bluuebunny/crossref_metadata_2025 huggingface dataset:
From Pediatric Covariate Model to Semiphysiological Function for Maturation: Part II—Sensitivity to Physiological and Physicochemical Properties
Authors: Krekels EHJ , Johnson TN , den Hoedt SM , Rostami‐Hodjegan A , Danhof M , Tibboel D , Knibbe CAJ
Published: January 2013

To develop a maturation function for drug glucuronidation in children, that can be used in population and physiologically based modeling approaches, the physiological and physicochemical basis of a semiphysiological glucuronidation function for children was untangled using Simcyp. The results show that using the currently available in vitro data, in vivo morphine and zidovudine clearances were under predicted by the physiologically based model in Simcyp. The maturation profile was similar to the clinically observed profile except for the first 2 weeks of life, and liver size and UGT2B7 ontogeny are the physiological drivers of the maturation of glucuronidation. Physicochemical drug parameters did not affect this maturation profile, although log P and pKa influenced the absolute value of clearance. The results suggest that the semiphysiological glucuronidation function for young children can be used to predict the developmental clearance profile of other UGT2B7 substrates, though scenarios with nonlinear kinetics and high‐extraction ratios require further investigation.

CPT: Pharmacometrics & Systems Pharmacology (2012) 1, e10; doi:10.1038/psp.2012.12; advance online publication 10 October 2012
Mitochondrial (dys)function and regulation of macrophage cholesterol efflux
Authors: Allen Anne Marie , Taylor Janice M. W. , Graham Annette
Published: January 2013

Cholesterol trafficking from the outer to the cholesterol-poor inner mitochondrial membrane requires energized, polarized and actively respiring mitochondria, mediated by a highly regulated multimeric (140–200 kDa) protein complex comprising StAR (steroidogenic acute regulatory protein), mitochondrial TSPO (translocator protein), VDAC (voltage-dependent anion channel), ANT (adenine nucleotide transporter) and associated regulatory proteins. Mitochondrial cholesterol transport is rate-limiting in the CYP27A1 (sterol 27-hydroxylase)-dependent generation of oxysterol ligands for LXR (liver X receptor) transcription factors that regulate the expression of genes encoding proteins in the cholesterol efflux pathway, such as ABC transporters (ATP-binding cassette transporters) ABCA1 and ABCG1. These transporters transfer cholesterol and/or phospholipids across the plasma membrane to (apo)lipoprotein acceptors, generating nascent HDLs (high-density lipoproteins), which can safely transport excess cholesterol through the bloodstream to the liver for excretion in bile. Utilizing information from steroidogenic tissues, we propose that perturbations in mitochondrial function may reduce the efficiency of the cholesterol efflux pathway, favouring accumulation of cholesteryl ester ‘foam cells’ and allowing the toxic accumulation of free cholesterol at the interface between the endoplasmic reticulum and the mitochondrial membrane. In turn, this will trigger opening of the permeability transition pore, allowing unregulated production of oxysterols via CYP27A1, allowing the accumulation of esterified forms of this oxysterol within human atherosclerotic lesions. Defective cholesterol efflux also induces endoplasmic reticulum stress, proteasomal degradation of ABCA1 and Fas-dependent apoptosis, replicating findings in macrophages in advanced atherosclerotic lesions. Small molecules targeted to mitochondria, capable of sustaining mitochondrial function or improving cholesterol trafficking may aid cholesterol efflux from macrophage ‘foam’ cells, regressing and stabilizing the atherosclerotic plaque.
Role of AMP-activated protein kinase in adipose tissue metabolism and inflammation
Authors: Bijland Silvia , Mancini Sarah J. , Salt Ian P.
Published: January 2013

AMPK (AMP-activated protein kinase) is a key regulator of cellular and whole-body energy balance. AMPK phosphorylates and regulates many proteins concerned with nutrient metabolism, largely acting to suppress anabolic ATP-consuming pathways while stimulating catabolic ATP-generating pathways. This has led to considerable interest in AMPK as a therapeutic target for the metabolic dysfunction observed in obesity and insulin resistance. The role of AMPK in skeletal muscle and the liver has been extensively studied, such that AMPK has been demonstrated to inhibit synthesis of fatty acids, cholesterol and isoprenoids, hepatic gluconeogenesis and translation while increasing fatty acid oxidation, muscle glucose transport, mitochondrial biogenesis and caloric intake. The role of AMPK in the other principal metabolic and insulin-sensitive tissue, adipose, remains poorly characterized in comparison, yet increasing evidence supports an important role for AMPK in adipose tissue function. Obesity is characterized by hypertrophy of adipocytes and the development of a chronic sub-clinical pro-inflammatory environment in adipose tissue, leading to increased infiltration of immune cells. This combination of dysfunctional hypertrophic adipocytes and a pro-inflammatory environment contributes to insulin resistance and the development of Type 2 diabetes. Exciting recent studies indicate that AMPK may not only influence metabolism in adipocytes, but also act to suppress this pro-inflammatory environment, such that targeting AMPK in adipose tissue may be desirable to normalize adipose dysfunction and inflammation. In the present review, we discuss the role of AMPK in adipose tissue, focussing on the regulation of carbohydrate and lipid metabolism, adipogenesis and pro-inflammatory pathways in physiological and pathophysiological conditions.
Dithienylbenzothiadiazole-Based Donor-Acceptor Organic Semiconductors and Effect of End Capping Groups on Organic Field Effect Transistor Performance
Authors: Sonar Prashant , Singh Samarendra P. , Lin Ting Ting , Dodabalapur Ananth
Published: January 2013

Donor-Acceptor-Donor (D-A-D) based conjugated molecules 4,7-bis(5-(4-butoxyphenyl)thiophen-2-yl)benzo[c][1,2,5]thiadiazole (BOP-TBT) and 4,7-bis(5-(4-trifluoromethyl)phenyl)thiophen-2-yl)benzo[c][1,2,5]thiadiazole (TFP-TBT) using thiophene-benzothiadiazole-thiophene central core with trifluoromethyl phenyl and butoxyphenyl end capping groups were designed and synthesised via Suzuki coupling. Optical, electrochemical, thermal, and organic field effect transistor (OFET) device properties of BOP-TBT and TFP-TBT were investigated. Both small molecules possess two absorption bands. Optical band gaps were calculated from the absorption cut off to be in the range of 2.06–2.25 eV. Cyclic voltammetry indicated reversible oxidation and reduction processes and the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO) energy levels were calculated to be in the range of 5.15–5.40 eV and 3.25–3.62 eV, respectively. Upon testing both materials for OFET, trifluoromethylphenyl end capped material (TFP-TBT) shows n-channel behaviour whereas butoxyphenyl end capped material (BOP-TBT) shows p-channel behaviour. Density functional theory calculations correlated with shifting of HOMO-LUMO energy levels with respect to end capping groups. Vacuum processed OFET of these materials have shown highest hole carrier mobility of 0.02 cm2/Vs and electron carrier mobility of 0.004 cm2/Vs, respectively using Si/SiO2 substrate. By keeping the central D-A-D segment and just by tuning end capping groups gives both p- and n-channel organic semiconductors which can be prepared in a single step using straightforward synthesis.
Silica Immobilized Hoveyda Type Pre-Catalysts: Convenient and Reusable Heterogeneous Catalysts for Batch and Flow Olefin Metathesis
Authors: Solodenko Wladimir , Doppiu Angelino , Frankfurter René , Vogt Carla , Kirschning Andreas
Published: January 2013

Two Hoveyda type ruthenium metathesis precatalysts, Umicore M51 and Umicore M71 SIMES, were immobilized on commercial silica in a simple and fast procedure through direct interaction with the support surface. These precatalysts exhibited good activity in ring-closing, cross, and enyne metathesis reactions and were stable in terms of reusability to be used for consecutive runs under both batch and flow conditions. In non-polar media, the catalytic activity of the precatalysts is truly based on a heterogeneous species, and the contamination of the products with ruthenium was very low with respect to starting catalyst (0.003–0.01 %; 0.13–0.44 ppm). If necessary, such as in solvents like toluene, the ruthenium content can easily be reduced to levels below 0.5 ppm by treatment of the crude metathesis products with the commercial scavenger QuadraSil AP or by use of an additional QuadraSil AP scavenger cartridge under flow conditions.
BroadPeak: a novel algorithm for identifying broad peaks in diffuse ChIP-seq datasets
Authors: Wang Jianrong , Lunyak Victoria V. , Jordan I. King
Published: January 2013

Summary: Although some histone modification chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-seq) signals show abrupt peaks across narrow and specific genomic locations, others have diffuse distributions along chromosomes, and their large contiguous enrichment landscapes are better modeled as broad peaks. Here, we present BroadPeak, an algorithm for the identification of such broad peaks from diffuse ChIP-seq datasets. We show that BroadPeak is a linear time algorithm that requires only two parameters, and we validate its performance on real and simulated histone modification ChIP-seq datasets. BroadPeak calls peaks that are highly coincident with both the underlying ChIP-seq tag count distributions and relevant biological features, such as the gene bodies of actively transcribed genes, and it shows superior overall recall and precision of known broad peaks from simulated datasets.

Availability: The source code and documentations are available at http://jordan.biology.gatech.edu/page/software/broadpeak/.

Contact:  king.jordan@biology.gatech.edu

Supplementary information:  Supplementary data are available at Bioinformatics online.
An ensemble analysis to predict future habitats of striped marlin (Kajikia audax) in the North Pacific Ocean
Authors: Su Nan-Jay , Sun Chi-Lu , Punt André E. , Yeh Su-Zan , DiNardo Gerard , Chang Yi-Jay
Published: January 2013

Su, N.-J., Sun, C.-L., Punt, A. E., Yeh, S.-Z., DiNardo, G., and Chang, Y.-J. 2013. An ensemble analysis to predict future habitats of striped marlin (Kajikia audax) in the North Pacific Ocean. – ICES Journal of Marine Science, 70: 1013–1022. Striped marlin is a highly migratory species distributed throughout the North Pacific Ocean, which shows considerable variation in spatial distribution as a consequence of habitat preference. This species may therefore shift its range in response to future changes in the marine environment driven by climate change. It is important to understand the factors determining the distribution of striped marlin and the influence of climate change on these factors, to develop effective fisheries management policies given the economic importance of the species and the impact of fishing. We examined the spatial patterns and habitat preferences of striped marlin using generalized additive models fitted to data from longline fisheries. Future distributions were predicted using an ensemble analysis, which represents the uncertainty due to several global climate models and greenhouse gas emission scenarios. The increase in water temperature driven by climate change is predicted to lead to a northward displacement of striped marlin in the North Pacific Ocean. Use of a simple predictor of water temperature to describe future distribution, as in several previous studies, may not be robust, which emphasizes that variables other than sea surface temperatures from bioclimatic models are needed to understand future changes in the distribution of large pelagic species.
How Much Is Minnesota Like Wisconsin? Assumptions and Counterfactuals in Causal Inference with Observational Data
Authors: Keele Luke , Minozzi William
Published: January 2013

Political scientists are often interested in estimating causal effects. Identification of causal estimates with observational data invariably requires strong untestable assumptions. Here, we outline a number of the assumptions used in the extant empirical literature. We argue that these assumptions require careful evaluation within the context of specific applications. To that end, we present an empirical case study on the effect of Election Day Registration (EDR) on turnout. We show how different identification assumptions lead to different answers, and that many of the standard assumptions used are implausible. Specifically, we show that EDR likely had negligible effects in the states of Minnesota and Wisconsin. We conclude with an argument for stronger research designs.
Transgenic Enhancement of High‐Molecular‐Weight Glutenin Subunit 1Dy10 Concentration: Effects in Wheat Flour Blends and Sponge and Dough Baking
Authors: Graybosch Robert A. , Seabourn Bradford , Chen Yuanhong R. , Blechl Ann E.
Published: January 2013

Dough strength is needed for efficient breadmaking quality. This property is strongly influenced in wheat (Triticum aestivum L.) by gluten seed storage proteins and, in particular, by high‐molecular‐weight (HMW) glutenin subunit composition. Experiments were designed to elevate expression of a key native HMW glutenin subunit (1Dy10) via genetic engineering and to determine whether resultant flours can be used in sponge and dough applications, the most common commercial bread‐baking procedure. Both unblended and blended samples from transgenic and nontransgenic sister lines were tested, with blended samples being formed by addition to a control sample. Dough properties, as determined by farinograph evaluation, were improved by the transgene‐encoded increases in 1Dy10 in both undiluted and blended flours. Mean farinograph stability of transgenic samples was twice that of the control, and blends with transgenic samples demonstrated increases in stabilities proportional to the amount of transgenic flour included. Mean farinograph quality numbers of transgenic samples, and of all blends containing transgenic flour, were significantly higher than both the control and all nontransgenic treatments. In the sponge and dough bake procedure, undiluted transgenic samples induced lower scores, relative to both control and undiluted nontransgenic samples, for water absorption, crumb body firmness, and loaf volume. In blends, however, the transgenic samples resulted in improvements in some sponge and dough loaf attributes, including loaf symmetry and crumb color score, without any concomitant loss of loaf volume in transgenic blends. These improved variables relate to finished product appearance and to consumer selection in markets. The use of transgenic flours with increased 1Dy10 glutenin content in commercial blends could provide advantages in sponge and dough bake applications.
Host Cell Ploidy Underlying the Fungal Feeding Site Is a Determinant of Powdery Mildew Growth and Reproduction
Authors: Chandran Divya , Rickert Joshua , Cherk Candice , Dotson Bradley R. , Wildermuth Mary C.
Published: January 2013

Golovinomyces orontii is an obligate biotrophic powdery mildew (PM) that colonizes Arabidopsis thaliana and agronomic species. It establishes a specialized feeding structure in epidermal cells to fuel its extensive surface hyphal growth and reproduction. Previously, endoreduplication was identified in Arabidopsis mesophyll cells underlying the fungal feeding site, presumably to meet the metabolic demands imposed by the fungus. Furthermore, the cell cycle transcription factor MYB3R4 was shown to regulate this process. Herein, PM-induced endoreduplication is further characterized and three additional factors influencing host ploidy in cells underlying the fungal feeding site are identified. While mutations in PUX2 and PMR6 reduce basal ploidy, mutations in PMR5 (and MYB3R4) abrogate the PM-induced ploidy increase. Moreover, analysis of pmr5 microarray data suggests that PMR5 acts upstream of a MYB3R transcription factor such as MYB3R4 to control PM-induced ploidy. Induced endoreduplication occurs exclusively in mesophyll cells underlying the fungal feeding site at 5 days postinoculation, concomitant with PM reproduction. Gene copy number increases and chromatin remains decondensed, suggesting active, elevated gene expression. Cell ploidy underlying the fungal feeding site is highly correlated with the extent of PM growth and reproduction for these mutants, indicating that (induced) mesophyll cell ploidy is a PM susceptibility determinant.
Developing a Real-Time PCR Assay for Detection and Quantification ofPratylenchus neglectusin Soil
Authors: Yan Guiping , Smiley Richard W. , Okubara Patricia A. , Skantar Andrea M. , Reardon Catherine L.
Published: January 2013

Pratylenchus neglectus is one of the most widespread and economically important nematodes that invades plant roots and restricts wheat productivity in the Pacific Northwest. It is challenging to quantify P. neglectus using microscopic methods for studies that require large-scale sampling, such as assessment of rotation crops, wheat cultivars, and other management practices. A real-time quantitative polymerase chain reaction (qPCR) assay was developed to detect and quantify P. neglectus from DNA extracts of soil. The primers, designed from the internal transcribed spacer region of rDNA, showed high specificity with a single melt curve peak to DNA from eight isolates of P. neglectus but did not amplify DNA from 28 isolates of other plant-parasitic and non-plant-parasitic nematodes. A standard curve (R2= 0.96; P < 0.001) was generated by amplifying DNA extracted from soil to which nematodes were added. The soil standard curve was validated using sterilized soil inoculated with lower numbers of P. neglectus. A significant positive relationship (R2= 0.66; P < 0.001) was observed for nematode numbers quantified from 15 field soils using qPCR and the Whitehead tray and microscopic method but the qPCR generally tended to provide higher estimates. Real-time PCR potentially provides a useful platform for efficient detection and quantification of P. neglectus directly from field soils.
Pathogenicity and Virulence of Pythium Species Obtained from Forest Nursery Soils on Douglas-Fir Seedlings
Authors: Weiland Jerry E. , Beck Bryan R. , Davis Anne
Published: January 2013

Pythium species are common soilborne oomycetes that occur in forest nursery soils throughout the United States. Numerous species have been described from nursery soils. However, with the exception of P. aphanidermatum, P. irregulare, P. sylvaticum, and P. ultimum, little is known about the potential for other Pythium species found in nursery soils to cause damping-off of tree seedlings. A greenhouse study was conducted to evaluate the pathogenicity and virulence of 44 Pythium isolates representing 16 species that were originally recovered from soil at three forest nurseries in Washington and Oregon. Seeds of Douglas-fir (Pseudotsuga menziesii) were planted into soil infested with each of the isolates. Seedling survival, the number of surviving seedlings with necrotic root lesions, and taproot length were evaluated 4 weeks later. Responses of Douglas-fir to inoculation varied significantly depending on Pythium species and isolate. Eight species (P. dissotocum, P. irregulare, P. aff. macrosporum, P. mamillatum, P. aff. oopapillum, P. rostratifingens, P. sylvaticum, and P. ultimum var. ultimum) significantly reduced the number of surviving seedlings compared to the noninoculated treatment. However, all Pythium species caused a greater percentage of seedlings to develop root lesions (total mean 40%) than was observed from noninoculated seedlings (17%). Taproot length varied little among Pythium treatments and was not a useful character for evaluating pathogenicity. Results confirm the ability of P. irregulare, P. mamillatum, and P. ultimum var. ultimum to cause damping-off of Douglas-fir seedlings, and are indicative that other species such as P. dissotocum, P. aff. macrosporum, P. aff. oopapillum, P. rostratifingens, and P. sylvaticum may also be responsible for seedling loss.
How the bat got its buzz
Authors: Ratcliffe John M. , Elemans Coen P. H. , Jakobsen Lasse , Surlykke Annemarie
Published: January 2013

Since the discovery of echolocation in bats, the final phase of an attack on a flying insect, the ‘terminal buzz’, has proved enigmatic. During the buzz, bats increase information update rates by producing vocalizations up to 220 times s
−1
. The buzz's ubiquity in hawking and trawling bats implies its importance for hunting success. Superfast muscles, previously unknown in mammals, are responsible for the extreme vocalization rate. Some bats produce a second phase—buzz II—defined by a large drop in the fundamental frequency (
F
0
) of their calls. By doing so, bats broaden their acoustic field of view and should thereby reduce the likelihood of insect escape. We make the case that the buzz was a critical adaptation for capturing night-flying insects, and suggest that the drop in
F
0
during buzz II requires novel, unidentified laryngeal mechanisms in order to counteract increasing muscle tension. Furthermore, we propose that buzz II represents a countermeasure against the evasive flight of eared prey in the evolutionary arms-race that saw the independent evolution of bat-detecting ears in various groups of night-flying insects.
Closed-form solutions for the effective conductivity of two-phase periodic composites with spherical inclusions
Authors: To Q. D. , Bonnet G. , To V. T.
Published: January 2013

In this paper, we use approximate solutions of Nemat-Nasser
et al.
to estimate the effective conductivity of two-phase periodic composites with non-overlapping spherical inclusions. Systems with different inclusion distributions are considered: cubic lattice distributions (simple cubic, body-centred cubic and face-centred cubic) and random distributions. The effective conductivities of the former are obtained in closed form and compared with exact solutions from the fast Fourier transform-based methods. For systems containing randomly distributed spherical inclusions, the solutions are shown to be directly related to the static structure factor, and we obtain its analytical expression in the infinite-volume limit.
Thermodynamic theory of nonlinear ultrasound in soft biological tissue
Authors: Vilensky Gregory G.
Published: January 2013

A new theoretical model of ultrasound propagation in soft biological media is presented based on an extended thermodynamics formalism. The long-standing experimental conjecture claiming that a continuous distribution of internal degrees of freedom can be used to model ultrasound in biological media is given theoretical justification. A strategy to derive a well-defined set of equations coupling the balance equations of mass, momentum, energy and entropy with relaxation kinetics of a medium characterized by a continuous distribution of internal states is presented. We demonstrate that new phenomenological coefficients of the proposed governing equations can be extracted directly from experimental data. Our theory successfully explains the anomalous attenuation law found in experiments with biological media that is inconsistent with the conventional models using a finite number of internal degrees of freedom. The results presented offer new possibilities for medical applications of high-intensity ultrasound and ultrasound emission methods to study matter with complex internal structure. These techniques include using pressure relaxation methods for accurate investigation of fast protein folding and a variety of other applications for media where irreversible thermodynamic simulations are essential.
The impact of host species and vector control measures on the fitness of African malaria vectors
Authors: Lyimo Issa N. , Haydon Daniel T. , Russell Tanya L. , Mbina Kasian F. , Daraja Ally A. , Mbehela Edgar M. , Reeve Richard , Ferguson Heather M.
Published: January 2013

Many malaria vector mosquitoes in Africa have an extreme preference for feeding on humans. This specialization allows them to sustain much higher levels of transmission than elsewhere, but there is little understanding of the evolutionary forces that drive this behaviour. In Tanzania, we used a semi-field system to test whether the well-documented preferences of the vectors,
Anopheles arabiensis
and
Anopheles gambiae
sensu stricto
(s.s.) for cattle and humans, respectively, are predicted by the fitness they obtain from host-seeking on these species relative to other available hosts. Mosquito fitness was contrasted, when humans were fully exposed and when they were protected by a typical bednet. The fitness of both vectors varied between host species. The predicted relationship between host preference and fitness was confirmed in
An. arabiensis
, but not in
An. gambiae
s.s., whose fitness was similar on humans and other mammals. Use of typical, imperfect bednets generated only minor reductions in
An. gambiae
s.s. feeding success and fitness on humans, but was predicted to generate a significant reduction in the lifetime reproductive success of
An. arabiensis
on humans relative to cows. This supports the hypothesis that such human-protective measures could additionally benefit malaria control by increasing selection for zoophily in vectors.
The Design of R&D Support Schemes for Industry
Authors: Thomson Russell , Webster Elizabeth
Published: January 2013

Scant discussion exists in the literature about the relative design merits of various R&D schemes, and most authors treat programme design as a black box. In this article, we assess the design features of three major forms of R&D support: entitlement schemes, competitive grant schemes and industry R&D boards. We use a combination of evidence to comment on how well these schemes perform in terms of firm engagement (how does the scheme recruit business interest?), project selection (what criteria are used and who selects the projects?), payment structure (how is financial support structured?) and administrative costs (what is the burden?).
Does Multiculturalism Pay? Empirical Evidence from the United States and Canada
Authors: Ratna Nazmun N. , Grafton Quentin , MacDonald Ian A.
Published: January 2013

We investigate the economic impacts of social diversity and the consequent barriers of communication in Canada and the United States. Social diversity is explained by linguistic, cultural and religious differences across the 48 contiguous states in the United States and the 10 provinces in Canada. The ordinary least squares (OLS) and instrumental variables estimation show that social diversity increases per capita gross domestic product at the state and province level, but the positive economic pay‐off from diversity diminishes as the level of fluency in official language declines. The empirical results provide an important economic rationale for overcoming linguistic divisions and “inclusive” multiculturalism in other pluralistic countries, such as Australia.
An Uneven Playing Field: Rankings and Ratings for Economics in ERA 2010
Authors: Bloch Harry
Published: January 2013

In the evaluation of research quality conducted under Excellence in Research for Australia 2010, the sub‐disciplines of econometrics and theory were rated more highly than the sub‐disciplines of applied economics and other economics. The rating in each sub‐discipline was benchmarked against a world standard, so the results suggest that Australian economists produce relatively better econometric or theory research than applied or other economics research. However, closer examination of the processes on which the ratings were based suggests built‐in biases that favour theory and econometric research over applied and other economics research, leaving the relative quality of research in the various sub‐disciplines open to question.
Cyclicality of Shadow Economy
Authors: Elgin Ceyhun
Published: January 2013

This article investigates the behaviour of the size of the shadow economy over the business cycle. To this end, it uses a panel dataset of 152 countries and finds strong evidence towards the counter‐cyclicality of the informal sector size, that is, the size of the shadow economy as a ratio of gross domestic product (GDP) is reduced in booms and becomes bigger in busts. Empirical results are robust to different econometric specifications. This has serious consequences over the business cycle as it implies that the presence of the shadow economy increases the amplitude of the business cycles.
Clinical impact of the publication of S3 guidelines for intensive care in cardiac surgery patients in Germany: results from a postal survey
Authors: KASTRUP M. , CARL M. , SPIES C. , SANDER M. , MARKEWITZ A. , SCHIRMER U.
Published: January 2013

Introduction

The development and implementation of practice guidelines might be an important tool to evaluate the different practices and to consider different local strategies.

Methods

A postal questionnaire with 37 questions was sent to the leading physicians of 80 intensive care units in Germany, treating patients after cardiothoracic surgery. The survey covered the same core questions on current practice of hemodynamic monitoring, volume replacement, inotropic/vasopressor support, and transfusions before and after the publication of an S3 guideline.

Results

A total of 77.5 % of the completed questionnaires were returned. Monitoring changed to increased use of central venous oxygen saturation (ScvO2) in 55.1% (2005: 20.9%), end‐tidal CO2‐monitoring 36.2% (2005: 24.3%), and decreased use of the left atrial pressure with 12.3% (2005: 23.3%) and pulmonary artery catheter 47.5% (2005: 58.2%). For volume therapy, there is a decreased use of Hydroxyethyl starch (HES) with 38.7% (2005: 63.4%) and an increased use of crystalloids 41.9% (2005: 22.4%). For inotropes, there is a trend to a decreased use of dopamine with 9.7% (2005: 29.1%, P = 0.074). The clinical relevance of the guidelines was judged ‘high’ by 43.5% and ‘medium’ by 50% of the responding physicians; however, change of treatments was reported by one quarter of respondents.

Conclusion

Despite ongoing variability in the use of monitoring devices, volume replacement and vasopressor/inotrope use in cardiac surgery patients, there have been some changes in the therapy of these patients after publication of the guidelines. Because the guideline has been considered as clinically relevant, further interdisciplinary development and implementation support should be considered.
Fibrosis Progression in HCV Carriers with Mild Hepatitis Who Possess the High‐Repetition Variant of the DRD4 Gene, a Genetic Marker for Binge‐Drinking and Risk‐Seeking Behavior: A Longitudinal Study
Authors: Minisini Rosalba , Boccato Elisa , Favretto Serena , Alaimo Emanuele , Smirne Carlo , Burlone Michela E. , Bocchetta Simone , Vandelli Carmen , Colletta Cosimo , Colletta Alessandro , Pirisi Mario
Published: January 2013

Background

Alcohol is a major determinant of the outcome of chronic hepatitis C virus (HCV) infection, but self‐reported drinking habits lack reliability. We hypothesized that carriage of high‐repetition variants (HRV) of the variable number of tandem repeats (VNTR) in exon III of the dopamine receptor D4 gene, linked to binge‐drinking and risk‐seeking behavior, might be a proxy measure of alcohol consumption, and aimed to verify whether it may affect histologic outcome.

Methods

A cohort of HCV patients with normal or near‐normal aminotransferases (N = 128) underwent a liver biopsy as part of diagnostic work‐up. None admitted to exceed low‐risk alcohol consumption; most (90/128, 70%) described themselves as teetotalers. They received advice on abstaining from alcohol, but not antiviral treatment. After a median follow‐up period of 10 years, all underwent a second liver biopsy. HRV allele frequencies were compared with those of a group of healthy blood donors (N = 128) and related to liver histology.

Results

HRV allele frequencies were 0.19 in patients and 0.16 in controls (p = 0.182). In the subgroup of patients who admittedly had consumed alcohol, 20/38 (53%) carried HRV, in comparison with 27/90 patients (30%) who had denied to consume alcohol (p = 0.026 by Fisher's exact test). Carriage of HRV was associated with higher histologic grade (p = 0.002) and stage (p = 0.009) at the final biopsy. At multivariate analysis, among a set of variables also including viral genotype, viral load, body mass index, gender, and history of alcohol consumption, only age (OR = 1.06, 95% CI 1.02 to 1.11) and HRV (OR = 3.13, 95% CI 1.28 to 7.68) were independent predictors of significant fibrosis at the end of follow‐up.

Conclusions

The link between HRV carriage and histologic outcome in a subgroup of HCV patients at low risk of progression underlines the need for intense scrutiny of alcohol habits in hepatitis C.
GDNF is a novel ethanol‐responsive gene in the VTA: implications for the development and persistence of excessive drinking
Authors: Ahmadiantehrani Somayeh , Barak Segev , Ron Dorit
Published: January 2013

Glial cell line‐derived neurotrophic factor (GDNF) is a potent inhibitor of ethanol consumption and relapse, and GDNF heterozygous knockout mice display increased reward sensitivity to ethanol and consume more ethanol after a period of abstinence than their wild‐type littermates. Here, we tested whether ethanol alters GDNF expression in the ventral tegmental area (VTA; GDNF's site of action) and/or the nucleus accumbens (NAc; the main source of GDNF), and if so, determine the role of the endogenous growth factor in the regulation of ethanol consumption. Systemic administration of ethanol increased GDNF expression and protein levels in the VTA, but not the NAc. Additionally, GDNF levels were elevated after an ethanol‐drinking session in rats that consumed ethanol in the intermittent‐access two‐bottle choice procedure for 1 week, but not 7 weeks. Deprivation following 7 weeks of excessive ethanol intake reduced GDNF levels, while a short ethanol binge drinking period following deprivation upregulated GDNF expression. Importantly, knockdown of GDNF within the VTA using adenovirus expressing short hairpin RNA facilitated the escalation of ethanol drinking by ethanol‐naïve rats, but not by rats with a history of excessive ethanol consumption. These results suggest that during initial ethanol‐drinking experiences, GDNF in the VTA is increased and protects against the development of excessive ethanol intake. However, the growth factor's protective response to ethanol breaks down after protracted excessive ethanol intake and withdrawal, resulting in persistent, excessive ethanol consumption.
Efficacy of laser‐driven irrigation versus ultrasonic in removing an airlock from the apical third of a narrow root canal
Authors: Peeters Harry Huiz , Gutknecht Norbert
Published: January 2013

The purpose of the study was to test the hypothesis that air entrapment occurs in the apical third of a root canal during irrigation. A second objective was to test the null hypothesis that there is no difference between laser‐driven irrigation (an erbium, chromium:yttrium‐scandium‐gallium‐garnet laser) and passive ultrasonic irrigation in removing an airlock from the apical third. One hundred twenty extracted human teeth with single narrow root canals were randomised into two experimental groups (n = 40) and two control groups (n = 20). The specimens were shaped using hand instruments up to a size 30/0.02 file. The teeth were irrigated with a mixture of saline, radiopaque contrast and ink in solution. In the passive ultrasonic irrigation group, the irrigant was activated with an ultrasonic device for 60 s. In the laser group, the irrigant was activated with a laser for 60 s. It was concluded that if the insertion of irrigation needle is shorter than the working length, air entrapment may develop in the apical third, but the use of laser‐driven irrigation is completely effective in removing it.
Which farmers benefit the most from Bt corn adoption? Estimating heterogeneity effects in the Philippines
Authors: Mutuc Maria , Rejesus Roderick M. , Yorobe, Jr. Jose M.
Published: January 2013

The potential contributions of new biotechnologies to sustainable food and income security have been the subject of widespread discussions around the turn of the 21st century. But distributional issues of which segments of adopters of genetically modified (GM) crops benefit the most have not been given ample attention). Using propensity scores, we apply the (a) stratification‐multilevel method of estimating heterogeneous treatment effects; and the (b) matching‐smoothing method of estimating heterogeneous treatment effects proposed by Xie et al. We find that the incidence of higher yields, lower insecticide use, and reduced seed utilization in the Philippines diminishes progressively as a farmer's propensity to adopt Bt corn increases. Farmers with a low propensity to adopt Bt are those who farm smaller, nonirrigated farms located farther from seed suppliers and farmers without previous training on pest identification. In most cases, while these farmers are typically poorer farmers in smaller parcels, cannot afford irrigation and are situated in remote areas away from easily accessible seed suppliers, there is no evidence, however, that profits differ across farmers with varying propensities to adopt the Bt variety.
Adult height of subjects with nonclassical 21‐hydroxylase deficiency
Authors: Eyal Ori , Tenenbaum‐Rakover Yardena , Shalitin Shlomit , Israel Shoshana , Weintrob Naomi
Published: January 2013

Aim

To determine whether nonclassical 21‐hydroxylase deficiency (NC21OHD) compromises adult height (AH), and to establish the clinical parameters affecting AH in subjects with NC21OHD.

Methods

This is a multicenter, retrospective review of medical records for clinical and biochemical parameters. The corrected height (CH) standard deviation score (SDS), defined as AH SDS minus mean parental height (MPH) SDS, was calculated for each patient, where MPH SDS is the average of the father's height SDS and the mother's height SDS.

Results

The study group consisted of 122 NC21OHD subjects whose median age at diagnosis was 8.7 years (range, 0.1–36). Seventy‐two patients had two mild mutations, 22 had one mild and one severe mutation, 10 were heterozygous for one mild mutation, and 18 did not undergo molecular analysis. The CH SDS of the 66 patients who initiated hydrocortisone treatment during childhood was significantly lower than those who presented after achieving AH (p = 0.03). However, there was a negative correlation between age at diagnosis and AH SDS in the former group (R = −0.7, p = 0.03). Being heterozygous for one mild and one severe mutation (R = −0.7, p < 0.02) and age at diagnosis (R = −0.7, p = 0.03) were negatively associated with CH SDS. The CH SDS was significantly lower in those who had bone age advancement at diagnosis compared to those who did not (p = 0.04).

Conclusion

The main determinants of AH in patients with NC21OHD are apparently age at diagnosis and initiation of therapy, and genotype. Early diagnosis and initiation of glucocorticoids therapy may improve height outcome in those presenting during childhood.
Retracted: Isolation, characterization, and effect of administration in vivo, a novel probiotic strain from pig feces
Authors: Ihara Yasuhiro , Hyodo Hideki , Sukegawa Shin , Murakami Hiroshi , Morimatsu Fumiki
Published: January 2013

From porcine rectal swabs or feces, we isolated lactic acid bacteria and used porcine Peyer's patch cells to select them for inducibility of IgA production as an indicator of probiotic effects. The strain selected as a new probiotic was named ‘Enterococcus faecium NHRD IHARA‘. To verify the probiotic effects of this strain in vivo, 536 piglets at age 25 days were assigned to either the trial group, which administrated the strain, or the control group. An increase in IgA in the feces was observed at age 45 days (P < 0.05 compared with the control group); a significant increase in serum IgA was also observed at the end of the study (P < 0.01) in the trial group. In addition, significant differences between the groups in terms of body weight (P < 0.05) and average daily gain (P < 0.01) were observed. The rate of detection of swine‐pathogenic Escherichia coli gene in the feces tended to be lower in the trial group than in the controls. The novel probiotic strain; E. faecium NHRD IHARA may have beneficial effects on swine growth by inducing IgA production and reducing rates of colonization by pathogens in the body.
Effect of co‐culture with intact embryos on development of bovine separated blastomeres
Authors: Nagai Makoto , Hori Noboru , Miyamoto Michiko , Sakaguchi Masanobu , Hayakawa Yuji , Kawai Megumi , Kita Mitsuo , Furuya Tetsuya , Imai Kei
Published: January 2013

To improve embryo development in bovine separated blastomeres, we evaluated applicability of co‐culture with intact embryos. The morphological quality of blastocysts derived from separated blastomeres and rate of blastocyst formation were only slightly increased when the cells were co‐cultured with intact embryos, which did not provide significant differences when statistically analyzed. However, the cell count of inner cell mass (ICM), trophectoderm (TE) and total number of cells in Day 8 blastocysts were significantly higher when the cells were co‐cultured with the intact embryos than those with the cells cultured individually (P < 0.05). Transfer of four monozygotic pairs of blastocysts derived from the cells co‐cultured with intact embryos led to three pregnancies even when the blastomeres were produced by in vitro maturation and in vitro fertilization of oocytes collected by ovum pick‐up from elite cows. These results suggest that co‐culturing with intact embryos may enhance development of bovine separated blastomere.
Glycogen synthase kinase‐3 (GSK‐3) regulatesTGF‐β1‐induced differentiation of pulmonary fibroblasts
Authors: Baarsma Hoeke A , Engelbertink Lilian HJM , van Hees Lonneke J , Menzen Mark H , Meurs Herman , Timens Wim , Postma Dirkje S , Kerstjens Huib AM , Gosens Reinoud
Published: January 2013

Background

Chronic lung diseases such as asthma,COPDand pulmonary fibrosis are characterized by abnormal extracellular matrix (ECM) turnover.TGF‐β is a key mediator stimulatingECMproduction by recruiting and activating lung fibroblasts and initiating their differentiation process into more active myofibroblasts. Glycogen synthase kinase‐3 (GSK‐3) regulates various intracellular signalling pathways; its role inTGF‐β1‐induced myofibroblast differentiation is currently largely unknown.

Purpose

To determine the contribution ofGSK‐3 signalling inTGF‐β1‐induced myofibroblast differentiation.

Experimental Approach

We usedMRC5 human lung fibroblasts and primary pulmonary fibroblasts of individuals with and withoutCOPD. Protein and mRNAexpression were determined by immunoblotting andRT‐PCRanalysis respectively.

Results

Stimulation ofMRC5 and primary human lung fibroblasts withTGF‐β1resulted in time‐ and dose‐dependent increases of α‐sm‐actin and fibronectin expression, indicative of myofibroblast differentiation. Pharmacological inhibition ofGSK‐3 bySB216763 dose‐dependently attenuatedTGF‐β1‐induced expression of these myofibroblasts markers. Moreover, silencing ofGSK‐3 by siRNAor pharmacological inhibition byCT/CHIR99021 fully inhibited theTGF‐β1‐induced expression of α‐sm‐actin and fibronectin. The effect ofGSK‐3 inhibition on α‐sm‐actin expression was similar in fibroblasts from individuals with and withoutCOPD. Neither smad,NF‐κBnorERK1/2 were involved in the inhibitory actions ofGSK‐3 inhibition bySB126763 on myofibroblast differentiation. Rather,SB216763 increased the phosphorylation ofCREB, which in its phosphorylated form acts as a functional antagonist ofTGF‐β/smad signalling.

Conclusion and Implication

We demonstrate thatGSK‐3 signalling regulatesTGF‐β1‐induced myofibroblast differentiation by regulatingCREBphosphorylation.GSK‐3 may constitute a useful target for treatment of chronic lung diseases.
Circulating endothelial cells and tumor blood volume as predictors in lung cancer
Authors: Wang Jing , Xiao Jianyu , Wei Xiyin , Wang Liuchun , Lin Li , Liu Zhujun , Wang Xinyue , Sun Baocun , Li Kai
Published: January 2013

The current criteria for evaluating antiangiogenic efficacy is insufficient as tumor shrinkage occurs after blood perfusion decreases. Tumor blood volume (BV) in computed tomography perfusion imaging and circulating endothelial cells (CEC) might predict the status of angiogenesis. The present study aimed to validate their representation as feasible predictors in non‐small‐cell lung carcinoma (NSCLC). A total of 74 patients was categorized randomly into two arms undergoing regimens of vinorelbine and cisplatin (Navelbine and platinum [NP]) with rh‐endostatin or single NP. The response rate, perfusion imaging indexes and activated CEC (aCEC) during treatment were recorded. Progression‐free survival (PFS) was determined through follow up. Correlations among the above indicators, response and PFS were analyzed: aCEC increased significantly in cases of progressive disease after single NP chemotherapy (P = 0.024). Tumor BV decreased significantly in cases with a clinical benefit in the combined arm (P = 0.026), whereas inverse correlations existed between ∆aCEC (post‐therapeutic value minus the pre‐therapeutic value) and PFS (P = 0.005) and between ∆BV and PFS (P = 0.044); a positive correlation existed between ∆aCEC and ∆BV. Therefore, both aCEC and tumor BV can serve as predictors, and detection of both indicators can help evaluate the chemo‐antiangiogenic efficacy in NSCLC more accurately.
Epithelial expression of interleukin-37b in inflammatory bowel disease
Authors: Imaeda H , Takahashi K , Fujimoto T , Kasumi E , Ban H , Bamba S , Sonoda H , Shimizu T , Fujiyama Y , Andoh A
Published: January 2013

Interleukin (IL)-37 is a member of the IL-1 cytokine family. We investigated IL-37b expression in the inflamed mucosa of inflammatory bowel disease (IBD) patients. Furthermore, we analysed IL-37b expression in human colonic epithelial cells. The human colonic epithelial cell line T84 and human colonic subepithelial myofibroblasts (SEMFs) were used. IL-37b expression in the IBD mucosa was evaluated by immunohistochemistry. IL-37b mRNA and protein expression were determined by real time-polymerase chain reaction (PCR) and Western blotting, respectively. IL-37b was not detected in the normal colonic mucosa. In the inflamed mucosa of IBD patients, epithelial IL-37b expression was increased markedly. In ulcerative colitis (UC) and Crohn's disease (CD) patients, IL-37b expression was enhanced in the affected mucosa. In the intestinal epithelial cell line T84, the expression of IL-37b mRNA and protein was enhanced by tumour necrosis factor (TNF)-α. This IL-37b induction by TNF-α was mediated by nuclear factor (NF)-κB and activator protein (AP)-1 activation. Furthermore, IL-37b inhibited TNF-α-induced interferon-γ-inducible protein (IP)-10 expression significantly in human colonic SEMFs. Epithelial IL-37b expression was increased in IBD patients, especially UC patients. IL-37b may be involved in the pathophysiology of IBD as an anti-inflammatory cytokine and an inhibitor of both innate and acquired immune responses.