bluuebunny/crossref_metadata_2025 huggingface dataset:
Nitrosation‐Dependent Caveolin 1 Phosphorylation, Ubiquitination, and Degradation and its Association with Idiopathic Pulmonary Arterial Hypertension
Authors: Bakhshi Farnaz R. , Mao Mao , Shajahan Ayesha N. , Piegeler Tobias , Chen Zhenlong , Chernaya Olga , Sharma Tiffany , Elliott W. Mark , Szulcek Robert , Bogaard Harm Jan , Comhair Suzy , Erzurum Serpil , van Nieuw Amerongen Geerten P. , Bonini Marcelo G. , Minshall Richard D.
Published: March 2014

In the present study, we tested the hypothesis that chronic inflammation and oxidative/nitrosative stress induce caveolin 1 (Cav‐1) degradation, providing an underlying mechanism of endothelial cell activation/dysfunction and pulmonary vascular remodeling in patients with idiopathic pulmonary arterial hypertension (IPAH). We observed reduced Cav‐1 protein despite increased Cav‐1 messenger RNA expression and also endothelial nitric oxide synthase (eNOS) hyperphosphorylation in human pulmonary artery endothelial cells (PAECs) from patients with IPAH. In control human lung endothelial cell cultures, tumor necrosis factor α–induced nitric oxide (NO) production and S‐nitrosation (SNO) of Cav‐1 Cys‐156 were associated with Src displacement and activation, Cav‐1 Tyr‐14 phosphorylation, and destabilization of Cav‐1 oligomers within 5 minutes that could be blocked by eNOS or Src inhibition. Prolonged stimulation (72 hours) with NO donor DETANONOate reduced oligomerized and total Cav‐1 levels by 40%–80%, similar to that observed in IPAH patient–derived PAECs. NO donor stimulation of endothelial cells for >72 hours, which was associated with sustained Src activation and Cav‐1 phosphorylation, ubiquitination, and degradation, was blocked by NOS inhibitor L‐NAME, Src inhibitor PP2, and proteosomal inhibitor MG132. Thus, chronic inflammation, sustained eNOS and Src signaling, and Cav‐1 degradation may be important causal factors in the development of IPAH by promoting PAEC dysfunction/activation via sustained oxidative/nitrosative stress.
The Peroxisome Proliferator–Activated Receptor β/δ Agonist GW0742 has Direct Protective Effects on Right Heart Hypertrophy
Authors: Kojonazarov Baktybek , Luitel Himal , Sydykov Akylbek , Dahal Bhola K. , Paul‐Clark Mark J. , Bonvini Sara , Reed Anna , Schermuly Ralph T. , Mitchell Jane A.
Published: March 2014

Pulmonary hypertension is a debilitating disease with no cure. We have previously shown that peroxisome proliferator–activated receptor (PPAR) α/α agonists protect the right heart in hypoxia‐driven pulmonary hypertension without affecting vascular remodeling. PPARα/α is an important receptor in lipid metabolism, athletic performance, and the sensing of prostacyclin. Treatment of right heart hypertrophy and failure in pulmonary hypertension is an emerging target for future therapy. Here we have investigated the potential of GW0742, a PPARα agonist, to act directly on the right heart in vivo and what transcriptomic signatures are associated with its actions. Right heart hypertrophy and failure was induced in mice using a pulmonary artery banding (PAB) model. GW0742 was administered throughout the study. Cardiovascular parameters were measured using echocardiography and pressure monitoring. Fibrosis and cellular changes were measured using immuno‐histochemistry. Transcriptomics were measured using the Illumina MouseRef‐8v3 BeadChip array and analyzed using GeneSpring GX (ver. 11.0). PAB resulted in right heart hypertrophy and failure and in increased fibrosis. GW0742 reduced or prevented the effects of PAB on all parameters measured. GW0742 altered a number of genes in the transcriptome, with Angptl4 emerging as the top gene altered (increased) in animals with PAB. In conclusion, the PPARα/α agonist GW0742 has direct protective effects on the right heart in vivo. These observations identify PPARα/α as a viable therapeutic target to treat pulmonary hypertension that may complement current and future vasodilator drugs.
Iloprost Improves Ventricular Function in the Hypertrophic and Functionally Impaired Right Heart by Direct Stimulation
Authors: Holmboe Sarah , Andersen Asger , Vildbrad Mads D. , Nielsen Jan M. , Ringgaard Steffen , Nielsen‐Kudsk Jens E.
Published: March 2014

Right heart function is an important predictor of morbidity and mortality in patients suffering from pulmonary arterial hypertension and congenital heart diseases. We investigated whether the prostacyclin analog iloprost has a direct inotropic effect in the pressure‐overloaded hypertrophic and dysfunctional right ventricle (RV). Rats were randomized to monocrotaline injection (60 mg/kg; n = 8), pulmonary trunk banding (PTB; n = 8), or a sham operation (n = 8). RV function was evaluated with magnetic resonance imaging, echocardiography, and invasive pressure measurements at baseline, after intravenous administration of placebo, iloprost 10 ng/kg/min, or iloprost 100 ng/kg/min (Ilo100). Infusion of Ilo100 induced a 12% ± 4% (P = 0.022) increase in stroke volume in the sham group and a 12% ± 3% (P = 0.005) increase in the PTB group. RV dP=dtmax was elevated by 11% ± 5% (P = 0.039) in the sham group and by 12% ± 3% (P = 0.016) in the PTB group. An elevation in cardiac output of 14% ±3% (P = 0.0008) and an 11% ± 2% (P = 0.0021) increase in RV systolic pressure were found in the PTB group. Iloprost caused a decrease in mean arterial blood pressure (MAP) in all groups of animals. An equal reduction in MAP induced by the arterial vasodilator nitroprusside did not improve any of the measured parameters of RV function. We conclude that iloprost has inotropic properties directly improving ventricular function in the hypertrophic and dysfunctional right heart of the rat.
Dysregulation of Ubiquitin‐Proteasome Pathway and Apolipoprotein a Metabolism in Sickle Cell Disease–Related Pulmonary Arterial Hypertension
Authors: Anjum Fatima , Lazar Jason , Soh James , Albitar Maher , Gowda Satish , Hussain M. Mahmood , Wadgaonkar Raj
Published: March 2014

Pulmonary arterial hypertension (PAH) is a major complication of sickle cell disease (SCD). Low levels of apolipoprotein A1 (Apo‐A1) have been implicated in the development of PAH in SCD. We speculate that lower levels of Apo‐A1 are related to dysregulation of the ubiquitin‐proteasome pathway (UPP). Of 36 recruited patients with SCD, 14 were found to have PAH on the basis of right heart catheterization. Levels of Apo‐A1 and Apo‐B, polyubiquitin, total protease, and specific and normalized activity of chymotrypsin‐like, trypsin‐like, and caspase‐like proteases in plasma were measured. Levels of Apo‐A1 were found to be lower and polyubiquitin levels were found to be significantly higher in the PAH group (P < 0.05) in SCD. Apo‐A levels were inversely correlated with polyubiquitin levels (r = −0.499, P = 0.009). These results indicate that lower levels of Apo‐A1 in SCD patients with PAH are likely related to enhance degradation by UPP, potentially contributing to pulmonary vascular pathology. These findings may provide significant insight in identifying suitable therapeutic targets in these patients.
Patients' Hand Hygiene at Home Predicts Their Hand Hygiene Practices in the Hospital
Authors: Barker Anna , Sethi Ajay , Shulkin Emily , Caniza Rachell , Zerbel Sara , Safdar Nasia
Published: March 2014

We examine factors associated with hand hygiene practices of hospital patients. Hygiene in the hospital decreased compared to that at home, and home practices were strongly associated with hospital practices. Understanding and leveraging the intrinsic value some patients associate with hand hygiene may be important for improving overall hospital hygiene and decreasing healthcare-associated infections.
Quotidian Changes of Genital Tract Cytokines in Human Immunodeficiency Virus-1-Infected Women During the Menstrual Cycle
Authors: Cortez Valerie , Odem-Davis Katherine , Lehman Dara A. , Mabuka Jennifer , Overbaugh Julie
Published: March 2014

The role of hormonal changes throughout the menstrual cycle on genital tract inflammation during chronic human immunodeficiency virus (HIV) infection is not well defined, but it has implications for HIV prevention. We assessed daily levels of 26 vaginal cytokines and chemokines from 15 women infected with HIV-1. Taking into account coexisting sexually transmitted infections, behavioral factors, and menstruation, this study illustrates cyclic patterns of granulocyte macrophage colony-stimulating factor, interferon-α2, interleukin (IL)-6, IL-10, macrophage inflammatory protein (MIP)-1α, MIP-1β, and tumor necrosis factor (TNF)-α. Progesterone was associated with levels of granulocyte colony-stimulating factor, IL-1α, and monocyte chemoattractant protein-1. Interferon-α2, IL-6, MIP-1α, MIP-1β, and TNF-α levels predicted HIV shedding, but these associations were heavily influenced by the menstrual cycle.
Cystatin C-Based Renal Function Changes After Antiretroviral Initiation: A Substudy of a Randomized Trial
Authors: Gupta Samir K. , Kitch Douglas , Tierney Camlin , Daar Eric S. , Sax Paul E. , Melbourne Kathleen , Ha Belinda , McComsey Grace A. ,   for the AIDS Clinical Trials Group Study A5224s Team
Published: March 2014

Background.  The effects of antiretrovirals on cystatin C-based renal function estimates are unknown.

Methods.  We analyzed changes in renal function using creatinine and cystatin C-based estimating equations in 269 patients in A5224s, a substudy of study A5202, in which treatment-naive patients were randomized to abacavir/lamivudine or tenofovir/emtricitabine with open-label atazanavir/ritonavir or efavirenz.

Results.  Changes in renal function significantly improved (or declined less) with abacavir/lamivudine treatment compared with tenofovir/emtricitabine using the Cockcroft-Gault formula (P = .016) and 2009 Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI; P = .030) and 2012 CKD-EPI cystatin C-creatinine (P = .025). Renal function changes significantly improved (or declined less) with efavirenz compared with atazanavir/ritonavir (P < .001 for all equations). Mean (95% confidence interval) renal function changes specifically for tenofovir/emtricitabine combined with atazanavir/ritonavir were −8.3 (−14.0, −2.6) mL/min with Cockcroft-Gault; −14.9 (−19.7, −10.1) mL/min per 1.732 with Modification of Diet in Renal Disease; −12.8 (−16.5, −9.0) mL/min per 1.732 with 2009 CKD-EPI; +8.9 (4.2, 13.7) mL/min per 1.732 with 2012 CKD-EPI cystatin C; and −1.2 (−5.1, 2.6) mL/min per 1.732 with 2012 CKD-EPI cystatin C-creatinine. Renal function changes for the other treatment arms were more favorable but similarly varied by estimating equation.

Conclusions.  Antiretroviral-associated changes in renal function vary in magnitude and direction based on the estimating equation used.
Multisensory constraints on awareness
Authors: Deroy Ophelia , Chen Yi-Chuan , Spence Charles
Published: March 2014

Given that multiple senses are often stimulated at the same time, perceptual awareness is most likely to take place in multisensory situations. However, theories of awareness are based on studies and models established for a single sense (mostly vision). Here, we consider the methodological and theoretical challenges raised by taking a multisensory perspective on perceptual awareness. First, we consider how well tasks designed to study unisensory awareness perform when used in multisensory settings, stressing that studies using binocular rivalry, bistable figure perception, continuous flash suppression, the attentional blink, repetition blindness and backward masking can demonstrate multisensory influences on unisensory awareness, but fall short of tackling multisensory awareness directly. Studies interested in the latter phenomenon rely on a method of subjective contrast and can, at best, delineate conditions under which individuals report experiencing a multisensory object or two unisensory objects. As there is not a perfect match between these conditions and those in which multisensory integration and binding occur, the link between awareness and binding advocated for visual information processing needs to be revised for multisensory cases. These challenges point at the need to question the very idea of multisensory awareness.
Can the meaning of multiple words be integrated unconsciously?
Authors: van Gaal Simon , Naccache Lionel , Meuwese Julia D. I. , van Loon Anouk M. , Leighton Alexandra H. , Cohen Laurent , Dehaene Stanislas
Published: March 2014

What are the limits of unconscious language processing? Can language circuits process simple grammatical constructions unconsciously and integrate the meaning of several unseen words? Using behavioural priming and electroencephalography (EEG), we studied a specific rule-based linguistic operation traditionally thought to require conscious cognitive control: the negation of valence. In a masked priming paradigm, two masked words were successively (Experiment 1) or simultaneously presented (Experiment 2), a modifier (‘not’/‘very’) and an adjective (e.g. ‘good’/‘bad’), followed by a visible target noun (e.g. ‘peace’/‘murder’). Subjects indicated whether the target noun had a positive or negative valence. The combination of these three words could either be contextually consistent (e.g. ‘very bad - murder’) or inconsistent (e.g. ‘not bad - murder’). EEG recordings revealed that grammatical negations could unfold partly unconsciously, as reflected in similar occipito-parietal N400 effects for conscious and unconscious three-word sequences forming inconsistent combinations. However, only conscious word sequences elicited P600 effects, later in time. Overall, these results suggest that multiple unconscious words can be rapidly integrated and that an unconscious negation can automatically ‘flip the sign’ of an unconscious adjective. These findings not only extend the limits of subliminal combinatorial language processes, but also highlight how consciousness modulates the grammatical integration of multiple words.
On the cyclic nature of perception in vision versus audition
Authors: VanRullen Rufin , Zoefel Benedikt , Ilhan Barkin
Published: March 2014

Does our perceptual awareness consist of a continuous stream, or a discrete sequence of perceptual cycles, possibly associated with the rhythmic structure of brain activity? This has been a long-standing question in neuroscience. We review recent psychophysical and electrophysiological studies indicating that part of our visual awareness proceeds in approximately 7–13 Hz cycles rather than continuously. On the other hand, experimental attempts at applying similar tools to demonstrate the discreteness of auditory awareness have been largely unsuccessful. We argue and demonstrate experimentally that visual and auditory perception are not equally affected by temporal subsampling of their respective input streams: video sequences remain intelligible at sampling rates of two to three frames per second, whereas audio inputs lose their fine temporal structure, and thus all significance, below 20–30 samples per second. This does not mean, however, that our auditory perception must proceed continuously. Instead, we propose that audition could still involve perceptual cycles, but the periodic sampling should happen only after the stage of auditory feature extraction. In addition, although visual perceptual cycles can follow one another at a spontaneous pace largely independent of the visual input, auditory cycles may need to sample the input stream more flexibly, by adapting to the temporal structure of the auditory inputs.
Enhanced expression of Bacillus subtilis yaaA can restore both the growth and the sporulation defects caused by mutation of rplB, encoding ribosomal protein L2
Authors: Suzuki Shota , Tanigawa Osamu , Akanuma Genki , Nanamiya Hideaki , Kawamura Fujio , Tagami Kazumi , Nomura Naofumi , Kawabata Teppei , Sekine Yasuhiko
Published: March 2014

A temperature-sensitive mutation inrplB,designatedrplB142, encodes a missense mutation at position 142 [His (CAT) to Leu (CTT)] ofBacillus subtilisribosomal protein L2. The strain carrying the mutation grew more slowly than the wild-type, even at low temperatures, probably due to the formation of defective 70S ribosomes and the accumulation of incomplete 50S subunits (50S* subunits). Gel analysis indicated that amounts of L2 protein and also of L16 protein were reduced in ribosomes prepared from therplB142mutant 90 min after increasing the growth temperature to 45 °C. These results suggest that the assembly of the L16 protein into the 50S subunit requires the native L2 protein. The H142L mutation in the defective L2 protein affected sporulation as well as growth, even at the permissive temperature. A suppressor mutation that restored both growth and sporulation of therplB142mutant at low temperature was identified as a single base deletion located immediately upstream of theyaaAgene that resulted in an increase in its transcription. Furthermore, genetic analysis showed that enhanced synthesis of YaaA restores the functionality of L2 (H142L) by facilitating its assembly into 50S subunits.
Measuring error rates in genomic perturbation screens: gold standards for human functional genomics
Authors: Hart Traver , Brown Kevin R. , Sircoulomb Fabrice , Rottapel Robert , Moffat Jason
Published: March 2014

Technological advancement has opened the door to systematic genetics in mammalian cells. Genome-scale loss-of-function screens can assay fitness defects induced by partial gene knockdown, using RNA interference, or complete gene knockout, using new CRISPR techniques. These screens can reveal the basic blueprint required for cellular proliferation. Moreover, comparing healthy to cancerous tissue can uncover genes that are essential only in the tumor; these genes are targets for the development of specific anticancer therapies. Unfortunately, progress in this field has been hampered by offtarget effects of perturbation reagents and poorly quantified error rates in large-scale screens. To improve the quality of information derived from these screens, and to provide a framework for understanding the capabilities and limitations of CRISPR technology, we derive gold-standard reference sets of essential and nonessential genes, and provide a Bayesian classifier of gene essentiality that outperforms current methods on both RNAi and CRISPR screens. Our results indicate that CRISPR technology is more sensitive than RNAi, and that both techniques have nontrivial false discovery rates that can be mitigated by rigorous analytical methods.
Analysis of stop-gain and frameshift variants in human innate immunity genes
Authors: Rausell Antonio , Mohammadi Pejman , McLaren Paul J , Xenarios Ioannis , Fellay Jacques , Telenti Amalio
Published: March 2014

Loss-of-function variants in innate immunity genes are associated with Mendelian disorders in the form of primary immunodeficiencies. Recent resequencing projects report that stop-gains and frameshifts are collectively prevalent in humans and could be responsible for some of the inter-individual variability in innate immune response. Current computational approaches evaluating loss-of-function in genes carrying these variants rely on gene-level characteristics such as evolutionary conservation and functional redundancy across the genome. However, innate immunity genes represent a particular case because they are more likely to be under positive selection and duplicated. To create a ranking of severity that would be applicable to the innate immunity genes we first evaluated 17764 stop-gain and 13915 frameshift variants from the NHLBI Exome Sequencing Project and 1000 Genomes Project. Sequence-based features such as loss of functional domains, isoform-specific truncation and non-sense mediated decay were found to correlate with variant allele frequency and validated with gene expression data. We integrated these features in a Bayesian classification scheme and benchmarked its use in predicting pathogenic variants against OMIM disease stop-gains and frameshifts. The classification scheme was applied in the assessment of 335 stop-gains and 236 frameshifts affecting 227 interferon-stimulated genes. The sequence-based score ranks variants in innate immunity genes according to their potential to cause disease, and complements existing gene-based pathogenicity scores.
The Arabidopsis LYSIN MOTIF-CONTAINING RECEPTOR-LIKE KINASE3 Regulates the Cross Talk between Immunity and Abscisic Acid Responses
Authors: Paparella Chiara , Savatin Daniel Valentin , Marti Lucia , De Lorenzo Giulia , Ferrari Simone
Published: March 2014

Transmembrane receptor-like kinases characterized by the presence of one or more lysin motif (LysM) domains in the extracytoplasmic portion (LysM-containing receptor-like kinases [LYKs]) mediate recognition of symbiotic and pathogenic microorganisms in plants. The Arabidopsis (Arabidopsis thaliana) genome encodes five putative LYKs; among them, AtLYK1/CHITIN ELICITOR RECEPTOR KINASE1 is required for response to chitin and peptidoglycan, and AtLYK4 contributes to chitin perception. More recently, AtLYK3 has been shown to be required for full repression, mediated by Nod factors, of Arabidopsis innate immune responses. In this work, we show that AtLYK3 also negatively regulates basal expression of defense genes and resistance to Botrytis cinerea and Pectobacterium carotovorum infection. Enhanced resistance of atlyk3 mutants requires PHYTOALEXIN-DEFICIENT3, which is crucial for camalexin biosynthesis. The expression of AtLYK3 is strongly repressed by elicitors and fungal infection and is induced by the hormone abscisic acid (ABA), which has a negative impact on resistance against B. cinerea and P. carotovorum. Plants lacking a functional AtLYK3 also show reduced physiological responses to ABA and are partially resistant to ABA-induced inhibition of PHYTOALEXIN-DEFICIENT3 expression. These results indicate that AtLYK3 is important for the cross talk between signaling pathways activated by ABA and pathogens.
The Political Power of Economic Ideas: The Case of ‘Expansionary Fiscal Contractions'
Authors: Dellepiane-Avellaneda Sebastian
Published: March 2014

Research Highlights and Abstract

This article

Provides the first systematic analysis of the rise and diffusion of the idea of expansionary fiscal contractions (besides Blyth's book). Uses comparative case studies to assess the actual influence of this policy idea during the Great Recession. Provides a better understanding of the social construction of the financial crisis. Contributes to the growing scholarship on ideational political economy, including works documenting the resilience of the neoliberal paradigm.

This article examines the rise and influence of a powerful economic idea: ‘expansionary fiscal contractions'. The counterintuitive policy belief that severe fiscal adjustments can be expansionary was originally advanced by economists Francesco Giavazzi and Marco Pagano in the early 1990s. Over the years, this idea became dominant in certain epistemic communities, mainly through the literature on lessons from successful consolidations. In the event, the relationship between budget reduction and economic growth turned out to be one of the most contested issues in the aftermath of the financial crash of 2008. This article is divided into three main sections. The first section documents the social diffusion of this singular economic idea, from academia to policy networks. The second reports the ‘battle of ideas'over fiscal consolidation during the Great Recession. The third section assesses the influence of the idea of expansionary contractions on actual policy choices by examining the politics of austerity in Ireland, Spain and the UK in the period 2008–2012.
Pre‐eclampsia, eclampsia and adverse maternal and perinatal outcomes: a secondary analysis of the World Health Organization Multicountry Survey on Maternal and Newborn Health
Authors: Abalos E , Cuesta C , Carroli G , Qureshi Z , Widmer M , Vogel JP , Souza JP ,   on behalf of the WHO Multicountry Survey on Maternal and Newborn Health Research Network
Published: March 2014

Objective

To assess the incidence of hypertensive disorders of pregnancy and related severe complications, identify other associated factors and compare maternal and perinatal outcomes in women with and without these conditions.

Design

Secondary analysis of the World Health Organization Multicountry Survey on Maternal and Newborn Health (WHOMCS) database.

Setting

Cross‐sectional study implemented at 357 health facilities conducting 1000 or more deliveries annually in 29 countries from Africa, Asia, Latin America and the Middle East.

Population

All women suffering from any hypertensive disorder during pregnancy, the intrapartum or early postpartum period in the participating hospitals during the study period.

Methods

We calculated the proportion of the pre‐specified outcomes in the study population and their distribution according to hypertensive disorders' severity. We estimated the association between them and maternal deaths, near‐miss cases, and severe maternal complications using a multilevel logit model.

Main outcome measures

Hypertensive disorders of pregnancy. Potentially life‐threatening conditions among maternal near‐miss cases, maternal deaths and cases without severe maternal outcomes.

Results

Overall, 8542 (2.73%) women suffered from hypertensive disorders. Incidences of pre‐eclampsia, eclampsia and chronic hypertension were 2.16%, 0.28% and 0.29%, respectively. Maternal near‐miss cases were eight times more frequent in women with pre‐eclampsia, and increased to up to 60 times more frequent in women with eclampsia, when compared with women without these conditions.

Conclusions

The analysis of this large database provides estimates of the global distribution of the incidence of hypertensive disorders of pregnancy. The information on the most frequent complications related to pre‐eclampsia and eclampsia could be of interest to inform policies for health systems organisation.
Eclampsia, a comparison within the International Network of Obstetric Survey Systems
Authors: Schaap TP , Knight M , Zwart JJ , Kurinczuk JJ , Brocklehurst P , van Roosmalen J , Bloemenkamp KWM
Published: March 2014

Objective

To compare incidences, characteristics, management and outcome of eclampsia in the Netherlands and the UK.

Design

A comparative analysis of two population‐based prospective cohort studies.

Setting

All hospitals with consultant‐led maternity units.

Population

Women with eclampsia in the Netherlands (226) and the UK (264).

Methods

Comparison of individual level data from national studies in the Netherlands and the UK (LEMMoN 2004–06; UKOSS 2005/06).

Main outcome measures

Incidence, maternal complications and differences in management strategies.

Results

Incidences of eclampsia differed significantly between both countries: the Netherlands 5.4/10 000 deliveries versus UK 2.7/10 000 (relative risk [RR] 1.94, 95% confidence intervals [95% CI] 1.6–2.4). The proportion of women with a preceding diagnosis of pre‐eclampsia was comparable between both countries (the Netherlands 42%; UK 43%), as was the proportion who received magnesium sulphate prophylaxis. Women in the Netherlands had a significantly higher maximum diastolic blood pressure (111 mmHg versus 95 mmHg, P < 0.001); significantly fewer received anti‐hypertensive medication (16% versus 71%; RR 0.2, 95% CI 0.1–0.3) and were treated less often with magnesium sulphate after their first fit (95% versus 99%; RR 0.96, 95% CI 0.92–0.99). Maternal death occurred in three cases in the Netherlands compared with zero in the UK.

Conclusions

The incidence of eclampsia in the Netherlands was twice as high compared with the UK when using uniform definitions. Women with eclampsia in the Netherlands were not managed according to guidelines, particularly with respect to blood pressure management. Changes in management practice may reduce both incidence and poor outcomes.
Detection of Gunshot Residue on Dark‐Colored Clothing Prior to Chemical Analysis
Authors: Kersh Kyla L. , Childers James M. , Justice Dale , Karim Greg
Published: March 2014

Detection of gunshot residue (GSR) is an arduous task for investigators. It is often accomplished with chemical tests, which can reveal elements and ions indicating the presence of GSR, but are likely to cause physical alteration to the pattern. In this study, the Spex Forensics Mini‐CrimeScope MCS 400, along with 16 accompanying wavelength filters, was applied to various GSR patterns and target types. Three dark shirt materials, four ammunition calibers, and eight ammunition manufacturers, along with the primer residue of the different manufacturer ammunitions were tested. Results indicate the alternate light source wavelength of 445 nm to be the optimal setting. In addition, target material plays a large role in the preservation of GSR patterns as particles burn. Furthermore, it can be extrapolated that residue, observed from a full round and firing distance of six inches, is mostly composed of unburnt gunpowder residue, not primer residue.
Acquired idiopathic lipoatrophic panniculitis in a 12‐month‐old infant
Authors: Ng Su Yuen , D'Arcy Colleen , Orchard David
Published: March 2014

Lipoatrophic panniculitis is a rare condition affecting mainly children, often associated with connective tissue disease. We report a healthy 12‐month‐old girl with no clinical or laboratory features of connective tissue disease who presented with the progressive appearance of annular atrophic plaques beginning at the left arm. A histopathological analysis revealed lobular panniculitis, with fat necrosis and an associated inflammatory infiltrate supporting the diagnosis of lipoatrophic panniculitis. Lipoatrophic panniculitis should be considered in infants and young children with clinical features of panniculitis and fat atrophy even without clinical or serologic evidence of connective tissue disease.
Type of delivery onset has a significant impact on post‐natal mortality in preterm infants of less than 30 weeks' gestation
Authors: Grill A , Olischar M , Weber M , Pollak A , Leitich H
Published: March 2014

Aim

Type of delivery onset is not currently evaluated for its predictive impact. This study explored whether the type of preterm delivery onset was an antenatal predictor for post‐natal mortality in preterm infants <30 weeks' gestation and should be included in antenatal counselling.

Methods

This retrospective cohort study included 1117 preterm infants <30 weeks' gestation born between 1999 and 2008 in a tertiary perinatal referral centre. Study patients were classified into spontaneous or iatrogenic preterm deliveries. Spontaneous deliveries included deliveries after preterm premature rupture of membranes (PPROM) and preterm labour. The study outcome was infant mortality before discharge from hospital.

Results

We included 499 patients born after PPROM (44.7%) and 247 born after preterm labour (22.1%). Iatrogenic preterm birth was noted in 282 patients (25.2%) and 89 patients fulfilled both criteria for spontaneous and iatrogenic preterm delivery (8.0%). Babies born after iatrogenic preterm delivery in gestational weeks 25–29 had significantly higher mortality rates. Logistic regression revealed that type of preterm delivery onset was an independent antenatal predictor for post‐natal mortality.

Conclusion

Type of preterm delivery onset had a significant impact on post‐natal mortality in preterm infants <30 weeks' gestation, with a higher mortality rate after iatrogenic preterm delivery.
High‐Content Analysis in Toxicology: Screening Substances for Human Toxicity Potential, Elucidating Subcellular Mechanisms and In Vivo Use as Translational Safety Biomarkers
Authors: O'Brien Peter J.
Published: March 2014

High‐content analysis (HCA) of in vitro biochemical and morphological effects of classic (small molecule) drugs and chemicals is concordant with potential for human toxicity. For hepatotoxicity, concordance is greater for cytotoxic effects assessed by HCA than for conventional cytotoxicity tests and for regulatory animal toxicity studies. Additionally, HCA identifies chronic toxicity potential, and drugs producing idiosyncratic adverse reactions and/or toxic metabolites are also identified by HCA. Mechanistic information on the subcellular basis for the toxicity is frequently identified, including various mitochondrial effects, oxidative stress, calcium dyshomeostasis, phospholipidosis, apoptosis and antiproliferative effects, and a fingerprinting of the sequence and pattern of subcellular events. As these effects are frequently non‐specific and affect many cell types, some toxicities may be detected and monitored by HCA of peripheral blood cells, such as for anticancer and anti‐infective drugs. Critical methodological and interpretive features are identified that are critical to the effectiveness of the HCA cytotoxicity assessment, including the need for multiple days of exposure of cells to drug, use of a human hepatocyte cell line with metabolic competence, assessment of multiple pre‐lethal effects in individual live cells, consideration of hormesis, the need for interpretation of relevance of cytotoxicity concentration compared to efficacy concentration and quality management. Limitations of the HCA include assessment of drugs that act on receptors, transporters or processes not found in hepatocytes. HCA may be used in a) screening lead candidates for potential human toxicity in drug discovery alongside of in vitro assessment of efficacy and pharmacokinetics, b) elucidating mechanisms of toxicity and c) monitoring in vivo toxicity of drugs with known toxicity of known mechanism.
Hearing problems in the learning disability population: is anybody listening?
Authors: McClimens Alex , Brennan Siobhan , Hargreaves Pauline
Published: March 2014

Accessible summary

people with learning disability tend to have more hearing problems than other people.

often these hearing problems are not picked up by doctors, nurses, carers or even by the people themselves.

living with undetected hearing loss means people miss out on information, social opportunities and entertainment.

routine screening for hearing loss would improve the lives of many people with learning disability.

We undertook this project because we believed that hearing loss experienced by the target population was greater than the referral figures suggested. Therefore, we set up a trial service initiative designed to examine the efficacy of different referral routes into audiology services for adults with learning disability. This retrospective analysis focuses on the generation of data on hearing loss on a small population sample (n = 136) gathered over a 6‐month period in 2012. We suggest remedial action now to prevent more problems in the future.
Angiotensin‐(1–7) attenuates angiotensin II‐induced signalling associated with activation of a tyrosine phosphatase in Sprague–Dawley rats cardiac fibroblasts
Authors: Tao Xiaoling , Fan Jinqi , Kao Guoying , Zhang Xiaoge , Su Li , Yin Yuehui , Zrenner Bernhard
Published: March 2014

Background information

Angiotensin‐(1–7) [ANG‐(1–7)] mediates vasodilation, antiproliferation, anti‐apoptosis and antifibrosis, therefore, it opposes the effects of angiotensin II (ANG II). However, the detailed signal transduction mechanism following the Mas receptor activated by ANG‐(1–7) is still poorly understood. Src homology2‐containing inositol phosphatase 1 (SHP‐1), a redoxsensitive protein tyrosine phosphatase, negatively influences downstream signalling molecules, such as mitogen‐activated protein kinases (MAPKs), through dephosphorylation, thereby inhibiting proliferative and profibrotic signalling induced by ANG II. Therefore, we hypothesised that SHP‐1 may mediate the antiproliferative signalling of ANG‐(1–7) through the regulation of the dynamic balance of MAPKs and SHP‐1 in isolated cardiac fibroblasts. Primary culture of neonatal Sprague–Dawley rats cardiac fibroblasts was treated separately with different interventions to investigate this issue.

Results

Our data revealed that ANG II increased the phosphorylation of extracellular signal‐related kinase (p‐ERK1/2) and the ratio of (p‐ERK1/2)/(ERK1/2), but ANG‐(1–7) decreased them. The effects of ANG‐(1–7) on the phosphorylation p‐ERK1/2 were blocked by the Mas receptor antagonist A‐779. Unlike ANG II, which decreased the activity of SHP‐1, ANG‐(1–7) increased its activity. Overexpression of SHP‐1 attenuated the ANG II‐stimulated phosphorylation of c‐Src, its downstream molecules ERK1/2, α‐smooth muscle actin and transforming growth factor‐β1 (TGF‐β1). These effects were also inhibited by the specific inhibitor of SHP‐1, sodium stibogluconate. ANG‐(1–7) had no significant effects on the gene expression of TGF‐β1, collagen I or collagen III, but was found to antagonise the stimulatory effects of ANG II on them.

Conclusions

ANG‐(1–7), through Mas receptor, activates SHP‐1 in cardiac fibroblasts, which can negatively modulate ANG II‐induced phosphorylation of c‐Src and MAPKs, and inhibits profibrotic factors TGF‐β1 and collagen production. ANG‐(1–7) can thereby serve as a protective role by counteracting the effects of ANG II.
Pharmacology and anti‐addiction effects of the novel κ opioid receptor agonist Mesyl Sal B, a potent and long‐acting analogue of salvinorin A
Authors: Simonson B , Morani A S , Ewald A W M , Walker L , Kumar N , Simpson D , Miller J H , Prisinzano T E , Kivell B M
Published: March 2014

Background and Purpose

Acute activation of κ opioid (KOP) receptors results in anticocaine‐like effects, but adverse effects, such as dysphoria, aversion, sedation and depression, limit their clinical development. Salvinorin A, isolated from the plant Salvia divinorum, and its semi‐synthetic analogues have been shown to have potent KOP receptor agonist activity and may induce a unique response with similar anticocaine addiction effects as the classic KOP receptor agonists, but with a different side effect profile.

Experimental Approach

We evaluated the duration of effects of Mesyl Sal B in vivo utilizing antinociception assays and screened for cocaine‐prime induced cocaine‐seeking behaviour in self‐administering rats to predict anti‐addiction effects. Cellular transporter uptake assays and in vitro voltammetry were used to assess modulation of dopamine transporter (DAT) function and to investigate transporter trafficking and kinase signalling pathways modulated by KOP receptor agonists.

Key Results

Mesyl Sal B had a longer duration of action than SalA, had anti‐addiction properties and increased DAT function in vitro in a KOP receptor‐dependent and Pertussis toxin‐sensitive manner. These effects on DAT function required ERK1/2 activation. We identified differences between Mesyl Sal B and SalA, with Mesyl Sal B increasing the Vmax of dopamine uptake without altering cell‐surface expression of DAT.

Conclusions and Implications

SalA analogues, such as Mesyl Sal B, have potential for development as anticocaine agents. Further tests are warranted to elucidate the mechanisms by which the novel salvinorin‐based neoclerodane diterpene KOP receptor ligands produce both anti‐addiction and adverse side effects.

Linked Articles

This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2
Robust Reputation in Decentralized Markets
Authors: Franks Henry , Griffiths Nathan
Published: March 2014

Establishing cooperation and protecting individuals from selfish and malicious behavior are key goals in open multiagent systems. Incomplete information regarding potential interaction partners can undermine typical cooperation mechanisms such as trust and reputation, particularly in lightweight systems designed for individuals with significant resource constraints. In this article, we (i) propose extending a low‐cost reputation mechanism to use gossiping to mitigate against the effect of incomplete information, (ii) define four simple aggregation strategies for incorporating gossiped information, and (iii) evaluate our model on a variety of synthetic and real‐world topologies and under a range of configurations. We show that (i) gossiping can significantly reduce the potentially detrimental influence of incomplete information and the underlying network structure on lightweight reputation mechanisms, (ii) basing decisions on the most recently received gossip results in up to a 25% reduction in selfishness, and (iii) gossiping is particularly effective at aiding agents with little or no interaction history, such as when first entering a system.
Neurotropic T‐cell lymphocytosis: a cutaneous expression of CLIPPERS
Authors: Smith Annika , Matthews Yasmin , Kossard Steven , Turner Jenny , Buckland Michael E. , Parratt John
Published: March 2014

Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) is an inflammatory disease of the central nervous system that predominantly involves the pons and cerebellum and that improves with immunosuppressive treatment. Only recently described, the etiology is unknown, diagnosis is difficult and long‐term neurological sequelae may occur without aggressive treatment. Herein, we describe a 59‐year‐old woman who presented with subcutaneous nodules affecting her face, trunk, limbs and an indurated annular erythematous lesion on her forearm. This was associated with marked dysesthesia of her skin, refractory to treatment. There was a 4‐year history of dysequilibrium, vertigo, truncal and gait ataxia with progressive neurological symptoms. Skin biopsy of the annular nodular lesion showed a lymphohistiocytic infiltrate in dermis and subcutis with a striking lymphocyte‐dominant infiltrate that was perineural and formed a nodular collection extending along a prominent subcutaneous nerve. Immunophenotyping indicated a marked predominance of T cells that were CD3 positive with a 2 : 1 CD4 : CD8 ratio. Scattered histiocytes were present but no well‐formed granulomas or vasculitis. Magnetic resonance imaging studies showed changes in the pontine, brain stem and cerebellar region, which subsequently were defined as characteristic for CLIPPERS, but no brain biopsy was pursued. The marked neural skin symptoms and the cutaneous histopathological findings indicate that the skin may be an additional target organ in CLIPPERS, and the immune response may be directed against a common neural antigen. In radiologically typical CLIPPERS, identification of clinical skin lesions particularly subcutaneous nodules and biopsy may potentially form a basis for tissue diagnosis in this syndrome.
Histopathologic characteristics of therapy‐associated cutaneous neoplasms with vemurafenib, a selective BRAF kinase inhibitor, used in the treatment of melanoma
Authors: Sufficool Kari E. , Hepper Donna M. , Linette Gerald P. , Hurst Eva A. , Lu Dongsi , Lind Anne C. , Cornelius Lynn A.
Published: March 2014

Background

Activating mutations in BRAF have been observed in up to 60% of melanomas, indicating a pivotal role for kinase deregulation in tumor progression. Vemurafenib is a specific inhibitor of BRAF for treatment of melanomas with activating BRAF V600E mutations and has been a major advancement in melanoma treatment. Treatment with vemurafenib, and to a lesser extent, sorafenib, a relatively non‐specific inhibitor of BRAF, has been associated with cutaneous squamous cell carcinoma (SCC).

Methods

Clinical and microscopic characteristics of cutaneous neoplasms were evaluated following vemurafenib administration.

Results

Twenty‐four of 47 (51%) patients receiving vemurafenib at our institution developed 146 total cutaneous neoplasms, with 75% developing multiple lesions. The median number of lesions in affected patients was three. Body distribution included head/neck (29%), chest/back (21%), upper (23%) and lower extremities (27%). Lesions were biopsied and pathologically showed multiple types of epidermal tumors including, but not limited to, verrucous keratoses with/without partial thickness dysplasia, actinic keratoses and well‐differentiated and invasive SCCs with/without keratoacanthomatous features.

Conclusions

We describe the histopathologic findings of skin lesions potentially associated with vemurafenib. Additional investigation is necessary to further elucidate cutaneous neoplasms associated with vemurafenib; however, frequent dermatologic evaluation is warranted in all patients receiving BRAF inhibitors.
Recurrent primary cutaneous mucinous carcinoma with neuroendocrine differentiation: case report and review of the literature
Authors: Miquelestorena‐Standley Elodie , Dujardin Fanny , Arbion Flavie , Touzé Antoine , Machet Laurent , Velut Stéphane , Guyétant Serge
Published: March 2014

We report the case of a 60‐year‐old woman presenting with primary cutaneous mucinous carcinoma (PCMC) with neuroendocrine differentiation, revealed by neuroendocrine tumor lymph node metastasis 7 years before identification of the skin tumor. Only five cases of PCMC with neuroendocrine differentiation have been reported to date. The frequency of this neuroendocrine component may be underestimated, as it can require immunohistochemistry for identification, rather than being obvious on initial histopathologic examination. In the case presented here, the prominent neuroendocrine component displayed the morphological features of a well‐differentiated neuroendocrine tumor with expression of common neuroendocrine markers, strong expression of estrogen and progesterone receptors and low Ki67 proliferation index (5%). This case shows that not all primary cutaneous neuroendocrine carcinomas are Merkel cell carcinomas (MCCs). In addition to rare primary cutaneous carcinoid tumors, the diagnosis of PCMC with neuroendocrine differentiation must be considered, particularly when confronted by a mucinous tumor or lymph node metastases of neuroendocrine carcinoma of unknown origin. On the basis of this case, identification of a neuroendocrine component in a PCMC might be an adverse prognostic indicator of recurrence or of lymph node metastasis and should support wider excision margins of the tumor.
Overexpression of EphB4 in the mammary epithelium shifts the differentiation pathway of progenitor cells and promotes branching activity and vascularization
Authors: Kaenel Philip , Hahnewald Stefan , Wotzkow Carlos , Strange Robert , Andres Anne‐Catherine
Published: March 2014

Postnatally, the mammary gland undergoes continuous morphogenesis and thereby is especially prone to malignant transformation. Thus, the maintenance of the epithelium depends on a tight control of stem cell recruitment. We have previously shown that epithelial overexpression of the EphB4 receptor results in defective mammary epithelial development and conferred a metastasizing tumor phenotype on experimental mouse mammary tumors accompanied by a preponderance of progenitor cells. To analyze the effect of EphB4 overexpression on mammary epithelial cell fate, we have used Fluorescence Activated Cell Sorting (FACS) analyses to quantify epithelial sub‐populations and repopulation assays of cleared fat pads to investigate their regenerative potential. These experiments revealed that deregulated EphB4 expression leads to an augmentation of bi‐potent progenitor cells and to a shift of the differentiation pathway towards the luminal lineage. The analyses of the ductal outgrowths indicated that EphB4 overexpression leads to enforced branching activity, impedes ductal differentiation and stimulates angiogenesis. To elucidate the mechanisms forwarding EphB4 signals, we have compared the expression profile of defined cell populations between EphB4 transgene and wild type mammary glands concentrating on the wnt signaling pathway and on genes implicated in cell migration. With respect to wnt signaling, the progenitor cell population was the most affected, whereas the stem cell‐enriched population showed the most pronounced deregulation of migration‐associated genes. Thus, the luminal epithelial EphB4 signaling contributes, most likely via wnt signaling, to the regulation of migration and cell fate of early progenitors and is involved in the determination of branching points along the ductal tree.