bluuebunny/crossref_metadata_2025 huggingface dataset:
Extreme heterogeneity of influenza virus infection in single cells
Authors: Russell Alistair B. , Trapnell Cole , Bloom Jesse D.
Published: September 2017

Viral infection can dramatically alter a cell’s transcriptome. However, these changes have mostly been studied by bulk measurements on many cells. Here we use single-cell mRNA sequencing to examine the transcriptional consequences of Influenza virus infection. We 1nd extremely wide cell-to-cell variation in production of viral gene transcripts – viral transcripts compose less than a percent of total mRNA in many infected cells, but a few cells derive over half their mRNA from virus. Some infected cells fail to express at least one viral gene, and this gene absence partially explains variation in viral transcriptional load. Despite variation in total viral load, the relative abundances of viral mRNAs are fairly consistent across infected cells. Activation of innate immune pathways is rare, but some cellular genes co-vary in abundance with the amount of viral mRNA. Overall, our results highlight the complexity of viral infection at the level of single cells.
Hippocampal atrophy and intrinsic brain network dysfunction relate to alterations in mind wandering in neurodegeneration
Authors: O’Callaghan Claire , Shine James M. , Hodges John R. , Andrews-Hanna Jessica R. , Irish Muireann
Published: September 2017

Mind wandering represents the human capacity for internally focussed thought, and relies upon the brain’s default network and its interactions with attentional networks. Studies have characterised mind wandering in healthy people, yet there is limited understanding of how this capacity is affected in clinical populations. This study used a validated thought-sampling task to probe mind wandering capacity in two neurodegenerative disorders: behavioural variant frontotemporal dementia (bvFTD; n=35) and Alzheimer’s disease (AD; n=24), compared to older controls (n=37). These patient groups were selected due to canonical structural and functional changes across sites of the default and frontoparietal networks, and well-defined impairments in cognitive processes that support mind wandering. Relative to controls, bvFTD patients displayed significantly reduced mind wandering capacity, offset by a significant increase in stimulus-bound thought. In contrast, AD patients demonstrated comparable levels of mind wandering to controls, in the context of a relatively subtle shift towards stimulus-/task-related forms of thought. In the patient groups, mind wandering was associated with grey matter integrity in the hippocampus/parahippocampus, striatum, insula and orbitofrontal cortex. Resting state functional connectivity revealed associations between mind wandering capacity and connectivity within and between regions of the frontoparietal and default networks, with distinct patterns evident in patients vs. controls. These findings support a relationship between altered mind wandering capacity in neurodegenerative disorders, and structural and functional integrity of the default and frontoparietal networks. This study highlights a dimension of cognitive dysfunction not well documented in neurodegenerative disorders, and validates current models of mind wandering in a clinical population.

Significance statement

Humans spend much of their waking life engaged in mind wandering. Underlying brain systems supporting this complex ability have been established in healthy individuals, yet it remains unclear how mind wandering is altered in neuropsychiatric populations. We reveal changes in the thought profiles elicited during periods of low cognitive demand in dementia, resulting in reduced mind wandering and an increased propensity towards stimulus-bound thought. These altered thought profiles were associated with structural and functional brain changes in the hippocampus, default and frontoparietal networks; key regions implicated in internal mentation in healthy individuals. Our findings provide a unique clinical validation of current theoretical models of mind wandering, and reveal a dimension of cognitive dysfunction that has received scant attention in dementia.
Plasma amyloid β levels are driven by genetic variants nearAPOE, BACE1, APP, PSEN2:A genome-wide association study in over 12,000 non-demented participants
Authors: Damotte Vincent , van der Lee Sven J , Chouraki Vincent , Grenier-Boley Benjamin , Simino Jeannette , Adams Hieab , Tosto Giuseppe , White Charles , Terzikhan Natalie , Cruchaga Carlos , Knol Maria J. , Li Shuo , Schraen Susanna , Grove Megan L. , Satizabal Claudia , Amin Najaf , Berr Claudine , Younkin Steven ,   Alzheimer’s Disease Neuroimaging Initiative, Gottesman Rebecca F. , Buée Luc , Beiser Alexa , Knopman David S. , Uitterlinden Andre , DeCarli Charles , Bressler Jan , DeStefano Anita , Dartigues Jean-François , Yang Qiong , Boerwinkle Eric , Tzourio Christophe , Fornage Myriam , Ikram M Arfan , Amouyel Philippe , de Jager Phil , Reitz Christiane , Mosley Thomas H , Lambert Jean-Charles , Seshadri Sudha , van Duijn Cornelia
Published: September 2017

INTRODUCTION

There is increasing interest in plasma Aβ as an endophenotype and biomarker of Alzheimer’s disease (AD). Identifying the genetic determinants of plasma Aβ levels may elucidate important processes that determine plasma Aβ measures.

METHODS

We included 12,369 non-demented participants derived from eight population-based studies. Imputed genetic data and plasma Aβ1-40, Aβ1-42 levels and Aβ1-42/Aβ1-40 ratio were used to perform genome-wide association studies, gene-based and pathway analyses. Significant variants and genes were followed-up for the association with PET Aβ deposition and AD risk.

RESULTS

Single-variant analysis identified associations acrossAPOEfor Aβ1-42 and Aβ1-42/Aβ1-40 ratio, andBACE1for Aβ1-40. Gene-based analysis of Aβ1-40 additionally identified associations forAPP,PSEN2,CCKandZNF397. There was suggestive interaction between aBACE1variant andAPOEε4 on brain Aβ deposition.

DISCUSSION

Identification of variants near/in known major Aβ-processing genes strengthens the relevance of plasma-Aβ levels both as an endophenotype and a biomarker of AD.
Goodness of fit checks for binomial N-mixture models
Authors: Knape Jonas , Arlt Debora , Barraquand Frédéric , Berg Åke , Chevalier Mathieu , Pärt Tomas , Ruete Alejandro , Zmihorski Michał
Published: September 2017

Binomial N-mixture models are commonly applied to analyze population survey data. By estimating detection probabilities, N-mixture models aim at extracting information about abundances in terms of actual and not just relative numbers. This separation of detection probability and abundance relies on parametric assumptions about the distribution of individuals among sites and of detections of individuals among repeat visits to sites. Current methods for checking assumptions are limited, and their computational complexity have hindered evaluations of their performances.

We develop computationally efficient graphical goodness of fit checks and measures of overdispersion for binomial N-mixture models. These checks are illustrated in a case study, and evaluated in simulations under two scenarios. The two scenarios assume overdispersion in the abundance distribution via a negative binomial distribution or in the detection probability via a beta-binomial distribution. We evaluate the ability of the checks to detect lack of fit, and how lack of fit affects estimates of abundances.

The simulations show that if the parametric assumptions are incorrect there can be severe biases in estimated abundances: negatively if there is overdispersion in abundance relative to the fitted model and positively if there is overdispersion in detection. Our goodness of fit checks performed well in detecting lack of fit when the abundance distribution is overdispersed, but struggled to detect lack of fit when detections were overdispersed. We show that the inability to detect lack of fit due to overdispersed detection is caused by a fundamental similarity between N-mixture models with beta-binomial detections and N-mixture models with negative binomial abundances.

The strong biases in estimated abundances that can occur in the binomial N-mixture model when the distribution of individuals among sites, or the detection model, is mis-specified implies that checking goodness of fit is essential for sound inference in ecological studies that use these methods. To check the assumptions we provide computationally efficient goodness of fit checks that are available in an R-package nmixgof. However, even when a binomial N-mixture model appears to fit the data well, estimates are not robust in the presence of overdispersion unless additional information about detection is collected.
Rare Variant Burden in Known Dystonia Genes in Population Controls and Sporadic Dystonia Patients
Authors: Cirulli Elizabeth T. , Hickey Patrick , Tracy Samantha , Johnson Julia , Caffall Zachary , Tsukayama Kaylin , Scott Burton , Stacy Mark , Calakos Nicole
Published: September 2017

Background

Rare mutations in genes associated with Mendelian forms of disease are a potential mechanism for sporadic disease. The need to assess the clinical significance of such variants is increasing as personalized medicine and genome sequencing increases.

Objective

To evaluate the rate of rare, functional variants in dystonia genes in the general population to improve interpretation of the clinical relevance of potentially pathogenic variants in dystonia cases.

Methods

We performed an “aggregated” collapsing analysis of exome sequence that considered rare coding variants in genes previously associated with dystonia, a rare neurological movement disorder, on 2,372 population controls of European ethnicity. We then performed a pilot study in sporadic dystonia to assess whether there was a substantially greater incidence of individuals with rare variation in dystonia genes.

Results

Nearly half of population controls had a rare coding variant when 148 genes associated with a dystonia phenotype were considered. When the subset of genes causing isolated dystonia (14 genes) was evaluated, 3-4% of controls harbored rare qualifying variants. Our pilot study of case exomes was powered to identify a five-fold higher or greater rate of qualifying variants in isolated dystonia genes in sporadic dystonia cases compared to population controls; we did not find such an enrichment.

Conclusions

We provide the first systematic analysis of rare variation in dystonia genes considered collectively. Our findings emphasize the need to consider the overall frequency of variants in rare disease-related genes in the general population when considering their potential role in clinical presentations.
MeDEStrand: an improved method to infer genome-wide absolute methylation level from DNA enrichment experiment
Authors: Xu Jingting , Liu Shimeng , Yin Ping , Bulun Serdar , Dai Yang
Published: September 2017

Background

DNA methylation of dinucleotide CpG is an essential epigenetic modification that plays a key role in transcription. Bisulfite conversion method is a “gold standard” for DNA methylation profiling that provides single nucleotide resolution. However, whole-genome bisulfite conversion is very expensive. Alternatively, DNA enrichment-based methods offer high coverage of methylated CpG dinucleotides with the lowest cost per CpG covered genome-wide and have been used widely. They measure the DNA enrichment of methyl-CpG binding, therefore do not directly provide absolute methylation levels. Further, the enrichment is influenced by confounding factors besides the methylation status, e.g., CpG density. Computational models that can accurately derive the absolute methylation levels from the enrichment data are necessary.

Results

We present ‘MeDEStrand’, a method uses sigmoid function to estimate and correct the CpG bias from the numbers of reads that fell within bins that divide the genome. In addition, unlike the previous methods, which estimate CpG bias based on reads mapped at the same genomic loci, ‘MeDEStrand’ processes the reads for the positive and negative DNA strands separately. We compare the performance of ‘MeDEStrand’ with three other state-of-the-art methods ‘MEDIPS’, ‘BayMeth’ and ‘QSEA’ on four independent datasets generated using immortalized cell lines (GM12878 and K562) and human patient primary cells (foreskin fibroblast and mammary epithelial). Based on the comparison between the inferred absolute methylation levels from MeDIP-seq and the corresponding RRBS data, ‘MeDEStrand’ shows the best performance at high resolution of 25, 50 and 100 base pairs.

Conclusions

‘MeDEStrand’ benefits from the estimation of CpG bias with a sigmoid function and the procedure to process reads mapped to the positive and negative DNA strands separately. ‘MeDEStrand’ is a tool to infer whole-genome absolute DNA methylation level at the cost of enrichment-based methods with adequate accuracy and resolution. R package ‘MeDEStrand’ and its tutorial is freely available for download athttps://github.com/jxu1234/MeDEStrand.git
Fundamentals of rapid injection molding for microfluidic cell-based assays
Authors: Lee Ulri N. , Su Xiaojing , Guckenberger David J. , Dostie Ashley M. , Zhang Tianzi , Berthier Erwin , Theberge Ashleigh B.
Published: September 2017

Microscale cell-based assays have demonstrated unique capabilities in reproducing important cellular behaviors for diagnostics and basic biological research. As these assays move beyond the prototyping stage and into biological and clinical research environments, there is a need to produce microscale culture platforms more rapidly, cost-effectively, and reproducibly. ‘Rapid’ injection molding is poised to meet this need as it enables some of the benefits of traditional high volume injection molding at a fraction of the cost. However, rapid injection molding has limitations due to the material and methods used for mold fabrication. Here, we characterize advantages and limitations of rapid injection molding for microfluidic device fabrication through measurement of key features for cell culture applications including channel geometry, feature consistency, floor thickness, and surface polishing. We demonstrate phase contrast and fluorescence imaging of cells grown in rapid injection molded devices and provide design recommendations to successfully utilize rapid injection molding methods for microscale cell-based assay development in academic laboratory settings.
Inhaled nicotine equivalent to cigarette smoking disrupts systemic and uterine hemodynamics and induces cardiac arrhythmia in pregnant rats
Authors: Shao Xuesi M. , López-Valdés Héctor E. , Liang Jing , Feldman Jack L.
Published: September 2017

Maternal smoking with obligatory nicotine inhalation is associated with preterm delivery, low birth weight, fetal growth retardation and developmental defects. We tested the hypothesis that cigarette smoking-relevant nicotine inhalation during pregnancy impairs cardiovascular function and uterine hemodynamics with consequential fetal ischemia. Pregnant rats exposed to episodic inhaled nicotine via a novel lung alveolar region-targeted aerosol method produced nicotine pharmacokinetics resembling cigarette smoking in humans. This clinically relevant nicotine aerosol inhalation (NAI) induced transient reduction and irregular fluctuations in uterine artery blood flow associated with cardiac arrhythmia and high magnitude irregular fluctuations of systemic blood pressure. The arrhythmia included sinoatrial (SA) block, sinus arrest, 2oand 3oatrioventricular (A-V) block and supraventricular escape rhythm. These effects were blocked by the nicotinic receptor (nAChR) antagonist mecamylamine. Resection of the ovarian nerve, which innervates uterine blood vessels, counteracted the NAI-induced reduction in uterine blood flow. We suggest that the rapid rise pattern of arterial blood nicotine concentration stimulates and then desensitizes autonomic nAChRs leading to disruptions of cardiac function as well as systemic and uterine hemodynamics that reduces uteroplacental blood flow, a mechanism underlying maternal smoking-associated pregnancy complications and developmental disorders. These findings challenge the safety of pure nicotine inhalation, i.e., E-cigarettes.
X-ray diffraction study on a (111)-textured palladium thin film under hydrogen loading and unloading: film structure evolution and its mechanism
Authors: Harumoto Takashi , Suzuki Yuichi , Shi Ji , Nakamura Yoshio
Published: September 2017

The incorporation of hydrogen normally results in degradation when applied to metals. In this diffraction study, however, improvement of the film structure, such as in-plane grain growth, lattice defect removal and texture enhancement, was observed in a (111)-textured palladium thin film during hydrogen loading and unloading cycles. Accordingly, diffraction stress analysis was performed to investigate the evolution mechanism. It was found that the formation of the β phase during the α-to-β phase transformation occurred at the same in-plane stress present in the α phase, andvice versa. This suggests that the cyclic α–β grain boundary motion during the transformation occurred mainly along the in-plane direction, contributing to the film structure evolution.
Pay ratio legislation in the United Kingdom: a prospect
Authors: Imai Akihito
Published: September 2017

Purpose

The article examines a current debate over pay ratio rulemaking in the United Kingdom. In the United States, the Securities and Exchange Commission issued a rule that requires public companies to disclose the ratio of the annual pay of their chief executive officer to the median of their employees’ pay in 2015. The United Kingdom has considered making a similar rule under Prime Minister Theresa May.

Design/methodology/approach

The article provides a concise analysis of the current debate over a rule regarding pay ratio in the United Kingdom. It also highlights characteristics and concerns by comparing pay ratio disclosure in the United States.

Findings

The United Kingdom seems to have taken the first step toward pay ratio rule, similar to Section 953(b) of the Dodd-Frank Wall Street Reform and Consumer Protection Act, the so-called pay ratio disclosure. Some differences can however be found in manifestos and many issues and uncertainties still remain for rulemaking.

Originality/value

This article provides information on a prospect for a pay ratio rule in the United Kingdom.
A review of the SEC Participating Affiliate No-Action Letters’ relief from Investment Advisers Act of 1940 registration for foreign investment advisers
Authors: Cohen Wendy E. , Dickstein David Y. , Hennion Christian B. , Marshall Richard D. , Yacker Allison C. , Zinman Lance A.
Published: September 2017

Purpose

To explain the US Securities and Exchange Commission (the “SEC”) staff’s (the “Staff”) participating affiliate exemption from investment adviser registration for foreign advisers set forth in a line of Staff no-action letters issued between 1992 and 2005 (the “Participating Affiliate Letters”) and to discuss recent guidance issued by the Staff in an information update published in March 2017 (the “Information Update”) with respect to complying with requirements of the Participating Affiliate Letters.

Design/methodology/approach

Reviews the development of the Staff’s approach regarding the non-registration of foreign advisers that rely on the Participating Affiliate Letters from prior to the issuance of those letters through the Information Update and sets forth recommendations for registered investment advisers and their participating affiliates.

Findings

While there are arguments that the Information Update goes beyond restating established standards and does not clearly explain whether submission of all listed documentation is required, the Information Update will likely standardize the information submitted to the SEC.

Originality/value

Practical guidance for advisers relying on the Participating Affiliate Letters from experienced securities and financial services lawyers.
Fifteen years of social media in emergencies: A retrospective review and future directions for crisis Informatics
Authors: Reuter Christian , Kaufhold Marc‐André
Published: September 2017

Social media has been established in many larger emergencies and crises. This process has not started just a few years ago, but already 15 years ago in 2001 after the terrorist attacks of 9/11. In the following years, especially in the last 10, sometimes summarized under the term crisis informatics, a variety of studies focusing on the use of ICT and social media before, during or after nearly every crisis and emergency has arisen. This article aimed to recapitulate 15 years of social media in emergencies and its research with a special emphasis on use patterns, role patterns and perception patterns that can be found across different cases to point out what has been achieved so far, and what future potentials exist.
Probiotic Mascarpone‐type cheese: Characterisation and cell viability during storage and simulated gastrointestinal conditions
Authors: de Almeida Júlia dos S Opuski , Dias Carolinne O , Pinto Stephanie S , Pereira Luiza C , Verruck Silvani , Fritzen‐Freire Carlise B , Amante Edna R , Prudêncio Elane S , Amboni Renata D M C
Published: September 2017

The aim of this study was to evaluate the effects of Bifidobacterium animalis subsp. lactis BB‐12 and the prebiotic inulin in a Mascarpone‐type cheese on its physicochemical parameters during storage, as well as the protective effects of the matrix on the viability of the probiotics and their survival after exposure to simulated gastrointestinal conditions. The incorporation of the probiotic and inulin into the Mascarpone‐type cheese affected specific physicochemical and textural properties. Viable cell counts remained above 6 log cfu/g throughout the whole storage period and after the simulated gastrointestinal conditions, indicating the protective effect of the matrix of the Mascarpone‐type cheese.
Differences in bioactive protein and vitamin status of milk from certified organic and conventional farms
Authors: Brodziak Aneta , Król Jolanta , Litwińczuk Zygmunt , Barłowska Joanna
Published: September 2017

The aim of the study was to determine differences in the status of selected bioactive whey proteins and lipophilic vitamins in milk obtained from certified organic farms as compared to conventional farms (using traditional and intensive production systems). Significant relationships were noted with regard to production system and individual bioactive milk compounds, that is β‐lactoglobulin, lactoferrin, lysozyme, vitamins A, D3 and E, and β‐carotene (P = 0.001) and bovine serum albumin (BSA) (P = 0.016). Milk obtained from extensive farms, especially certified organic ones, was a valuable source of certain antioxidant compounds: β‐lactoglobulin (3.32 g/L), lactoferrin (123.8 mg/L), vitamin E (2.044 mg/L) and β‐carotene (0.257 mg/L) in the case of organic farms.
IRF7 gene expression profile and methylation of its promoter region in patients with systemic sclerosis
Authors: Rezaei Ramazan , Mahmoudi Mahdi , Gharibdoost Farhad , Kavosi Hoda , Dashti Navid , Imeni Vahideh , Jamshidi Ahmadreza , Aslani Saeed , Mostafaei Shayan , Vodjgani Mohammad
Published: September 2017

Objective

The aim of the current study was to evaluate if methylation status of CpG sites of interferon regulatory factor 7 (IRF7) promoter in peripheral blood mononuclear cells (PBMCs) of systemic sclerosis (SSc) patients is involved in pathogenesis of the disease.

Methods

PBMCs were isolated from whole blood of 50 SSc patients and 30 controls. After the extraction of total RNA and DNA contents from PBMCs, complementary DNA (cDNA) was synthesized. Afterwards, quantitative analysis of IRF7 messenger RNA (mRNA) was conducted by real‐time polymerase chain reaction (PCR). To evaluate the methylation status of the promoter region of IRF7 gene, PCR products of bisulfite‐treated DNA from SSc patients and controls were sequenced.

Results

The mRNA expression of IRF7 in PBMCs from patients compared with controls was significantly upregulated. While limited cutaneous SSc patients expressed the mRNA of IRF7 higher than controls, the diffuse cutaneous SSc group did not demonstrate significantly increased expression in comparison to controls. Insignificant promoter hypomethylation of IRF7 was observed in SSc patients compared with the control group. However, CpG2 hypomethylation was significantly associated with increased SSc risk. Furthermore, overall promoter methylation and mRNA level of IRF7 were significantly correlated with each other. Nonetheless, none of them correlated with Rodnan score of SSc patients. There was significant difference in IRF7 mRNA expression between CpG8 methylated and unmethylated SSc patients. Moreover, the difference of methylation and expression was not significant between anti‐nuclear antibody (ANA)‐positive and ANA‐negative SSc patients.

Conclusions

It is suggested that hypomethylation of the IRF7 promoter might play a role in SSc pathogenesis, probably through promoting the IRF7 expression in PBMCs of patients with SSc.
Ideal Cricoid Pressure Is Biomechanically Impossible During Laryngoscopy
Authors: Trethewy Christopher E. , Doherty Steven R. , Burrows Julie M. , Clausen Don
Published: September 2017

Objective

This study was a prospective, randomized controlled trial of rapid sequence intubation (RSI) with cricoid pressure (CP) within the emergency department (ED). The primary aim of the study was to examine the link between ideal CP and the incidence of aspiration.

Method

Patients > 18 years of age undergoing RSI in the ED of two hospitals in New South Wales, Australia, were randomly assigned to receive measured CP using weighing scales to target the ideal CP range (3.060–4.075 kg) or control CP where the weighing scales were used, but the CP operator was blinded to the amount of CP applied during the RSI. A data logger recorded all CP delivered during each RSI. Immediately after intubation, tracheal and esophageal samples were taken and underwent pepsin analysis.

Results

Fifty‐four RSIs were analyzed (25 measured/29 control). Macroscopic contamination of the larynx at RSI was observed in 14 patients (26%). During induction (0–50 seconds), both groups delivered in‐range CP. During intubation (51–223 seconds), laryngoscopy was associated with a reduction in mean CP below 3.060 kg in both groups. When compared, there was no statistically significant difference between the groups. For 11 patients, pepsin was detected in the oropharyngeal sample, while three were positive for tracheal pepsin. Seven patients (four control/three measured) were treated for clinical aspiration during hospitalization. As a result of the finding that neither group could maintain ideal range CP during laryngoscopy, the trial was abandoned.

Conclusion

Laryngoscopy provides a counter force to CP, which is negated to facilitate tracheal intubation. The concept that a static 3.060 to 4.075 kg CP could be maintained during laryngoscopy and intubation was rejected by our study. Whether a lower CP range could prevent aspiration during RSI was not explored by this study.
How climate influences the biology and behaviour of Phyllophaga capillata (Coleoptera: Melolonthidae) in the Brazilian Cerrado
Authors: Oliveira Charles M , Frizzas Marina R
Published: September 2017

Phyllophaga capillata (Blanchard) is the most important soil pest in soybean crops in Central Brazil (Federal District and Goiás state). The objective of this work was to study the bio‐ecology of P. capillata in the field in the Cerrado of Central Brazil, relating its biology and behaviour to the climatic characteristics of this biome. The study was conducted over three years in a soybean [Glycine max (L.) Merr.] production area (≈6000 ha) in the Federal District. Field samplings were taken to observe the biological stages of P. capillata, preferred oviposition sites and the adult swarming period. Phyllophaga capillata presented an univoltine cycle that lasted about 10 months of egg to inactive adults, and 12 months until the appearance of active adults. Eggs were found in the field in October and November. The larval stage occurred between November and June. Pre‐pupae were observed in June and the pupae between July and August. Inactive adults were observed in August and September, and the swarming period was between September and December. Females preferred to oviposit in sites with taller plants. This species synchronises its active phases (larvae and active adults) with soybean cultivation and the rainy season (October/March) in the Brazilian Cerrado. Alternatives for pest management based on their bio‐ecological characteristics are presented.
Nasal protein profiles in work‐related asthma caused by different exposures
Authors: Suojalehto H. , Lindström I. , Wolff H. , Puustinen A.
Published: September 2017

Background

The mechanisms of work‐related asthma (WRA) are incompletely delineated. Nasal cell samples may be informative about processes in the lower airways. Our aim was to determine the nasal protein expression profiles of WRA caused by different kind of exposures.

Methods

We collected nasal brush samples from 82 nonsmoking participants, including healthy controls and WRA patients exposed to (i) protein allergens, (ii) isocyanates and (iii) welding fumes the day after relevant exposure. The proteome changes in samples were analysed by two‐dimensional difference gel electrophoresis, and the differentially regulated proteins found were identified by mass spectrometry. Immunological comparison was carried out using Western blot.

Results

We detected an average of 2500 spots per protein gel. Altogether, 228 protein spots were chosen for identification, yielding 77 different proteins. Compared to the controls, exposure to protein allergens had the largest effects on the proteome. Hierarchical clustering revealed that protein allergen‐ and isocyanate‐related asthma had similar profiles, whereas asthma related to welding fumes differed. The highly overrepresented functional categories in the asthma groups were defence response, protease inhibitor activity, inflammatory and calcium signalling, complement activation and cellular response to oxidative stress. Immunological analysis confirmed the found abundance differences in galectin 10 and protein S100‐A9 between the groups.

Conclusions

Work‐related asthma patients exposed to protein allergens and isocyanates elicit similar nasal proteome responses and the profiles of welders and healthy controls were alike. Revealed biological activities of the protein expression changes are associated with allergic inflammation and asthma.
Near‐infrared spectroscopy is a promising noninvasive technique for monitoring the effects of feeding regimens on the cerebral and splanchnic regions
Authors: Grometto Alice , Pizzo Benedetta , Strozzi Maria Chiara , Gazzolo Francesca , Gazzolo Diego
Published: September 2017

Aim

The effects of different milk and, or, administration regimens on cerebro‐splanchnic perfusion are still a matter of debate. We investigated the effects of the bolus administration of breast milk or formula on cerebro‐splanchnic oximetry, function and perfusion, assessed by near‐infrared spectroscopy (NIRS).

Methods

This observational study of 30 infants fed with breast (n = 15) or formula (n = 15) milk, and matched for gestational age and birth weight, was carried out in the neonatal intensive care unit of the C Arrigo Children's Hospital, Alessandria, Italy, a tertiary‐level referral centre, from October 2015 to December 2016. NIRS monitoring parameters, such as cerebral and splanchnic oximetry, fraction of tissue oxygen extraction and the cerebral–splanchnic ratio, were recorded before, during and after feeding.

Results

Breast milk led to a significant increase in cerebro‐splanchnic oximetry and tissue oxygen extraction (p < 0.001) during and after feeding, and the cerebro‐splanchnic perfusion ratio was significantly higher (p < 0.001) in the breast than formula group.

Conclusion

Our study results suggest that breast milk was better tolerated than formula, requiring lower energy expenditure and lower cerebro‐splanchnic haemodynamic redistribution. The findings could prompt investigations using NIRS as a promising noninvasive tool for cerebral and splanchnic longitudinal monitoring during neonatal feeding.
Population pharmacodynamic modelling of midazolam induced sedation in terminally ill adult patients
Authors: Franken Linda G. , de Winter Brenda C. M. , Masman Anniek D. , van Dijk Monique , Baar Frans P. M. , Tibboel Dick , Koch Birgit C. P. , van Gelder Teun , Mathot Ron A. A.
Published: September 2017

Aims

Midazolam is the drug of choice for palliative sedation and is titrated to achieve the desired level of sedation. A previous pharmacokinetic (PK) study showed that variability between patients could be partly explained by renal function and inflammatory status. The goal of this study was to combine this PK information with pharmacodynamic (PD) data, to evaluate the variability in response to midazolam and to find clinically relevant covariates that may predict PD response.

Method

A population PD analysis using nonlinear mixed effect models was performed with data from 43 terminally ill patients. PK profiles were predicted by a previously described PK model and depth of sedation was measured using the Ramsay sedation score. Patient and disease characteristics were evaluated as possible covariates. The final model was evaluated using a visual predictive check.

Results

The effect of midazolam on the sedation level was best described by a differential odds model including a baseline probability, Emax model and interindividual variability on the overall effect. The EC50 value was 68.7 μg l–1 for a Ramsay score of 3–5 and 117.1 μg l–1 for a Ramsay score of 6. Comedication with haloperidol was the only significant covariate. The visual predictive check of the final model showed good model predictability.

Conclusion

We were able to describe the clinical response to midazolam accurately. As expected, there was large variability in response to midazolam. The use of haloperidol was associated with a lower probability of sedation. This may be a result of confounding by indication, as haloperidol was used to treat delirium, and deliria has been linked to a more difficult sedation procedure.
Experimental Design for Multi-drug Combination Studies Using Signaling Networks
Authors: Huang Hengzhen , Fang Hong-Bin , Tan Ming T.
Published: September 2017

Combinations of multiple drugs are an important approach to maximize the chance for therapeutic success by inhibiting multiple pathways/targets. Analytic methods for studying drug combinations have received increasing attention because major advances in biomedical research have made available large number of potential agents for testing. The preclinical experiment on multi-drug combinations plays a key role in (especially cancer) drug development because of the complex nature of the disease, the need to reduce development time and costs. Despite recent progresses in statistical methods for assessing drug interaction, there is an acute lack of methods for designing experiments on multi-drug combinations. The number of combinations grows exponentially with the number of drugs and dose-levels and it quickly precludes laboratory testing. Utilizing experimental dose–response data of single drugs and a few combinations along with pathway/network information to obtain an estimate of the functional structure of the dose–response relationship in silico, we propose an optimal design that allows exploration of the dose–effect surface with the smallest possible sample size in this article. The simulation studies show our proposed methods perform well.
Fully Bayesian Spectral Methods for Imaging Data
Authors: Reich Brian J. , Guinness Joseph , Vandekar Simon N. , Shinohara Russell T. , Staicu Ana-Maria
Published: September 2017

Medical imaging data with thousands of spatially correlated data points are common in many fields. Methods that account for spatial correlation often require cumbersome matrix evaluations which are prohibitive for data of this size, and thus current work has either used low-rank approximations or analyzed data in blocks. We propose a method that accounts for nonstationarity, functional connectivity of distant regions of interest, and local signals, and can be applied to large multi-subject datasets using spectral methods combined with Markov Chain Monte Carlo sampling. We illustrate using simulated data that properly accounting for spatial dependence improves precision of estimates and yields valid statistical inference. We apply the new approach to study associations between cortical thickness and Alzheimer's disease, and find several regions of the cortex where patients with Alzheimer's disease are thinner on average than healthy controls.
Treatment of gastric eosinophilia by epicutaneous immunotherapy in piglets sensitized to peanuts
Authors: Mondoulet L. , Kalach N. , Dhelft V. , Larcher T. , Delayre‐Orthez C. , Benhamou P. H. , Spergel J. , Sampson H. A. , Dupont C.
Published: September 2017

Background

Eosinophilic gastrointestinal disorders (EGIDs) are hypersensitivity disorders frequently triggered by food allergy and manifested by mucosal eosinophilic infiltration at any level of the gastrointestinal tract. This study established a model of gastric eosinophilia in peanut‐sensitized piglets to evaluate the efficacy of epicutaneous immunotherapy (EPIT) for its treatment.

Methods

Experiments were carried out in piglets first sensitized by three intra‐peritoneal injections of peanut protein extract (PPE) with adjuvant, and then given PPE orally for 10 days, a sequence leading to gastric eosinophilia assessed by endoscopy. For 3 months, eight piglets received active EPIT, using Viaskin® loaded with PPE, applied daily on the ear, while eight received placebo EPIT (Placebo). Piglets were exposed to a second 10‐day period of PPE orally. Lesions were scored by endoscopy on the last day of PPE exposure. After killing, all parts of the digestive tract were analysed by a pathologist unaware of the piglets’ status. IgE response was measured, and mechanistic parameters were analysed in the spleen.

Results

After sensitization, a significant increase of total IgE was observed in sensitized compared to naive animals (61.1 ± 13.3 vs 27.8 ± 6 ng/mL, P < .01). Following oral intake of PPE, sensitized piglets developed moderate gastritis compared to naive piglets (1.5 vs 1.0, median score). After 3 months of immunotherapy, median IgE was significantly reduced in EPIT vs placebo piglets (61.4 ± 16.3 vs 105.9 ± 25.6 ng/mL, P < .01). Active EPIT significantly reduced gastric mucosal lesions induced by PPE oral intake (macroscopic score 0 [0‐2] vs 2 [1‐3], P < .01, respectively, active vs placebo) and gastric mucosa eosinophils counts (239 eosinophils/mm2 [59‐645] vs 2554 eosinophils/mm2 [462‐8057], P < .01, respectively active vs placebo). GATA‐3, IL‐5 and eotaxin mRNA expression decreased significantly after EPIT (P < .05).

Conclusions

This study describes a large animal model of gastric eosinophil in peanut‐sensitized piglets. Utilizing this model, we demonstrated the efficacy of EPIT in treating peanut‐induced EGIDs.
Increased prevalence of fracture and hypoglycaemia in young adults with concomitant type 1 diabetes mellitus and coeliac disease
Authors: Thong Eleanor P. , Wong Phillip , Dev Anouk , Ebeling Peter R. , Teede Helena J. , Milat Frances
Published: September 2017

Background

Both Type 1 diabetes mellitus (T1DM) and coeliac disease (CD) are independently associated with reduced bone mineral density (BMD) and increased fracture risk. Whilst poorer glycaemic control and increased microvascular complications have been described, the literature examining bone health and fractures in adults with concomitant T1DM and CD (T1DM + CD) is limited.

Objective

To evaluate fracture prevalence and explore associations with glycaemic control, hypoglycaemia and microvascular disease in T1DM + CD compared with T1DM alone.

Methods

We conducted a retrospective cross‐sectional study of young adults with T1DM, who attended diabetes clinics at a large tertiary referral centre between August 2016 and February 2017. Clinical information, radiological and biochemistry results were extracted from medical records. Patients with comorbid chronic kidney disease, glucocorticoid use, hypogonadism and untreated hyperthyroidism were excluded.

Results

A total of 346 patients with T1DM alone (median age 23 years) and 49 patients with T1DM + CD (median age 24 years) were included. Median age, gender distribution, BMI, haemoglobin A1c, daily insulin dose and serum 25‐hydroxyvitamin D levels were similar between groups. Higher adjusted fracture risk was observed in T1DM + CD compared with T1DM (12.2% vs 3.5%; OR 3.50, 95% CI 1.01‐12.12, P = .01), yet BMD was only measured in 6% of patients. The adjusted risk of hypoglycaemia ≥2/week was greater for T1DM + CD (55% vs 38%, OR 3.28, 95% CI 1.61‐6.69, P = .001); however, this was not independently associated with fractures. Replete vitamin D (≥ 50 nmol/L) was associated with less hypoglycaemia (OR 0.48, 95% CI 0.29‐0.80; P = .005), but not with fractures.

Conclusions

Coeliac disease status was independently associated with increased fracture prevalence in young adults with T1DM. Recurrent hypoglycaemia was also increased in T1DM + CD, although hypoglycaemia was not independently associated with fractures. Prospective studies are required to determine the long‐term impacts of CD on bone health and glycaemic control in patients with T1DM.
Utilization of high donor sequence number grafts in cardiac transplantation
Authors: Squiers John J. , DiMaio J. Michael , Saracino Giovanna , Qin Huanying , Felius Joost , Chamogeorgakis Themistokles , MacHannaford Juan C. , Rafael Aldo E. , Kale Parag , Joseph Susan M. , Hall Shelley A. , Gonzalez‐Stawinski Gonzalo V. , Lima Brian
Published: September 2017

Donor sequence number (DSN) represents the number of candidates to whom a graft was offered and declined prior to acceptance for transplantation. We sought to investigate the outcomes of patients receiving high DSN grafts. Consecutive isolated adult cardiac transplantations performed at a single‐center were reviewed. Recipients were grouped into standard (≤75th percentile) DSN and high (>75th percentile) DSN. A previously validated donor risk index was used to quantify the risk associated with donor grafts, and recipient outcomes were assessed. Overall, 254 patients were included: 194 standard DSN (range 1‐79) and 60 high DSN (range 82‐1723). High DSN grafts were harvested at greater distance (P < .001) with increased ischemia time (P < .001), resulting in a modest increase in donor risk index (1 point median difference, P = .014). High DSN recipients were less frequently listed as UNOS status 1A (P < .001). Despite a nonsignificant trend toward increased in‐hospital/30‐day mortality in high DSN recipients, there were no differences in primary graft dysfunction or 1‐year survival (high DSN 89% vs standard DSN 88%, P = .82). After adjustment for risk factors, high DSN was not associated with increased 1‐year mortality (hazard ratio 1.18, 95%‐CI 0.54‐2.58, P = .68).
Epithelial oral mucosal cells: Do they behave differently when exposed to oral carcinogens?
Authors: da Silva A. D. , Daroit N. B. , Cardoso F. B. , Laureano N. K. , Maraschin B. J. , Bündrich L. , Danilevicz C. K. , Magnusson A. S. , Visioli F. , Rados P. V.
Published: September 2017

Objective

To assess the level of maturation and proliferation of epithelial cells and the correlation with immunocytochemical expression of adhesion (E‐cadherin) and cell differentiation (involucrin) markers.

Methods

Cytopathological samples were obtained from four groups of patients: control (CG, n=30); alcohol/tobacco (ATG, n=31), leucoplakia (LG, n=31), and squamous cell carcinoma (SCCG, n=22). Cytopathological smears were collected from all groups for AgNOR, Papanicolaou and immunocytochemical staining.

Results

There was an increase in anucleated cells in ATG compared to CG and in LG compared to lesion‐free groups (P<.05). In addition, there was a higher rate of intermediate cells in lesion‐free groups than in LG (P=.001). When these findings were correlated with positive E‐cadherin expression, there was a smaller number of anucleated and intermediate cells (P<.05). The proliferation rate was higher in the SCCG than in the CG (P<.05) and in the ATG compared to LG (P<.05). Moreover, cell proliferation increased in the presence of positive E‐cadherin expression in the ATG and LG. No statistically significant results were obtained for involucrin analysis.

Conclusion

Cytopathology combined with quantitative techniques such as Papanicolaou, AgNOR, and immunocytochemical expression of E‐cadherin detects changes associated with oral carcinogenesis. The innovative approach used in this study allows assessing the expression of cell adhesion (E‐cadherin) and differentiation (involucrin) markers by means of oral mucosal cytopathology. The E‐cadherin imunocytochemical expression indicated changes associated with the oral carcinogenesis process. An increase in cell proliferation rate in oral squamous cell carcinoma group was associated with the lower immunoexpression of E‐cadherin. Cytopathology combined with quantitative techniques and immunocytochemical expression of E‐cadherin may detect early alterations associated with oral carcinogenesis.
Introduced megafauna are rewilding the Anthropocene
Authors: Lundgren Erick J. , Ramp Daniel , Ripple William J. , Wallach Arian D.
Published: September 2017

Large herbivorous mammals, already greatly reduced by the late‐Pleistocene extinctions, continue to be threatened with decline. However, many herbivorous megafauna (body mass ≥ 100 kg) have populations outside their native ranges. We evaluate the distribution, diversity and threat status of introduced terrestrial megafauna worldwide and their contribution towards lost Pleistocene species richness. Of 76 megafauna species, 22 (∼29%) have introduced populations; of these eleven (50%) are threatened or extinct in their native ranges. Introductions have increased megafauna species richness by between 10% (Africa) and 100% (Australia). Furthermore, between 15% (Asia) and 67% (Australia) of extinct species richness, from the late Pleistocene to today, have been numerically replaced by introduced megafauna. Much remains unknown about the ecology of introduced herbivores, but evidence suggests that these populations are rewilding modern ecosystems. We propose that attitudes towards introduced megafauna should allow for broader research and management goals.