bluuebunny/crossref_metadata_2025 huggingface dataset:
Therapeutic activity of an interleukin‐4/interleukin‐13 dual antagonist on oxazolone‐induced colitis in mice
Authors: Kasaian Marion T. , Page Karen M. , Fish Susan , Brennan Agnes , Cook Timothy A. , Moreira Karen , Zhang Melvin , Jesson Michael , Marquette Kimberly , Agostinelli Rita , Lee Julie , Williams Cara M. M. , Tchistiakova Lioudmila , Thakker Paresh
Published: May 2014

Interleukin‐4 (IL‐4) and IL‐13 are critical drivers of immune activation and inflammation in ulcerative colitis, asthma and other diseases. Because these cytokines may have redundant function, dual targeting holds promise for achieving greater efficacy. We have recently described a bifunctional therapeutic targeting IL‐4 and IL‐13 developed on a novel protein scaffold, generated by combining specific binding domains in an optimal configuration using appropriate linker regions. In the current study, the bifunctional IL‐4/IL‐13 antagonist was evaluated in the murine oxazolone‐induced colitis model, which produces disease with features of ulcerative colitis. The bifunctional IL‐4/IL‐13 antagonist reduced body weight loss throughout the 7‐day course of the model, and ameliorated the increased colon weight and decreased colon length that accompany disease. Colon tissue gene expression was modulated in accordance with the treatment effect. Concentrations of serum amyloid P were elevated in proportion to disease severity, making it an effective biomarker. Serum concentrations of the bifunctional IL‐4/IL‐13 antagonist were inversely proportional to disease severity, colon tissue expression of pro‐inflammatory genes, and serum amyloid P concentration. Taken together, these results define a panel of biomarkers signifying engagement of the IL‐4/IL‐13 pathway, confirm the T helper type 2 nature of disease in this model, and demonstrate the effectiveness of dual cytokine blockade.
Are the Discounts in Seasoned Equity Offers Due to Inelastic Demand?
Authors: Armitage Seth , Dionysiou Dionysia , Gonzalez Angelica
Published: May 2014

This paper investigates the large and diverse discounts in UK open offers and placings. Large discounts are a substantial cost to shareholders who do not buy new shares. The existing literature mainly examines US firm‐commitment offers and private placements. The institutional setting differs in the UK, in ways that make the theory of inelastic demand for shares more important as an explanation for discounts than in the US. The paper finds that inelastic demand, or illiquidity of the issuer's shares, and financial distress, are key determinants of the discount. We expect these results to apply to other stock markets.
Glycated hemoglobin for the diagnosis of diabetes and prediabetes: Diagnostic impact on obese and lean subjects, and phenotypic characterization
Authors: Incani Michela , Sentinelli Federica , Perra Laura , Pani Maria Grazia , Porcu Marta , Lenzi Andrea , Cavallo Maria Gisella , Cossu Efisio , Leonetti Frida , Baroni Marco Giorgio
Published: May 2014

Aims/Introduction

Measurement of glycated hemoglobin (HbA1c) has been recommended for the diagnosis of diabetes and prediabetes. However, epidemiological studies have shown significant discordance between HbA1c and glucose‐based tests. Of the factors that could influence agreement between HbA1c and the oral glucose tolerance test (OGTT), bodyweight has not been fully evaluated. The aims of the present study were to evaluate the impact of HbA1c criteria to diagnose diabetes and prediabetes compared with OGTT, and to examine HbA1c in relation to body mass index.

Materials and Methods

Two cohorts were studied, one from an obesity clinic (n = 592) and one from subjects undergoing screening for diabetes (n = 462). All underwent OGTT and HbA1c measurement.

Results

In the obese cohort, HbA1c ≥6.5% (≥48 mmol/mol) showed a sensitivity of 69.3% for diabetes, whereas HbA1c 5.7–6.4% (39–46 mmol/mol) did not identify prediabetes well (sensitivity 39.1%). In the diabetes screening cohort, HbA1c had low sensitivities for both diabetes (39.2%) and prediabetes (53.3%). When participants were stratified according to body mass index class I–III, HbA1c agreement with the OGTT for diabetes was much higher (80%, P < 0.005) in class I obesity compared with class II–III obesity; whereas for prediabetes, HbA1c had a low sensitivity in all obesity classes.

Conclusions

The agreement between HbA1c, fasting plasma glucose and 2‐h glucose post‐OGTT for the diagnosis of prediabetes was poor in our Italian population; whereas HbA1c ≥6.5% showed a relatively good agreement with OGTT for the diagnosis of diabetes. For the first time, we have shown that obesity class influences the diagnostic performance of HbA1c.
Morphological and Molecular Characterization of a New Species of Stephanopogon, Stephanopogon pattersoni n. sp.
Authors: Lee Won Je , Miller Kai , Simpson Alastair G.B.
Published: May 2014

Stephanopogon is a taxon of multiciliated protists that is now known to belong to Heterolobosea. Small subunit ribosomal DNA (SSU rDNA) phylogenies indicate that Stephanopogon is closely related to or descended from Percolomonas, a small tetraflagellate with a different feeding structure, thus these morphologically dissimilar taxa are of ongoing evolutionary interest. A new strain of Stephanopogon, KM041, was cultured, then characterized by light microscopy, electron microscopy, and SSU rDNA sequencing. KM041 is 18–35 μm (mean 26.8 μm) long, with six main ventral ciliary rows, one ventro‐lateral ciliary row, and three anterior barbs. It closely resembles Stephanopogon minuta Lei et al. in morphology, and is very closely related to an extinct culture “S. aff. minuta”, yet is markedly dissimilar in SSU rDNA sequence from a different isolate identified as S. minuta. This confirms that there are at least two distinct lineages of S. minuta‐like cells, and we describe KM041 as a new species, Stephanopogon pattersoni n. sp. The ultrastructure of KM041 resembles that of previously studied Stephanopogon species, though it has a novel paraxonemal structure in a few cilia. We note that a sub‐basal‐body pad and bulbous axosome are unlikely to be apomorphies for the Stephanopogon–Percolomonas clade.
Flood frequency analyses, statistical trends and seasonality analyses of discharge data: a case study of theLitija station on theSavaRiver
Authors: Bezak N. , Brilly M. , Šraj M.
Published: May 2014

The identification of statistical trends and seasonality is significant for understanding current global climate change. In this study, discharge data from theLitija gauging station on theSavaRiver were used to perform flood frequency and seasonality analyses and identify trends. A linear regression analysis and aMann–Kendall (MK) test were performed to identify trends in differently defined samples, namely, annual maximum (AM) samples and peaks over threshold (POT) samples. Two types of discharge data series [discharge data with included local maxima (QM) and discharge data without local maxima (QD)] were considered. In the flood frequency analyses, the use of three‐parameter distributions produced better test statistics than the use of distribution functions with two parameters. A statistically significant decreasing trend was detected in the mean monthly discharge values; however, the magnitudes of extreme events increased for the Litija station. The results of the study showed that the identified trends and their statistical significance depended on how the samples were defined.
Life Cycle Assessment of ICT
Authors: Malmodin Jens , Lundén Dag , Moberg Åsa , Andersson Greger , Nilsson Mikael
Published: May 2014

The use of information and communication technology (ICT) is growing throughout society, and new products and solutions are developed at an increasing rate. To enable environmental assessment of specific ICT products and other products that rely on ICT in some way, a more complete, detailed, and up‐to‐date study based on real measurements is needed. To date, similar studies have not been readily available or fully comprehensive. This study assessed the overall operational electricity use and life‐cycle–based carbon footprint (CF) relating to ICT in Sweden, including activities not commonly addressed previously, such as shared data transport networks and data centers and manufacturing of network infrastructure. Specific, detailed inventory data are presented and used for assessment of the Internet Protocol core network, data transmission, operator activities, and access network. These specific data, in combination with secondary, more generic data for end‐user equipment, allow a comprehensive overall assessment. The majority of the ICT network CF is the result of end‐user equipment, mainly personal computers, followed by third‐party enterprise networks and data centers and then access networks. The parts closest to the user proved to be clearly responsible for the majority of the impact. The results are presented for Swedish ICT networks and for ICT networks in general based on a global average electricity mix.
Use of cysteine‐reactive cross‐linkers to probe conformational flexibility of human DJ‐1 demonstrates that Glu18 mutations are dimers
Authors: Prahlad Janani , Hauser David N. , Milkovic Nicole M. , Cookson Mark R. , Wilson Mark A.
Published: May 2014

The oxidation of a key cysteine residue (Cys106) in the parkinsonism‐associated protein DJ‐1 regulates its ability to protect against oxidative stress and mitochondrial damage. Cys106 interacts with a neighboring protonated Glu18 residue, stabilizing the Cys106‐SO2− (sulfinic acid) form of DJ‐1. To study this important post‐translational modification, we previously designed several Glu18 mutations (E18N, E18D, E18Q) that alter the oxidative propensity of Cys106. However, recent results suggest these Glu18 mutations cause loss of DJ‐1 dimerization, which would severely compromise the protein's function. The purpose of this study was to conclusively determine the oligomerization state of these mutants using X‐ray crystallography, NMR spectroscopy, thermal stability analysis, circular dichroism spectroscopy, sedimentation equilibrium ultracentrifugation, and cross‐linking. We found that all of the Glu18 DJ‐1 mutants were dimeric. Thiol cross‐linking indicates that these mutant dimers are more flexible than the wild‐type protein and can form multiple cross‐linked dimeric species due to the transient exposure of cysteine residues that are inaccessible in the wild‐type protein. The enhanced flexibility of Glu18 DJ‐1 mutants provides a parsimonious explanation for their lower observed cross‐linking efficiency in cells. In addition, thiol cross‐linkers may have an underappreciated value as qualitative probes of protein conformational flexibility.

image

DJ‐1 is a homodimeric protein that protects cells against oxidative stress. Designed mutations that influence the regulatory oxidation of a key cysteine residue have recently been proposed to disrupt DJ‐1 dimerization. We use cysteine cross‐linking and various biophysical techniques to show that these DJ‐1 mutants form dimers with increased conformational flexibility.
Soluble urokinase plasminogen activator receptor levels are elevated and associated with complications in patients with type 1 diabetes
Authors: Theilade S. , Lyngbæk S. , Hansen T. W. , Eugen‐Olsen J. , Fenger M. , Rossing P. , Jeppesen J. L.
Published: May 2014

Objectives

Soluble urokinase plasminogen activator receptor (suPAR) is a marker of inflammation and endothelial dysfunction. We investigated the associations between suPAR and diabetes, including diabetes duration and complications, in patients with type 1 diabetes.

Design, setting and subjects

From 2009 to 2011, 667 patients with type 1 diabetes and 51 nondiabetic control subjects were included in a cross‐sectional study at Steno Diabetes Center, Gentofte, Denmark. suPAR levels were measured with an enzyme‐linked immunosorbent assay.

Main outcome measures

The investigated diabetic complications were cardiovascular disease (CVD: previous myocardial infarction, revascularisation, peripheral arterial disease and stroke), autonomic dysfunction (heart rate variability during deep breathing <11 beats min−1), albuminuria [urinary albumin excretion rate (UAER) ≥30 mg/24 h] or a high degree of arterial stiffness (pulse wave velocity ≥10 m s−1). Analyses were adjusted for gender, age, systolic blood pressure, estimated glomerular filtration rate, UAER, glycated haemoglobin (HbA1c), total cholesterol, body mass index, C‐reactive protein, antihypertensive treatment and smoking.

Results

Soluble urokinase plasminogen activator receptor levels were lower in control subjects versus all patients, in control subjects versus normoalbuminuric patients (UAER <30 mg/24 h), in normoalbuminuric patients with short (<10 years) versus long diabetes duration and were increased with degree of albuminuria (adjusted P < 0.001 for all). Furthermore, suPAR levels were higher in patients with versus without CVD (n = 144; 21.3%), autonomic dysfunction (n = 369; 59.2%), albuminuria (n = 357; 53.1%) and a high degree of arterial stiffness (n = 298; 47.2%) (adjusted P ≤ 0.024). The adjusted odds ratio (95% confidence interval) values per 1 ln unit increase in suPAR were as follows: 2.5 (1.1–5.7) for CVD: 2.7 (1.2–6.2) for autonomic dysfunction; 3.8 (1.3–10.9) for albuminuria and 2.5 (1.1–6.1) for a high degree of arterial stiffness (P ≤ 0.039).

Conclusion

The suPAR level is higher in patients with type 1 diabetes and is associated with diabetes duration and complications independent of other risk factors. suPAR is a potential novel risk marker for the management of diabetes.
Pneumonia and the incidence of cancer: a Danish nationwide cohort study
Authors: Søgaard K. K. , Farkas D. K. , Pedersen L. , Weiss N. S. , Thomsen R. W. , Sørensen H.T.
Published: May 2014

Objectives

To examine the risk of a subsequent pulmonary or extra‐pulmonary cancer diagnosis following a first‐time hospital‐based diagnosis of pneumonia.

Design

Population‐based cohort study using Danish medical registries.

Setting

All hospitals in Denmark.

Subjects

A total of 342 609 patients with a first‐time hospital‐based (inpatient, emergency room or outpatient clinic) diagnosis of pneumonia between 1995 and 2011.

Main outcome measures

We quantified the excess risk of various cancers amongst pneumonia patients compared to the expected risk in the general population, using relative [standardised incidence ratios (SIRs)] and absolute risk calculations. Follow‐up started 1 month after a hospital‐based diagnosis of pneumonia and ended on 31 December 2011.

Results

A total of 28 496 cancers were observed, compared with 21 625 expected, amongst 342 609 pneumonia patients followed for a median of 4.2 years. The absolute risk of a cancer diagnosis 1 to <6 months following a pneumonia diagnosis was 1.4%, with a corresponding SIR of 2.48 [95% confidence interval (CI) 2.41–2.55]. This was mainly due to an increased risk of lung cancer (eightfold) and haematological cancers (fourfold). The SIR for any cancer remained increased at 1.35 (95% CI 1.30–1.40) during 6–12 months of follow‐up, and 1.20 (95% CI 1.18–1.22) during 1–5 years of follow‐up. Beyond 5 years, an increased risk was maintained for lung, oesophageal, liver and bladder cancers, squamous cell carcinoma of the skin, lymphoma and multiple myeloma.

Conclusions

A hospital‐based pneumonia diagnosis was associated with an increased risk of a cancer diagnosis, especially in the ensuing months, but the absolute risk was small.
Evidence of Cotton leaf curl Burewala virus Variant and its Associate Betasatellite Causing Yellow Mosaic of Eggplant (Solanum melongena) in Pakistan
Authors: Ullah Rahim , Akhtar Khalid P. , Hassan Ishtiaq , Saeed Muhammad , Sarwar Nighat , Mansoor Shahid
Published: May 2014

Eggplant (Solanum melongena L.) plants with severe leaf mosaic and mottling were found in a kitchen garden near cotton fields in Pakistan. Rolling Circle Amplification products from six of the naturally infected eggplant plants, subjected to PCR, successfully amplified expected products of 2.8 and 1.4 kb using begomovirus and betasatellite‐specific primers, respectively. Based on 99% nucleotide sequence identity, the virus was identified as a variant of Cotton leaf curl Burewala virus (CLCuBuV) (GenBank Accession No. HG428709). Likewise, the sequenced betasatellite with a maximum of 97% nucleotide sequence identity was recognized as a new variant of Cotton leaf curl Multan betasatellite (CLCuMuBMul) (GenBank Accession No. HG428708). The symptomatic induction of Cotton leaf curl disease in CLCuBuV susceptible cotton genotype CIM‐496 by back‐indexing further confirmed the presence of CLCuBuV in eggplant. This is the first report of CLCuBuV and its associate betasatellite in naturally infected plants of eggplant.
Identification and Characterization of the Causal Agent of Gummy Stem Blight from Muskmelon and Watermelon in East China
Authors: Li Ping‐Fang , Ren Run‐Sheng , Yao Xie‐Feng , Xu Jin‐Hua , Babu Binoy , Paret Mathews L. , Yang Xing‐Ping
Published: May 2014

Gummy stem blight (GSB) is one of the most destructive foliar diseases of cucurbits, worldwide. To identify and characterize the pathogen which causes GSB on watermelon and muskmelon in East China, morphological characteristics, pathogenicity assays as well as sequence characterization of the rDNA internal transcribed spacer (ITS) were performed on 41 isolates collected from Jiangsu, Zhejiang, Anhui and Jiangxi provinces. The mycelia of all the isolates were white on top and olivaceous green to black with concentric circles at the bottom on potato‐dextrose agar medium. The isolates differed significantly on aggressiveness based on pathogenicity assays. rDNA‐ITS sequences and phylogenetic analysis confirmed the isolates as Didymella bryoniae. The isolates were found to be highly identical with the exception of 13 isolates, which had a guanine substitution instead of adenine at position 131 of the ITS.
Medical Hypothesis: Loss of the Endocrine Function of the Prostate Is Important to the Pathophysiology of Postprostatectomy Erectile Dysfunction
Authors: Kacker Ravi , Morgentaler Abraham , Traish Abdulmaged
Published: May 2014

Introduction

Three decades after the first nerve-sparing radical prostatectomy, postoperative erectile dysfunction (ED) remains a challenging and common problem. Despite considerable advances and improvements in surgical techniques, full recovery of erectile function remains elusive even for young, potent men. This suggests, ipso facto, that factors other than surgical technique must be important to recovery of erectile function.

Aim

This study aims to review evidence that the prostate is an endocrine gland with contributions to local and systemic concentrations of 5α-dihydrotestosterone (5α-DHT), a potent androgen shown to be critical to penile physiology.

Methods

Literature review of human and animal studies related to endocrine role of prostate and postoperative recovery of erectile function.

Main Outcome Measures

Effect of 5α-DHT on erectile function and recovery after surgical injury.

Results

We advance the following hypothesis: “Loss of endocrine function of the prostate, specifically reduced local 5α-DHT concentration plays a major role in the failure of full recovery of erectile function following anatomic nerve-sparing radical prostatectomy.”

Conclusions

We propose two separate, yet interrelated, mechanisms whereby the loss of 5α-DHT interferes with postoperative recovery of erectile function: (i) 5α-DHT contributes to cavernous nerve integrity and its ability to recover from surgical insult. (ii) 5α-DHT is important to the structural/functional integrity of penile tissues and erectile physiology.
Human microRNA hsa‐miR‐1231 suppresses hepatitis B virus replication by targeting core mRNA
Authors: Kohno T. , Tsuge M. , Murakami E. , Hiraga N. , Abe H. , Miki D. , Imamura M. , Ochi H. , Hayes C. N. , Chayama K.
Published: May 2014

Pathogen‐specific miRNA profiles might reveal potential new avenues for therapy. To identify miRNAs directly associated with hepatitis B virus (HBV) in hepatocytes, we performed a miRNA array analysis using urokinase‐type plasminogen activator (uPA)–severe combined immunodeficiency (SCID) mice where the livers were highly repopulated with human hepatocytes and human immune cells are absent. Mice were inoculated with HBV‐infected patient serum samples. Eight weeks after HBV infection, human hepatocytes were collected from liver tissues, and miRNAs were analysed using the Toray 3D array system. The effect of miRNAs on HBV replication was analysed using HBV‐transfected HepG2 cells. Four miRNAs, hsa‐miR‐486‐3p, hsa‐miR‐1908, hsa‐miR‐675 and hsa‐miR‐1231 were upregulated in mouse and human livers with HBV infection. These miRNAs were associated with immune response pathways such as inflammation mediated by chemokine and cytokine signalling. Of these miRNAs, hsa‐miR‐1231, which showed high homology with HBV core and HBx sequences, was most highly upregulated. In HBV‐transfected HepG2 cells, overexpression of hsa‐miR‐1231 resulted in suppression of HBV replication with HBV core reduction. In conclusion, a novel interaction between hsa‐miR‐1231 and HBV replication was identified. This interaction might be useful in developing new therapeutic strategies against HBV.
Radioembolization of hepatocellular carcinoma activates liver regeneration, induces inflammation and endothelial stress and activates coagulation
Authors: Fernandez‐Ros Nerea , Iñarrairaegui Mercedes , Paramo Jose A. , Berasain Carmen , Avila Matias A. , Chopitea Ana , Varo Nerea , Sarobe Pablo , Bilbao Jose I. , Dominguez Ines , D'Avola Delia , Herrero J. Ignacio , Quiroga Jorge , Sangro Bruno
Published: May 2014

Background & Aims

Radioembolization may rarely induce liver disease resulting in a syndrome that is similar to veno‐occlusive disease complicating bone marrow transplantation where inflammation, endothelial cell activation and thrombosis are likely involved. We hypothesized that similar mechanisms could be implicated in radioembolization‐induced liver disease (REILD). Moreover, lobar radioembolization may induce hypertrophy of the non‐treated hemiliver most probably by inducing liver regeneration.

Methods

In patients with hepatocellular carcinoma, we prospectively studied serum levels of markers of liver regeneration, oxidative stress, pro‐inflammatory pathways, endothelial activation and coagulation parameters over 2 months after radioembolization.

Results

Although REILD did not occur among 14 treated patients, a decrease in effective liver blood flow was observed. Radioembolization was followed by a persistent increase in pro‐inflammatory (interleukin 6 and 8) and oxidative stress (malondyaldehide) markers, an induction of endothelial injury markers (vW factor and PAI‐1) and an activation of the coagulation cascade (factor VIII, PAI‐1, D‐Dimer) as well as a significant increase in factors related to liver regeneration (FGF‐19 and HGF).

Conclusion

Radioembolization activates liver regeneration, produces oxidative stress, activates inflammatory cytokines and induces endothelial injury with partial activation of the coagulation cascade. These findings may have implications in the pathogenesis, prevention and therapy of REILD and in the development of new therapies to enhance hypertrophy with a surgical perspective.
Artificial Marine Micro‐Reserves Networks (AMMRNs): an innovative approach to conserve marine littoral biodiversity and protect endangered species
Authors: García‐Gómez José C. , Guerra‐García José M. , Espinosa Free , Maestre Manuel J. , Rivera‐Ingraham Georgina , Fa Darren , González Alexander R. , Ruiz‐Tabares Aurora , López‐Fé Carlos M.
Published: May 2014

Coastal engineering works, especially the outer breakwaters of ports where environmental conditions are usually good, often constitute new habitats for marine littoral species. Their potential indirect contribution to the regeneration and conservation of protected species opens up a new perspective in protection of marine biodiversity. This is particularly true when these works harbour, as we show here, important reproductive populations of species that are threatened or even in danger of extinction. We provide integrated data on protected marine species in Southern Iberia established on different substrata (quarried dolomitic rocks, concrete cubic blocks, concrete tetrapods and vertical concrete walls) that are used in the construction of artificial levees that could potentially be Artificial Marine Micro‐Reserves (AMMRs). We also present the first evidence of the ‘reserve effect’ in potential AMMRs and we discuss the need for the creation of AMMRs including their effective networking (AMMRNs), supporting data for which has been observed by studying coastal facilities subjected to strict access restrictions (for security reasons, not conservation). These facilities have acted as valuable proxies and, in reality, potentially act as AMMRs, as well as having a role in helping to detect and control invasive species. We discuss the ecological engineering aspects related to the design and type of materials used in coastal constructions with a view to aiding the integration of these into existing coastal ecosystems as well as promoting greater settlement of species and therefore increases in biodiversity. Finally, the environmental implications of AMMRNs within the future implementation strategy of the Water Framework Directive 2000/60 EC are also discussed.
Temporal variation in cannibalistic infanticide by the shore crab Hemigrapsus oregonensis: implications for reproductive success
Authors: Miller Seth H. , Morgan Steven G.
Published: May 2014

Larvae of benthic marine organisms are released amid high densities of suspension feeding and predatory adults and are highly subject to being consumed, even by conspecifics or their own parent. During laboratory feeding trials conducted in June 2006, female shore crabs (Hemigrapsus oregonensis) from Stege Marsh in San Francisco Bay (37°54.530′ N, 122°19.734′ W) that released their larvae during the previous 24 h ate fewer conspecific larvae than females that had not recently released larvae, though the behavior was not repeated during similar trials in 2007. Additionally, the number of larvae eaten increased with increasing starvation time, and hungrier females showed a trend toward eating more larvae from a different species (Carcinus maenas) than larvae of conspecifics. Thus, suppression of suspension feeding may reduce conspecific predation of newly released larvae, but this response partially depends on hunger level. This is the first time crabs have been shown to suppress feeding to reduce cannibalism of larvae, and this behavior could affect reproductive success and population dynamics.
Generation of a ToxA knockout strain of the wheat tan spot pathogen Pyrenophora tritici‐repentis
Authors: Moffat Caroline S. , See Pao Theen , Oliver Richard P.
Published: May 2014

The necrotrophic fungal pathogen Pyrenophora tritici‐repentis causes tan spot, a major disease of wheat, throughout the world. The proteinaceous effector ToxA is responsible for foliar necrosis on ToxA‐sensitive wheat genotypes. The single copy ToxA gene was deleted from a wild‐type race 1 P. tritici‐repentis isolate via homologous recombination of a knockout construct. Expression of the ToxA transcript was found to be absent in transformants (toxa), as was ToxA protein production in fungal culture filtrates. Plant bioassays were conducted to test transformant pathogenicity. The toxa strains were unable to induce necrosis on ToxA‐sensitive wheat genotypes. To our knowledge, this is the first demonstration of a targeted gene knockout in P. tritici‐repentis. The ability to undertake gene deletions will facilitate the characterization of other pathogenicity effectors of this economically significant necrotroph.
A transcription factor FgSte12 is required for pathogenicity in Fusarium graminearum
Authors: Gu Qin , Zhang Chengqi , Liu Xin , Ma Zhonghua
Published: May 2014

A conserved mitogen‐activated protein kinase (MAPK) cascade homologous to the yeast Fus3/Kss1 mating/filamentation pathway is involved in the regulation of vegetative development and pathogenicity in Fusarium graminearum. However, little is known about the downstream transcription factors of this pathway. In Saccharomyces cerevisiae, the homeodomain protein Ste12 is a key transcription factor activated by Fus3/Kss1. In this study, we characterized a Ste12 orthologue FgSte12 in F. graminearum. The FgSTE12 deletion mutant (ΔFgSte12) was impaired in virulence and in the secretion of cellulase and protease, although it did not show recognizable phenotype changes in hyphal growth, conidiation or deoxynivalenol (DON) biosynthesis. In addition, ΔFgSte12 and the FgGPMK1 (a FUS3/KSS1‐related MAPK gene) mutant shared several phenotypic traits. Furthermore, we found that FgGpmk1 controls the nuclear localization of FgSte12. Yeast two‐hybrid and affinity capture assays indicated that FgSte12 interacts with the FgSte11–Ste7–Gpmk1 complex. Taken together, these results indicate that FgSte12 is a downstream target of FgSte11–Ste7–Gpmk1 and plays an important role in pathogenicity in F. graminearum.
TRPM8 has a key role in experimental colitis‐induced visceral hyperalgesia in mice
Authors: Hosoya T. , Matsumoto K. , Tashima K. , Nakamura H. , Fujino H. , Murayama T. , Horie S.
Published: May 2014

Background

Transient receptor potential channel melastatin 8 (TRPM8) is activated by cold temperatures and cooling agents (menthol and icilin). Recent studies showed TRPM8 is expressed in visceral organs and peripheral sensory pathways. However, the role of TRPM8 in visceral hyperalgesia is poorly understood in pathological states such as inflammatory bowel disease. Hence, we investigated the distribution of TRPM8 and its involvement in visceral hyperalgesia in experimental colitis mice.

Methods

TRPM8 immunoreactivity was detected using immunohistochemical staining with fluorescein‐conjugated tyramide amplification. Visceral hyperalgesia was measured by the intracolonic administration of TRPM8 agonist, WS‐12, in control and dextran sodium sulfate (DSS)‐induced colitis mice.

Key Results

TRPM8 immunoreactivity in the distal colon was much higher than in the transverse and proximal colon under physiological conditions. TRPM8 immunoreactivity markedly increased in the distal colon mucosa of DSS‐induced colitis mice compared with control mice. The number of TRPM8 nerve fibers in mucosa of DSS‐ or 2,4,6‐trinitrobenzene sulfonic acid‐induced colitis model mice drastically increased compared with control mice. TRPM8 immunoreactivities colocalized with the calcitonin gene‐related peptide‐ and substance P‐immunoreactive nerve fibers in the mucosa. Intracolonic administration of WS‐12 induced behavioral visceral pain‐like responses. The numbers of these responses in the colitis model mice were 3 times higher than in control mice, and were decreased by pretreatment with the TRPM8 channel blocker AMTB.

Conclusions & Inferences

Increased expression of TRPM8 may contribute to the visceral hyperalgesia of experimental colitis.
Atrial Tachycardias Utilizing the Ligament of Marshall Region Following Single Ring Pulmonary Vein Isolation for Atrial Fibrillation
Authors: CHIK WILLIAM W.B. , CHAN JACKY KIT , ROSS DAVID L. , WAGSTAFF JACKIE , KIZANA EDDY , THIAGALINGAM ARAVINDA , KOVOOR PRAMESH , THOMAS STUART P.
Published: May 2014

Background

Organized atrial tachycardias (OATs) after pulmonary vein isolation (PVI) procedure are common. Arrhythmia mechanisms include mitral annular, ring gap, or roof‐dependent gap‐related flutters. In this series, we describe a mechanism of arrhythmia utilizing the ridge between left pulmonary vein (PV) and left atrial appendage (LAA) in the Ligament of Marshall (LOM) region.

Methods and Results

Five tachycardias involving the LOM region were identified from a group of 240 patients who underwent a single ring PVI procedure for symptomatic atrial fibrillation. The common characteristics of these tachycardias were the endocardial breakout over a broad area adjacent to the LOM region, presence of presystolic or mid‐diastolic potentials, and abolition by ablation of the presystolic or mid‐diastolic potentials remote from the endocardial breakout site. In all five cases, tachycardias were present after isolation of the veins and posterior left atria. All demonstrated characteristic areas of very slow conduction in the LOM region highlighted by presence of either low voltage, long duration fractionated potentials, or mid‐diastolic potentials with a fixed temporal relationship to the subsequent endocardial activation. The pattern of activation and termination of tachycardia during ablation was consistent with an arrhythmia utilizing an electrically insulated tract within LOM and the PV‐LAA ridge region.

Conclusions

We identified a pattern of arrhythmias involving a concealed presystolic component and a broad endocardial breakout site related to the LOM region. Successful ablation site involved careful identification of small diastolic potentials in the LAA/ridge region or adjacent to the coronary sinus.
Acute Decrease of Cerebral Oxygen Saturation during Rapid Ventricular and Supraventricular Rhythm: A Pilot Study
Authors: WUTZLER ALEXANDER , OTTO NATALIE , GRÄSER SASKIA , BOLDT LEIF‐HENDRIK , HUEMER MARTIN , PARWANI ABDUL , HAVERKAMP WILHELM , STORM CHRISTIAN
Published: May 2014

Background

Monitoring of cerebral tissue oxygen saturation (SctO2) reflects cerebral microcirculation. We sought to characterize the decrease in SctO2 during supraventricular tachycardia (SVT) and ventricular tachycardia (VT) in adults.

Methods

Twenty patients (mean age: 46.3 ± 18.1 years, 40% men) were included. Rapid atrial and ventricular pacing (200/min) was used as a model for VT and SVT. Near‐infrared spectroscopy (NIRS) was used to measure SctO2.

Results

Atrial stimulation decreased right (P = 0.014) and left (P = 0.019) hemispheric SctO2 compared to baseline. Ventricular stimulation also decreased right (P < 0.001) and left (P < 0.001) hemispheric SctO2. A negative correlation between age and minimal value under stimulation was found for atrial (right SctO2 r = –0.641, P = 0.034; left SctO2 r = –0.694, P = 0.018) and ventricular pacing (right SctO2 r = –0.564, P = 0.01; left SctO2 r = –0.604, P = 0.005). A positive correlation was found between left ventricular ejection fraction (LVEF) and minimal value under ventricular stimulation (right SctO2 r = 0.567, P = 0.009; left SctO2 r = 0.471, P = 0.036).

Conclusion

Cerebral perfusion decreased during simulated SVT and VT and is influenced by age and LVEF. Clinicians can consider NIRS monitoring in patients during ablation procedures and in critical care. NIRS may especially be appropriate for the elderly and for patients with impaired LVEF.
Left Ventricular Hypertrophy and Antiarrhythmic Drugs in Atrial Fibrillation: Impact on Mortality
Authors: CHUNG ROY , HOUGHTALING PENNY L. , TCHOU MICHAEL , NIEBAUER MARK J. , LINDSAY BRUCE D. , TCHOU PATRICK J. , CHUNG MINA K.
Published: May 2014

Background

Despite sparse clinical data, current atrial fibrillation (AF) guidelines favor amiodarone as a drug of choice for patients with left ventricular hypertrophy (LVH).

Objective

This study tested the hypothesis that patients with persistent AF and LVH on nonamiodarone antiarrhythmics have higher mortality compared to patients on amiodarone.

Methods

In an observational cohort analysis of patients who underwent cardioversion for AF, patients with LVH, defined as left ventricular wall thickness ≥1.4 cm, by echocardiogram prior to their first cardioversion, were included; clinical data, including antiarrhythmic drugs and ejection fraction (LVEF), were collected. Mortality, determined via the Social Security Death Index, was analyzed using Kaplan‐Meier and Cox proportional hazards models to determine whether antiarrhythmic drugs were associated with higher mortality.

Results

In 3,926 patients, echocardiographic wall thickness was available in 1,399 (age 66.8 ± 11.8 years, 67% male, LVEF 46 ± 15%, septum 1.3 ± 0.4, posterior wall 1.2 ± 0.2 cm), and 537 (38%) had LVH ≥1.4 cm. Among 537 patients with LVH, mean age was 67.5 ± 11.7 years, 76.4% were males, and mean LVEF was 48.3 ± 13.3%. Amiodarone was associated with lower survival (log rank P = 0.001), including after adjusting for age, LVEF, and coronary artery disease (P = 0.023). In propensity‐score matched cohorts with LVH treated with no drugs, nonamiodarone antiarrhythmic drugs (non‐AADs), or amiodarone (N = 65 each group), there was early lower survival in patients on amiodarone (P = 0.05).

Conclusions

Patients with persistent AF and LVH on non‐AADs do not have higher mortality compared to patients on amiodarone. Importantly, these findings do not support amiodarone as a superior choice in patients with LVH.
Does cognitive‐behavioural therapy promote meaning making? A preliminary test in the context of geriatric depression
Authors: Holland Jason M. , Chong Gabriella , Currier Joseph M. , O'Hara Ruth , Gallagher‐Thompson Dolores
Published: May 2014

Objectives

This study examined the extent to which cognitive‐behavioural therapy (CBT) for geriatric depression promoted meaning made of stress.

Design

Fifty‐one participants received CBT and were assessed at pre‐ and post‐treatment.

Methods

The primary outcome was the Integration of Stressful Life Experiences Scale (ISLES) and demographic factors were examined as moderators of changes over time.

Results

Those with more education showed improvement in their ability to regain positive values, worldviews, and purpose in life after a stressor.

Conclusions

It appears that CBT promotes some forms of meaning made of stress for those with higher education.

Practitioner points

Cognitive‐behavioural therapy as it is routinely practiced may help highly educated older adults regain their Footing in the World (e.g., maintain positive values, worldviews, and purpose in life) in the aftermath of a stressful life event.

Cognitive‐behavioural therapy appears to offer fewer gains for less educated older adults (in terms of Footing in the World) as well as for other aspects of meaning‐making, such as the ability to ‘make sense’ of a significant stressor.

Although more empirical work is necessary, meaning‐oriented interventions (e.g., ‘re‐authoring’ a fragmented self‐narrative; Neimeyer, 2009, p. 97) hold promise as useful adjuncts to routine therapy that could augment outcomes.
Celiac Disease in Children with Atopic Dermatitis
Authors: Ress Krista , Annus Triine , Putnik Urve , Luts Katrin , Uibo Raivo , Uibo Oivi
Published: May 2014

Celiac disease (CD) is an autoimmune disorder of the small intestine with highly variable clinical presentation and frequently associated with various immune‐mediated diseases. Among these immune‐mediated diseases, atopy has been found frequently in individuals with CD. We aimed to study the prevalence of CD in Estonian children with atopic dermatitis (AD), a common multifactorial chronic inflammatory skin disease. We recruited 351 consecutive children with active AD (mean age 5.8 yrs, 57.6% boys) at Tallinn Children's Hospital, Estonia. Sera of all patients were tested for total serum immunoglobulin (Ig) A, for IgA‐ and IgG‐type autoantibodies to tissue transglutaminase (IgA‐anti‐TG2, IgG‐anti‐TG2) and to deamidated gliadin peptides (IgA‐anti‐DGP, IgG‐anti‐DGP). The diagnosis of CD was confirmed histologically by small intestine biopsy according to the European Society of Paediatric Gastroenterology, Hepatology and Nutrition diagnostic criteria. IgA deficiency was detected in nine patients with AD (2.6%), none of whom had IgG‐anti‐TG2 or IgG‐anti‐DGP seropositivity. IgA‐anti‐TG2 positivity was found in 4 (1.1%), IgG‐anti‐TG2 positivity in 2 (0.6%), IgA‐anti‐DGP positivity in 11 (3.1%), and IgG‐anti‐DGP in 10 (2.8%) patients. Celiac disease was confirmed in five (1.4%) patients with AD (95% confidence interval 0.46, 3.32) and all were histologically characterized as Marsh IIIa–IIIc stages and two presented with silent CD. In AD patients, CD prevalence was more than four times as high as in previously studied randomly selected schoolchildren in Estonia. Two patients with AD diagnosed with CD had no symptoms indicative of CD, in spite of extensive histologic changes in the small intestine mucosa. Therefore our study emphasizes the need for evaluating the cost‐effectiveness of screening individuals with AD for CD in time to prevent long‐term complications.
Stability of some microginins synthesized by the cyanobacterium Woronichinia naegeliana (Unger) Elenkin
Authors: Bober Beata , Kaminski Ariel , Chrapusta Ewelina , Bialczyk Jan
Published: May 2014

Microginins are linear oligopeptides synthesized by cyanobacteria. The literature data on their characteristics are scant. This study examined the influence of abiotic factors including pH, temperature, visible and ultraviolet radiation on the stability of the microginins FR3 (MG‐FR3), FR4 (MG‐FR4) and 757 (MG‐757) synthesized by Woronichinia naegeliana. In alkaline conditions (pH 9) only the concentration of MG‐757 was reduced significantly, by 14.3%. The tested microginins were stable at room temperature (half‐life 7–17 weeks). Boiling for one hour caused 26.1% decomposition of MG‐FR4 and 26.8% decomposition of MG‐757; MG‐FR3 was not significantly affected. Under visible radiation the initial content of MG‐FR4 declined 23.0%, but MG‐FR3 and MG‐757 proved insensitive to it. Treatment with a high dose of UV radiation (36 μmol m−2 s−1) caused the tested microginins to degrade by 13.8% to 21.4%. The study showed these microginins to be oligopeptides of high stability, the most stable of them being MG‐FR3.
PM10‐stimulated airway epithelial cells activate primary human dendritic cells independent of uric acid: Application of an in vitro model system exposing dendritic cells to airway epithelial cell‐conditioned media
Authors: Hirota Jeremy A. , Alexis Neil E. , Pui Mandy , Wong SzeWing , Fung Elkie , Hansbro Phillip , Knight Darryl A. , Sin Don D. , Carlsten Chris
Published: May 2014

Background and objective

Airway epithelial cells represent the first line of defence against inhaled insults, including air pollution. Air pollution can activate innate immune signalling in airway epithelial cells leading to the production of soluble mediators that can influence downstream inflammatory cells. Our objective was to develop and validate a model of dendritic cell exposure to airway epithelial cell‐conditioned media. After establishing the model, we explored how soluble mediators released from airway epithelial cells in response to air pollution influenced the phenotype of dendritic cells.

Methods

Human airway epithelial cells were cultured under control and urban particulate matter (PM10) exposure conditions with or without pharmacological inhibitors of the uric acid pathway. Culture supernatants were collected for conditioned media experiments with peripheral blood mononuclear cell‐derived dendritic cells analysed by flow cytometry.

Results

Monocytes derived from peripheral blood mononuclear cells cultured in interleukin‐4 and granulocyte macrophage colony stimulating factor differentiated into immature dendritic cells that phenotypically differentiated into mature dendritic cells in response to conditioned media from phorbol myristate acetate‐activated THP‐1 monocytes. Exposure of immature dendritic cells to conditioned media from airway epithelial cells exposed to PM10 resulted in dendritic cell maturation that was independent of uric acid.

Conclusions

We present a conditioned media model useful for interrogating the contribution of soluble mediators produced by airway epithelial cells to dendritic cell phenotype and function. Furthermore, we demonstrate that PM10 exposure induces airway epithelial cell production of soluble mediators that induce maturation of dendritic cells independent of uric acid.
The Global Climate Regime: Explaining Lagging Reform
Authors: Ovodenko Alexander
Published: May 2014

There have been growing calls for reform of the United Nations Framework Convention on Climate Change (UNFCCC). How have governments met the demand for action on climate change despite the lagging pace of UNFCCC reform? New qualitative data demonstrate that the institutional, sectoral, and technical characteristics of multilateral institutions have guided government choices in managing climate change issues. Institutional resources and sectoral participation in multilateral institutions have enabled governments to handle climate change issues outside the UNFCCC, reducing the need to invest in its reform as demand for action has grown. These specialized institutions are able to mitigate political disputes and facilitate greater efficacy in handling specific issues such as financing and emissions mitigation. They have mandates that overlap with the cross‐cutting nature of climate change, requiring no new mandates, which mitigates political disputes in managing specific climate issues.
Exaggerated root respiration accounts for growth retardation in a starchless mutant of Arabidopsis thaliana
Authors: Brauner Katrin , Hörmiller Imke , Nägele Thomas , Heyer Arnd G.
Published: May 2014

The knock‐out mutation of plastidial phosphoglucomutase (pgm) causes a starchless phenotype in Arabidopsis thaliana, and results in a severe growth reduction of plants cultivated under diurnal conditions. It has been speculated that high soluble sugar levels accumulating during the light phase in leaf mesophyll might cause a reduction of photosynthetic activity or that shortage of reduced carbon during the night is the reason for the slow biomass gain of pgm. Separate simultaneous measurements of leaf net photosynthesis and root respiration demonstrate that photosynthetic activity per unit fresh weight is not reduced in pgm, whereas root respiration is strongly elevated. Comparison with a mutant defective in the dominating vacuolar invertase (AtβFruct4) revealed that high sucrose concentration in the cytosol, but not in the vacuole, of leaf cells is responsible for elevated assimilate transport to the root. Increased sugar supply to the root, as observed in pgm mutants, forces substantial respiratory losses. Because root respiration accounts for 80% of total plant respiration under long‐day conditions, this gives rise to retarded biomass formation. In contrast, reduced vacuolar invertase activity leads to reduced net photosynthesis in the shoot and lowered root respiration, and affords an increased root/shoot ratio. The results demonstrate that roots have very limited capacity for carbon storage but exert rigid control of supply for their maintenance metabolism.