bluuebunny/crossref_metadata_2025 huggingface dataset:
Maximum Arterial Contrast Concentrations With Computed Tomography and Left Ventriculography: Implications for Contrast Nephrotoxicity Risk
Authors: Gutierrez Nicholas M. , Newhouse Jeffrey H.
Published: May 2017

Purpose

Contrast nephropathy occurs more frequently after cardiac angiography, which usually includes left ventriculography via direct left ventricular injection, than after contrast-enhanced computed tomography (CT), despite the usually higher intravenous contrast dose used for CT. To determine whether maximum renal arterial contrast concentration is higher after left ventriculography, we assessed this parameter for both procedures.

Materials and Methods

Contrast concentration in abdominal aortic blood during contrast-enhanced CT was measured by performing CT densitometry of aortic blood before contrast, and in the arterial phase, in 100 adults undergoing abdominal CT. Densities were converted to contrast concentrations by scanning water phantoms containing 20 graded concentrations of contrast and comparing their densities to patient data. Because it was impossible to perform CT densitometry during cardiac angiography, aortic contrast concentrations were calculated from standard contrast doses and injection rates with the range of clinically encountered cardiac output rates, assuming ultimate steady state for blood/contrast mixing and normal data distribution.

Results

Maximum aortic (and hence renal arterial) concentrations were significantly higher (range, 6.68%–15.90%) after ventriculography than after CT (1.22%–5.80%). Because ventricular injection times are much shorter than published initial-appearance-to-maximum-concentration times after intravenous administration, the rate of change of contrast concentration is also higher after ventriculography than after CT.

Conclusion

Higher maximum renal arterial contrast concentration may be responsible for the greater risk of nephropathy after cardiac angiography than after doses for CT. The faster rate of change of renal arterial contrast concentration after ventriculography may also increase the likelihood of renal toxicity.

Clinical Relevance/Application

Maximum renal arterial contrast concentration, and/or the rapidity of change of this parameter, may be partly responsible for the risk of nephropathy. Controlling these factors might permit reduction of nephropathy risk; they also suggest avenues of research into the pathophysiology of contrast nephropathy.
Interreader Reliability and Clinical Validity of a Magnetic Resonance Imaging Grading System for Cervical Foraminal Stenosis
Authors: Lee Jung Eun , Park Hee Jin , Lee So Yeon , Lee Yong Taek , Kim Yong Bum , Lee Kyu Hong , Shin Hyunchul , Kwon Young Joon
Published: May 2017

Objective

Park system is a magnetic resonance imaging (MRI) grading system for cervical neural foraminal stenosis (CNFS) and consists of 4 grades (0–3) based on the foraminal shape of 45-degree T2-weighted oblique sagittal images. The objective of this study was to evaluate the interreader reliability of the Park system among radiologists, residents, and clinicians. This study also assessed the correlations between radiologic and clinical findings.

Material and Methods

A total of 289 patients (men:women = 155:134, mean age = 50 years) who underwent oblique sagittal MRI of the cervical spine at our hospital were included. According to the MR grading system suggested by Park et al (Br J Radiol 2013;86:20120515), 2 radiologists, 2 trainees, and 2 clinicians measured CNFS grade at the most narrow point. A neurosurgeon assessed the associated clinical manifestations. κ statistics were used to analyze the interreader agreement among the radiologists and clinicians. The clinical correlations between grade and positive clinical manifestations were assessed with R using nonparametric correlation analysis (Spearman correlation).

Results

The overall interreader agreements between radiologists, between trainees, between clinicians, and between radiologists and clinicians were almost perfect (κ = 0.80–0.96). There were moderate correlations between grade and clinical manifestations in each group (R = 0.562–0.669). There were moderate to relatively high correlations between grade and neurologic manifestations based on cervical level (R = 0.570–0.715) (all P < 0.05).

Conclusions

Regardless of reader experience, there was substantial to almost perfect interreader reliability with the Park system for CNFS based on oblique sagittal MRI.
Age Shock Index is Superior to Shock Index and Modified Shock Index for Predicting Long-Term Prognosis in Acute Myocardial Infarction
Authors: Yu Tongtong , Tian Chunyang , Song Jia , He Dongxu , Sun Zhijun , Sun Zhaoqing
Published: May 2017

Background:

Shock index (SI) has been reported to help us predict adverse prognosis in patients with acute myocardial infarction (AMI) undergoing percutaneous coronary intervention (PCI). However, the prognostic value of age SI and modified shock index (MSI) in AMI undergoing PCI is unknown. Moreover, the prognostic performance of admission age SI is not compared with SI, MSI, and the Global Registry of Acute Coronary Events (GRACE) risk score.

Methods:

One thousand eight hundred sixty-four AMI patients undergoing PCI were analyzed in a retrospective cohort study. Clinical endpoint was all-cause mortality. The predictive performance of new models was assessed by C-statistic, Hosmer–Lemeshow test, Nagelkerke-R2, Brier scores, integrated discrimination improvement (IDI), and net reclassification improvement (NRI).

Results:

Multivariate analysis showed that higher age SI and MSI were both associated with a higher rate of all-cause mortality [age SI: hazard ratios (HR) = 1.025, 95% CI = 1.010–1.040, P = 0.001; MSI: HR = 2.902, 95% CI = 1.180–7.137, P = 0.020]. The prognostic performance of admission age SI was similar to the GRACE systems for predicting all-cause mortality (C-statistic: z = 0.437, P = 0.662; IDI: −0.005, P = 0.474; NRI: −0.028, P = 0.257), but better than admission SI (C-statistic: z = 3.944, P < 0.001; IDI: 0.012, P = 0.016; NRI: 0.472, P < 0.001) and admission MSI (C-statistic: z = 3.214, P = 0.001; IDI: 0.011, P = 0.001; NRI: 0.561, P < 0.001).

Conclusions:

Age SI alone can identify patients at high risk of death in AMI patients undergoing PCI. It is similar to GRACE but better than SI and MSI for predicting all-cause mortality. However, age SI is easier to calculate than GRACE.
A persistent lack of International representation on editorial boards in environmental biology
Authors: Espin Johanna , Palmas Sebastian , Carrasco-Rueda Farah , Riemer Kristina , Allen Pablo E. , Berkebile Nathan , Hecht Kirsten A. , Kastner-Wilcox Kay , Núñez-Regueiro Mauricio M. , Prince Candice , Rios Constanza , Ross Erica , Sangha Bhagatveer , Tyler Tia , Ungvari-Martin Judit , Villegas Mariana , Cataldo Tara T. , Bruna Emilio M.
Published: May 2017

The scholars comprising journal editorial boards play a critical role in defining the trajectory of knowledge in their field. Nevertheless, studies of editorial board composition remain rare, especially those focusing on journals publishing research in the increasingly globalized fields of science, technology, engineering, and math (STEM). Using metrics for quantifying the diversity of ecological communities, we quantified international representation on the 1985-2014 editorial boards of twenty-four environmental biology journals. Over the course of three decades there were 3831 unique scientists based in 70 countries that served as editors. The size of the editorial community increased over time – there were 420% more editors serving in 2014 than in 1985 – as did the number of countries in which editors were based. Nevertheless, editors based outside the ‘Global North’ (the group of economically developed countries with high per capita Gross Domestic Product (GDP) that collectively concentrate most global wealth) were extremely rare. Furthermore, 67.06% of all editors were based in either the USA or UK. Consequently, Geographic Diversity – already low in 1985 – remained unchanged through 2014. We argue that this limited geographic diversity can detrimentally affect the creativity of scholarship published in journals, the progress and direction of research, the composition of the STEM workforce, and the development of science in Latin America, Africa, the Middle East, and much of Asia (i.e., the ‘Global South’).
taxMaps - Ultra-comprehensive and highly accurate taxonomic classification of short-read data in reasonable time
Authors: Corvelo André , Clarke Wayne E. , Robine Nicolas , Zody Michael C.
Published: May 2017

High-throughput sequencing is a revolutionary technology for the analysis of metagenomic samples. However, querying large volumes of reads against comprehensive DNA/RNA databases in a sensitive manner can be compute-intensive. Here, we present taxMaps, a highly efficient, sensitive and fully scalable taxonomic classification tool, capable of delivering classification accuracy comparable to that of BLASTn, but at up to 3 orders of magnitude less computational cost. taxMaps is freely available for academic and non-commercial research purposes athttps://github.com/nygenome/taxmaps.
Selecting short DNA fragments in plasma improves detection of circulating tumour DNA
Authors: Mouliere Florent , Piskorz Anna M. , Chandrananda Dineika , Moore Elizabeth , Morris James , Smith Christopher G. , Goranova Teodora , Heider Katrin , Mair Richard , Supernat Anna , Gounaris Ioannis , Ros Susana , Wan Jonathan C. M. , Jimenez-Linan Mercedes , Gale Davina , Brindle Kevin , Massie Charles E. , Parkinson Christine A. , Brenton James D. , Rosenfeld Nitzan
Published: May 2017

Introductory paragraph

Non-invasive analysis of cancer genomes using cell-free circulating tumour DNA (ctDNA) is being widely implemented for clinical indications. The sensitivity for detecting the presence of ctDNA and genomic changes in ctDNA is limited by its low concentration compared to cell-free DNA of non-tumour origin. We studied the feasibility for enrichment of ctDNA by size selection, in plasma samples collected before and during chemotherapy treatment in 13 patients with recurrent high-grade serous ovarian cancer. We evaluated the effects using targeted and whole genome sequencing. Selecting DNA fragments between 90-150 bp before analysis yielded enrichment of mutated DNA fraction of up to 11-fold. This allowed identification of adverse copy number alterations, includingMYCamplification, otherwise not observed. Size selection allows detection of tumour alterations masked by non-tumour DNA in plasma and could help overcome sensitivity limitations of liquid biopsy for applications in early diagnosis, detection of minimal residual disease, and genomic profiling.
Effect of initial body orientation on escape probability in prey fish escaping from predators
Authors: Kimura Hibiki , Kawabata Yuuki
Published: May 2017

Since the escape response is crucial to survival and hence to the fitness of species, several studies have attempted to elucidate the kinematic and behavioral components of the response that affect evasion outcome. The prey’s body orientation relative to a predator at the onset of the escape response (initial orientation) could affect evasion outcome, because the turn angle and its duration before the initiation of escape locomotion would be smaller when the initial orientation is more away from the predator. We tested this hypothesis by recording the escape responses of juvenile red sea bream (Pagrus major) in response to the predatory scorpion fish (Sebastiscus marmoratus) using a high-speed video camera. Our results show that an increased initial orientation (i.e., more away from the predator) increases escape probability. Our results also indicate that an increase in the initial orientation decreases the turn angle and its duration. The flight initiation distance tends to be small when the initial orientation is away from the predator, suggesting that the prey might have a blind zone of sensory perception. These findings highlight the importance of incorporating initial orientation into both empirical and theoretical studies of the kinematics of predator-prey interactions.

Summary statement

Our predator-prey experiments reveal that the prey’s initial body orientation relative to a predator affects the prey’s turn angle and its duration, and consequently affects escape probability.
Genetic stratification of depression in UK Biobank suggests a subgroup linked to age of natural menopause
Authors: Howard David M. , Folkersen Lasse , Coleman Jonathan R. I. , Adams Mark J. , Glanville Kylie , Werge Thomas , Hagenaars Saskia P. , Han Buhm , Porteous David , Campbell Archie , Clarke Toni-Kim , Breen Gerome , Sullivan Patrick F. , Wray Naomi R. , Lewis Cathryn M. , McIntosh Andrew M.
Published: May 2017

Depression is a common and clinically heterogeneous mental health disorder that is frequently comorbid with other diseases and conditions. Stratification of depression may align sub-diagnoses more closely with their underling aetiology and provide more tractable targets for research and effective treatment. In the current study, we investigated whether genetic data could be used to identify subgroups within people with depression using the UK Biobank. Examination of cross-locus correlations was used to test for evidence of subgroups by examining whether there was clustering of independent genetic variants associated with eleven other complex traits and disorders in people with depression. We found evidence of a subgroup within depression using age of natural menopause variants (P= 1.69 × 10−3) and this effect remained significant in females (P= 1.18 × 10−3), but not males (P= 0.186). However, no evidence for this subgroup (P> 0.05) was found in Generation Scotland, iPSYCH, a UK Biobank replication cohort or the GERA cohort. In the UK Biobank, having depression was also associated with a later age of menopause (beta = 0.34, standard error = 0.06,P= 9.92 × 10−8). A potential age of natural menopause subgroup within depression and the association between depression and a later age of menopause suggests that they partially share a developmental pathway.
The equivalent arc ratio for auditory space
Authors: Brimijoin W. Owen
Published: May 2017

The minimum audible movement angle increases as a function of source azimuth. If listeners do not perceptually compensate for this change in acuity, then sounds rotating around the head should appear to move faster at the front than at the side. We examined whether judgments of relative amounts of acoustic motion depend on signal center angle and found that the azimuth of two signals strongly affects their point of subjective similarity for motion. Signal motion centered at 90° had to be roughly twice as large as motion centered at 0° to be judged as equivalent. This distortion of acoustic space around the listener suggests that the perceived velocity of moving sound sources changes as a function of azimuth around the head. The “equivalent arc ratio,” a mathematical framework based on these results, is used to successfully provide quantitative explanations for previously documented discrepancies in spatial localization, motion perception, and head-to-world coordinate transformations.
Quantitative RNA-seq meta analysis of alternative exon usage in C. elegans
Authors: Tourasse Nicolas , Millet Jonathan R. M. , Dupuy Denis
Published: May 2017

Almost twenty years after the completion of the C. elegans genome sequence, gene structure annotation is still an ongoing process with new evidence for gene variants still being regularly uncovered by additional in-depth transcriptome studies. While alternative splice forms can allow a single gene to encode several functional isoforms the question of how much spurious splicing is tolerated is still heavily debated.

Here we gathered a compendium of 1,682 publicly available C. elegans RNA-seq datasets to increase the dynamic range of detection of RNA isoforms and obtained robust measurements of the relative abundance of each splicing event. While most of the splicing reads come from reproducibly detected splicing events, a large fraction of purported junctions are only supported by a very low number of reads. We devised an automated curation method that takes into account the expression level of each gene to discriminate robust splicing events from potential biological noise. We found that rarely used splice sites disproportionately come from highly expressed genes and are significantly less conserved in other nematode genomes than splice sites with a higher usage frequency.

Our increased detection power confirmed trans-splicing for at least 84% of C. elegans protein coding genes. The genes for which trans-splicing was not observed are overwhelmingly low expression genes, suggesting that the mechanism is pervasive but not full captured by organism-wide RNA-Seq.

We generated annotated gene models including quantitative exon usage information for the entire C. elegans genome. This allows users to visualize at a glance the relative expression of each isoform for their gene of interest.
The unfolded protein response switches from pro-survival to pro-apoptotic to cap the extent of endoplasmic reticulum expansion
Authors: Vitale Milena , Orsi Andrea , Bakunts Anush , Lari Federica , Tadè Laura , Cattaneo Angela , Sitia Roberto , Raimondi Andrea , Bachi Angela , Anken Eelco van
Published: May 2017

Insufficient folding capacity of the endoplasmic reticulum (ER) activates the unfolded protein response (UPR) to restore homeostasis. Yet, how the UPR achieves and evaluates ER homeostatic readjustment is poorly understood. In a HeLa cell model we show that, upon a severe proteostatic insult that eclipses the ER chaperone BiP, the UPR transitions from acute full-gear activation to chronic submaximal activation, when BiP is in excess again. As such, the UPR-driven ER expansion is pro-survival, primarily via the UPR transducer ATF6α. Simultaneous abrogation of ER-associated degradation (ERAD) leads to chronic full-gear UPR activation and further ER expansion, but the UPR transducers IRE1α and PERK turn pro-apoptotic. Pro-survivalXBP1mRNA processing by IRE1α is then trumped since unsplicedXBP1mRNA is depleted and IRE1α’s endonuclease activity is unleashed against other RNAs. Thus, the IRE1α/XBP1relay serves as a capacitor of ER expansion that heralds cell death if the expansion is deemed excessive.
Central amygdala CRF pathways in alcohol dependence
Authors: de Guglielmo Giordano , Kallupi Marsida , Pomrenze Matthew B. , Crawford Elena , Simpson Sierra , Schweitzer Paul , Koob George F. , Messing Robert O. , George Olivier
Published: May 2017

Alcohol withdrawal activates a neuronal ensemble in the central nucleus of the amygdala (CeA) that is responsible for high levels of uncontrolled alcohol drinking. However, the neuronal phenotypes and circuits controlled by these neurons are unknown. We investigated the cellular identity of this CeA neuronal ensemble and found that most neurons expressed corticotropin-releasing factor (CRF). UsingCrh-Cre transgenic rats combined within vivooptogenetics, we tested the role of CeA CRF neurons and their projections in excessive alcohol self-administration during withdrawal. Rats were injected with AAV-DIO-NpHR-eYFP or AAV-DIO-eYFP and implanted with optical fibers over the CeA. Animals were then exposed to chronic intermittent ethanol vapor to induce alcohol dependence. Inactivation of CeA CRF neurons decreased alcohol drinking in dependent rats to non-dependent levels and completely suppressed activation of the CeA neuronal ensemble (Fos+neurons) during withdrawal. No effects were observed on water or saccharin self-administration. In a second experiment, CeA CRF neurons were infected with AAV-DIO-NpHR-eYFP and optical fibers were implanted into downstream projection regions, including the bed nucleus of the stria terminalis (BNST), lateral hypothalamus (LH), parasubthalamic nucleus (pSTN), substantia innominata (SI), and parabrachial nuclei (PBN). Optogenetic inactivation of CRF terminals in the BNST reduced alcohol drinking and withdrawal signs, whereas inactivation of all other projections had no effect. These results demonstrate that CeA CRF neurons and their projections to the BNST drive excessive alcohol drinking and withdrawal in dependent rats.
Transcriptomic correlates of neuron electrophysiological diversity
Authors: Tripathy Shreejoy J. , Toker Lilah , Li Brenna , Crichlow Cindy-Lee , Tebaykin Dmitry , Ogan Mancarci B. , Pavlidis Paul
Published: May 2017

How neuronal diversity emerges from complex patterns of gene expression remains poorly understood. Here we present an approach to understand electrophysiological diversity through gene expression by integrating transcriptomics with intracellular electrophysiology. Using a brain-wide dataset of 34 neuron types, we identified 420 genes whose expression levels significantly correlated with variability in one or more of 11 electrophysiological parameters. The majority of these correlations were consistent in an independent sample of 12 visual cortex cell types. Many associations reported here have the potential to provide new insights into how neurons generate functional diversity, and correlations of ion channel genes likeGabrdandScn1a(Nav1.1) with resting potential and spiking frequency are consistent with known causal mechanisms. These results suggest that despite the complexity linking gene expression to electrophysiology, there are likely some general principles that govern how individual genes establish phenotypic diversity across very different cell types.
Spindle assembly checkpoint strength is governed by cell size and PAR-mediated cell fate determination inC. elegans
Authors: Gerhold Abigail R. , Poupart Vincent , Labbé Jean-Claude , Maddox Paul S.
Published: May 2017

The spindle assembly checkpoint (SAC) is a conserved mitotic regulator that preserves genome stability. Despite its central role in preserving the fidelity of mitosis, the strength of the SAC varies widely between cell types. How the SAC is adapted to different cellular contexts remains largely unknown. Here we show that both cell size and cell fate impact SAC strength. While smaller cells have a stronger SAC, cells with a germline fate show increased SAC activity relative to their somatic counterparts across all cell sizes. We find that enhanced SAC activity in the germline blastomere P1requires proper specification of cell fate downstream of the conserved PAR polarity proteins, supporting a model in which checkpoint factors are distributed asymmetrically during early germ cell divisions. Our results indicate that size scaling of SAC activity is modulated by cell fate and reveal a novel interaction between asymmetric cell division and the SAC.
Food Webs Over Time: Evaluating the Variability of Degree Distribution on Ecological Networks
Authors: Lopez Daniela N , Camus Patricio A , Valdivia Nelson , Estay Sergio A
Published: May 2017

Although networks analysis has moved from static to dynamic, ecological networks are still analyzed as time-aggregated units where time-specific interactions are aggregated into one single network. As a result, several questions arise such as what is the functional form of and how variable is the topology of time-specific versus time-aggregated ecological networks? Furthermore, it is yet unknown to what extent the structure of time-aggregated networks is representative of the dynamics of the community. Here, we compared the topology of time-specific and time-aggregated networks by analyzing a set of intertidal networks containing more than 1,000 interactions, and assessed the spatiotemporal dynamics of their degree distributions. By fitting different distribution models, we found that the out-degree distributions of seasonal and time-aggregated networks were best described by an exponential model while the in-degree distributions were best described by a discrete generalized beta model. The degree distributions of the seasonal networks were highly temporally variable and are significantly different from those of time-aggregated networks. We observed that seasonal degree distributions converged toward time-aggregated network distributions after 1.5 years of sampling. Our results highlight the importance of understanding the dynamics of ecological networks, which can show topological characteristics significantly different from those of time-aggregated networks.
Tumor-infiltrating immune repertoires captured by single-cell barcoding in emulsion
Authors: Briggs Adrian W. , Goldfless Stephen J. , Timberlake Sonia , Belmont Brian J. , Clouser Christopher R. , Koppstein David , Sok Devin , Heiden Jason Vander A. , Tamminen Manu V. , Kleinstein Steven H. , Burton Dennis R. , Church George M. , Vigneault Francois
Published: May 2017

Tumor-infiltrating lymphocytes (TILs) are critical to anti-cancer immune responses, but their diverse phenotypes and functions remain poorly understood and challenging to study. We therefore developed a single-cell barcoding technology for deep characterization of TILs without the need for cell-sorting or culture. Our emulsion-based method captures full-length, natively paired B-cell and T-cell receptor (BCR and TCR) sequences from lymphocytes among millions of input cells. We validated the method with 3 million B-cells from healthy human blood and 350,000 B-cells from an HIV elite controller, before processing 400,000 cells from an unsorted dissociated ovarian adenocarcinoma and recovering paired BCRs and TCRs from over 11,000 TILs. We then extended the barcoding method to detect DNA-labeled antibodies, allowing ultra-high throughput, simultaneous protein detection and RNA sequencing from single cells.
Inhibitory effect of the urothelium/lamina propria on female porcine urethral contractility & effect of age
Authors: Folasire Oladayo S , Chess‐Williams Russ , Sellers Donna J
Published: May 2017

The urethral uroepithelium has been implicated in urethral sensation and maintenance of continence. However, relatively little is known about the function of the urethral urothelium compared with that of the bladder. The aim of the study was to examine the role of the urothelium/lamina propria on contractility of the porcine urethra, along with the influence of nitric oxide, prostaglandins and ageing. Porcine urethral tissues, intact and denuded of urothelium/lamina propria, were mounted in tissue baths and contractions to noradrenaline, phenylephrine and carbachol obtained. Contractions in the presence of Nώ–nitro‐l‐arginine (100 μmol/L) and indomethacin (10 μmol/L) were examined, along with contractions of tissues from young (6 months) and older (3 years) animals. The urothelium/lamina propria of the urethra significantly inhibited contractions to carbachol, noradrenaline and phenylephrine. This inhibitory effect was not significantly different for the three agonists (58.7±10.3%, 60.4±12.6% and 39.4±12.2% inhibition; n=4‐7), and was also observed when denuded tissues were co‐incubated with a second tissue with intact urothelium/lamina propria (40.6±7.5% inhibition; n=6). Inhibition of nitric oxide and prostaglandin production did not attenuate the inhibitory effect of the urothelium/lamina propria on noradrenaline contractions. In addition, ageing did not alter the inhibitory effect for either phenylephrine contractions (33.9±2.2% vs 41.0±9.7%, young vs older urethral tissues) or noradrenaline contractions (32.9±11.1% vs 53.7±11.0%). In conclusion the urothelium/lamina propria of the urethra has an inhibitory effect on receptor‐mediated urethral contraction. This inhibition is due to the release of a diffusible factor, and the effect is not mediated by nitric oxide or prostaglandins, or affected by age.
Highly expressed long non‐coding RNA CRNDE promotes cell proliferation through PI3K/AKT signalling in non‐small cell lung carcinoma
Authors: Liu Xiao‐Xiong , Xiong Han‐Peng , Huang Jiu‐Sheng , Qi Kai , Xu Jian‐Jun
Published: May 2017

Recently, numerous studies have revealed that long non‐coding RNAs (lncRNAs) play complex roles in various lung diseases, while the colorectal neoplasia differentially expressed (CRNDE) functions in non‐small cell lung carcinomas (NSCLC) remain largely unknown. In the present study, we investigate the role and mechanism of CRNDE in the progression of NSCLC. The mRNA level of CRNDE in NSCLC patients and cells was detected by qRT‐PCR. The influence of CRNDE silencing or over‐expression on NSCLC cell proliferation and growth were assessed by MTT and flow cytometry, respectively. We also investigated the effect of abnormal CRNDE expression on cyclins and PI3K/AKT pathway. Furthermore, si‐CRNDE NSCLC cell lines were injected subcutaneously into nude mice to explore tumour formation in vivo. The expression of CRNDE was significantly upregulated in NSCLC patients and cells. In addition, both loss and gain function assays revealed that CRNDE promoted NSCLC cell proliferation and growth both in vitro and in vivo. Moreover, CRNDE regulated the cell cycle transition from G0/G1 stage to S stage and modulated the expression of CDK4, CDK6 and CCNE1. We further illustrated that CRNDE activated PI3K/AKT signalling in NSCLC cell lines. In conclusion, CRNDE was highly expressed in NSCLC malignant tissues and the heightened CRNDE strongly promoted NSCLC cell proliferation and growth through activating PI3K/AKT signalling; our results shed a light on utilizing CRNDE as a potential novel therapeutic target for the treatment of NSCLC.
Dose discrepancy between planning system estimation and measurement in spine stereotactic body radiation therapy: A case report
Authors: Arumugam Sankar , Berry Megan , Ochoa Cesar , Xing Aitang , Beeksma Bradley , Vial Philip
Published: May 2017

Stereotactic body radiation therapy (SBRT) to treat spinal metastases has shown excellent clinical outcomes for local control. High dose gradients wrapping around spinal cord make this treatment technically challenging. In this work, we present a spine SBRT case where a dosimetric error was identified during pre‐treatment dosimetric quality assurance (QA). A patient with metastasis in T7 vertebral body consented to undergo SBRT. A dual arc volumetric modulated arc therapy plan was generated on the Pinnacle treatment planning system (TPS) with a 6 MV Elekta machine using gantry control point spacing of 4°. Standard pre‐treatment QA measurements were performed, including ArcCHECK, ion chamber in CTV and spinal cord (SC) region and film measurements in multiple planes. While the dose measured at CTV region showed good agreement with TPS, the dose measured to the SC was significantly higher than reported by TPS in the original and repeat plans. Acceptable agreement was only achieved when the gantry control point spacing was reduced to 3°. A potentially harmful dose error was identified by pre‐treatment QA. TPS parameter settings used safely in conventional treatments should be re‐assessed for complex treatments.
Comparative analysis of DNA extraction methods to study the body surface microbiota of insects: A case study with ant cuticular bacteria
Authors: Birer Caroline , Tysklind Niklas , Zinger Lucie , Duplais Christophe
Published: May 2017

High‐throughput sequencing of the 16S rRNA gene has considerably helped revealing the essential role of bacteria living on insect cuticles in the ecophysiology and behaviour of their hosts. However, our understanding of host‐cuticular microbiota feedbacks remains hampered by the difficulties of working with low bacterial DNA quantities as with individual insect cuticle samples, which are more prone to molecular biases and contaminations. Herein, we conducted a methodological benchmark on the cuticular bacterial loads retrieved from two Neotropical ant species of different body size and ecology: Atta cephalotes (~15 mm) and Pseudomyrmex penetrator (~5 mm). We evaluated the richness and composition of the cuticular microbiota, as well as the amount of biases and contamination produced by four DNA extraction protocols. We also addressed how bacterial community characteristics would be affected by the number of individuals or individual body size used for DNA extraction. Most extraction methods yielded similar results in terms of bacterial diversity and composition for A. cephalotes (~15 mm). In contrast, greater amounts of artefactual sequences and contaminations, as well as noticeable differences in bacterial community characteristics were observed between extraction methods for P. penetrator (~5 mm). We also found that large (~15 mm) and small (~5 mm) A. cephalotes individuals harbour different bacterial communities. Our benchmark suggests that cuticular microbiota of single individual insects can be reliably retrieved provided that blank controls, appropriate data cleaning, and individual body size and functional role within insect society are considered in the experiment.
Sound levels in a neonatal intensive care unit significantly exceeded recommendations, especially inside incubators
Authors: Parra Johanna , de Suremain Aurelie , Berne Audeoud Frederique , Ego Anne , Debillon Thierry
Published: May 2017

Aim

This study measured sound levels in a 2008 built French neonatal intensive care unit (NICU) and compared them to the 2007 American Academy of Pediatrics (AAP) recommendations. The ultimate aim was to identify factors that could influence noise levels.

Methods

The study measured sound in 17 single or double rooms in the NICU. Two dosimeters were installed in each room, one inside and one outside the incubators, and these conducted measurements over a 24‐hour period. The noise metrics measured were the equivalent continuous sound level (Leq), the maximum noise level (Lmax) and the noise level exceeded for 10% of the measurement period (L10).

Results

The mean Leq, L10 and Lmax were 60.4, 62.1 and 89.1 decibels (dBA), which exceeded the recommended levels of 45, 50 and 65 dBA (p < 0.001), respectively. The Leq inside the incubator was significantly higher than in the room (+8 dBA, p < 0.001). None of the newborns’ characteristics, the environment or medical care was correlated to an increased noise level, except for a postconceptional age below 32 weeks.

Conclusion

The sound levels significantly exceeded the AAP recommendations, particularly inside incubators. A multipronged strategy is required to improve the sound environment and protect the neonates’ sensory development.
The pharmacokinetic interaction between ivacaftor and ritonavir in healthy volunteers
Authors: Liddy Anne Marie , McLaughlin Gavin , Schmitz Susanne , D'Arcy Deirdre M. , Barry Michael G.
Published: May 2017

Aims

The aim of this study was to determine the pharmacokinetic interaction between ivacaftor and ritonavir.

Methods

A liquid chromatography mass spectrometry (LC–MS) method was developed for the measurement of ivacaftor in plasma. An open‐label, sequential, cross‐over study was conducted with 12 healthy volunteers. Three pharmacokinetic profiles were assessed for each volunteer: ivacaftor 150 mg alone (study A), ivacaftor 150 mg plus ritonavir 50 mg daily (study B), and ivacaftor 150 mg plus ritonavir 50 mg daily after two weeks of ritonavir 50 mg daily (study C).

Results

Addition of ritonavir 50 mg daily to ivacaftor 150 mg resulted in significant inhibition of the metabolism of ivacaftor. Area under the plasma concentration–time curve from time 0 to infinity (AUC0‐inf obv) increased significantly in both studies B and C compared to study A (GMR [95% CI] 19.71 [13.18–31.33] and 19.77 [14.0–27.93] respectively). Elimination half‐life (t1/2) was significantly longer in both studies B and C compared to study A (GMR [95% CI] 11.14 [8.72–13.62] and 9.72 [6.68–12.85] respectively). There was no significant difference in any of the pharmacokinetic parameters between study B and study C.

Conclusion

Ritonavir resulted in significant inhibition of the metabolism of ivacaftor. These data suggest that ritonavir may be used to inhibit the metabolism of ivacaftor in patients with cystic fibrosis (CF). Such an approach may increase the effectiveness of ivacaftor in ‘poor responders’ by maintaining higher plasma concentrations. It also has the potential to significantly reduce the cost of ivacaftor therapy.
Cognitive deficits caused by prefrontal cortical and hippocampal neural disinhibition
Authors: Bast Tobias , Pezze Marie , McGarrity Stephanie
Published: May 2017

We review recent evidence concerning the significance of inhibitory GABA transmission and of neural disinhibition, that is, deficient GABA transmission, within the prefrontal cortex and the hippocampus, for clinically relevant cognitive functions. Both regions support important cognitive functions, including attention and memory, and their dysfunction has been implicated in cognitive deficits characterizing neuropsychiatric disorders. GABAergic inhibition shapes cortico‐hippocampal neural activity, and, recently, prefrontal and hippocampal neural disinhibition has emerged as a pathophysiological feature of major neuropsychiatric disorders, especially schizophrenia and age‐related cognitive decline. Regional neural disinhibition, disrupting spatio‐temporal control of neural activity and causing aberrant drive of projections, may disrupt processing within the disinhibited region and efferent regions. Recent studies in rats showed that prefrontal and hippocampal neural disinhibition (by local GABA antagonist microinfusion) dysregulates burst firing, which has been associated with important aspects of neural information processing. Using translational tests of clinically relevant cognitive functions, these studies showed that prefrontal and hippocampal neural disinhibition disrupts regional cognitive functions (including prefrontal attention and hippocampal memory function). Moreover, hippocampal neural disinhibition disrupted attentional performance, which does not require the hippocampus but requires prefrontal‐striatal circuits modulated by the hippocampus. However, some prefrontal and hippocampal functions (including inhibitory response control) are spared by regional disinhibition. We consider conceptual implications of these findings, regarding the distinct relationships of distinct cognitive functions to prefrontal and hippocampal GABA tone and neural activity. Moreover, the findings support the proposition that prefrontal and hippocampal neural disinhibition contributes to clinically relevant cognitive deficits, and we consider pharmacological strategies for ameliorating cognitive deficits by rebalancing disinhibition‐induced aberrant neural activity.

Linked Articles

This article is part of a themed section on Pharmacology of Cognition: a Panacea for Neuropsychiatric Disease? To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.19/issuetoc
α‐Conotoxins active at α3‐containing nicotinic acetylcholine receptors and their molecular determinants for selective inhibition
Authors: Cuny Hartmut , Yu Rilei , Tae Han‐Shen , Kompella Shiva N , Adams David J
Published: May 2017

Neuronal α3‐containing nicotinic acetylcholine receptors (nAChRs) in the peripheral nervous system (PNS) and non‐neuronal tissues are implicated in a number of severe disease conditions ranging from cancer to cardiovascular diseases and chronic pain. However, despite the physiological characterization of mouse models and cell lines, the precise pathophysiology of nAChRs outside the CNS remains not well understood, in part because there is a lack of subtype‐selective antagonists. α‐Conotoxins isolated from cone snail venom exhibit characteristic individual selectivity profiles for nAChRs and, therefore, are excellent tools to study the determinants for nAChR‐antagonist interactions. Given that human α3β4 subtype selective α‐conotoxins are scarce and this is a major nAChR subtype in the PNS, the design of new peptides targeting this nAChR subtype is desirable. Recent studies using α‐conotoxins RegIIA and AuIB, in combination with nAChR site‐directed mutagenesis and computational modelling, have shed light onto specific nAChR residues, which determine the selectivity of the α‐conotoxins for the human α3β2 and α3β4 subtypes. Publications describing the selectivity profile and binding sites of other α‐conotoxins confirm that subtype‐selective nAChR antagonists often work through common mechanisms by interacting with the same structural components and sites on the receptor.

Linked Articles

This article is part of a themed section on Nicotinic Acetylcholine Receptors. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.11/issuetoc
A de novo missense mutation in SLC12A5 found in a compound heterozygote patient with epilepsy of infancy with migrating focal seizures
Authors: Saito T. , Ishii A. , Sugai K. , Sasaki M. , Hirose S.
Published: May 2017

Epilepsy of infancy with migrating focal seizures (EIMFS) is an infantile epileptic encephalopathy characterized by refractory seizures, severe psychomotor delay, and multiple moving epileptic discharges. The genetic etiology of EIMFS is relatively homogeneous with the majority of causative mutations found in KCNT1. Currently, gene panel or whole‐exome sequencing is used for testing. To verify the pathogenicity of a variant, co‐segregation of the variant and the disorder in a pedigree is important; hence, de novo mutations that are judged to be deleterious may be considered pathogenic because the patients are isolated. In contrast, in cases from non‐consanguineous families, genes that cause disorders in a recessive manner should remain as potential candidates. Herein, we performed gene panel sequencing of a patient with EIMFS from a non‐consanguineous family, and found a compound heterozygous constellation consisting of a maternally inherited p.Ser399Leu and a de novo p.Arg880Leu in SLC12A5, which encodes the neuronal KCC2 cotransporter. These unique mutations show gene variants that act in a recessive manner may be pathogenic for patients from non‐consanguineous families.
Do glycoalbumin levels preferentially reflect changes in postprandial glucose excursions?
Authors: Paul S. K. , Holman R. R.
Published: May 2017

Aims

To evaluate whether plasma glycated albumin, which provides an integrated measure of plasma glucose levels over the preceding 2–4 weeks, better reflects changes in postprandial glucose excursions than HbA1c.

Methods

People with suboptimum glycaemic control on dual oral therapy were enrolled in the Treating‐to‐Target‐in‐Type 2 diabetes (4‐T) trial, in which participants were randomized to the addition of once‐daily basal insulin, twice‐daily biphasic insulin or thrice‐daily prandial insulin. Glycated albumin levels were assayed enzymatically from baseline and 1‐year fasting plasma samples. We evaluated robust correlations of glycated albumin and HbA1c both with fasting and postprandial glucose levels at these two time points, and with insulin‐induced changes in the postprandial excursion.

Results

Requisite data were available for 625 of the participants in the 4‐T trial. Their mean (±sd) age was 62 ± 10 years and body weight was 85.8 ± 15.9 kg, and their median (interquartile range) diabetes duration was 9 (6, 13) years. Partial correlations at baseline and 1 year between postprandial glucose excursions and glycated albumin/HbA1c, after adjusting for fasting glucose, were 0.27/0.15 and 0.22/0.18, respectively. Glycated albumin, compared with HbA1c, explained 66% more of the variation in postprandial glucose excursions at baseline. At 1 year, postprandial glucose excursions on basal, biphasic and prandial and insulin therapy were reduced by 0.43, 0.78 and 1.88 mmol/l, respectively. These reductions were associated with changes in both glycated albumin and HbA1c (P < 0.01), with a stronger association for glycated albumin.

Conclusion

Changes in glycated albumin and HbA1c reflect changes in postprandial glucose excursions to a similar extent.
Developing preference‐based measures for diabetes: DHP‐3D and DHP‐5D
Authors: Mulhern B. , Labeit A. , Rowen D. , Knowles E. , Meadows K. , Elliott J. , Brazier J.
Published: May 2017

Aims

The aim of this study was to develop two diabetes‐specific preference‐based measures [the Diabetes Health Profile–3 Dimension (DHP‐3D) and the Diabetes Health Profile–5 Dimension (DHP‐5D)] for use in the calculation of Quality Adjusted Life Years, a key outcome in economic evaluation. These measures were based on the non‐preference‐based instrument the Diabetes Health Profile.

Methods

For DHP‐3D, psychometric and Rasch analyses were used to develop a health state classification system based on the Diabetes Health Profile–18 (DHP‐18). The DHP‐5D added two dimensions to the DHP‐3D to extend the range of impacts measured. Each classification system was valued by 150 general public respondents in the United Kingdom using Time Trade Off (TTO). Multivariate regression was used to estimate utility value sets. The matched dimensions across each measure were compared using z‐score tests.

Results

The DHP‐3D included three dimensions defined as mood, eating and social limitations, and the DHP‐5D added dimensions defined as hypoglycaemic attacks and vitality. For both, the random effects generalized least squares regression model produced consistent value sets, with the DHP‐3D and DHP‐5D ranging from 0.983 (best state) to 0.717 (worst state), and 0.979 to 0.618 respectively. The addition of the two extra dimensions leads to significant differences for the more severe levels of each matched dimension.

Conclusions

We have developed two diabetes‐specific preference‐based measures that, subject to psychometric assessment, can be used to provide condition‐specific utility values to complement generic utilities from more widely validated measures such as the EuroQol‐5 Dimension.
Adiposity and incident diabetes within 4 years of follow‐up: the Guangzhou Biobank Cohort Study
Authors: Xu L. , Lam T. H. , Jiang C. Q. , Zhang W. S. , Jin Y. L. , Zhu T. , Zhu F. , Thomas G. N. , Cheng K. K.
Published: May 2017

Aim

Whether different adiposity measures predict incident diabetes differentially in general Chinese populations is unclear. We investigated this in Chinese people aged 50+ years in the Guangzhou Biobank Cohort Study.

Methods

Waist circumference and BMI were measured at baseline, and fasting glucose was measured at both baseline and follow‐up examinations. Incident diabetes was defined as fasting glucose ≥ 7.0 mmol/l, glucose after 2‐h oral glucose tolerance test ≥ 11.1 mmol/l, and/or self‐reported physician‐diagnosed diabetes during the follow‐up period.

Results

Of 15 752 people without diabetes at baseline from 2003 to 2008, 1779 (11.3%) developed incident diabetes during the follow‐up from 2008 to 2012 (mean = 3.6 years, sd = 1.0). After mutually adjusting each other and adjusting for other potential confounders, waist circumference showed a higher predictive value than BMI. The odds ratio (OR) (95% confidence interval (CI) was 1.50 (95% CI 1.37–1.64) for a 1 sd increment in waist circumference and 1.21 (95% CI 1.11–1.33), for a 1 sd increment in BMI. Similarly, after mutual adjustment, abdominal obesity was associated with an almost twofold odds of incident diabetes (OR 1.93, 95% CI 1.71–2.17), which was higher than that for general obesity (OR 1.76, 95% CI 1.50–2.06). The area under receiver operating characteristic curve (AUC) for waist circumference was higher than that for BMI [AUC = 0.676 (95% CI 0.660–0.686) vs. 0.665 (95% CI 0.651–0.678), P = 0.02].

Conclusion

Abdominal obesity predicted incident diabetes in older people better than general obesity. Our findings may be an early warning signal for local government or public health practitioners to develop and investigate more effective intervention programmes for diabetes, and should also be disseminated to the public to pay more attention to this important public health issue.