Deviant trajectories of cortical maturation in 22q11.2 deletion syndrome (22q11DS): a cross-sectional and longitudinal study.

22q11.2 deletion syndrome (22q11DS) is associated with an increased susceptibility to develop schizophrenia. Despite a large body of literature documenting abnormal brain structure in 22q11DS, cerebral changes associated with brain maturation in 22q11DS remained largely unexplored. To map cortical maturation from childhood to adulthood in 22q11.2 deletion syndrome, we used cerebral MRI from 59 patients with 22q11DS, aged 6 to 40, and 80 typically developing controls; three year follow-up assessments were also available for 32 patients and 31 matched controls. Cross-sectional cortical thickness trajectories during childhood and adolescence were approximated in age bins. Repeated-measures were also conducted with the longitudinal data. Within the group of patients with 22q11DS, exploratory measures of cortical thickness differences related to COMT polymorphism, IQ, and schizophrenia were also conducted. We observed deviant trajectories of cortical thickness changes with age in patients with 22q11DS. In affected preadolescents, larger prefrontal thickness was observed compared to age-matched controls. Afterward, we observed greater cortical loss in 22q11DS with a convergence of cortical thickness values by the end of adolescence. No compelling evidence for an effect of COMT polymorphism on cortical maturation was observed. Within 22q11DS, significant differences in cortical thickness were related to cognitive level in children and adolescents, and to schizophrenia in adults. Deviant trajectories of cortical thickness from childhood to adulthood provide strong in vivo cues for a defect in the programmed synaptic elimination, which in turn may explain the susceptibility of patients with 22q11DS to develop psychosis.

The (partisan) role of the press in direct democratic campaigns : Evidence from a Swiss vote on European integration

This article analyzes the role of the press in direct democratic campaigns. The paper argues the press has a dual role: On news pages, newspapers ought to inform citizens about the issue positions and frames of the pro and con camps in a balanced way. In editorials, newspapers act as political advocates that promote their own issue frames and try to shape public opinion through voting recommendations. Comparing the issue positions and frames in editorials and news reports in the run-up to the vote on the popular initiative "Yes to Europe" in Switzerland, this article shows that newspapers give similar visibility to the pro and con camps regardless of the papers' own editorial position. However, some newspapers favor issue frames that are in line with their editorial perspectives. In conclusion, newspapers are more similar in news report content than in editorial views.

Extraction and concentration of vapors from fire debris for forensic purposes: evaluation of the use of Radiello Passive Air Sampler

The Radiello Passive Air Sampler is one of the latest innovations developed for the sampling of pollutants in the air by passive headspace. It has been reported that its properties allow an enhanced sensitivity, reproducibility and adsorption capacity. It therefore appears to be of interest in the extraction of potential residues of ignitable liquids present in fire debris when arson is suspected. A theoretical approach and several laboratory tests have made it possible to precisely characterize in a forensic perspective the potential of the device in extracting and concentrating the vapors of ignitable liquids found in fire debris. Despite some advantages, the Radiello device appears to be less efficient than traditional axial symmetry samplers.

Prediction of resting energy expenditure from fat-free mass and fat mass.

On the basis of literature values, the relationship between fat-free mass (FFM), fat mass (FM), and resting energy expenditure [REE (kJ/24 h)] was determined for 213 adults (86 males, 127 females). The objectives were to develop a mathematical model to predict REE based on body composition and to evaluate the contribution of FFM and FM to REE. The following regression equations were derived: 1) REE = 1265 + (93.3 x FFM) (r2 = 0.727, P < 0.001); 2) REE = 1114 + (90.4 x FFM) + (13.2 x FM) (R2 = 0.743, P < 0.001); and 3) REE = (108 x FFM) + (16.9 x FM) (R2 = 0.986, P < 0.001). FM explained only a small part of the variation remaining after FFM was accounted for. The models that include both FFM and FM are useful in examination of the changes in REE that occur with a change in both the FFM and FM. To account for more of the variability in REE, FFM will have to be divided into organ mass and skeletal muscle mass in future analyses.

Evolution of the P-type II ATPase gene family in the fungi and presence of structural genomic changes among isolates of Glomus intraradices.

BACKGROUND: The P-type II ATPase gene family encodes proteins with an important role in adaptation of the cell to variation in external K+, Ca2+ and Na2+ concentrations. The presence of P-type II gene subfamilies that are specific for certain kingdoms has been reported but was sometimes contradicted by discovery of previously unknown homologous sequences in newly sequenced genomes. Members of this gene family have been sampled in all of the fungal phyla except the arbuscular mycorrhizal fungi (AMF; phylum Glomeromycota), which are known to play a key-role in terrestrial ecosystems and to be genetically highly variable within populations. Here we used highly degenerate primers on AMF genomic DNA to increase the sampling of fungal P-Type II ATPases and to test previous predictions about their evolution. In parallel, homologous sequences of the P-type II ATPases have been used to determine the nature and amount of polymorphism that is present at these loci among isolates of Glomus intraradices harvested from the same field. RESULTS: In this study, four P-type II ATPase sub-families have been isolated from three AMF species. We show that, contrary to previous predictions, P-type IIC ATPases are present in all basal fungal taxa. Additionally, P-Type IIE ATPases should no longer be considered as exclusive to the Ascomycota and the Basidiomycota, since we also demonstrate their presence in the Zygomycota. Finally, a comparison of homologous sequences encoding P-type IID ATPases showed unexpectedly that indel mutations among coding regions, as well as specific gene duplications occur among AMF individuals within the same field. CONCLUSION: On the basis of these results we suggest that the diversification of P-Type IIC and E ATPases followed the diversification of the extant fungal phyla with independent events of gene gains and losses. Consistent with recent findings on the human genome, but at a much smaller geographic scale, we provided evidence that structural genomic changes, such as exonic indel mutations and gene duplications are less rare than previously thought and that these also occur within fungal populations.

Predictive analysis and mapping of indoor radon concentrations in Switzerland

It is estimated that around 230 people die each year due to radon (222Rn) exposure in Switzerland. 222Rn occurs mainly in closed environments like buildings and originates primarily from the subjacent ground. Therefore it depends strongly on geology and shows substantial regional variations. Correct identification of these regional variations would lead to substantial reduction of 222Rn exposure of the population based on appropriate construction of new and mitigation of already existing buildings. Prediction of indoor 222Rn concentrations (IRC) and identification of 222Rn prone areas is however difficult since IRC depend on a variety of different variables like building characteristics, meteorology, geology and anthropogenic factors. The present work aims at the development of predictive models and the understanding of IRC in Switzerland, taking into account a maximum of information in order to minimize the prediction uncertainty. The predictive maps will be used as a decision-support tool for 222Rn risk management. The construction of these models is based on different data-driven statistical methods, in combination with geographical information systems (GIS). In a first phase we performed univariate analysis of IRC for different variables, namely the detector type, building category, foundation, year of construction, the average outdoor temperature during measurement, altitude and lithology. All variables showed significant associations to IRC. Buildings constructed after 1900 showed significantly lower IRC compared to earlier constructions. We observed a further drop of IRC after 1970. In addition to that, we found an association of IRC with altitude. With regard to lithology, we observed the lowest IRC in sedimentary rocks (excluding carbonates) and sediments and the highest IRC in the Jura carbonates and igneous rock. The IRC data was systematically analyzed for potential bias due to spatially unbalanced sampling of measurements. In order to facilitate the modeling and the interpretation of the influence of geology on IRC, we developed an algorithm based on k-medoids clustering which permits to define coherent geological classes in terms of IRC. We performed a soil gas 222Rn concentration (SRC) measurement campaign in order to determine the predictive power of SRC with respect to IRC. We found that the use of SRC is limited for IRC prediction. The second part of the project was dedicated to predictive mapping of IRC using models which take into account the multidimensionality of the process of 222Rn entry into buildings. We used kernel regression and ensemble regression tree for this purpose. We could explain up to 33% of the variance of the log transformed IRC all over Switzerland. This is a good performance compared to former attempts of IRC modeling in Switzerland. As predictor variables we considered geographical coordinates, altitude, outdoor temperature, building type, foundation, year of construction and detector type. Ensemble regression trees like random forests allow to determine the role of each IRC predictor in a multidimensional setting. We found spatial information like geology, altitude and coordinates to have stronger influences on IRC than building related variables like foundation type, building type and year of construction. Based on kernel estimation we developed an approach to determine the local probability of IRC to exceed 300 Bq/m3. In addition to that we developed a confidence index in order to provide an estimate of uncertainty of the map. All methods allow an easy creation of tailor-made maps for different building characteristics. Our work is an essential step towards a 222Rn risk assessment which accounts at the same time for different architectural situations as well as geological and geographical conditions. For the communication of 222Rn hazard to the population we recommend to make use of the probability map based on kernel estimation. The communication of 222Rn hazard could for example be implemented via a web interface where the users specify the characteristics and coordinates of their home in order to obtain the probability to be above a given IRC with a corresponding index of confidence. Taking into account the health effects of 222Rn, our results have the potential to substantially improve the estimation of the effective dose from 222Rn delivered to the Swiss population.

International Society of Urological Pathology (ISUP) Consensus Conference on Handling and Staging of Radical Prostatectomy Specimens. Working group 4: seminal vesicles and lymph nodes.

The 2009 International Society of Urological Pathology Consensus Conference in Boston made recommendations regarding the standardization of pathology reporting of radical prostatectomy specimens. Issues relating to the infiltration of tumor into the seminal vesicles and regional lymph nodes were coordinated by working group 4. There was a consensus that complete blocking of the seminal vesicles was not necessary, although sampling of the junction of the seminal vesicles and prostate was mandatory. There was consensus that sampling of the vas deferens margins was not obligatory. There was also consensus that muscular wall invasion of the extraprostatic seminal vesicle only should be regarded as seminal vesicle invasion. Categorization into types of seminal vesicle spread was agreed by consensus to be not necessary. For examination of lymph nodes, there was consensus that special techniques such as frozen sectioning were of use only in high-risk cases. There was no consensus on the optimal sampling method for pelvic lymph node dissection specimens, although there was consensus that all lymph nodes should be completely blocked as a minimum. There was also a consensus that a count of the number of lymph nodes harvested should be attempted. In view of recent evidence, there was consensus that the diameter of the largest lymph node metastasis should be measured. These consensus decisions will hopefully clarify the difficult areas of pathological assessment in radical prostatectomy evaluation and improve the concordance of research series to allow more accurate assessment of patient prognosis.

Efficient targeted transcript discovery via array-based normalization of RACE libraries.

Rapid amplification of cDNA ends (RACE) is a widely used approach for transcript identification. Random clone selection from the RACE mixture, however, is an ineffective sampling strategy if the dynamic range of transcript abundances is large. To improve sampling efficiency of human transcripts, we hybridized the products of the RACE reaction onto tiling arrays and used the detected exons to delineate a series of reverse-transcriptase (RT)-PCRs, through which the original RACE transcript population was segregated into simpler transcript populations. We independently cloned the products and sequenced randomly selected clones. This approach, RACEarray, is superior to direct cloning and sequencing of RACE products because it specifically targets new transcripts and often results in overall normalization of transcript abundance. We show theoretically and experimentally that this strategy leads indeed to efficient sampling of new transcripts, and we investigated multiplexing the strategy by pooling RACE reactions from multiple interrogated loci before hybridization.

ADME pharmacogenetics: investigation of the pharmacokinetics of the antiretroviral agent lopinavir coformulated with ritonavir.

BACKGROUND: An ADME (absorption, distribution, metabolism and excretion)-pharmacogenetics association study may identify functional variants relevant to the pharmacokinetics of lopinavir co-formulated with ritonavir (LPV/r), a first-line anti-HIV agent. METHODS: An extensive search of literature and web resources helped select ADME genes and single nucleotide polymorphisms (SNPs, functional and HapMap tagging SNPs) with a proven or potentially relevant role in LPV/r pharmacokinetics. The study followed a two-stage design. Stage 1 (discovery) considered a Caucasian population (n=638) receiving LPV/r, where we selected 117 individuals with low LPV clearance (cases) and 90 individuals with high clearance (controls). Genotyping was performed by a 1536-SNP customized GoldenGate Illumina BeadArray. Stage 2 (confirmation) represented a replication study of candidate SNPs from the stage 1 in 148 individuals receiving LPV/r. The analysis led to formal population pharmacokinetic-pharmacogenetic modeling of demographic, environmental and candidate SNP effects. RESULTS: One thousand three hundred and eighty SNPs were successfully genotyped. Nine SNPs prioritized by the stage 1 analysis were brought to replication. Stage 2 confirmed the contribution of two functional SNPs in SLCO1B1, one functional SNP in ABCC2 and a tag SNP of the CYP3A locus in addition to body weight effect and ritonavir coadministration. According to the population pharmacokinetic-pharmacogenetic model, genetic variants explained 5% of LPV variability. Individuals homozygous rs11045819 (SLCO1B1*4) had a clearance of 12.6 l/h, compared with 5.4 l/h in the reference group, and 3.9 l/h in individuals with two or more variant alleles of rs4149056 (SLCO1B1*5), rs717620 (ABCC2) or rs6945984 (CYP3A). A subanalysis confirmed that although a significant part of the variance in LPV clearance was attributed to fluctuation in ritonavir levels, genetic variants had an additional effect on LPV clearance. CONCLUSION: The two-stage strategy successfully identified genetic variants affecting LPV/r pharmacokinetics. Such a general approach of ADME pharmacogenetics should be generalized to other drugs.

Apparent stable-isotope heterogeneities in gangue carbonates of the Mississippi Valley-type Zn-Pb deposits of San-Vicente, Central Peru

The aim of the present communication is to emphasize that some variations of the measured delta(13)C and delta(18)O values are apparent, and due to analytical interferences caused by the presence of sulfur and organosulfur compounds in the analyzed carbonates. This is particularly relevant for isotopic studies on carbonate-hosted mineral deposits, where the nearly ubiquitous association of the host carbonates with organic matter and sulfides can certainly affect the metallogenetic interpretations. In this work two methods were used to overcome the disturbing effects of sulfides and organic matter: (1) sample pretreatment following the method proposed by Charef and Sheppard (1984), combining the oxidation of organic matter with sodium hypochlorite and trapping of the sulfur species with silver phosphate; and (2) laser-based microprobe extraction. Apparent isotopic variations in sparry dolomite from a single hand sample of zebra ore from the MVT Zn-Pb deposit, San Vicente, central Peru, are as large as 6 parts per thousand delta(13)C and 4 parts per thousand delta(18)O. These variations are reduced to several tenths of a per mil when the samples are pretreated. A careful examination of the effects of treatment with NaOCl and/or Ag3PO4 in relation to the concentration of sulfide inclusions indicates that the main disturbing effects for delta(13)C values are the presence of sulfur species and organic matter, whereas the delta(18)O values are mainly affected by the presence of sulfides. Fine- and medium-grained replacement carbonates from MVT and other sediment-hosted base metal deposits are potentially the most affected during isotope analysis, due to the common presence of organic matter and sulfides. Using in situ laser microprobe techniques, it is possible to determine isotopic variations at a sub-millimeter scale. Our results show that laser extraction analysis allows a more precise sampling of the carbonate minerals, and minimizes contamination of the sample with sulfides and to some extent with intergrown organic matter. However, there is an isotopic shift associated with the laser extraction technique, of the order of 0.5-1 parts per thousand for delta(13)C and delta(18)O values.

Local optima networks of hard combinatorial landscapes

Combinatorial optimization involves finding an optimal solution in a finite set of options; many everyday life problems are of this kind. However, the number of options grows exponentially with the size of the problem, such that an exhaustive search for the best solution is practically infeasible beyond a certain problem size. When efficient algorithms are not available, a practical approach to obtain an approximate solution to the problem at hand, is to start with an educated guess and gradually refine it until we have a good-enough solution. Roughly speaking, this is how local search heuristics work. These stochastic algorithms navigate the problem search space by iteratively turning the current solution into new candidate solutions, guiding the search towards better solutions. The search performance, therefore, depends on structural aspects of the search space, which in turn depend on the move operator being used to modify solutions. A common way to characterize the search space of a problem is through the study of its fitness landscape, a mathematical object comprising the space of all possible solutions, their value with respect to the optimization objective, and a relationship of neighborhood defined by the move operator. The landscape metaphor is used to explain the search dynamics as a sort of potential function. The concept is indeed similar to that of potential energy surfaces in physical chemistry. Borrowing ideas from that field, we propose to extend to combinatorial landscapes the notion of the inherent network formed by energy minima in energy landscapes. In our case, energy minima are the local optima of the combinatorial problem, and we explore several definitions for the network edges. At first, we perform an exhaustive sampling of local optima basins of attraction, and define weighted transitions between basins by accounting for all the possible ways of crossing the basins frontier via one random move. Then, we reduce the computational burden by only counting the chances of escaping a given basin via random kick moves that start at the local optimum. Finally, we approximate network edges from the search trajectory of simple search heuristics, mining the frequency and inter-arrival time with which the heuristic visits local optima. Through these methodologies, we build a weighted directed graph that provides a synthetic view of the whole landscape, and that we can characterize using the tools of complex networks science. We argue that the network characterization can advance our understanding of the structural and dynamical properties of hard combinatorial landscapes. We apply our approach to prototypical problems such as the Quadratic Assignment Problem, the NK model of rugged landscapes, and the Permutation Flow-shop Scheduling Problem. We show that some network metrics can differentiate problem classes, correlate with problem non-linearity, and predict problem hardness as measured from the performances of trajectory-based local search heuristics.

A systematic review of existing data on long-term lithium therapy: neuroprotective or neurotoxic?

Lithium is an efficacious agent for the treatment of bipolar disorder, but it is unclear to what extent its long-term use may result in neuroprotective or toxic consequences. Medline was searched with the combination of the word 'Lithium' plus key words that referred to every possible effect on the central nervous system. The papers were further classified into those supporting a neuroprotective effect, those in favour of a neurotoxic effect and those that were neutral. The papers were classified into research in humans, animal and in-vitro research, case reports, and review/opinion articles. Finally, the Natural Standard evidence-based validated grading rationale was used to validate the data. The Medline search returned 970 papers up to February 2006. Inspection of the abstracts supplied 214 papers for further reviewing. Eighty-nine papers supported the neuroprotective effect (6 human research, 58 animal/in vitro, 0 case reports, 25 review/opinion articles). A total of 116 papers supported the neurotoxic effect (17 human research, 23 animal/in vitro, 60 case reports, 16 review/opinion articles). Nine papers supported no hypothesis (5 human research, 3 animal/in vitro, 0 case reports, 1 review/opinion articles). Overall, the grading suggests that the data concerning the effect of lithium therapy is that of level C, that is 'unclear or conflicting scientific evidence' since there is conflicting evidence from uncontrolled non-randomized studies accompanied by conflicting evidence from animal and basic science studies. Although more papers are in favour of the toxic effect, the great difference in the type of papers that support either hypothesis, along with publication bias and methodological issues make conclusions difficult. Lithium remains the 'gold standard' for the prophylaxis of bipolar illness, however, our review suggests that there is a rare possibility of a neurotoxic effect in real-life clinical practice even in closely monitored patients with 'therapeutic' lithium plasma levels. It is desirable to keep lithium blood levels as low as feasible with prophylaxis.

Compendium of projects in the European nanosafety cluster

This is the fourth edition of the Nanosafety Cluster compendium. It documents the status of important projects on nanomaterial toxicity and exposure monitoring, integrated risk management, research infrastructure and coordination and support activities. The compendium is not intended to be a guidance document for human health and environmental safety management of nanotechnologies, as such guidance documents already exist and are widely available. Neither is the compendium intended to be a medium for the publication of scientific papers and research results, as this task is covered by scientific conferences and the peer reviewed press. The compendium aims to bring researchers closer together and show them the potential for synergy in their work. It is a means to establish links and communication between them during the actual research phase and well before the publication of their results. It thus focuses on the communication of projects' strategic aims, extensively covers specific work objectives and the methods used in research, and documents human capacities and available laboratory infrastructure. As such, the compendium supports collaboration on common goals and the joint elaboration of future plans, whilst compromising neither the potential for scientific publication, nor intellectual property rights.

Physicochemical characterization of nebulized superparamagnetic iron oxide nanoparticles (SPIONs)

Abstract Background: Aerosol-mediated delivery of nano-based therapeutics to the lung has emerged as a promising alternative for treatment and prevention of lung diseases. Superparamagnetic iron oxide nanoparticles (SPIONs) have attracted significant attention for such applications due to their biocompatibility and magnetic properties. However, information is lacking about the characteristics of nebulized SPIONs for use as a therapeutic aerosol. To address this need, we conducted a physicochemical characterization of nebulized Rienso, a SPION-based formulation for intravenous treatment of anemia. Methods: Four different concentrations of SPION suspensions were nebulized with a one-jet nebulizer. Particle size was measured in suspension by transmission electron microscopy (TEM), photon correlation spectroscopy (PCS), and nanoparticle tracking analysis (NTA), and in the aerosol by a scanning mobility particle sizer (SMPS). Results: The average particle size in suspension as measured by TEM, PCS, and NTA was 9±2 nm, 27±7 nm, and 56±10 nm, respectively. The particle size in suspension remained the same before and after the nebulization process. However, after aerosol collection in an impinger, the suspended particle size increased to 159±46 nm as measured by NTA. The aerosol particle concentration increased linearly with increasing suspension concentration, and the aerodynamic diameter remained relatively stable at around 75 nm as measured by SMPS. Conclusions: We demonstrated that the total number and particle size in the aerosol were modulated as a function of the initial concentration in the nebulizer. The data obtained mark the first known independent characterization of nebulized Rienso and, as such, provide critical information on the behavior of Rienso nanoparticles in an aerosol. The data obtained in this study add new knowledge to the existing body of literature on potential applications of SPION suspensions as inhaled aerosol therapeutics.

Spatial variation in the decline of European birds as shown by the barn owl Tyto alba diet

Capsule The analysis of 635 papers about the diet of the European Barn Owl Tyto alba showed that 83 751 birds were captured out of 3.44 million prey items (2.4%). Birds were more frequently captured on islands than mainland, in southern than northern Europe and in eastern than western Europe. Between 1860 and 2012, the consumption of birds decreased in northern and eastern Europe. Among avian prey, the House Sparrow Passer domesticus, the most frequently captured bird (65.7%), decreased in frequency during the last 150 years in eastern Europe.