A randomized crossover trial assessing patient preference for two different types of portable infusion-pump devices

Background: A variety of anticancer agents are better tolerated and more effective if given as continuous compared to bolus administration. Portable pump devices are needed to allow outpatient continuous infusion. Different types of portable pumps are available and we tested patient preference in a randomized crossover design. Patients and methods: Patients on continuous infusion fluorouracil were randomly assigned to start treatment with an elastomeric infusor (Baxter) or a mechanical, electronically controlled pump (CADD-1™, Pharmacia) and crossed over to the alternative model after three weeks. After exposure to both pump types patients were asked to indicate their preferred device. Results: After 10 patients the study was closed because all study participants preferred the elastomeric pump (P < 0.01). Reasons were pump weight (100%), smaller pump size (89%), interference with daily activities (89%), user friendliness (56%), impact on sleep (44%), and lack of technical problems (22%). Although the mechanical pump required more handling time for the first two refillings, the learning curve suggested about equal time requirement thereafter. Conclusion: In the interest of patient comfort, the disposable elastomeric infusor is an acceptable alternative to the more accurate electronically controlled pumps especially for drugs with a short half-life and a favorable toxicity profil

Fine-scale habitat heterogeneity favours the coexistence of supergene-controlled social forms in Formica selysi.

Social insects vary widely in social organization, yet the genetical and ecological factors influencing this variation remain poorly known. In particular, whether spatially varying selection influences the maintenance of social polymorphisms in ants has been rarely investigated. To fill this gap, we examined whether fine-scale habitat heterogeneity contributes to the co-existence of alternative forms of social organization within populations. Single-queen colonies (monogyne social form) are generally associated with better colonization abilities, whereas multiple-queen colonies (polygyne social form) are predicted to be better competitors and monopolize saturated habitats. We hypothesize that each social form colonizes and thrives in distinct local habitats, as a result of their alternative dispersal and colony founding strategies. Here, we test this hypothesis in the Alpine silver ant, in which a supergene controls polymorphic social organization. Monogyne and polygyne colonies predominate in distinct habitats of the same population. The analysis of 59 sampling plots distributed across six habitats revealed that single-queen colonies mostly occupy unconnected habitats that were most likely reached by flight. This includes young habitats isolated by water and old habitats isolated by vegetation. In contrast, multiple-queen colonies were abundant in young, continuous and saturated habitats. Hence, alternative social forms colonize and monopolize distinct niches at a very local scale. Alternative social forms colonized and monopolized different local habitats, in accordance with differences in colonization and competition abilities. The monogyne social form displays a colonizer phenotype, by efficiently occupying empty habitats, while the polygyne social form exhibits a competitor phenotype, thriving in saturated habitats. The combination of the two phenotypes, coupled with fine-scale habitat heterogeneity, may allow the coexistence of alternative social forms within populations. Overall, these results suggest that spatially varying selection may be one of the mechanisms contributing to the maintenance of genetic polymorphisms in social organization

No mate preference associated with the supergene controlling social organization in Alpine silver ants.

Disassortative mating is a powerful mechanism stabilizing polymorphisms at sex chromosomes and other supergenes. The Alpine silver ant, Formica selysi, has two forms of social organization-single-queen and multiple-queen colonies-determined by alternate haplotypes at a large supergene. Here, we explore whether mate preference contributes to the maintenance of the genetic polymorphism at the social supergene. With mate choice experiments, we found that females and males mated randomly with respect to social form. Moreover, queens were able to produce offspring irrespective of whether they had mated with a male from the same or the alternative social form. Yet, females originating from single-queen colonies were more fertile, suggesting that they may be more successful at independent colony founding. We conclude that the pattern of asymmetric assortative mating documented from mature F. selysi colonies in the field is not caused by mate preferences or major genetic incompatibilities between social forms. More generally, we found no evidence that disassortative mate preference contributes to the maintenance of polymorphism at this supergene controlling ant social organization

Species recognition limits mating between hybridizing ant species

Identifying mechanisms limiting hybridization is a central goal of speciation research. Here, we studied pre-mating and post-mating barriers to hybridization between two ant species, Formica selysi and Formica cinerea. These species hybridize in the Rhône valley in Switzerland, where they form a mosaic hybrid zone, with limited introgression from F. selysi into F. cinerea. There was no sign of temporal isolation between the two species in the production of queens and males. With choice experiments, we showed that queens and males strongly prefer to mate with conspecifics. Yet, we did not detect post-mating barriers caused by genetic incompatibilities. Specifically, hybrids of all sexes and castes were found in the field and F1 hybrid workers did not show reduced viability compared to non-hybrid workers. To gain insights into the cues involved in species recognition, we analyzed the cuticular hydrocarbons of queens, males and workers and staged dyadic encounters between workers. Cuticular hydrocarbon profiles differed markedly between species, but were similar in F. cinerea and hybrids. Accordingly, workers also discriminated species, but they did not discriminate F. cinerea and hybrids. We discuss how the CHC-based recognition system of ants may facilitate the establishment of pre-mating barriers to hybridization, independent of hybridization costs. This article is protected by copyright. All rights reserved

AER Building Blocks for Multi-Layer Multi-Chip Neuromorphic Vision Systems

A 5-layer neuromorphic vision processor whose components communicate spike events asychronously using the address-eventrepresentation (AER) is demonstrated. The system includes a retina chip, two convolution chips, a 2D winner-take-all chip, a delay line chip, a learning classifier chip, and a set of PCBs for computer interfacing and address space remappings. The components use a mixture of analog and digital computation and will learn to classify trajectories of a moving object. A complete experimental setup and measurements results are shown.Unión Europea IST-2001-34124 (CAVIAR)Ministerio de Ciencia y Tecnología TIC-2003-08164-C0

OCT-measured plaque free wall angle is indicative for plaque burden: overcoming the main limitation of OCT?

textabstractThe aim of this study was to investigate the relationship between the plaque free wall (PFW) measured by optical coherence tomography (OCT) and the plaque burden (PB) measured by intravascular ultrasound (IVUS). We hypothesize that measurement of the PFW could help to estimate the PB, thereby overcoming the limited ability of OCT to visualize the external elastic membrane in the presence of plaque. This could enable selection of the optimal stent-landing zone by OCT, which is traditionally defined by IVUS as a region with a PB < 40 %. PB (IVUS) and PFW angle (OCT and IVUS) were measured in 18 matched IVUS and OCT pullbacks acquired in the same coronary artery. We determined the relationship between OCT measured PFW (PFWOCT) and IVUS PB (PBIVUS) by non-linear regression analysis. An ROC-curve analysis was used to determine the optimal cut-off value of PFW angle for the detection of PB < 40 %. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were calculated. There is a significant correlation between PFWOCT and PBIVUS (r2 = 0.59). The optimal cut-off value of the PFWOCT for the prediction of a PBIVUS < 40 % is ≥220° with a PPV of 78 % and an NPV of 84 %. This study shows that PFWOCT can be considered as a surrogate marker for PBIVUS, which is currently a common criterion to select an optimal stent-landing zone

Ants exhibit asymmetric hybridization in a mosaic hybrid zone

Research on hybridization between species provides unparalleled insights into the pre- and postzygotic isolating mechanisms that drive speciation. In social organisms, colony-level incompatibilities may provide additional reproductive barriers not present in solitary species, and hybrid zones offer an opportunity to identify these barriers. Here, we use genotyping-by-sequencing to sequence hundreds of markers in a hybrid zone between two socially polymorphic ant species, Formica selysi and Formica cinerea. We characterize the zone, determine the frequency of hybrid workers, infer whether hybrid queens or males are produced and investigate whether hybridization is influenced by colony social organization. We also compare cuticular hydrocarbon profiles and aggression levels between the two species. The hybrid zone exhibits a mosaic structure. The asymmetric distribution of hybrids skewed towards F. cinerea suggests a pattern of unidirectional nuclear gene flow from F. selysi into F. cinerea. The occurrence of backcrossed individuals indicates that hybrid queens and/or males are fertile, and the presence of the F. cinerea mitochondrial haplotype in 97% of hybrids shows that successful F1 hybrids will generally have F. cinerea mothers and F. selysi fathers. We found no evidence that social organization contributes to speciation, because hybrids occur in both single-queen and multiple-queen colonies. Strongly differentiated cuticular hydrocarbon profiles and heightened interspecific aggression further reveal that species recognition cues are both present and perceived. The discovery of fertile hybrids and asymmetrical gene flow is unusual in ants, and this hybrid zone will therefore provide an ideal system with which to investigate speciation in social insects

Population Structure Analyses Provide Insight into the Source Populations Underlying Rural Isolated Communities in Illinois

We have previously hypothesized that relatively small and isolated rural communities may experience founder effects, defined as the genetic ramifications of small population sizes at the time of a community’s establishment. To explore this, we used an Illumina Infinium Omni2.5Exome-8 chip to collect data from 157 individuals from four Illinois communities, three rural and one urban. Genetic diversity estimates of 999,259 autosomal markers suggested that the reduction in heterozygosity due to shared ancestry was approximately 0, indicating a randomly mating population. An eigenanalysis, which is similar to a principal component analysis but ran on a genetic coancestry matrix, conducted in the SNPRelate R package revealed that the majority of these individuals formed one cluster with a few putative outliers obscuring population variation. An additional eigenanalysis on the same markers in a combined data set including the 2,504 individuals in the 1000 Genomes database found that most of the 157 Illinois individuals clustered into one group in close proximity to individuals of European descent. A final eigenanalysis of the Illinois individuals with the 503 individuals of European descent (within the 1000 Genomes Project) revealed two clusters of individuals and likely two source populations; one British and one consisting of multiple European subpopulations. We therefore demonstrate the feasibility of examining genetic relatedness across Illinois populations and assessing the number of source populations using publicly available databases. When assessed, it becomes possible for population structure information to contribute to the understanding of genetic history in rural populations

In Vivo Binding and Retention of CD4-Specific DARPin 57.2 in Macaques

The recently described Designed Ankyrin Repeat Protein (DARPin) technology can produce highly selective ligands to a variety of biological targets at a low production cost.To investigate the in vivo use of DARPins for future application to novel anti-HIV strategies, we identified potent CD4-specific DARPins that recognize rhesus CD4 and followed the fate of intravenously injected CD4-specific DARPin 57.2 in rhesus macaques. The human CD4-specific DARPin 57.2 bound macaque CD4(+) cells and exhibited potent inhibitory activity against SIV infection in vitro. DARPin 57.2 or the control E3_5 DARPin was injected into rhesus macaques and the fate of cell-free and cell-bound CD4-specific DARPin was evaluated. DARPin-bound CD4(+) cells were detected in the peripheral blood as early as 30 minutes after the injection, decreasing within 6 hours and being almost undetectable within 24 hours. The amount of DARPin bound was dependent on the amount of DARPin injected. CD4-specific DARPin was also detected on CD4(+) cells in the lymph nodes within 30 minutes, which persisted with similar kinetics to blood. More extensive analysis using blood revealed that DARPin 57.2 bound to all CD4(+) cell types (T cells, monocytes, dendritic cells) in vivo and in vitro with the amount of binding directly proportional to the amount of CD4 on the cell surface. Cell-free DARPins were also detected in the plasma, but were rapidly cleared from circulation.We demonstrated that the CD4-specific DARPin can rapidly and selectively bind its target cells in vivo, warranting further studies on possible clinical use of the DARPin technology

New Binding Mode to TNF-Alpha Revealed by Ubiquitin-Based Artificial Binding Protein

A variety of approaches have been employed to generate binding proteins from non-antibody scaffolds. Utilizing a beta-sheet of the human ubiquitin for paratope creation we obtained binding proteins against tumor necrosis factor (TNF)-alpha. The bioactive form of this validated pharmacological target protein is a non-covalently linked homo-trimer. This structural feature leads to the observation of a certain heterogeneity concerning the binding mode of TNF-alpha binding molecules, for instance in terms of monomer/trimer specificity. We analyzed a ubiquitin-based TNF-alpha binder, selected by ribosome display, with a particular focus on its mode of interaction. Using enzyme-linked immunosorbent assays, specific binding to TNF-alpha with nanomolar affinity was observed. In isothermal titration calorimetry we obtained comparable results regarding the affinity and detected an exothermic reaction with one ubiquitin-derived binding molecule binding one TNF-alpha trimer. Using NMR spectroscopy and other analytical methods the 1∶3 stoichiometry could be confirmed. Detailed binding analysis showed that the interaction is affected by the detergent Tween-20. Previously, this phenomenon was reported only for one other type of alternative scaffold-derived binding proteins – designed ankyrin repeat proteins – without further investigation. As demonstrated by size exclusion chromatography and NMR spectroscopy, the presence of the detergent increases the association rate significantly. Since the special architecture of TNF-alpha is known to be modulated by detergents, the access to the recognized epitope is indicated to be restricted by conformational transitions within the target protein. Our results suggest that the ubiquitin-derived binding protein targets a new epitope on TNF-alpha, which differs from the epitopes recognized by TNF-alpha neutralizing antibodies