The importance of moral construal: moral versus non-moral construal elicits faster, more extreme, universal evaluations of the same actions.
Over the past decade, intuitionist models of morality have challenged the view that moral reasoning is the sole or even primary means by which moral judgments are made. Rather, intuitionist models posit that certain situations automatically elicit moral intuitions, which guide moral judgments. We present three experiments showing that evaluations are also susceptible to the influence of moral versus non-moral construal. We had participants make moral evaluations (rating whether actions were morally good or bad) or non-moral evaluations (rating whether actions were pragmatically or hedonically good or bad) of a wide variety of actions. As predicted, moral evaluations were faster, more extreme, and more strongly associated with universal prescriptions-the belief that absolutely nobody or everybody should engage in an action-than non-moral (pragmatic or hedonic) evaluations of the same actions. Further, we show that people are capable of flexibly shifting from moral to non-moral evaluations on a trial-by-trial basis. Taken together, these experiments provide evidence that moral versus non-moral construal has an important influence on evaluation and suggests that effects of construal are highly flexible. We discuss the implications of these experiments for models of moral judgment and decision-making.


Octopamine-like immunoreactivity in the honey bee and cockroach: comparable organization in the brain and subesophageal ganglion.
A serum raised against octopamine reveals in cockroaches and honey bees structurally comparable systems of perikarya and their extensive yet discrete systems of arborizations in neuropils. Numerous and prominent clusters of lateral cell bodies in the brain as well as many midline perikarya provide octopamine-like immunoreactive processes to circumscribed regions of the subesophageal ganglion, antennal lobe glomeruli, optic neuropils, and neuropils of the protocerebrum. There is dense octopaminergic innervation in the protocerebral bridge and ellipsoid body of the central complex. The antennal lobes are supplied by at least three octopamine-immunoreactive neurons. In contrast, the mushroom bodies show the fewest immunoreactive elements. In Apis a single axon supplies sparse immunoreactive processes to the calyces' basal ring, collar, and lip. A diffuse arrangement of immunoreactive processes invades all zones of the mushroom body calyces in Periplaneta. These processes derive from an ascending axon ascribed to a dorsal unpaired median neuron at the maxillary segment of the subesophageal ganglion. In both taxa octopamine-immunoreactive processes invade only the gamma lobes of the mushroom bodies, omitting their other divisions. The present observations are discussed with respect to possible roles of octopamine in sensory integration and association.


Respiratory syncytial virus prophylaxis in preterm infants: a cost-effectiveness study from Turkey.
The main aim of this study was to evaluate the cost-effectiveness of respiratory syncytial virus (RSV) prophylaxis with palivizumab in Turkey, by comparing hospitalization rates and costs as well as results of risk analyses in preterm infants who were treated either with palivizumab or conservatively. This retrospective study was undertaken in two centers on infants born with a gestational age of ≤32 weeks during the 2010-2011 seasons. Patients were divided into two groups based on status of RSV prophylaxis. The records of 272 infants were included in the final analysis, 201 (73.9%) of which had received palivizumab (Group 1), while 71 (26.1%) were not given any form of RSV prophylaxis. The difference between groups in terms of demographic characteristics and risk factors for RSV infection was statistically insignificant (p>0.05). Thirteen patients (6.5%) in Group 1 and 5 patients (7%) in Group 2 were hospitalized for lower respiratory tract infections (LRTIs) (p>0.05). In newborns born at ≤286/7 weeks of gestation, RSV prophylaxis with palivizumab was associated with a 38.75% decrease in hospitalization rates due to LRTIs compared to the untreated group (8% in the untreated group vs. 4.9% in the palivizumab group; p=0.577). The hospitalization rate due to LRTIs for infants in Group 1 born after 29-32 weeks of gestation was 7.5% compared to a rate of 6.5% in Group 2, with a statistically insignificant difference (p=0.828). In infants with bronchopulmonary dysplasia (BPD) born at ≤286/7 weeks of gestation, treatment with palivizumab was associated with a 39.1% decrease in LRTI-related hospitalization rates (14.3% in the untreated group vs. 8.7% in the palivizumab group; p=0.677). This clinical study is the first of its kind from Turkey to evaluate the cost-effectiveness of palivizumab treatment as prophylaxis against RSV infections in preterm infants, where hospitalization rates and costs of patients treated with palivizumab were compared with those of infants who were treated conservatively. Our study results suggest that administration of palivizumab does not have any cost benefit, regardless of gestational age. However, a reduction in hospitalization rates in association with palivizumab treatment was observed in infants born at ≤286/7 weeks of gestation with or without BPD.


The gynogenetic reproduction of diploid and triploid hybrid spined loaches (Cobitis: Teleostei), and their ability to establish successful clonal lineages--on the evolution of polyploidy in asexual vertebrates.
Polyploidisation is assumed to have played a significant role in the evolution of hybrid asexual lineages. The virtual absence of natural asexual systems in which more than a single ploidy level successfully establishes successful independent clonal lineages is generally explained by the strong effects of polyploidisation on fitness. Experimental crosses were made between diploid and triploid asexual Cobitis elongatoides x C. taenia hybrids (female) and both parental spined loach species (male). Genotyping of the progeny using allozymes and multilocus DNA fingerprinting, along with flow cytometric measurement of ploidy level, demonstrated the occurrence of gynogenetic reproduction in both female biotypes. The incorporation of the sperm genome occurred in some progeny, giving rise to a higher ploidy level, but the rate of polyploidisation differed significantly between the diploid and triploid females. These outcomes are consistent with the existence of developmental constraints on tetraploidy, which determine the rarity of tetraploids in natural populations. No cases of ploidy level reduction were observed. Since diploid and triploid hybrid populations occur where the lack of potential progenitor excludes the possibility of de novo origin, it is probable that both diploid and triploid females can establish successful clonal lineages. Spined loaches represent a unique example, among asexual vertebrates, where more than one ploidy level can establish persistent clonal lineages, which are reproductively independent of one another.


STRetch: detecting and discovering pathogenic short tandem repeat expansions.
Short tandem repeat (STR) expansions have been identified as the causal DNA mutation in dozens of Mendelian diseases. Most existing tools for detecting STR variation with short reads do so within the read length and so are unable to detect the majority of pathogenic expansions. Here we present STRetch, a new genome-wide method to scan for STR expansions at all loci across the human genome. We demonstrate the use of STRetch for detecting STR expansions using short-read whole-genome sequencing data at known pathogenic loci as well as novel STR loci. STRetch is open source software, available from github.com/Oshlack/STRetch .


Semantic clustering of answers to clinical questions.
Access to clinical evidence is a critical component of the practice of evidence-based medicine. Advanced retrieval systems can supplement precompiled secondary sources to assist physicians in making sound clinical decisions. This study explores one particular issue related to the design of such retrieval systems: the effective organization of search results to facilitate rapid understanding and synthesis of potentially relevant information. We hypothesize that grouping retrieved MEDLINE citations into semantically-coherent clusters, based on automatically-extracted interventions from the abstract text, represents an effective strategy for presenting results, compared to a traditional ranked list. Experiments with our implemented system appear to support this claim.


An open source automatic quality assurance (OSAQA) tool for the ACR MRI phantom.
Routine quality assurance (QA) is necessary and essential to ensure MR scanner performance. This includes geometric distortion, slice positioning and thickness accuracy, high contrast spatial resolution, intensity uniformity, ghosting artefact and low contrast object detectability. However, this manual process can be very time consuming. This paper describes the development and validation of an open source tool to automate the MR QA process, which aims to increase physicist efficiency, and improve the consistency of QA results by reducing human error. The OSAQA software was developed in Matlab and the source code is available for download from http://jidisun.wix.com/osaqa-project/. During program execution QA results are logged for immediate review and are also exported to a spreadsheet for long-term machine performance reporting. For the automatic contrast QA test, a user specific contrast evaluation was designed to improve accuracy for individuals on different display monitors. American College of Radiology QA images were acquired over a period of 2 months to compare manual QA and the results from the proposed OSAQA software. OSAQA was found to significantly reduce the QA time from approximately 45 to 2 min. Both the manual and OSAQA results were found to agree with regard to the recommended criteria and the differences were insignificant compared to the criteria. The intensity homogeneity filter is necessary to obtain an image with acceptable quality and at the same time keeps the high contrast spatial resolution within the recommended criterion. The OSAQA tool has been validated on scanners with different field strengths and manufacturers. A number of suggestions have been made to improve both the phantom design and QA protocol in the future.


The cytokinesis-blocked micronucleus assay as a strong predictor of lung cancer: extension of a lung cancer risk prediction model.
There is an urgent need to improve lung cancer outcome by identifying and validating markers of risk. We previously reported that the cytokinesis-blocked micronucleus assay (CBMN) is a strong predictor of lung cancer risk. Here, we validate our findings in an independent external lung cancer population and test discriminatory power improvement of the Spitz risk prediction model upon extension with this biomarker. A total of 1,506 participants were stratified into a test set of 995 (527 cases/468 controls) from MD Anderson Cancer Center (Houston, TX) and a validation set of 511 (239 cases/272 controls) from Massachusetts General Hospital (Boston, MA). An epidemiologic questionnaire was administered and genetic instability was assessed using the CBMN assay. Excellent concordance was observed between the two populations in levels and distribution of CBMN endpoints [binucleated-micronuclei (BN-MN), binucleated-nucleoplasmic bridges (BN-NPB)] with significantly higher mean BN-MN and BN-NPB values among cases (P < 0.0001). Extension of the Spitz model led to an overall improvement in the AUC (95% confidence intervals) from 0.61 (55.5-65.7) with epidemiologic variables to 0.92 (89.4-94.2) with addition of the BN-MN endpoint. The most dramatic improvement was observed with the never-smokers extended model followed by the former and current smokers. The CBMN assay is a sensitive and specific predictor of lung cancer risk, and extension of the Spitz risk prediction model led to an AUC that may prove useful in population screening programs to identify the "true" high-risk individuals. Identifying high-risk subgroups that would benefit from screening surveillance has immense public health significance.


Balanced Exploration and Exploitation Model search for efficient epipolar geometry estimation.
The estimation of the epipolar geometry is especially difficult when the putative correspondences include a low percentage of inlier correspondences and/or a large subset of the inliers is consistent with a degenerate configuration of the epipolar geometry that is totally incorrect. This work presents the Balanced Exploration and Exploitation Model Search (BEEM) algorithm that works very well especially for these difficult scenes. The algorithm handles these two problems in a unified manner. It includes the following main features: (1) Balanced use of three search techniques: global random exploration, local exploration near the current best solution and local exploitation to improve the quality of the model. (2) Exploits available prior information to accelerate the search process. (3) Uses the best found model to guide the search process, escape from degenerate models and to define an efficient stopping criterion. (4) Presents a simple and efficient method to estimate the epipolar geometry from two SIFT correspondences. (5) Uses the locality-sensitive hashing (LSH) approximate nearest neighbor algorithm for fast putative correspondences generation. The resulting algorithm when tested on real images with or without degenerate configurations gives quality estimations and achieves significant speedups compared to the state of the art algorithms.


Bronchiolitis in young female smokers.
Smoking is a growing concern among young women. However, the pulmonary effects of smoking in young female smokers in their 20's are unknown. The purpose of this study was to determine whether young female smokers demonstrate smoking-related lung abnormalities such as bronchiolitis in their 20's. We recruited young females (20-30 yr) from Izmir, Turkey; 29 smokers and 31 lifetime non-smokers. They were all asymptomatic. All subjects performed complete lung function measurements and underwent thoracic computed tomography (CT) scanning at suspended full inspiration using a Toshiba "Aquilion" multi-slice CT scanner. The CT images were analyzed using custom software (Emphylx-J) and published equations to calculate total lung volume, mean lung density, lung mass, and the extent of emphysema. CT images were also read semi-quantitatively for respiratory bronchiolitis and emphysema by 2 experienced chest radiologists. When there was substantial difference in scoring, a 3rd (independent) radiologist read the CT scans. Plasma biomarkers of smoking were also measured in these subjects. Although none of the subjects demonstrated emphysema on CT images, 41% of smokers (compared with only 15% of non-smokers) had evidence for respiratory bronchiolitis (with a score of 2 or more; p = 0.0301). There was a significant relationship between pack-years of smoking and the severity of respiratory bronchiolitis in smokers. Plasma interleukin (IL)-6 levels were also higher in smokers than in non-smokers (p = 0.028). Quantitative analysis for emphysema or airways disease on CT scans did not reveal any significant differences in the two groups with the exception of lung mass, which was higher in the smokers than in non-smokers. Lung function was similar between the two groups. Young female smokers in their 20's and 30's demonstrate CT changes consistent with respiratory bronchiolitis and elevated plasma IL-6 levels. They also have "heavier" lungs compared with lifetime non-smokers. These data indicate that pathologic changes of smoking occur early in young female smokers in the absence of demonstrable airflow limitation or symptoms. Public health efforts to curb smoking in young women are clearly needed to reduce the burden of smoking related lung disease in women.


Evaluation of bronchodilator responsiveness in mechanically ventilated patients.
Airway pressure, flow, and volume were measured before and after administration of aerosolized metaproterenol during controlled mechanical inflation and stepwise deflation of the relaxed respiratory system in 13 mechanically ventilated patients. An increase in passive expiratory flow at constant respiratory system recoil pressure was considered evidence of bronchodilatation. In 10 patients, at a respiratory system recoil pressure of 6 cm H2O (VP6), expiratory flow increased 21 to 500% above prebronchodilator level. In these 10 dynamically hyperinflated patients, an increase in VP6 was associated with a decrease in peak inspiratory pressure (Ppeak) (mean delta = -4.7 cm H2O) and a decrease in intrinsic positive end-expiratory pressure (Peepi) (mean delta = -2.4 cm H2O). The elastance of the respiratory system was not affected by metaproterenol, and the delta Peepi corresponded to a mean decrease in end-expiratory lung volume of 0.20 L. The results are consistent with predictions based on a single-compartment model. When mean expiratory flow is determined only by the tidal volume and expiratory time, a decrease in airway resistance results in a decrease in lung volume at which patients are ventilated. Therefore, the decrease in Ppeak is caused not only by a decrease in the resistive pressure cost but also by a decrease in the elastic pressure cost of inflating the respiratory system. It is emphasized that Ppeak and Peepi provide valuable information about bronchodilator-induced changes in lung function during controlled mechanical ventilation.


Bioconjugation and Applications of Amino Functional Fluorescence Polymers.
Synthesis and novel applications of biofunctional polymers for diagnosis and therapy are promising area involving various research domains. Herein, three fluorescent polymers, poly(p-phenylene-co-thiophene), poly(p-phenylene), and polythiophene with amino groups (PPT-NH2 , PPP-NH2 , and PT-NH2 , respectively) are synthesized and investigated for cancer cell targeted imaging, drug delivery, and radiotherapy. Polymers are conjugated to anti-HER2 antibody for targeted imaging studies in nontoxic concentrations. Three cell lines (A549, Vero, and HeLa) with different expression levels of HER2 are used. In a model of HER2 expressing cell line (A549), radiotherapy experiments are carried out and results show that all three polymers increase the efficacy of radiotherapy. This effect is even more increased when conjugated to anti-HER2. In the second part of this work, one of the selected polymers (PT-NH2 ) is conjugated with a drug model; methotrexate via pH responsive hydrazone linkage and a drug carrier property of PT-NH2 is demonstrated on neuroblastoma (SH-SY5Y) cell model. Our results indicate that, PPT-NH2 , PPP-NH2 , and PT-NH2 have a great potential as biomaterials for various bioapplications in cancer research.


Pathophysiology and epidemiology of peripartum cardiomyopathy.
Cardiovascular diseases are a major cause of complications in pregnancy worldwide, and the number of patients who develop cardiac problems during pregnancy is increasing. Peripartum cardiomyopathy (PPCM) is a potentially life-threatening heart disease that emerges towards the end of pregnancy or in the first months postpartum, in previously healthy women. Symptoms and signs of PPCM are similar to those in patients with idiopathic dilated cardiomyopathy. The incidence varies geographically, most likely because of socioeconomic and genetic factors. The syndrome is associated with a high morbidity and mortality, and diagnosis is often delayed. Various mechanisms have been investigated, including the hypothesis that unbalanced peripartum or postpartum oxidative stress triggers the proteolytic cleavage of the nursing hormone prolactin into a potent antiangiogenic, proapoptotic, and proinflammatory 16 kDa fragment. This theory provides the basis for the discovery of disease-specific biomarkers and promising novel therapeutic targets. In this Review, we describe the latest understanding of the epidemiology, pathophysiology, and novel treatment strategies for patients with PPCM.


Relationship Between Regional Atherosclerosis and Adjacent Spinal Cord Histology.
Scant data are available regarding ischemic insult to the spinal cord and the responsible blood supply. Therefore, we aimed to investigate a correlation between atherosclerosis of adjacent vessels and spinal cord ischemia. In 20 unembalmed adult cadavers, samples of the vertebral arteries and aorta were removed and the degree of atherosclerosis with subsequent luminal occlusion was histologically analyzed. Next, adjacent segments of the spinal cord were harvested and submitted for immunohistological analysis of both neural and glial elements and blood supply. We identified proximal atherosclerosis in the majority of cadavers but with varying degrees of luminal occlusion. The greatest degree of luminal occlusion was found in the descending abdominal aorta. No specimen was found to have atherosclerosis of the anterior or posterior spinal or radicular arteries. No spinal cord histology showed signs of ischemia, even in specimens with a significant large parent vessel (vertebral artery and aorta) occlusion due to atherosclerosis. Neuropathology of these adjacent cord segments revealed no signs of ischemia or demyelination. Spinal cord ischemia is often misdiagnosed and can cause significant neurological compromise. However, based on our study, the degree of atherosclerosis of the adjacent parent vessel supply does not appear to be a predictor of neuronal and glial tissue damage of the adjacent spinal cord.


Mapping the drivers of within-host pathogen evolution using massive data sets.
Differences among hosts, resulting from genetic variation in the immune system or heterogeneity in drug treatment, can impact within-host pathogen evolution. Genetic association studies can potentially identify such interactions. However, extensive and correlated genetic population structure in hosts and pathogens presents a substantial risk of confounding analyses. Moreover, the multiple testing burden of interaction scanning can potentially limit power. We present a Bayesian approach for detecting host influences on pathogen evolution that exploits vast existing data sets of pathogen diversity to improve power and control for stratification. The approach models key processes, including recombination and selection, and identifies regions of the pathogen genome affected by host factors. Our simulations and empirical analysis of drug-induced selection on the HIV-1 genome show that the method recovers known associations and has superior precision-recall characteristics compared to other approaches. We build a high-resolution map of HLA-induced selection in the HIV-1 genome, identifying novel epitope-allele combinations.


Opioid growth factor is present in human and mouse gastrointestinal tract and inhibits DNA synthesis.
Native opioid peptides serve as growth factors in a number of normal and neoplastic cells and tissues. This study investigated the influence of opioids on circadian rhythm-dependent DNA synthesis in mouse esophagus during homeostatic renewal. In contrast to a labeling index (LI) of 24.0% at 0630 and 5.5% at 1600, disruption of opioid-receptor interaction by the potent opioid antagonist naltrexone hydrochloride (NTX; 10 mg/kg) in mice resulted in an elevation of 49% in DNA synthesis of esophageal epithelial cells at 1600, but had no effect at 0630. Mice subjected to [Met5]enkephalin (1 mg/kg) had an LI that was decreased 23% from control levels at 0630, but was unaffected at 1600. This decrease in DNA synthesis was blocked by concomitant administration of naloxone (10 mg/kg); naloxone alone had no influence on cell replicative processes. In tissue culture studies, NTX and OGF markedly increased and decreased, respectively, the LI from control values. Both opioid growth factor (OGF) and its receptor, zeta, were detected in all but the cornified layer of mouse esophageal epithelium and in the epithelial cells of the stomach and small and large intestines. In addition, both peptide and receptor were observed in the basal and suprabasal cells of human esophageal epithelium. These results indicate that an endogenous opioid peptide (OGF) and its receptor (zeta) reside in gastrointestinal epithelium and play a role in cellular renewal processes in a tonically inhibitory, direct, and circadian rhythm-dependent fashion.


Developmental patterns of anger from infancy to middle childhood predict problem behaviors at age 8.
Anger is a central characteristic of negative affect and is relatively stable from infancy onward. Absolute levels of anger typically peak in early childhood and diminish as children become socialized and better able to regulate emotions. From infancy to school age, however, there are also individual differences in rank-order levels of anger. For example, although decreasing in absolute levels, some children may stay the same and others may increase in rank order relative to their peers. Although change in rank order of anger over time may provide unique insight into children's social development, little is known concerning variations in developmental patterns of anger from a rank-order perspective and how these patterns are related to children's behavioral adjustment. The current study (N = 361) used group-based trajectory analysis and identified 6 distinct patterns of parent-reported child anger by rank across 9 months to 7 years: low-stable rank, average-stable rank, average-decreasing rank, average-increasing rank, high-decreasing rank, and high-stable rank. Most children (65.1%) were in low- to average-rank groups. However, 28.2% and 6.7% of the children were in average-increasing and high-stable groups, respectively. Children in the high-stable group showed elevated levels of externalizing and internalizing problems at age 8 compared to children in the average-stable, average-decreasing, and high-decreasing groups. These findings help to clarify different patterns of anger development across childhood and how they may relate to later problem behaviors. (PsycINFO Database Record (c) 2018 APA, all rights reserved).


Gorgonian disease outbreak in the Gulf of Naples: pathology reveals cyanobacterial infection linked to elevated sea temperatures.
In recent years, mass mortality events of benthic invertebrates in the Mediterranean Sea have been documented to coincide with the increased seawater temperatures associated with global climate change. Following a disease outbreak in gorgonians during the summer seasons of 2008 and 2009 in the Gulf of Naples (Tyrrhenian Sea), we conducted gross and microscopic analyses of healthy and diseased specimens of Eunicella cavolinii and E. singularis using both light and electron microscopy (SEM). Macroscopically, diseased colonies exhibited evident tissue thinning, and dead colonies showed a complete loss of polyps and coenenchyme, exposing their skeletons to settlement by fouling organisms. Histopathology revealed chronic inflammatory lesions at the polyp and axial level, characterized by amoebocyte infiltration of tissue accompanied by new apposition of melanin/gorgonin sheets. We interpreted this response as a defense against different kinds of pathogens-identified as mainly a heterogeneous consortium of filamentous cyanobacteria-and which gradually led to enlargement and hardening of the coral axis, which resembled a wood-like structure at the final stage of the disease. These processes elicited the formation of multiple inflammatory nodules and capsules, some of which were macroscopically visible. A parallel 16S rRNA and ITS analysis of the diseased tissue identified Synechococcus, Arthrospira and other uncultured cyanobacteria grouped within the Oscillatoriales. These results suggest that a cyanobacterial consortium is involved in the pathogenesis of the inflammatory disease leading to the mortality of Gorgoniaceae in the area. Finally, there were anomalously high temperatures (up to 25°C) between 10 and 20 m depth during the sampling period, particularly in June 2009. This supports the hypothesis that the coral skeleton may serve as a reservoir for the pathogens in cooler seasons, with warmer conditions leading to pathogen reactivation and recurring mortality events.


PMA-induced up-regulation of TBX3 is mediated by AP-1 and contributes to breast cancer cell migration.
The T-box transcription factor TBX3 provides an important link between embryonic development and cancer. TBX3 mediates limb, mammary gland and heart development and, in humans, mutations resulting in haplo-insufficiency of TBX3 lead to ulnar-mammary syndrome. Importantly, the de-regulation of TBX3 gene expression has been linked to several cancers, where it acts to suppress senescence and promotes proliferation and tumour invasion. Despite the negative impact of de-regulated TBX3 expression as seen by developmental defects and cancer, surprisingly little is known about the regulation of the TBX3 gene. In the present paper, we show that the phorbol ester PMA increases TBX3 protein and mRNA levels in a protein kinase C-dependent manner via the AP-1 (activator protein 1) transcription factors c-Jun and JunB. Furthermore, these AP-1 factors are shown to mediate the activation of the TBX3 gene by binding a non-consensus PMA-response element in the TBX3 promoter in vitro and in vivo. We also demonstrate that TBX3 contributes to the PMA-induced migration previously observed for the MCF-7 breast epithelium cancer cell line. Our present results reveal a previously unidentified pathway that up-regulates TBX3 expression and provides additional evidence that increased levels of TBX3 contribute to metastasis.


An update of miRNASNP database for better SNP selection by GWAS data, miRNA expression and online tools.
MicroRNAs (miRNAs) are key regulators of gene expression involved in a broad range of biological processes. MiRNASNP aims to provide single nucleotide polymorphisms (SNPs) in miRNAs and genes that may impact miRNA biogenesis and/or miRNA target binding. Advanced miRNA research provided abundant data about miRNA expression, validated targets and related phenotypic variants. In miRNASNP v2.0, we have updated our previous database with several new data and features, including: (i) expression level and expression correlation of miRNAs and target genes in different tissues, (ii) linking SNPs to the results of genome-wide association studies, (iii) integrating experimentally validated miRNA:mRNA interactions, (iv) adding multiple filters to prioritize functional SNPs. In addition, as a supplement of the database, we have set up three flexible online tools to analyse the influence of novel variants on miRNA:mRNA binding. A new nice web interface was designed for miRNASNP v2.0 allowing users to browse, search and download. We aim to maintain the miRNASNP as a solid resource for function, genetics and disease studies of miRNA-related SNPs. Database URL: http://bioinfo.life. hust.edu.cn/miRNASNP2/


Associations between drugs administered during pregnancy and congenital abnormalities of the fetus.
In a retrospective study to compare the drug consumption during pregnancy of mothers of infants with congenital abnormalities and of those without, over 97% of 1,369 mothers took prescribed drugs and 65% self-administered drugs. Significantly more mothers of infants with congenital abnormalities took aspirin, antacids, dextroamphetamine, phenobarbitone, sodium amytal, other barbiturates, cough medicines, iron, sulphonamides, and nicotinamide than mothers in the control group. However, most mothers taking analgesics, antacids, appetite suppressants, barbiturates, cough medicines, iron, sulphonamides, and vitamins produced normal infants. Any teratogenic effect of these drugs is therefore one of low potency. On the other hand, deficiencies such as those of ascorbic acid and folic acid may have a teratogenic effect. There is need for caution in presuming teratogenic effects on the basis of the associations shown here. During pregnancy, however, it would appear wise to avoid the administration of any drug which carries a suspicion of teratogenicity unless that drug is specifically indicated, and self-medication with common household remedies such as aspirin and antacids should be avoided. These recommendations would also apply to any woman of childbearing age in whom conception is likely.


Episodic activity in a heterogeneous excitatory network, from spiking neurons to mean field.
Many developing neural systems exhibit spontaneous activity (O'Donovan, Curr Opin Neurobiol 9:94-104, 1999; Feller, Neuron 22:653-656, 1999) characterized by episodes of discharge (active phases) when many cells are firing, separated by silent phases during which few cells fire. Various models exhibit features of episodic behavior by means of recurrent excitation for supporting an episode and slow activity-dependent depression for terminating one. The basic mechanism has been analyzed using mean-field, firing-rate models. Firing-rate models are typically formulated ad hoc, not derived from a spiking network description, and the effects of substantial heterogeneity amongst the units are not usually considered. Here we develop an excitatory network of spiking neurons (N-cell model) with slow synaptic depression to model episodic rhythmogenesis. This N-cell model displays episodic behavior over a range of heterogeneity in bias currents. Important features of the episodic behavior include orderly recruitment of individual cells during silent phases and existence of a dynamical process whereby a small critical subpopulation of intermediate excitability conveys synaptic drive from active to silent cells. We also derive a general self-consistency equation for synaptic drive that includes cell heterogeneity explicitly. We use this mean-field description to expose the dynamical bistability that underlies episodic behavior in the heterogeneous network. In a systematic numerical study we find that the robustness of the episodic behavior improves with increasing heterogeneity. Furthermore, the heterogeneity of depression variables (imparted by the heterogeneity in cellular firing thresholds) plays an important role in this improvement: it renders the network episodic behavior more robust to variations in excitability than if depression is uniformized. We also investigate the effects of noise vs. heterogeneity on the robustness of episodic behavior, especially important for the developing nervous system. We demonstrate that noise-induced episodes are very fragile, whereas heterogeneity-produced episodic rhythm is robust.


Are hummingbirds facultatively ammonotelic? Nitrogen excretion and requirements as a function of body size.
Most birds are uricotelic. An exception to this rule may be nectar-feeding birds, which excrete significant amounts of ammonia under certain conditions. Although ammonia is toxic, because it is highly water soluble its excretion may be facilitated in animals that ingest and excrete large amounts of water. Bird-pollinated plants secrete carbohydrate- and water-rich floral nectars that contain exceedingly little protein. Thus, nectar-feeding birds are faced with the dual challenge of meeting nitrogen requirements while disposing of large amounts of water. The peculiar diet of nectar-feeding birds suggests two hypotheses: (1) these birds must have low protein requirements, and (2) when they ingest large quantities of water their primary nitrogen excretion product may be ammonia. To test these hypotheses, we measured maintenance nitrogen requirements (MNR) and total endogenous nitrogen losses (TENL) in three hummingbird species (Archilochus alexandri, Eugenes fulgens, and Lampornis clemenciae) fed on diets with varying sugar, protein, and water content. We also quantified the form in which the by-products of nitrogen metabolism were excreted. The MNR and TENL of the hummingbirds examined were exceptionally low. However, no birds excreted more than 50% of nitrogen as ammonia or more nitrogen as ammonia than urates. Furthermore, ammonia excretion was not influenced by either water or protein intake. The smallest species (A. alexandri) excreted a significantly greater proportion (>25%) of their nitrogenous wastes as ammonia than the larger hummingbirds ( approximately 4%). Our results support the hypothesis that nectar-feeding birds have low protein requirements but cast doubt on the notion that they are facultatively ammonotelic. Our data also hint at a possible size-dependent dichotomy in hummingbirds, with higher ammonia excretion in smaller species. Differences in proportionate water loads and/or postrenal modification of urine may explain this dichotomy.


Silent Brain Infarction and Risk of Future Stroke: A Systematic Review and Meta-Analysis.
Silent brain infarction (SBI) on magnetic resonance imaging has been proposed as a subclinical risk marker for future symptomatic stroke. We performed a systematic review and meta-analysis to summarize the association between magnetic resonance imaging-defined SBI and future stroke risk. We searched the medical literature to identify cohort studies involving adults with SBI detected by magnetic resonance imaging who were subsequently followed up for incident clinically defined stroke. Study data and quality assessment were recorded in duplicate with disagreements in data extraction resolved by a third reader. Strength association between magnetic resonance imaging-detected SBI and future symptomatic stroke was measured by an hazard ratio. The meta-analysis included 13 studies (14 764 subjects) with a mean follow-up ranging from 25.7 to 174 months. SBI predicted the occurrence of stroke with a random effects crude relative risk of 2.94 (95% confidence interval, 2.24-3.86, P<0.001; Q=39.65, P<0.001). In the 8 studies of 10 427 subjects providing hazard ratio adjusted for cardiovascular risk factors, SBI was an independent predictor of incident stroke (hazard ratio, 2.08 [95% confidence interval, 1.69-2.56; P<0.001]; Q=8.99; P=0.25). In a subgroup analysis pooling 9483 stroke-free individuals from large population-based studies, SBI was present in ≈18% of participants and remained a strong predictor of future stroke (hazard ratio, 2.06 [95% confidence interval, 1.64-2.59]; P<0.01). SBI is present in ≈1 in 5 stroke-free older adults and is associated with a 2-fold increased risk of future stroke. Future studies of in-depth stroke risk evaluations and intensive prevention measures are warranted in patients with clinically unrecognized radiologically evident brain infarctions.


Chitinase 3-like-1 regulates both visceral fat accumulation and asthma-like Th2 inflammation.
Obesity, especially truncal obesity, is a risk factor for asthma incidence, prevalence, and severity. Chitinase 3-like-1 (Chi3l1) is an evolutionarily conserved moiety that plays a critical role in antipathogen and Th2 responses. However, the mechanisms that underlie the association between asthma and obesity and the role(s) of Chi3l1 in fat accumulation have not been defined. To determine whether Chi3l1 is regulated by a high-fat diet (HFD) and simultaneously plays an important role(s) in the pathogenesis of asthma and obesity. We evaluated the regulation of Chi3l1 by an HFD and Th2 inflammation. We also used genetically modified mice to define the roles of Chi3l1 in white adipose tissue (WAT) accumulation and Th2 inflammation and blockers of sirtuin 1 (Sirt1) to define its roles in these responses. Finally, the human relevance of these findings was assessed with a case-control study involving obese and lean control subjects and those with asthma. These studies demonstrate that an HFD and aeroallergen challenge augment the expression of WAT and pulmonary Chi3l1. Chi3l1 also played a critical role in WAT accumulation and lung Th2 inflammation. In addition, Chi3l1 inhibited Sirt1 expression, and the deficient visceral fat and Th2 responses in Chi3l1 null mice were reversed by Sirt1 inhibition. Finally, serum and sputum Chi3l1 were positively associated with truncal adiposity, and serum Chi3l1 was associated with persistent asthma and low lung function in obese subjects with asthma. Chi3l1 is induced by an HFD and Th2 inflammation, and simultaneously contributes to the genesis of obesity and asthma.


Long-term bromocriptine therapy may restore the inhibitory control of prolactin release in some patients with pathological hyperprolactinemia.
While bromocriptine is effective in controlling hyperprolactinemia, it is not known if bromocriptine therapy can restore the abnormal regulation of prolactin (PRL) release found in patients with pathological hyperprolactinemia. We report 15 hyperprolactinemic patients treated for a mean duration of 5.5 +/- 0.6 years (mean +/- SE) in whom stimulation tests to assess PRL control mechanisms [thyrotropin releasing hormone (TRH) and metoclopramide] were performed before and at least one month after withdrawal of bromocriptine therapy. The basal PRL level after withdrawal of bromocriptine therapy was significantly lower (p less than 0.001) than that before therapy. All patients had blunted PRL stimulatory responses to TRH and metoclopramide (% delta 16.0 +/- 5.6%) before treatment. After withdrawal of bromocriptine, PRL responses to stimulatory tests were significantly improved in seven patients (termed 'responders', % delta 376 +/- 55%) but remained unchanged in eight patients (termed 'non-responders', % delta 9.2 +/- 3.0%). Basal PRL levels were significantly lower (p less than 0.01) in responders (290 +/- 35 mIU/l) than in non-responders (10360 +/- 6790 mIU/l). Four of the responders have maintained normoprolactinemia and normal stimulated PRL responses for 15 months to three years following cessation of bromocriptine therapy and appear to be in remission. Favourable factors amongst the responders were the female sex, absence of a macroadenoma, and a pre-treatment PRL level below 3000 mlU/l. PRL stimulation tests performed before therapy could not predict which patients would respond. No relationship was found between duration of therapy, or age at presentation, and improvement after bromocriptine.(ABSTRACT TRUNCATED AT 250 WORDS)


Exaggerated cardiovascular stress responses and impaired beta-adrenergic-mediated pressor recovery in obese Zucker rats.
Clinical studies have demonstrated that the pressor response to acute stress is larger in obese versus lean individuals. We therefore tested the hypotheses that the pressor response to behavioral stress is greater in obese (OZRs) versus lean Zucker rats (LZRs) and that reduced beta-adrenergic-mediated vasodilation contributes to the enhanced pressor response. Animals were restrained and subjected to acute pulsatile air jet stress (3 minutes), followed by a poststress period of 20 minutes; beta-adrenergic blockade was achieved with propranolol (5 mg/kg, IV) given 15 minutes before the start of air jet stress. Mean arterial pressure (MAP) was continuously monitored by telemetry. Untreated OZRs responded with a greater integrated pressor response (area under the curve [AUC]) to acute stress (41.2+/-6.1 versus 21.2+/-3.3 mm Hgx3 minutes, OZR versus LZR; P<0.05) and significantly reduced poststress recovery of MAP. Beta-adrenergic blockade had no effect on stress AUC in either LZRs or OZRs but significantly attenuated the poststress recovery of MAP in LZRs only (poststress AUC: -100.1+/-48.1 versus 49.0+/-13.5 mm Hgx20 minutes, untreated versus propranolol; P<0.05). In anesthetized animals, significantly smaller increases in mesenteric vascular conductance contributed to blunted depressor responses to isoproterenol in OZRs versus LZRs, suggesting that beta-adrenergic stimulation causes a greater reduction in total peripheral resistance in lean versus obese animals. We conclude that beta-adrenergic-mediated vasodilation facilitates blood pressure recovery after stress and that this pathway is compromised in an animal model of morbid obesity, resulting in the impaired ability to regulate blood pressure during stress.


Relation between bond-length alternation and second electronic hyperpolarizability of conjugated organic molecules.
The solvent dependence of the second hyperpolarizability, gamma, of a variety of unsaturated organic compounds has been measured by third harmonic generation at 1907 nanometers. It is seen that the measured gamma is a function of solvent polarity. These solvent-dependent hyperpolarizabilities are associated with changes in molecular geometry from a highly bond-length alternated, polyene-like structure for a formyl-substituted compound in non-polar solvents, to a cyanine-like structure, with little bond-length alternation, for a dicyanovinyl-substituted compound in polar solvents. By tuning bond-length alternation, gamma can be optimized in either a positive or negative sense for polymethine dyes of a given conjugation length.


Receipt of standard breast cancer treatment by African American and White women.
Breast cancer mortality is higher among African Americans than for Whites, though their breast cancer incidence is lower. This study examines whether this disparity may be due to differential receipt of treatment defined as "standard of care" or "addition to standard of care" by the National Comprehensive Cancer Network (NCCN). Incident, female breast cancer cases, 2,203 African American and 7,518 White, diagnosed during 1996-2002 were identified from the Alabama Statewide Cancer Registry. Breast cancer treatment was characterized as whether or not a woman received standard of care as defined by the NCCN. For cases characterized as receiving standard of care, addition to standard of care was also evaluated, defined as receiving at least one additional treatment modality according to NCCN guidelines. Logistic models were used to evaluate racial differences in standard and addition to standard of care and to adjust for age, stage at diagnosis, year of diagnosis and area of residence. No racial differences were found for standard (Prevalence Ratio (PR)=1.00) or for addition to standard of care (PR=1.00) after adjustment for confounders. When the adjusted models were examined separately by age, stage, and area of residence, overall no racial differences were found. No racial differences in standard of care and addition to standard of care for breast cancer treatment were found. Therefore, both African Americans and Whites received comparable treatment according to NCCN guidelines.


Does COVID-19 contribute to development of neurological disease?
Although coronavirus disease 2019 (COVID-19) has been associated primarily with pneumonia, recent data show that the causative agent of COVID-19, the coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), can infect a large number of vital organs beyond the lungs, such as the heart, kidneys, and the brain. Thus, there is evidence showing possible retrograde transmission of the virus from the olfactory epithelium to regions of the brain stem. This is a literature review article. The research design method is an evidence-based rapid review. The present discourse aim is first to scrutinize and assess the available literature on COVID-19 repercussion on the central nervous system (CNS). Standard literature and database searches were implemented, gathered relevant material, and extracted information was then assessed. The angiotensin-converting enzyme 2 (ACE2) receptors being the receptor for the virus, the threat to the central nervous system is expected. Neurons and glial cells express ACE2 receptors in the CNS, and recent studies suggest that activated glial cells contribute to neuroinflammation and the devastating effects of SARS-CoV-2 infection on the CNS. The SARS-CoV-2-induced immune-mediated demyelinating disease, cerebrovascular damage, neurodegeneration, and depression are some of the neurological complications discussed here. This review correlates present clinical manifestations of COVID-19 patients with possible neurological consequences in the future, thus preparing healthcare providers for possible future consequences of COVID-19.


Intraocular pressure in genetically distinct mice: an update and strain survey.
Little is known about genetic factors affecting intraocular pressure (IOP) in mice and other mammals. The purpose of this study was to determine the IOPs of genetically distinct mouse strains, assess the effects of factors such as age, sex and time of day on IOP in specific strain backgrounds, and to assess the effects of specific candidate gene mutations on IOP. Based on over 30 studied mouse strains, average IOP ranges from approximately 10 to 20 mmHg. Gender does not typically affect IOP and aging results in an IOP decrease in some strains. Most tested strains exhibit a diurnal rhythm with IOP being the highest during the dark period of the day. Homozygosity for a null allele of the carbonic anhydrase II gene (Car2n) does not alter IOP while homozygosity for a mutation in the leptin receptor gene (Leprdb) that causes obesity and diabetes results in increased IOP. Albino C57BL/6J mice homozygous for a tyrosinase mutation (Tyrc-2J) have higher IOPs than their pigmented counterparts. Genetically distinct mouse strains housed in the same environment have a broad range of IOPs. These IOP differences are likely due to interstrain genetic differences that create a powerful resource for studying the regulation of IOP. Age, time of day, obesity and diabetes have effects on mouse IOP similar to those in humans and other species. Mutations in two of the assessed candidate genes (Lepr and Tyr) result in increased IOP. These studies demonstrate that mice are a practical and powerful experimental system to study the genetics of IOP regulation and disease processes that raise IOP to harmful levels.


Possession of HLA class II DRB1*1303 associates with reduced viral loads in chronic HIV-1 clade C and B infection.
The HLA class II molecules play a central role in the generation of human immunodeficiency virus (HIV)-specific CD4(+) T-helper cells, which are critical for the induction of cytotoxic CD8(+) T cell responses. However, little is known about the impact of HLA class II alleles on HIV disease progression. In this study we investigated the effect of HLA class II alleles on HIV disease outcome and HIV-specific T cell responses in a cohort of 426 antiretroviral therapy-naive, HIV-1 clade C-infected, predominantly female black South Africans. The HLA class II allele DRB1*1303 was independently associated with lower plasma viral loads in this population (P = .02), an association that was confirmed in a second cohort of 1436 untreated, HIV-1 clade B-infected, male European Americans, suggesting that DRB1*1303-mediated protection is independent of ethnicity, sex, and viral clade. Interestingly, DRB1*1303 carriage was not associated with an increased frequency of interferon (IFN) γ-positive HIV-specific CD4(+) T cell responses. These data demonstrate the independent effect of an HLA class II allele, DRB1*1303, on HIV disease progression, in the absence of increased IFN-γ-positive HIV-specific CD4(+) T cell frequencies, suggesting that the protective activity of DRB1*1303 may be mediated via an alternative mechanism.


[Therapeutic effects of the Feldenkrais method "awareness through movement" in patients with eating disorders].
Based on the movement-pedagogical concept of Feldenkrais and the findings-of disturbed body perception by eating disordered patients this research aimed at studying the therapeutical effects of the Feldenkrais Method "Awareness through Movement" with eating disorder patients, 15 eating disordered patients treated at the Roseneck hospital for behavioural medicine rated-by means of a questionnaire consisting of scales of the Body Cathexis Scale (BCS), the Body Parts Satisfaction Scale (BPSS), the questionnaire for body perception (Fragebogen zum Körpererleben; FKE), the Emotion inventory (Emotionalitätsinventar; EMI-B), the Anorexia-Nervosa-Inventory for Self-rating (ANIS) and the Eating Disorder Inventory-2 (EDI)-various aspects of their eating disorder before and after participating in a nine hour course of the Feldenkrais Method. The data of these patients were compared to those of the members of a control group, also consisting of 15 eating disordered patients who did not participate in a Feldenkrais course. The participants of the Feldenkrais-course showed increasing contentment with regard to problematic zones of their body and their own health as well as concerning acceptance and familiarity with their own body. Other results were a more spontaneous, open and self-confident behaviour, the decrease of feelings of helplessness and decrease of the wish to return to the security of the early childhood, which indicates the development of felt sense of self, self-confidence and a general process of maturation of the whole personality. The outcome points to the therapeutical effectiveness of the Feldenkrais Method with eating-disorder patients within a multimodal treatment program.


Cross-sectional analysis of the reporting of continuous outcome measures and clinical significance of results in randomized trials of non-pharmacological interventions.
Reporting the scoring details of continuous outcome measures in randomized trials allows readers to interpret the size of any effect of the intervention. This study aimed to determine, in a sample of randomized trials: 1) the completeness of reporting of scoring details for continuous outcome measures, and 2) whether trial authors comment on the clinical significance of statistically significant trial results. A descriptive analysis of randomized trials of non-pharmacological interventions published during 2009 in the six leading general medical journals (n = 138), and which used at least one continuous outcome measure (n = 85). From each trial report, two authors independently extracted the following information about each continuous outcome measure: the reporting of its scoring details, presentation of its results, and the reporting and justification of the clinical significance of the results. Across the 84 trials, we identified 336 continuous outcome measures. A total of 146 (44%) were published measures, 12 (4%) were adapted from published measures, 5 (1%) were developed for the trial, and 173 (51%) were 'conventional measures' for which scoring details are not necessary (such as weight). For 57 (35%) of the 163 non-conventional outcome measures no scoring details or reference to the outcome measure were provided in the trial report. Of the 159 outcome measures with a statistically significant result, clinical significance was not mentioned for 81 (51%) and was reported without any elaboration or justification for 39 (25%) of them. Scoring details of continuous outcome measures used in this sample of randomized trials of non-pharmacological interventions were incompletely reported, which hampers interpretation of a trial's results. Complete reporting of scoring details is important when considering the clinical significance of the results. When deciding about an intervention, having this information may help clinicians in their conversations with patients about the possible benefits and harms, and their size, of the intervention.


Environmental degradation & role of financialisation, economic development, industrialisation and trade liberalisation.
This paper is a pioneering endeavour to investigate the determinants of environmental degradation in Australia through a comprehensive framework of EKC and STIRPAT. Specifically, the impacts of multiple factors of socio-economic development including economic growth, trade openness, industrialization, energy consumption on CO2 emissions are analysed. Furthermore, the influences of financial development through different dimensions (financial efficiency, access and depth) in two subsectors (financial markets and institutions) and other proxies of financial development are focused over the period 1980-2014. Empirical results show short as well as long-run differences in the association among the variables. Short-term bidirectional causality prevails between economic growth, energy consumption, industrialization, and stock market development with carbon dioxide (CO2) emissions. However, there is no significant evidence found on EKC. This is due to the long-run positive impact of financial development, energy consumption, and trade openness on CO2 emissions. Interestingly, the industrialization process is found to does not affect CO2 emissions. Empirical findings provide insight into why the quality of the Australian environment is truncated with frequent and widespread bushfires and suggest policymakers to have selective and strict environmental-friendly strategies to fulfil a sustainable development goal.


Frequency and severity of adverse effects of iodinated and gadolinium contrast materials: retrospective review of 456,930 doses.
The purpose of this study was to determine the frequency and characteristics of adverse effects of low-osmolar iodinated and gadolinium contrast agents in a single-center experience with a large number of cases. A retrospective review of all intravascular doses of low-osmolar iodinated and gadolinium contrast materials administered from 2002 through 2006 was conducted. Adverse effects were identified through the use of radiologist and nurse event recording. Adverse effects were examined for type and severity of reaction, treatment required, and outcome. A total of 456,930 contrast doses (298,491 low-osmolar iodinated, 158,439 gadolinium) were administered over the study period. A total of 522 cases of adverse effects (0.11% of total) were identified (458 low-osmolar iodinated, 64 gadolinium). The most common adverse effects were hives (274, 52.5%) and nausea (92, 17.6%). Of all adverse effects, 79 of low-osmolar iodinated and 15 of gadolinium contrast material necessitated treatment. Most treatments were performed in the radiology department alone. Only 16 cases of adverse effects necessitated transfer for further observation or treatment. Epinephrine was used to manage an adverse effect in nine instances. Thirty-two of the adverse effects of low-osmolar iodinated contrast material (6.9%) occurred in patients with a history of allergy who received premedication. Only two of these premedication reactions necessitated transfer to the emergency department. The one death in the study period occurred after administration of low-osmolar iodinated contrast material. The patient had no symptoms during the contrast administration or imaging but died suddenly within 30 minutes of receiving the dose. Both iodinated and gadolinium contrast agents are associated with a very low rate of adverse effects. Most adverse effects are mild and can be managed in the radiology department. Transfer for additional treatment or observation is rarely needed.


Clinical Utility of a Genomic Classifier in Men Undergoing Radical Prostatectomy: The PRO-IMPACT Trial.
The optimal management of men with prostate cancer at high risk of recurrence postradical prostatectomy is controversial. The clinical utility of the Decipher test was evaluated prospectively on postoperative treatment decisions and patient-reported outcomes. In the study, 246 eligible men across 19 centers were enrolled. Patients were dichotomized into those considering adjuvant or salvage radiation therapy (ART or SRT). Participating providers submitted a management recommendation before and after receiving the Decipher test results. Treatment received within 12 months and a validated survey on prostate cancer-related anxiety were collected longitudinally. Pre-Decipher, treatment was recommended for 12% and 40% for the ART and SRT arms, respectively. Post-Decipher, 17% and 30% of treatment recommendations changed in the ART and SRT arms, respectively. Post-Decipher treatment recommendation was administered 78% and 76% of the time in the ART and SRT arms, respectively. Multivariable analysis confirmed that the Decipher score was an independent predictor for change in management for both adjuvant and salvage patients. The number needed to test to change management for one patient was 4. Cancer-specific anxiety decreased among Decipher risk categories in both arms. Use of Decipher postradical prostatectomy test was associated with postoperative treatment decisions. Overall, high Decipher risk was associated with an increase in treatment intensity whereas low risk scores were associated with a decrease in therapy administered independent of clinical and pathologic risk factors.


HGTector: an automated method facilitating genome-wide discovery of putative horizontal gene transfers.
First pass methods based on BLAST match are commonly used as an initial step to separate the different phylogenetic histories of genes in microbial genomes, and target putative horizontal gene transfer (HGT) events. This will continue to be necessary given the rapid growth of genomic data and the technical difficulties in conducting large-scale explicit phylogenetic analyses. However, these methods often produce misleading results due to their inability to resolve indirect phylogenetic links and their vulnerability to stochastic events. A new computational method of rapid, exhaustive and genome-wide detection of HGT was developed, featuring the systematic analysis of BLAST hit distribution patterns in the context of a priori defined hierarchical evolutionary categories. Genes that fall beyond a series of statistically determined thresholds are identified as not adhering to the typical vertical history of the organisms in question, but instead having a putative horizontal origin. Tests on simulated genomic data suggest that this approach effectively targets atypically distributed genes that are highly likely to be HGT-derived, and exhibits robust performance compared to conventional BLAST-based approaches. This method was further tested on real genomic datasets, including Rickettsia genomes, and was compared to previous studies. Results show consistency with currently employed categories of HGT prediction methods. In-depth analysis of both simulated and real genomic data suggests that the method is notably insensitive to stochastic events such as gene loss, rate variation and database error, which are common challenges to the current methodology. An automated pipeline was created to implement this approach and was made publicly available at: https://github.com/DittmarLab/HGTector. The program is versatile, easily deployed, has a low requirement for computational resources. HGTector is an effective tool for initial or standalone large-scale discovery of candidate HGT-derived genes.


In vitro field potential monitoring on a multi-microelectrode array for the electrophysiological long-term screening of neural stem cell maturation.
Due to the lack of appropriate cell models as well as automated electrophysiology monitoring technologies, the standardized identification of neurotoxic or protective effects in vitro remains a major problem in today's pharmaceutical ingredient development. Over the past few years, in vivo-like human pluripotent stem cell-derived neuronal networks have turned out to be a promising physiological cell source, if the establishment of robust and time-saving functional maturation strategies based on stable and expandable neural progenitor populations can be achieved. Here, we describe a multi-microelectrode array (MMEA)-based bioelectronics platform that was optimized for long-term electrophysiological activity monitoring of neuronal networks via field potential measurements. Differentiation of small molecule-based neuronal progenitors on MMEAs led to functional neurons within 15 days. More strikingly, these functional neuronal cultures could remain electrophysiologically stable on the MMEAs for more than four weeks. The observed electrophysiological properties correlated with the expression of typical neuron subtype markers and were further validated by specific neurotransmitter applications. With our established monitoring platform, we could show for the first time the long-term stability of the neural stem cell-like progenitor population to differentiate to electrophysiologically active dopaminergic neuronal networks for more than 80 passages. In conclusion, we provide a comprehensive long-term stable field potential monitoring platform based on stem cell-derived human neuronal networks that can be automated and up-scaled for standardized high-content screening applications e.g. in the field of neurotoxic and neuroprotective therapeutics identification.


Cognitive Remediation Therapy for Brain Tumor Survivors with Cognitive Deficits.
Cognitive deficits have been widely observed in patients with primary brain tumors consequent to diagnosis and treatment. Given the early onset and the relatively long survival rate of patients, it seems pertinent to study and refine the techniques used to treat these deficits. The purpose of this article is to discuss cognitive deficits that follow neurosurgical treatment for low-grade gliomas as well as to outline a neuropsychological intervention to treat these deficits, specifically working memory and attention. Cognitive remediation therapy is a neuropsychological intervention that aims to enhance attention, working memory, and executive functioning, thereby diminishing the impact of these deficits on daily functioning. Computerized cognitive remediation training programs facilitate access to treatment through providing online participation. The authors include preliminary results of three participants who have completed the computerized training program as part of an ongoing study that is investigating the efficacy of this program in patients who have undergone treatment for low-grade gliomas. The results so far suggest some improvement in working memory and attention from baseline scores. It is the hope of the present authors to highlight the importance of this treatment in the continuity of care of brain tumor survivors.


Asymmetric division of Drosophila male germline stem cell shows asymmetric histone distribution.
Stem cells can self-renew and generate differentiating daughter cells. It is not known whether these cells maintain their epigenetic information during asymmetric division. Using a dual-color method to differentially label "old" versus "new" histones in Drosophila male germline stem cells (GSCs), we show that preexisting canonical H3, but not variant H3.3, histones are selectively segregated to the GSC, whereas newly synthesized histones incorporated during DNA replication are enriched in the differentiating daughter cell. The asymmetric histone distribution occurs in GSCs but not in symmetrically dividing progenitor cells. Furthermore, if GSCs are genetically manipulated to divide symmetrically, this asymmetric mode is lost. This work suggests that stem cells retain preexisting canonical histones during asymmetric cell divisions, probably as a mechanism to maintain their unique molecular properties.


Stabilization of a molecular water oxidation catalyst on a dye-sensitized photoanode by a pyridyl anchor.
Understanding and controlling the properties of water-splitting assemblies in dye-sensitized photoelectrosynthesis cells is a key to the exploitation of their properties. We demonstrate here that, following surface loading of a [Ru(bpy)3]2+ (bpy = 2,2'-bipyridine) chromophore on nanoparticle electrodes, addition of the molecular catalysts, Ru(bda)(L)2 (bda = 2,2'-bipyridine-6,6'-dicarboxylate) with phosphonate or pyridyl sites for water oxidation, gives surfaces with a 5:1 chromophore to catalyst ratio. Addition of the surface-bound phosphonate derivatives with L = 4-pyridyl phosphonic acid or diethyl 3-(pyridin-4-yloxy)decyl-phosphonic acid, leads to well-defined surfaces but, following oxidation to Ru(III), they undergo facile, on-surface dimerization to give surface-bound, oxo-bridged dimers. The dimers have a diminished reactivity toward water oxidation compared to related monomers in solution. By contrast, immobilization of the Ru-bda catalyst on TiO2 with the 4,4'-dipyridyl anchoring ligand can maintain the monomeric structure of catalyst and gives relatively stable photoanodes with photocurrents that reach to 1.7 mA cm-2 with an optimized, applied bias photon-to-current efficiency of 1.5%.


Evaluation of the coagulation and inflammatory responses in solid organ transplant recipients and donors.
New strategies that modify the coagulation/inflammatory cascades may be applicable to solid organ transplant (SOT) recipients in the treatment of complications. However, data on kinetics of post-SOT cascades are needed before considering these strategies. Prospectively collected pre-transplant serum measurements of inflammatory (high-sensitive C-reactive protein, HS-CRP) and coagulation (d-Dimer, DD; protein C, PC) markers were compared to post-operative (day 1-90) values in deceased-donor liver (DDLT) and renal (DDRT) transplant recipients, living-related renal recipients (LRT) and donors (LRD). A total of 85 SOT were enrolled: 25 DDLT, 32 DDRT/LRT, 28 LRD. HS-CRP increased in all groups, mainly immediate post-SOT and in LRDs. DD had a similar pattern mainly in LRT and LRD. PC increased significantly over time in the DDLT group ( p < 0.01). Compared to those with no complications (infection, rejection or thrombosis), day 30 HS-CRP (p = 0.04) and DD (p = 0.06) were elevated in the DDRT/LRT group with complications; PC was decreased at day 7 (p = 0.04) and day 30 (p = 0.009) in DDLT and DDRT/LRT groups with complications, respectively. In conclusion, activation of the inflammatory/coagulation cascades occurs after SOT and is least pronounced in DDLT. This activation diminishes over time unless transplant complications occur. Our results support further research in approaches to altering these cascades in SOT recipients.


Development of interpretive criteria and quality control limits for macrolide and clindamycin susceptibility testing of Streptococcus pneumoniae.
A six-laboratory collaborative study was conducted to develop MIC and zone diameter quality control limits and interpretive criteria for antimicrobial susceptibility testing of Streptococcus pneumoniae with azithromycin, clarithromycin, dirithromycin, and clindamycin. The MICs of all of the agents plus erythromycin for 302 clinical isolates of pneumococci that had been selected with an emphasis on resistant strains were determined by use of the National Committee for Clinical Laboratory Standards (NCCLS)-recommended broth microdilution procedure. The zone diameters of the isolates were also determined for the same agents except erythromycin by the NCCLS disk diffusion test procedure. Repeated testing of S. pneumoniae ATCC 49619 with different sources and lots of media and disks allowed development of MIC and zone diameter quality control ranges for these agents. Interpretive criteria for the MIC of azithromycin were established and were as follows: susceptible, < or = 0.5 microgram/ml; intermediate, 1 microgram/ml; and resistant, > or = 2 micrograms/ml. The interpretive criteria advocated for the MICs of clarithromycin and clindamycin were as follows: susceptible, < or = 0.25 microgram/ml; intermediate, 0.5 microgram/ml; and resistant, > or = 1 microgram/ml. Comparison of MICs and disk diffusion zone diameters led to the development of interpretive criteria for the zone diameters for azithromycin, clarithromycin, and clindamycin that correlated well with these MIC breakpoints. Testing of this organism collection also led to the reestablishment of the erythromycin MIC breakpoints as being identical to those of clarithromycin, which resulted in equivalent cross-susceptibility and cross-resistance for the three macrolides that are currently marketed in the United States. Thus, the susceptibility of pneumococci to azithromycin and clarithromycin can be predicted accurately by testing only erythromycin in clinical laboratories. This recommendation, as well as the interpretive and quality control criteria that are described, have been accepted by NCCLS and are included in the latest NCCLS susceptibility testing guidelines.


Passive Detection of Atrial Fibrillation Using a Commercially Available Smartwatch.
Atrial fibrillation (AF) affects 34 million people worldwide and is a leading cause of stroke. A readily accessible means to continuously monitor for AF could prevent large numbers of strokes and death. To develop and validate a deep neural network to detect AF using smartwatch data. In this multinational cardiovascular remote cohort study coordinated at the University of California, San Francisco, smartwatches were used to obtain heart rate and step count data for algorithm development. A total of 9750 participants enrolled in the Health eHeart Study and 51 patients undergoing cardioversion at the University of California, San Francisco, were enrolled between February 2016 and March 2017. A deep neural network was trained using a method called heuristic pretraining in which the network approximated representations of the R-R interval (ie, time between heartbeats) without manual labeling of training data. Validation was performed against the reference standard 12-lead electrocardiography (ECG) in a separate cohort of patients undergoing cardioversion. A second exploratory validation was performed using smartwatch data from ambulatory individuals against the reference standard of self-reported history of persistent AF. Data were analyzed from March 2017 to September 2017. The sensitivity, specificity, and receiver operating characteristic C statistic for the algorithm to detect AF were generated based on the reference standard of 12-lead ECG-diagnosed AF. Of the 9750 participants enrolled in the remote cohort, including 347 participants with AF, 6143 (63.0%) were male, and the mean (SD) age was 42 (12) years. There were more than 139 million heart rate measurements on which the deep neural network was trained. The deep neural network exhibited a C statistic of 0.97 (95% CI, 0.94-1.00; P < .001) to detect AF against the reference standard 12-lead ECG-diagnosed AF in the external validation cohort of 51 patients undergoing cardioversion; sensitivity was 98.0% and specificity was 90.2%. In an exploratory analysis relying on self-report of persistent AF in ambulatory participants, the C statistic was 0.72 (95% CI, 0.64-0.78); sensitivity was 67.7% and specificity was 67.6%. This proof-of-concept study found that smartwatch photoplethysmography coupled with a deep neural network can passively detect AF but with some loss of sensitivity and specificity against a criterion-standard ECG. Further studies will help identify the optimal role for smartwatch-guided rhythm assessment.


Characteristics of Emergency Medicine Residency Programs in Colombia.
Emergency medicine (EM) is in different stages of development around the world. Colombia has made significant strides in EM development in the last two decades and recognized it as a medical specialty in 2005. The country now has seven EM residency programs: three in the capital city of Bogotá, two in Medellin, one in Manizales, and one in Cali. The seven residency programs are in different stages of maturity, with the oldest founded 20 years ago and two founded in the last two years. The objective of this study was to characterize these seven residency programs. We conducted semi-structured interviews with faculty and residents from all the existing programs in 2013-2016. Topics included program characteristics and curricula. Colombian EM residencies are three-year programs, with the exception of one four-year program. Programs accept 3-10 applicants yearly. Only one program has free tuition and the rest charge tuition. The number of EM faculty ranges from 2-15. EM rotation requirements range from 11-33% of total clinical time. One program does not have a pediatric rotation. The other programs require 1-2 months of pediatrics or pediatric EM. Critical care requirements range from 4-7 months. Other common rotations include anesthesia, general surgery, internal medicine, obstetrics, gynecology, orthopedics, ophthalmology, radiology, toxicology, psychiatry, neurology, cardiology, pulmonology, and trauma. All programs offer 4-6 hours of protected didactic time each week. Some programs require Advanced Cardiac Life Support, Pediatric Advanced Life Support and Advanced Trauma Life Support, with some programs providing these trainings in-house or subsidizing the cost. Most programs require one research project for graduation. Resident evaluations consist of written tests and oral exams several times per year. Point-of-care ultrasound training is provided in four of the seven programs. As emergency medicine continues to develop in Colombia, more residency programs are expected to emerge. Faculty development and sustainability of academic pursuits will be critically important. In the long term, the specialty will need to move toward certifying board exams and professional development through a national EM organization to promote standardization across programs.


RNA sequencing reveals differential expression of mitochondrial and oxidation reduction genes in the long-lived naked mole-rat when compared to mice.
The naked mole-rat (Heterocephalus glaber) is a long-lived, cancer resistant rodent and there is a great interest in identifying the adaptations responsible for these and other of its unique traits. We employed RNA sequencing to compare liver gene expression profiles between naked mole-rats and wild-derived mice. Our results indicate that genes associated with oxidoreduction and mitochondria were expressed at higher relative levels in naked mole-rats. The largest effect is nearly 300-fold higher expression of epithelial cell adhesion molecule (Epcam), a tumour-associated protein. Also of interest are the protease inhibitor, alpha2-macroglobulin (A2m), and the mitochondrial complex II subunit Sdhc, both ageing-related genes found strongly over-expressed in the naked mole-rat. These results hint at possible candidates for specifying species differences in ageing and cancer, and in particular suggest complex alterations in mitochondrial and oxidation reduction pathways in the naked mole-rat. Our differential gene expression analysis obviated the need for a reference naked mole-rat genome by employing a combination of Illumina/Solexa and 454 platforms for transcriptome sequencing and assembling transcriptome contigs of the non-sequenced species. Overall, our work provides new research foci and methods for studying the naked mole-rat's fascinating characteristics.


The efficacy of absorbable polysaccharide haemostats in wound healing.
Wound healing represents an ancient problem for humans, and various materials and methods have been tried for wound dressing. A dressing should protect against infection and shorten healing; moreover, it should not cause tissue damage and should be nonallergenic, cost effective and easy to apply. These are characteristics that may be found in herbal extracts. An absorbable polysaccharide haemostat (APH) is a plant-based haemostatic agent. We aimed to evaluate the effect of APH on wound healing. A total of 24 Wistar rats were divided into three groups, each consisting of eight rats. We generated triangular tissue defects on the dorsal regions of the rats. The wound size of each rat was drawn on acetate paper on the 3rd, 7th and 14th days and dressed with APH, saline and wheat meal. Wound healing rates were calculated using planimetric software. Scar tissue excision was performed on the 14th day and histopathological examination was carried out. The mean wound contraction rate was statistically higher in the APH group than in the wheat meal and saline groups on the 14th day (P < 0.05). There was no significant difference in polymorphonuclear leukocytes intensity between the saline and APH groups when stained with haematoxylin and eosin (P > 0.05). However, the intensities of fibroblasts (P < 0.01), vascular proliferation (P = 0.01) and inflammatory score (P = 0.02) were significantly different in the saline and APH groups. APH has favourable effect on wound healing. In addition to its blood-stopping effect, APH may be useful for tissue defects, which arise after trauma or surgical procedures.


InterPro protein classification.
Improvements in nucleotide sequencing technology have resulted in an ever increasing number of nucleotide and protein sequences being deposited in databases. Unfortunately, the ability to manually classify and annotate these sequences cannot keep pace with their rapid generation, resulting in an increased bias toward unannotated sequence. Automatic annotation tools can help redress the balance. There are a number of different groups working to produce protein signatures that describe protein families, functional domains or conserved sites within related groups of proteins. Protein signature databases include CATH-Gene3D, HAMAP, PANTHER, Pfam, PIRSF, PRINTS, ProDom, PROSITE, SMART, SUPERFAMILY, and TIGRFAMs. Their approaches range from characterising small conserved motifs that can identify members of a family or subfamily, to the use of hidden Markov models that describe the conservation of residues over entire domains or whole proteins. To increase their value as protein classification tools, protein signatures from these 11 databases have been combined into one, powerful annotation tool: the InterPro database (http://www.ebi.ac.uk/interpro/) (Hunter et al., Nucleic Acids Res 37:D211-D215, 2009). InterPro is an open-source protein resource used for the automatic annotation of proteins, and is scalable to the analysis of entire new genomes through the use of a downloadable version of InterProScan, which can be incorporated into an existing local pipeline. InterPro provides structural information from PDB (Kouranov et al., Nucleic Acids Res 34:D302-D305, 2006), its classification in CATH (Cuff et al., Nucleic Acids Res 37:D310-D314, 2009) and SCOP (Andreeva et al., Nucleic Acids Res 36:D419-D425, 2008), as well as homology models from ModBase (Pieper et al., Nucleic Acids Res 37:D347-D354, 2009) and SwissModel (Kiefer et al., Nucleic Acids Res 37:D387-D392, 2009), allowing a direct comparison of the protein signatures with the available structural information. This chapter reviews the signature methods found in the InterPro database, and provides an overview of the InterPro resource itself.


Method for the discrimination of superficial and deep absorption variations by time domain fNIRS.
A method for the discrimination of superficial and deep absorption variations by time domain functional near infrared spectroscopy is presented. The method exploits the estimate of the photon time-dependent pathlength in different domains of the sampled medium and makes use of an approach based on time-gating of the photon distribution of time-of-flights. Validation of the method is performed in the two-layer geometry to focus on muscle and head applications. Numerical simulations varied the thickness of the upper layer, the interfiber distance, the shape of the instrument response function and the photon counts. Preliminary results from in vivo data are also shown.


Pathobiological implications of MUC16/CA125 expression in intrahepatic cholangiocarcinoma-mass forming type.
MUC16 carries the peptide epitope CA125, which is well known as a marker of ovarian cancer. High serum levels of MUC16 (CA125) have been reported not only in patients with ovarian cancer but also in patients with liver diseases. We evaluated the expression of MUC16 in intrahepatic cholangiocarcinoma-mass forming type (ICC-MF) tissues. We examined the expression of MUC16 by immunohistochemical analyses using the monoclonal antibody M11 in ICC-MF tissues from 63 patients. To compare the prevalence of each mucin expression by clinicopathological features, appropriate statistical analysis was performed. MUC16 was detected in 48% of samples (30/63). After adjusting for the effects of other prognostic factors, multivariate survival analysis revealed that MUC16 expression is a significant independent factor of poor prognosis (p = 0.005). The current results indicate that MUC16 expression is a prognostic factor of poor survival in ICC-MF.


Identification and activation of TLR4-mediated signalling pathways by alginate-derived guluronate oligosaccharide in RAW264.7 macrophages.
Alginate, a natural acidic polysaccharide extracted from marine brown seaweeds, is composed of different blocks of β-(1, 4)-D-mannuronate (M) and its C-5 epimer α-(1, 4)-L-guluronate (G). Alginate-derived guluronate oligosaccharide (GOS) readily activates macrophages. However, to understand its role in immune responses, further studies are needed to characterize GOS transport and signalling. Our results show that GOS is recognized by and upregulates Toll-like receptor 4 (TLR4) on RAW264.7 macrophages, followed by its endocytosis via TLR4. Increased expression of TLR4 and myeloid differentiation protein 2 (MD2) results in Akt phosphorylation and subsequent activation of both nuclear factor-κB (NF-κB) and mechanistic target of rapamycin (mTOR). Moreover, GOS stimulates mitogen-activated protein kinases (MAPKs); notably, c-Jun N-terminal kinase (JNK) phosphorylation depends on TLR4 initiation. All these events contribute to the production of inflammatory mediators, either together or separately. Our findings also reveal that GOS induces cytoskeleton remodelling in RAW264.7 cells and promotes macrophage proliferation in mice ascites, both of which improve innate immunity. Conclusively, our investigation demonstrates that GOS, which is dependent on TLR4, is taken up by macrophages and stimulates TLR4/Akt/NF-κB, TLR4/Akt/mTOR and MAPK signalling pathways and exerts impressive immuno-stimulatory activity.


An innovative and efficient route to the synthesis of metal-based glycoconjugates: proof-of-concept and potential applications.
With a view to developing more efficient strategies to the functionalization of metallodrugs with carbohydrates, we here report on an innovative and efficient synthetic route to generate gold(iii) glycoconjugates in high yields and purity. The method is based on the initial synthesis of the zinc(ii)-dithiocarbamato intermediate [ZnII(SSC-Inp-GlcN)2] (Inp = isonipecotic moiety; GlcN = amino-glucose) followed by the transfer of the glucoseisonipecoticdithiocarbamato ligand to the gold(iii) center via transmetallation reaction between the zinc(ii) intermediate and K[AuIIIBr4] in 1 : 2 stoichiometric ratio, yielding the corresponding glucose-functionalized gold(iii)-dithiocarbamato derivative [AuIIIBr2(SSC-Inp-GlcN)]. No protection/deprotection of the amino-glucose scaffold and no chromatographic purification were needed. The synthetic protocol was optimized for glucose precursors bearing the amino function at either the C2 or the C6 position, and works in the case of both α and β anomers. The application of the synthetic strategy was also successfully extended to other metal ions of biomedical interest, such as gold(i) and platinum(ii), to obtain [AuI(SSC-Inp-GlcN)(PPh3)] and [PtII(SSC-Inp-GlcN)2], respectively. All compounds were fully characterized by elemental analysis, mid- and far-IR, mono- and multidimensional NMR spectroscopy, and, where possible, X-ray crystallography. Results and potential applications are here discussed.


Sparseness of the neuronal representation of stimuli in the primate temporal visual cortex.
1. To analyze the selectivity and the sparseness of firing to visual stimuli of single neurons in the primate temporal cortical visual area, neuronal responses were measured to a set of 68 visual stimuli in macaques performing a visual fixation task. The population of neurons analyzed had responses that occurred primarily to faces. The stimuli included 23 faces, and 45 nonface images of real-world scenes, so that the function of this brain region could be analyzed when it was processing natural scenes. 2. The neurons were selected to meet the previously used criteria of face selectivity by responding more than twice as much to the optimal face as to the optimal nonface stimulus in the set. Application of information theoretic analyses to the responses of these neurons confirmed that their responses contained much more information about which of 20 face stimuli had been seen (on average 0.4 bits) than about which (of 20) nonface stimuli had been seen (on average 0.07 bits). 3. The sparseness of the representation of a scene or object provided by each of these neurons (which can be thought of as the proportion of stimuli to which the neuron responds, and which is fundamental to understanding the network operation of the system) can be defined as [formula: see text] where ri is the firing rate to the ith stimulus in the set of n stimuli. The sparseness has a maximal value of 1.0. It was found that the sparseness of the representation of the 68 stimuli by each neuron had an average across all neurons of 0.65. This indicates a rather distributed representation. 4. If the spontaneous firing rate was subtracted from the firing rate of the neuron to each stimulus, so that the changes of firing rate, i.e., the responses of the neurons, were used in the sparseness calculation, then the "response sparseness" had a lower value, with a mean of 0.33 for the population of neurons, or 0.60 if calculated over the set of faces. 5. Multidimensional scaling to produce a stimulus space represented by this population of neurons showed that the different faces were well separated in the space created, whereas the different nonface stimuli were grouped together in the space. 6. The information analyses and multidimensional scaling provided evidence that what was made explicit in the responses of these neurons was information about which face had been seen.(ABSTRACT TRUNCATED AT 400 WORDS)


Quantitative evaluation of local drug delivery using the InfusaSleeve catheter.
Restenosis is the most common long-term complication after angioplasty. Local delivery of pharmacologic agents at the site of angioplasty holds promise as a means of achieving higher concentrations of drug in the arterial wall than can be obtained by systemic infusion. In this study, a novel local drug delivery catheter system, the InfusaSleeve catheter, was evaluated in a porcine coronary balloon injury model. The purpose of the study was to evaluate the efficacy of solute transfer to the arterial wall and the influence of varying supporting angioplasty balloon pressure. Ten pigs (total of 22 arterial segments) underwent overstretch balloon injury (artery/balloon ratio 1:1.29) with a standard angioplasty balloon. In 7 animals (16 arterial segments) horseradish peroxidase (HRP; 10 mg/ml) was administered locally after injury, by tracking the local infusion catheter as a sheath over the angioplasty balloon to the intended site of arterial drug delivery. Supporting angioplasty balloons were inflated to one of the three different pressures. In 3 pigs HRP (10 mg/ml) was administered intravenously. No significant arterial injury caused by the local delivery device was evident on histological examination (disruption of the internal lamina elastica, arterial media, or thrombosis). Radial concentrations of the HRP reaction product in the first 150 microns of the arterial wall were quantified against known standards by measurement of light transmission through tissue sections. Mean HRP concentrations were not significantly different from those obtained by intravenous infusion using a supporting pressure of 1 atm or a supporting pressure of 3 atm of the underlying angioplasty balloon. However, a supporting pressure of 6 atm resulted in a 6-fold greater mean HRP concentration in the arterial wall than that which could be achieved by systemic administration of an equal volume of tracer (P < 0.001). Thus solute can be delivered throughout the coronary media by the InfusaSleeve, with the magnitude of wall uptake related to support pressure. Local delivery at 6 atm support pressure produced substantially greater uptake than did systemic delivery.


Utility of the 5-Minute Apgar Score as a Research Endpoint.
Although Apgar scores are commonly used as proxy outcomes, little evidence exists in support of the most common cutpoints (<7, <4). We used 2 data sets to explore this issue: one contained planned community births from across the United States (n = 52,877; 2012-2016), and the other contained hospital births from California (n = 428,877; 2010). We treated 5-minute Apgars as clinical "tests," compared against 18 known outcomes; we calculated sensitivity, specificity, positive and negative predictive values, and the area under the receiver operating characteristic curve for each. We used 3 different criteria to determine optimal cutpoints. Results were very consistent across data sets, outcomes, and all subgroups: The cutpoint that maximizes the trade-off between sensitivity and specificity is universally <9. However, extremely low positive predictive values for all outcomes at <9 indicate more misclassification than is acceptable for research. The areas under the receiver operating characteristic curves (which treat Apgars as quasicontinuous) were generally indicative of adequate discrimination between infants destined to experience poor outcomes and those not; comparing median Apgars between groups might be an analytical alternative to dichotomizing. Nonetheless, because Apgar scores are not clearly on any causal pathway of interest, we discourage researchers from using them unless the motivation for doing so is clear.


Biochemical and antigenic comparison of the envelope glycoproteins of Venezuelan equine encephalomyelitis virus strains.
Pulse-chase experiments after synchronous initiation of translation indicate that the larger Venzuelan equine encephalomyelitis (VEE) virus membrane glycoprotein E2, is derived by proteolytic cleavage of the precursor, PE2. The structural proteins of VEE virus strains representing each of the antigenic subtypes and varieties have been compared by discontinuous SDS-polyacrylamide gel electrophoresis. Nucleocapsid proteins of all isolates were similar in size (mol. wt. 35 to 36 X 10(3). The mol. wt. of E1 varied from 48 to 51 X 10(3) and the mol. wt. of E2 glycoproteins ranged from 53 to 59 X 10(3). Pixuna virus contained a third envelope glycoprotein of 59 X 10(3) mol. wt. in addition to the two major glycoproteins of mol. wt. 53 X 10(3) and 48 X 10(3) respectively. The isoelectric points (pI) of E1 and E2 for all VEE strains studied were approx. 7 and 9 respectively. Both glycoproteins of TC-83 virus induced precipitating antibodies which reacted only with the homologous purified E1 and E2 glycoproteins. Antibodies to E2 protein of each virus neutralized virus infectivity and inhibited the agglutination of goose erythrocytes by virions. Haemagglutination-inhibition tests using antisera to E2 glycoproteins of prototype viruses, representing each of the antigenic subtypes and varieties, differentiated the viruses into subtypes I, II, III and IV with subtype I divided into variants 1AB, 1C, 1D and 1E.


Third-wave cognitive behaviour therapies for weight management: systematic review and network meta-analysis protocol.
Behavioural and cognitive behavioural programmes are commonly used to assist with weight management, but there is considerable scope to improve their effectiveness, particularly in the longer term. Third-wave cognitive behaviour therapies (CBTs) have this potential and are increasingly used. This systematic review will assess the effect of third-wave CBTs for weight management on weight, psychological and physical health outcomes in adults with overweight or obesity. The systematic review will be reported according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidance. We will include studies of any third-wave CBTs focusing on weight loss or weight maintenance for adults with a body mass index (BMI) ≥25kg/m2. Eligible study designs will be randomised control trials, non-randomised trials, prospective cohort and case series. Outcomes of interest will be body weight/BMI, psychological and physical health, and adherence. We will search the following databases from inception to 16 January 2018: MEDLINE, CINAHL, Embase, Cochrane database (CENTRAL), PsycINFO, AMED, ASSIA and Web of Science. The search strategy will be based on the concepts: (1) third-wave CBTs and (2) overweight, obesity or weight management. No restrictions will be applied. We will search reference lists of relevant reviews and included articles. Two independent reviewers will screen articles for eligibility using a two-stage process. Two independent reviewers will extract data, assess risk of bias using Risk of Bias 2.0, Risk of Bias in Non-randomised studies of Interventions or Risk of Bias in Non-randomised Studies of Exposures checklist and assess quality using the Grading of Recommendations Assessment, Development and Evaluation tool. A random-effects network meta-analysis of outcomes, and sub-group analyses and meta-regression will be conducted, where data permit. If not appropriate, a narrative synthesis will be undertaken. Ethical approval is not required as no primary data will be collected. The completed systematic review will be disseminated in a peer-reviewed journal, presented at conferences and used to inform the development of a weight management programme. CRD42018088255.


The effects of cultural learning in populations of neural networks.
Population learning can be described as the iterative Darwinian process of fitness-based selection and genetic transfer of information leading to populations of higher fitness and is often simulated using genetic algorithms. Cultural learning describes the process of information transfer between individuals in a population through non-genetic means. Cultural learning has been simulated by combining genetic algorithms and neural networks using a teacher-pupil scenario where highly fit individuals are selected as teachers and instruct the next generation. By examining the innate fitness of a population (i.e., the fitness of the population measured before any cultural learning takes place), it is possible to examine the effects of cultural learning on the population's genetic makeup. Our model explores the effect of cultural learning on a population and employs three benchmark sequential decision tasks as the evolutionary task for the population: connect-four, tic-tac-toe, and blackjack. Experiments are conducted with populations employing population learning alone and populations combining population and cultural learning. The article presents results showing the gradual transfer of knowledge from genes to the cultural process, illustrated by the simultaneous decrease in the population's innate fitness and the increase of its acquired fitness measured after learning takes place.