outcomes: The woman was raped with very severe consequences for her future life vs. rape with only minor consequences for her future life vs. no rape (assailant was forced to retreat by the strong defense of the victim) vs. no outcome information. To test motivational predictions the hindsight bias and the derogation effect were analyzed as a consequence of the sex of participants, the seriousness of the consequences of the rape, the belief in a just world and the acceptance of rape myths. Results supported the assumption that derogation effects are at least partly driven by hindsight bias and that motivational processes work via the hindsight bias. However, in this study we did not find a classical hindsight bias but a reversed hindsight bias: Especially female participants in the severe consequences of rape condition and those participants who did not accept rape myths rated the likelihood of rape in the rape outcome condition as smaller than participants in the no outcome information control group. They also derogated the victim less than participants in the no information control group. These effects were interpreted in terms of self-serving or in-group serving functions of the hindsight bias. Finally no support was found for the assumption that derogation effects are driven by the motive to believe in a just world.

Overcoming Liability of Newness through Socialization : How Legitimation Strategies of a New Venture evolve

Liability of newness, the tendency of new ventures to die early after market entry, results from lacking legitimacy in their new cultural context and according failure to acquire resources. Based on a longitudinal case study on repeated resource acquisition attempts of a new venture, we found that overcoming liability of newness depended on the socialization of the new venture to the normative environment on which it depended on for resources. Over time and across repeated resource acquisition attempts, socialization - the process of learning the use of legitimate symbols and their culturally contingent meanings - enabled the new venture to become the skillful cultural operator on which legitimation and resource acquisition was contingent. From our data, 'Accumulating a repertoire of legitimate symbols' and 'Assimilating the evaluations of resource-holders' emerged as the two primary mechanisms for new venture socialization. The study's contributions to related literature and its broader theoretical implications are discussed

[Chronic right-sided pain-associated nondermatomal somatosensory deficit following an accident]

We present the case of a 48-year old man who, eight years after an industrial accident, presents with chronic right-sided nondermatomal pain and hypaesthesia to heat and touch. During symmetric peripheral touch functional magnetic resonance imaging revealed hypometabolism in the left thalamus, somatosensory cortex, and anterior cingulate cortex. Pain-associated nondermatomal somatosensory deficits (NDSDs) localizing to one side of the body are a frequent clinical entity, which are often triggered by an accident. The tendency of NDSDs to extend to adjunct ipsilateral body parts and to become chronic points to maladaptive adjustment of pain-processing areas in the central nervous system. Psychological stress prior to or around the triggering event seems an important risk factor for NDSDs.