bluuebunny/crossref_metadata_2025 huggingface dataset:
Role of radiotherapy in treating patients with primary malignant mediastinal non‐seminomatous germ cell tumor: A 21‐year experience at a single institution
Authors: Wang Jianyang , Bi Nan , Wang Xiaozhen , Hui Zhouguang , Liang Jun , Lv Jima , Zhou Zongmei , Feng Qin Fu , Xiao Zefen , Chen Dongfu , Zhang Hongxing , Yin Weibo , Wang Luhua
Published: October 2014

Background

The aim of this study was to investigate the clinical characteristics and outcomes of patients with primary malignant mediastinal non‐seminomatous germ cell tumor (MMNSGCT) by comparing the efficacies of different treatment modalities.

Methods

The charts of 62 consecutive patients with MMNSGCT between 1990 and 2010 were reviewed. Analyses included Kaplan‐Meier survival and Cox multivariate regression.

Results

There was sufficient data of 61 patients for inclusion in the study. The median age was 25 years. At diagnosis, 35 patients had tumors located in the mediastinum, 26 had lung and/or distant metastases. At a median follow‐up of 47.2 months, 32 patients had died and 43 had developed progressive disease. The one, three, and five‐year overall survival (OS) and progression‐free survival (PFS) rates were 72.1%, 50.8%, 49.2% and 47.5%, 32.8%, 32.8%, respectively. Patients who received radiotherapy in the primary treatment regimen showed improved five‐year OS (68.2% vs. 38.5%, P = 0.043), PFS (45.5% vs. 20.5%, P = 0.023), and local recurrence‐free survival (LRFS) (77.3% vs. 38.5%, P = 0.003) compared with those who did not receive radiotherapy. Multivariate analysis revealed that radiotherapy was an independent prognostic factor of five‐year OS (hazard ratio [HR] 0.39, P = 0.037), PFS (HR 0.42, P = 0.017), and LRFS (HR 0.31, P = 0.019).

Conclusion

Radiotherapy in a chemotherapy‐based treatment regimen could significantly reduce local recurrence and improve survival of MMNGCT patients.
Clinicopathological characteristics and outcomes of ROS1‐rearranged patients with lung adenocarcinoma without EGFR, KRAS mutations and ALK rearrangements
Authors: Wu Shafei , Wang Jinghui , Zhou Lijuan , Su Dan , Liu Yuanyuan , Liang Xiaolong , Zhang Shucai , Zeng Xuan
Published: October 2014

Background

c‐ros oncogene 1 (ROS1) rearrangement presents one of the newest molecular targets in non‐small cell lung cancer (NSCLC). ROS1 rearrangement is predominantly found in adenocarcinoma cases and is exclusive to other oncogenes, such as epidermal growth factor receptor (EGFR), Kirsten rat sarcoma viral oncogene homolog (KRAS), and anaplastic lymphoma kinase (ALK). The aim of this study was to investigate the clinicopathological characteristics and outcomes of ROS1‐rearranged patients with lung adenocarcinoma without EGFR and KRAS mutations and ALK rearrangements.

Methods

Wild‐type EGFR/KRAS/ALK patients with lung adenocarcinoma were selected from Beijing Chest Hospital. Specimens were conducted in tissue microarrays. ROS1 rearrangement was screened using fluorescence in situ hybridization.

Results

Our study included 127 patients with lung adenocarcinoma without EGFR and KRAS mutations and ALK rearrangements. ROS1 rearrangement was detected in five (3.9%) of the 127 patients. Compared with ROS1‐negative patients, the positive rate of ROS1 in female patients was significantly higher than in male patients (9.8% vs. 0.0%, P = 0.009). There were no differences in age, smoking status, stage or histological subtype between ROS1‐positive and ROS1‐negative patients. No significant difference in survival was detected between the ROS1‐positive and ROS1‐negative patients.

Conclusions

ROS1 rearrangement is a rare subset of lung adenocarcinoma. In 127 patients with lung adenocarcinoma, 3.9% of ROS1‐positive patients with wild‐type EGFR/KRAS/ALK were found.
Institutional Sources of Legitimate Authority: An Experimental Investigation
Authors: Dickson Eric S. , Gordon Sanford C. , Huber Gregory A.
Published: October 2014

Unelected officials with coercive powers (e.g., police, prosecutors, bureaucrats) vary markedly in the extent to which citizens view their actions as legitimate. We explore the institutional determinants of legitimate authority in the context of a public goods laboratory experiment. In the experiment, an “authority” can target one “citizen” for punishment following citizen contribution choices. Untargeted citizens can then choose to help or hinder the authority. This latter choice may be interpreted as a behavioral measure of the authority's legitimacy. We find that legitimacy is affected by how authorities are compensated, the transparency with which their decisions are observed, and an interaction between these. When transparency is high, citizens are more willing to assist authorities who receive fixed salaries than those who personally benefit from collected penalties, even when citizens' material incentives are controlled for. Lower transparency reduces support, but only for salaried enforcers.
Reduction in alkaline phosphatase is associated with longer survival in primary sclerosing cholangitis, independent of dominant stenosis
Authors: Rupp C. , Rössler A. , Halibasic E. , Sauer P. , Weiss K.‐H. , Friedrich K. , Wannhoff A. , Stiehl A. , Stremmel W. , Trauner M. , Gotthardt D. N.
Published: October 2014

Background

Alkaline phosphatase (ALP) is an important serum marker in primary sclerosing cholangitis (PSC). Patients with obstruction of the large bile ducts due to dominant strictures (DS) are a special, clinically important phenotype.

Aim

To determine the impact of ALP reduction on liver transplantation‐free survival in PSC patients with DS.

Methods

Prospective cohort study in 215 PSC patients. We performed subgroup analysis for patients without DS (no DS, n = 84), DS at first presentation (DS early, n = 72) and development of DS during the course of the study (DS late, n = 59). We evaluated two scores of ALP reduction. ALP reduction 1 was defined as ALP normalisation, 50% reduction compared with baseline values, or reduction below 1.5 times of upper limit of normal (ULN) within 6 months. ALP reduction 2 was defined as ALP reduction below 1.5 times of ULN within 12 months.

Results

Of the patients, 59.5% reached an ALP reduction 1 and 56.7% according to ALP reduction 2. Achievement of each score was associated with longer transplantation‐free survival in all three groups (ALP reduction 1: no DS P = 0.001; DS early P < 0.001; DS late P = 0.022; ALP reduction 2: no DS P = 0.014; DS early P = 0.001; DS late P = 0.002). Cox‐regression analysis revealed each score as an independent predictor for improved transplantation‐free survival (ALP reduction 1 and 2 P < 0.001 each). We further analysed previously published scores of ALP improvement in PSC showing also improved survival in patients with ALP normalisation or a reduction below 1.5 times of ULN (P = 0.003, P = 0.001, respectively), whereas the score determined by 40% reduction did not show significant differences in survival (P = 0.55).

Conclusions

Reduction in alkaline phosphatase values within the first year is associated with improved transplantation‐free survival in patients with primary sclerosing cholangitis independent of the presence of dominant strictures. Alkaline phosphatase might be an adequate surrogate marker for outcome assessment in clinical studies both for patients with and without dominant strictures.
Review article: the diagnosis and management of food allergy and food intolerances
Authors: Turnbull J. L. , Adams H. N. , Gorard D. A.
Published: October 2014

Background

Adverse reactions to food include immune mediated food allergies and non‐immune mediated food intolerances. Food allergies and intolerances are often confused by health professionals, patients and the public.

Aim

To critically review the data relating to diagnosis and management of food allergy and food intolerance in adults and children.

Methods

MEDLINE, EMBASE and the Cochrane Database were searched up until May 2014, using search terms related to food allergy and intolerance.

Results

An estimated one‐fifth of the population believe that they have adverse reactions to food. Estimates of true IgE‐mediated food allergy vary, but in some countries it may be as prevalent as 4–7% of preschool children. The most common food allergens are cow's milk, egg, peanut, tree nuts, soy, shellfish and finned fish. Reactions vary from urticaria to anaphylaxis and death. Tolerance for many foods including milk and egg develops with age, but is far less likely with peanut allergy. Estimates of IgE‐mediated food allergy in adults are closer to 1–2%. Non‐IgE‐mediated food allergies such as Food Protein‐Induced Enterocolitis Syndrome are rarer and predominantly recognised in childhood. Eosinophilic gastrointestinal disorders including eosinophilic oesophagitis are mixed IgE‐ and non‐IgE‐mediated food allergic conditions, and are improved by dietary exclusions. By contrast food intolerances are nonspecific, and the resultant symptoms resemble other common medically unexplained complaints, often overlapping with symptoms found in functional disorders such as irritable bowel syndrome. Improved dietary treatments for the irritable bowel syndrome have recently been described.

Conclusions

Food allergies are more common in children, can be life‐threatening and are distinct from food intolerances. Food intolerances may pose little risk but since functional disorders are so prevalent, greater efforts to understand adverse effects of foods in functional disorders are warranted.
Vegetation dynamics of managed Mediterranean forests 16 yr after large fires in southeastern Spain
Authors: Alfaro‐Sánchez Raquel , Sánchez‐Salguero Raúl , De las Heras Jorge , Hernández‐Tecles Enrique , Moya Daniel , López‐Serrano Francisco R.
Published: October 2014

Question

Adaptive forest management requires scientific knowledge about post‐fire vegetation dynamics, mainly on initial and transitional stages. We hypothesized that management practices are as important as the timing of the operations themselves, with respect to diversity and species composition of the understorey post‐fire regenerated Pinus halepensis forests.

Location

Two post‐fire regenerated P. halepensis stands burned in 1994 under contrasting climatic conditions (Dry ‐595 mm·yr−1‐ and Semi‐arid ‐340 mm·yr−1‐ sites) in southeast Spain.

Methods

At both sites, we set experimental plots to test early treatments, including removal of the understorey vegetation (scrubbing, at post‐fire year 5), thinning (at post‐fire years 5 and 10) and control plots. Alpha diversity indices, including species richness, Shannon diversity index and plant cover, as a measure of vegetation abundance, and beta diversity indices, such as Jaccard index and non‐metric multidimensional scaling were diachronically analysed at post‐fire years 5 (before the treatments) and 16.

Results

At both sites, the most abundant species were obligate seeders or grass resprouters. Low overlap in the occurrence of species was also found between sites on both dates, but the number of shared species increased by the end of the study period. Significant differences in the diversity indices were detected between sites. Despite the silvicultural treatments, the species richness and Shannon diversity index values at the Dry site were similar in the treated and control plots at 16 yr. Conversely, at the Semi‐arid site, the species richness and Shannon diversity index values were enhanced by the thinning treatments carried out 10 yr after the fire. Plant cover increased despite the treatments (scrubbing and thinning) on both the pine and understorey layers in every treated plot.

Conclusion

Our forest management trials enhanced the diversity indices when applied to very high tree density post‐fire regenerated stands, even applied to areas with very limited resources (nutrients, water, etc.) such as semi‐arid ecosystems. Thus, scrubbing at post‐fire year 5 plus thinning carried out at post‐fire year 10 proved to be a suitable option to reduce fire hazards in the short term at both sites and to enhance plant diversity at the Semi‐arid site.
Bayesian Nonparametric Estimation of Targeted Agent Effects on Biomarker Change to Predict Clinical Outcome
Authors: Graziani Rebecca , Guindani Michele , Thall Peter F.
Published: October 2014

The effect of a targeted agent on a cancer patient's clinical outcome putatively is mediated through the agent's effect on one or more early biological events. This is motivated by pre-clinical experiments with cells or animals that identify such events, represented by binary or quantitative biomarkers. When evaluating targeted agents in humans, central questions are whether the distribution of a targeted biomarker changes following treatment, the nature and magnitude of this change, and whether it is associated with clinical outcome. Major difficulties in estimating these effects are that a biomarker's distribution may be complex, vary substantially between patients, and have complicated relationships with clinical outcomes. We present a probabilistically coherent framework for modeling and estimation in this setting, including a hierarchical Bayesian nonparametric mixture model for biomarkers that we use to define a functional profile of pre-versus-post-treatment biomarker distribution change. The functional is similar to the receiver operating characteristic used in diagnostic testing. The hierarchical model yields clusters of individual patient biomarker profile functionals, and we use the profile as a covariate in a regression model for clinical outcome. The methodology is illustrated by analysis of a dataset from a clinical trial in prostate cancer using imatinib to target platelet-derived growth factor, with the clinical aim to improve progression-free survival time.
Ten ways remote sensing can contribute to conservation
Authors: Rose Robert A. , Byler Dirck , Eastman J. Ron , Fleishman Erica , Geller Gary , Goetz Scott , Guild Liane , Hamilton Healy , Hansen Matt , Headley Rachel , Hewson Jennifer , Horning Ned , Kaplin Beth A. , Laporte Nadine , Leidner Allison , Leimgruber Peter , Morisette Jeffrey , Musinsky John , Pintea Lilian , Prados Ana , Radeloff Volker C. , Rowen Mary , Saatchi Sassan , Schill Steve , Tabor Karyn , Turner Woody , Vodacek Anthony , Vogelmann James , Wegmann Martin , Wilkie David , Wilson Cara
Published: October 2014

In an effort to increase conservation effectiveness through the use of Earth observation technologies, a group of remote sensing scientists affiliated with government and academic institutions and conservation organizations identified 10 questions in conservation for which the potential to be answered would be greatly increased by use of remotely sensed data and analyses of those data. Our goals were to increase conservation practitioners’ use of remote sensing to support their work, increase collaboration between the conservation science and remote sensing communities, identify and develop new and innovative uses of remote sensing for advancing conservation science, provide guidance to space agencies on how future satellite missions can support conservation science, and generate support from the public and private sector in the use of remote sensing data to address the 10 conservation questions. We identified a broad initial list of questions on the basis of an email chain‐referral survey. We then used a workshop‐based iterative and collaborative approach to whittle the list down to these final questions (which represent 10 major themes in conservation): How can global Earth observation data be used to model species distributions and abundances? How can remote sensing improve the understanding of animal movements? How can remotely sensed ecosystem variables be used to understand, monitor, and predict ecosystem response and resilience to multiple stressors? How can remote sensing be used to monitor the effects of climate on ecosystems? How can near real‐time ecosystem monitoring catalyze threat reduction, governance and regulation compliance, and resource management decisions? How can remote sensing inform configuration of protected area networks at spatial extents relevant to populations of target species and ecosystem services? How can remote sensing‐derived products be used to value and monitor changes in ecosystem services? How can remote sensing be used to monitor and evaluate the effectiveness of conservation efforts? How does the expansion and intensification of agriculture and aquaculture alter ecosystems and the services they provide? How can remote sensing be used to determine the degree to which ecosystems are being disturbed or degraded and the effects of these changes on species and ecosystem functions?
Constraint therapy, the panacea for unilateral cerebral palsy?
Authors: Hoare Brian
Published: October 2014

This commentary is on the original article by Eliasson and Holmefur on pages 89–94 of this issue.
Hydrogel baits with low‐dose thiamethoxam for sustainable Argentine ant management in commercial orchards
Authors: Buczkowski Grzegorz , Roper Elray , Chin Darren , Mothapo Natasha , Wossler Theresa
Published: October 2014

Argentine ants, Linepithema humile (Mayr) (Hymenoptera: Formicidae), are a significant pest in various agricultural systems around the world, and are often associated with outbreaks of phloem‐feeding hemipteran insects. Previous research has evaluated a number of active ingredients and management approaches for controlling Argentine ant populations in agricultural systems, but various regulatory and economic issues have limited the development of effective management tools. Current chemical controls rely on residual sprays or toxic baits, each one posing unique disadvantages that limit their usefulness and efficacy. This study evaluated the potential of water‐storing crystals to effectively deliver liquid baits to Argentine ants. The efficacy of bait crystals containing 0.007% thiamethoxam was first evaluated in laboratory colonies. In addition, field studies were performed in a commercial plum orchard to determine the efficacy of the bait crystals. Protein marking was used within the orchard to examine the distribution of the bait in Argentine ant populations when delivered via water‐storing crystals. Results of laboratory tests showed that water‐storing crystals containing 0.007% thiamethoxam are highly attractive and effective against Argentine ants and require ca. 3–5 days to kill all castes and life stages. Results of the protein‐marking study demonstrated that the percentage of ants carrying protein‐labeled sugar water decreases sharply with increasing distance from the bait station. Bait movement was limited to within 17 m of the bait dispenser. Furthermore, bait efficacy tests in the field showed that Argentine ants can be effectively controlled using liquid thiamethoxam baits deployed via water‐storing crystals. The bait was highly effective and ant densities throughout the baited plots declined by 94 ± 2% within 14 days. The results of this study demonstrate that (1) thiamethoxam is highly effective for Argentine ant control in fruit orchards when used in low concentrations (0.007%), and (2) water‐storing crystals are an effective tool for delivering liquid baits to Argentine ants in agricultural settings.
Statistical sampling approaches for soil monitoring
Authors: Brus D. J.
Published: October 2014

This paper describes three statistical sampling approaches for regional soil monitoring, a design‐based, a model‐based and a hybrid approach. In the model‐based approach a space‐time model is exploited to predict global statistical parameters of interest such as the space‐time mean. In the hybrid approach this model is a time‐series model of the spatial means. In the design‐based approach no model is used: estimates are model‐free. Full design‐based inference requires that both sampling locations and times are selected by probability sampling, whereas the hybrid approach requires probability sampling of locations only. In a case study on soil eutrophication and acidification, a rotational panel design was implemented with probability sampling of locations and non‐probability sampling of times. The hybrid and model‐based predictions of the space‐time means and trend of the mean for pH and ammonium at three depths in the soil profile were very similar. For pH the standard errors of the space‐time means were about equal, but for ammonium the full model‐based predictor was more precise than the hybrid predictor. For soil monitoring I advocate the selection of sampling locations by probability sampling so that the statistical inference approach is flexible. Selecting locations by a self‐weighting probability sampling design ensures that the model‐based predictor is not affected by selection bias.
Can sexual selection theory inform genetic management of captive populations? A review
Authors: Chargé Rémi , Teplitsky Céline , Sorci Gabriele , Low Matthew
Published: October 2014

Captive breeding for conservation purposes presents a serious practical challenge because several conflicting genetic processes (i.e., inbreeding depression, random genetic drift and genetic adaptation to captivity) need to be managed in concert to maximize captive population persistence and reintroduction success probability. Because current genetic management is often only partly successful in achieving these goals, it has been suggested that management insights may be found in sexual selection theory (in particular, female mate choice). We review the theoretical and empirical literature and consider how female mate choice might influence captive breeding in the context of current genetic guidelines for different sexual selection theories (i.e., direct benefits, good genes, compatible genes, sexy sons). We show that while mate choice shows promise as a tool in captive breeding under certain conditions, for most species, there is currently too little theoretical and empirical evidence to provide any clear guidelines that would guarantee positive fitness outcomes and avoid conflicts with other genetic goals. The application of female mate choice to captive breeding is in its infancy and requires a goal‐oriented framework based on the needs of captive species management, so researchers can make honest assessments of the costs and benefits of such an approach, using simulations, model species and captive animal data.
Calmodulin 4 is dispensable for epidermal barrier formation and wound healing in mice
Authors: Lessard Juliane C. , Kalinin Alexandr , Bible Paul W. , Morasso Maria I.
Published: October 2014

Calcium‐mediated signals play important roles in epidermal barrier formation, skin homoeostasis and wound repair. Calmodulin 4 (Calm4) is a small, Ca2+‐binding protein with strong expression in suprabasal keratinocytes. In mice, Calm4 first appears in the skin at the time of barrier formation, and its expression increases in response to epidermal barrier challenges. In this study, we report the generation of Calm4 knockout mice and provide evidence that Calm4 is dispensable for epidermal barrier formation, maintenance and repair.
Effective capture of proteins inside living cells by antibodies indirectly linked to a novel cell‐penetrating polymer‐modified protein A derivative
Authors: Itakura Shoko , Hama Susumu , Ikeda Hisafumi , Mitsuhashi Naoto , Majima Eiji , Kogure Kentaro
Published: October 2014

Antibodies against cytoplasmic proteins are useful tools that can control cellular function and clarify signaling mechanisms. However, it is difficult to capture proteins inside living cells, and thus appropriate methods for antibody delivery to the cytoplasm of living cells are required. Cell‐penetrating materials, such as the TAT‐peptide, have received attention for their ability to deliver various cargos into living cells. However, the direct modification of cargos with cell‐penetrating materials is time‐consuming and lacks versatility. Therefore, we conceived that protein A, which can bind to the fragment crystallizable region of an antibody, could indirectly link antibodies with cell‐penetrating materials, creating an efficient and simple antibody delivery system. Here, we constructed a novel antibody delivery system using a cell‐penetrating polymer‐modified protein A derivative (CPP‐pAd). Living cells treated with CPP‐pAd/antibody complexes showed significantly higher antibody levels than those achieved with the commercially available reagent HVJ‐E. Pre‐treatment with sucrose prevented cellular uptake of the CPP‐pAd/antibody complex, suggesting that the CPP‐pAd/antibody internalization mechanism occurs through clathrin‐dependent endocytosis. Interestingly, intracellularly delivered antibodies did not colocalize with endosome/lysosome markers, further suggesting that antibodies were delivered to the cytoplasm by escape from endosome/lysosome. Moreover, we observed that anti‐nuclear pore complex antibodies, delivered to cells using CPP‐pAd, localized to the nuclear membrane and inhibited nuclear factor κB dependent luciferase activity. Together, these results suggest that the antibodies delivered by CPP‐pAd captured functional proteins, making CPP‐pAd a promising strategy for effective capture of proteins inside living cells.
Non‐muscle invasive bladder cancer and bacillus Calmette‐Guerin treatment: a review of the literature
Authors: Alcorn Jason , Burton Rob L , Topping Annie
Published: October 2014

Bladder cancer is the second most common urological cancer in the UK, with over 10 000 cases diagnosed annually. With 80% of urothelial bladder cancers being non‐muscle invasive, it is important to understand the treatments available. This review aims to identify and review the literature regarding bacillus Calmette‐Guerin (BCG) treatment. An integrative‐based review was conducted to generate a broad overview of the existing knowledge for BCG treatment. An open search of online databases was conducted to identify articles published in English from the earliest date available to September 2013, using key terms related to BCG. A significant number of articles were identified. To narrow the results and identify the most relevant articles, the search terms were cross‐referenced. The resulting articles were then reviewed using the critical appraisal skills programme framework. The tools provided by CASP give a systematic, transparent and rigorous approach to the quality assessment of research studies. The research articles were then categorized under the following headings: side effects, including local, systemic and age; quality of life; and attrition. The major conclusion from this literature review is that BCG treatment, when given through an induction and maintenance regime, significantly reduces the risk of progression and recurrence. However, there are potential side effects which the patient and the nurse need to be aware. This review also highlighted that there is a lack of research from the UK and that there is a paucity of research showing why patients withdraw from BCG treatment
Cytochrome P450s from the fall armyworm (Spodoptera frugiperda): responses to plant allelochemicals and pesticides
Authors: Giraudo M. , Hilliou F. , Fricaux T. , Audant P. , Feyereisen R. , Le Goff G.
Published: October 2014

Spodoptera frugiperda is a polyphagous lepidopteran pest that encounters a wide range of toxic plant metabolites in its diet. The ability of this insect to adapt to its chemical environment might be explained by the action of major detoxification enzymes such as cytochrome P450s (or CYP). Forty‐two sequences coding for P450s were identified and most of the transcripts were found to be expressed in the midgut, Malpighian tubules and fat body of S. frugiperda larvae. Relatively few P450s were expressed in the established cell line Sf9. In order to gain information on how these genes respond to different chemical compounds, larvae and Sf9 cells were exposed to plant secondary metabolites (indole, indole‐3‐carbinol, quercetin, 2‐tridecanone and xanthotoxin), insecticides (deltamethrin, fipronil, methoprene, methoxyfenozide) or model inducers (clofibrate and phenobarbital). Several genes were induced by plant chemicals such as P450s from the 6B, 321A and 9A subfamilies. Only a few genes responded to insecticides, belonging principally to the CYP9A family. There was little overlap between the response in vivo measured in the midgut and the response in vitro in Sf9 cells. In addition, regulatory elements were detected in the promoter region of these genes. In conclusion, several P450s were identified that could potentially be involved in the adaptation of S. frugiperda to its chemical environment.
Epigenomics of macrophages
Authors: Gosselin David , Glass Christopher K.
Published: October 2014

Macrophages play essential roles in tissue homeostasis, pathogen elimination, and tissue repair. A defining characteristic of these cells is their ability to efficiently adapt to a variety of abruptly changing and complex environments. This ability is intrinsically linked to a capacity to quickly alter their transcriptome, and this is tightly associated with the epigenomic organization of these cells and, in particular, their enhancer repertoire. Indeed, enhancers are genomic sites that serve as platforms for the integration of signaling pathways with the mechanisms that regulate mRNA transcription. Notably, transcription is pervasive at active enhancers and enhancer RNAs (eRNAs) are tightly coupled to regulated transcription of protein‐coding genes. Furthermore, given that each cell type possesses a defining enhancer repertoire, studies on enhancers provide a powerful method to study how specialization of functions among the diverse macrophage subtypes may arise. Here, we review recent studies providing insights into the distinct mechanisms that contribute to the establishment of enhancers and their role in the regulation of transcription in macrophages.
Mononuclear phagocytes of the intestine, the skin, and the lung
Authors: Scott Charlotte L. , Henri Sandrine , Guilliams Martin
Published: October 2014

Tissues that are in direct contact with the outside world face particular immunological challenges. The intestine, the skin, and the lung possess important mononuclear phagocyte populations to deal with these challenges, but the cellular origin of these phagocytes is strikingly different from one subset to another, with some cells derived from embryonic precursors and some from bone marrow‐derived circulating monocytes. Here, we review the current knowledge regarding the developmental pathways that control the differentiation of mononuclear phagocytes in these barrier tissues. We have also attempted to build a theoretical model that could explain the distinct cellular origin of mononuclear phagocytes in these tissues.
Platelets and atherosclerosis
Authors: WHITE J. G.
Published: October 2014

Abstract. Despite the broad array of mechanisms designed to protect the endothelial lining of every blood vessel in the body and maintain the fluid state of blood, injury does occur. Chronic and recurrent damage result in development of lesions characteristic of atherosclerosis. The loss of vascular integrity associated with the pathological process of atherogenesis triggers the haemostatic mechanism. As a result, fibrin and platelets become a part of atherosclerotic lesions and play a role in their progression. Growth of the plaques and destruction of normal endothelium triggers further involvement of platelets leading to occlusion of arteries in the heart and brain, resulting in myocardial infarction and stroke. Understanding the role of platelets in atherosclerosis and limiting its contribution may reduce morbidity and mortality of this dread disease.
Platelet function in patients with hypercholesterolaemia
Authors: BETTERIDGE D. J. , COOPER M. B. , SAGGERSON E. D. , PRICHARD B. N. C. , TAN K. C. B. , LING E. , BARBERA G. , McCARTHY S. , SMITH C. C. T.
Published: October 2014

Abstract. Platelets and plasma lipoproteins, particularly low density lipoprotein, have important roles in atherogenesis. Evidence from several sources suggests that important interactions occur between these individual components of the atherogeneic process. Here we review work from our own laboratory on platelet function in normal individuals and patients heterozygous for familial hypercholesterolaemia (FH). Data is presented on the role of platelet noradrenaline and also on altered cellular signalling in platelets from FH individuals who have plasma low density lipoprotein concentrations which are approximately double those seen in normal subjects.
Antiplatelet drugs
Authors: FITZGERALD G. A. , MEAGHER E. A.
Published: October 2014

Abstract. The evidence in support of the safety and efficacy of aspirin in the secondary prevention of platelet dependent vascular occlusion is compelling. The utility of this drug has stalled the development of potential competitors, such as thromboxane antagonists. The emergence of glycoprotein IIb/IIIa antagonists as the most promising competitors for aspirin has focused attention on the possibility of delivering these drugs at an effective dose safely.
Testosterone treatment enhances thromboxane A2 mimetic induced coronary artery vasoconstriction in guinea pigs
Authors: SCHRÖR K. , MORINELLI T. A. , MASUDA A. , MATSUDA K. , MATHUR R. S. , HALUSHKA P. V.
Published: October 2014

Abstract. Thromboxane A2 (TXA2) has been implicated as an important mediator of cardiovascular diseases. There have been several clinical reports of acute myocardial infarctions occurring in young male athletes abusing anabolic steroids. The effects of treatment of male Guinea pigs with testosterone on the responses to U46619, a TXA2 receptor agonist, in the isolated perfused heart were determined. The maximum pressor responses of the isolated perfused Guinea pig heart to U46619 were significantly (P < 0·05) greater in the Guinea pigs treated with testosterone compared to the controls. These results indicate that testosterone can enhance coronary artery vascular reactivity to TXA2.
Allelic variation at innate immune genes (avian β‐defensins), within a natural population of great tits
Authors: Hellgren Olof
Published: October 2014

In order to fully understand pathogen induced natural variation in fitness in wild animal populations it is important to identify and study the degree of non‐synonymous alleles in genes that code for components of the immune system. This study investigates the degree of natural genetic variation at 6 innate immune genes belonging to the β‐defensin family within a single population of birds, the great tits Parus major. In 40 adult individuals, all belonging to the same local population in Wytham Woods, Oxford, UK, screened across 6 different β‐defensin genes, all but one individual showed non‐synonymous heterozygosity within the exon coding for the mature defensin peptide. The non‐synonomous variation was thus associated with the part of the defensin gene that directly interacts with potential pathogens. Within the sample, 31 different genotypes were identified across the 6 different loci. Much of the found allelic variation affected the amino acid composition, which in turn alter the net charge and hydrophilicity of the produced peptide; properties associated with the efficiency of binding to and rupture pathogens.

This study demonstrates that non‐synonymous genetic variation exists at β‐defensins genes, a part of the immune system that forms an important first line of defence against various pathogens. Understanding the degree of underlying genetic variation at different parts of the immune system will help achieve a holistic view of the reasons behind individual variation in pathogen susceptibility, as well as why individuals are affected differently once they become infected.
Testis asymmetry in birds: the influences of sexual and natural selection
Authors: Calhim Sara , Montgomerie Robert
Published: October 2014

Gonad size and shape asymmetries are particularly common in birds. Although some obvious size and shape differences between the left and right testes in birds were first documented more than a century ago, little is known about what influences the variation across species in either the degree or the direction of these asymmetries. Here we show that a left bias in size is the most likely ancestral state in most orders and families, and that there is a weak but significant negative relation between the degree of size and shape asymmetries. In extant species, testis size and shape symmetries increase with the degree of sperm competition (relative testes mass), but those relations are significant only in those species with left bias in each of these traits. When space is particularly constrained on the left side of the body cavity due to a large gizzard (e.g. in granivores), the left testis is more elongated and the degree of size symmetry is larger. Despite significant patterns, relative testes mass and gizzard complexity together explain < 10% of the variation in testis asymmetry in species with left biases. Thus our analyses suggest that some other factor is largely responsible for the evolution of gonad asymmetry in birds: 1) that a left bias in testis size might be a correlated response to selection for a left bias in the development of a single (left) ovary in females of most bird species, and/or 2) that physiological efficiency due to the dramatic and rapid increase in testis size of most species during the breeding season might favour enlargement of one testis. Our conclusions highlight the need to rethink and improve our understanding of the physiological processes underlying the investment in gonads by male birds.
Deep‐sea bigscales, pricklefishes, gibberfishes and whalefishes (Teleostei: Stephanoberycoidei) off Brazil: new records, range extensions for the south‐western Atlantic Ocean and remarks on the taxonomy of Poromitra
Authors: Mincarone M. M. , Di Dario F. , Costa P. A. S.
Published: October 2014

The Stephanoberycoidei includes 23 genera and c. 94 species of deep‐sea teleosts commonly known as bigscales, pricklefishes, gibberfishes and whalefishes. Stephanoberycoidei is one of the least known groups of deep‐sea fishes, in spite of their apparent relative abundance in meso and bathypelagic depths. Nine species of the Stephanoberycoidei are reported here for the first time in Brazilian waters, and most of them represent new range extensions for the south‐western Atlantic Ocean. Those species are Melamphaes polylepis, Melamphaes typhlops, Poromitra sp. and Scopeloberyx robustus (Melamphaidae), Acanthochaenus luetkenii and Stephanoberyx monae (Stephanoberycidae), Rondeletia bicolor and Rondeletia loricata (Rondeletiidae) and Gyrinomimus sp. (Cetomimidae). Occurrences of the pricklefish Scopelogadus mizolepis (Melamphaidae), the gibberfish Gibberichthys pumilus (Gibberichthyidae) and the velvet whalefish Barbourisia rufa (Barbourisiidae) are confirmed in the Brazilian exclusive economic zone, but previously published records of Poromitra capito and Melamphaes simus (Melamphaidae) in the region most likely represent misidentifications. Validities of the recently described Poromitra kukuevi and Poromitra indooceanica are discussed in light of new specimens of the genus collected in the south‐western Atlantic Ocean. An identification key for the 13 species of Stephanoberycoidei reported off Brazil is also provided.
Identifying Stakeholders’ Views on the Eco‐efficiency Assessment of a Municipal Solid Waste Management System
Authors: Meylan Grégoire , Stauffacher Michael , Krütli Pius , Seidl Roman , Spoerri Andy
Published: October 2014

Life cycle assessment (LCA) is one of the most popular methods of technical‐environmental assessment for informing environmental policies, as, for instance, in municipal solid waste (MSW) management. Because MSW management involves many stakeholders with possibly conflicting interests, the implementation of an LCA‐based policy can, however, be blocked or delayed. A stakeholder assessment of future scenarios helps identify conflicting interests and anticipate barriers of sustainable MSW management systems. This article presents such an approach for Swiss waste glass‐packaging disposal, currently undergoing a policy review. In an online survey, stakeholders (N = 85) were asked to assess disposal scenarios showing different LCA‐based eco‐efficiencies with respect to their desirability and probability of occurrence. Scenarios with higher eco‐efficiency than the current system are more desirable and considered more probable than those with lower eco‐efficiency. A combination of inland recycling and downcycling to foam glass (insulation material) in Switzerland is desired by all stakeholders and is more eco‐efficient than the current system. In contrast, institutions of MSW management, such as national and regional environmental protection agencies, judge a scenario in which nearly all cullet would be recycled in the only Swiss glass‐packaging factory as more desirable than supply and demand stakeholders of waste glass‐packaging. Such a scenario involves a monopsony rejected by many municipalities and scrap traders. Such an assessment procedure can provide vital information guiding the formulation of environmental policies.
Transforming growth factor β-mediated site-specific Smad linker region phosphorylation in vascular endothelial cells
Authors: Kamato Danielle , Rostam Muhamad Ashraf , Piva Terence J , Babaahmadi Rezaei Hossein , Getachew Robel , Thach Lyna , Bernard Rebekah , Zheng Wenhua , Little Peter J , Osman Narin
Published: October 2014

Objectives

Transforming growth factor (TGF)-β regulates the function of vascular endothelial cells and may be involved in endothelial dysfunction. The canonical TGF-β pathway involves TGF-β receptor-mediated carboxy-terminal phosphorylation of Smad2; however, TGF-β signalling also activates numerous serine/threonine kinases that phosphorylate Smad2 in its linker region. The expression of phosphorylated Smad linker proteins were determined following TGF-β stimulation in the absence and presence of different serine/threonine kinase inhibitors in vascular endothelial cells.

Methods

Proteins were quantified by Western blotting using specific antibodies to individual phosphorylated Smad2 linker region residues.

Key findings

TGF-β mediated the phosphorylation of all four Smad2 linker region residues of interest. Erk and Jnk specifically phosphorylate Ser245 while all mitogen-activated protein kinases phosphorylate Ser250 and Ser255. Thr220 and Ser245 are phosphorylated by phosphoinositide 3 kinase (PI3K), while Ser255 was phosphorylated by the PI3K/Akt pathway. CDK and GSK-3 were shown to phosphorylate Thr220 and Ser245. TGF-β also mediated plasminogen activator inhibitor-1 gene expression that was attenuated by p38 and CDK inhibitors.

Conclusions

TGF-β-mediated phosphorylation of individual serine/threonine sites in the linker region of Smad2 occurs in a highly specific manner by kinases. These phosphorylations provide an opportunity to further understand a therapeutically targeted and very specific signalling pathway in vascular endothelial cells.
Glucose transport and milk secretion during manipulated plasma insulin and glucose concentrations and during LPS‐induced mastitis in dairy cows
Authors: Gross J. J. , van Dorland H. A. , Wellnitz O. , Bruckmaier R. M.
Published: October 2014

In dairy cows, glucose is essential as energy source and substrate for milk constituents. The objective of this study was to investigate effects of long‐term manipulated glucose and insulin concentrations in combination with a LPS‐induced mastitis on mRNA abundance of glucose transporters and factors involved in milk composition. Focusing on direct effects of insulin and glucose without influence of periparturient endocrine adaptations, 18 dairy cows (28 ± 6 weeks of lactation) were randomly assigned to one of three infusion treatments for 56 h (six animals each). Treatments included a hyperinsulinemic hypoglycaemic clamp (HypoG), a hyperinsulinemic euglycaemic clamp (EuG) and a control group (NaCl). After 48 h of infusions, an intramammary challenge with LPS from E. coli was performed and infusions continued for additional 8 h. Mammary gland biopsies were taken before, at 48 (before LPS challenge) and at 56 h (after LPS challenge) of infusion, and mRNA abundance of genes involved in mammary gland metabolism was measured by RT‐qPCR. During the 48 h of infusions, mRNA abundance of glucose transporters GLUT1, 3, 4, 8, 12, SGLT1, 2) was not affected in HypoG, while they were downregulated in EuG. The mRNA abundance of alpha‐lactalbumin, insulin‐induced gene 1, κ‐casein and acetyl‐CoA carboxylase was downregulated in HypoG, but not affected in EuG. Contrary during the intramammary LPS challenge, most of the glucose transporters were downregulated in NaCl and HypoG, but not in EuG. The mRNA abundance of glucose transporters in the mammary gland seems not to be affected by a shortage of glucose, while enzymes and milk constituents directly depending on glucose as a substrate are immediately downregulated. During LPS‐induced mastitis in combination with hypoglycaemia, mammary gland metabolism was more aligned to save glucose for the immune system compared to a situation without limited glucose availability during EuG.
Dynamic Clinical Measurements of Voluntary Vaginal Contractions and Autonomic Vaginal Reflexes
Authors: Broens Paul M.A. , Spoelstra Symen K. , Weijmar Schultz Willibrord C.M.
Published: October 2014

Introduction

The vaginal canal is an active and responsive canal. It has pressure variations along its length and shows reflex activity. At present, the prevailing idea is that the vaginal canal does not have a sphincter mechanism. It is hypothesized that an active vaginal muscular mechanism exists and might be involved in the pathophysiology of genito-pelvic pain/penetration disorder.

Aim

The aim of this study was to detect the presence of a canalicular vaginal “sphincter mechanism” by measuring intravaginal pressure at different levels of the vaginal canal during voluntary pelvic floor contractions and during induced reflexive contractions.

Methods

Sixteen nulliparous women, without sexual dysfunction and pelvic floor trauma, were included in the study. High-resolution solid-state circumferential catheters were used to measure intravaginal pressures and vaginal contractions at different levels in the vaginal canal. Voluntary intravaginal pressure measurements were performed in the left lateral recumbent position only, while reflexive intravaginal pressure measurements during slow inflation of a vaginal balloon were performed in the left lateral recumbent position and in the sitting position.

Main Outcome Measures

Intravaginal pressures and vaginal contractions were the main outcome measures. In addition, a general demographic and medical history questionnaire was administered to gain insight into the characteristics of the study population.

Results

Fifteen out of the sixteen women had deep and superficial vaginal high-pressure zones. In one woman, no superficial high-pressure zone was found. The basal and maximum pressures, as well as the duration of the autonomic reflexive contractions significantly exceeded the pressures and the duration of the voluntary contractions. There were no significant differences between the reflexive measurements obtained in the left lateral recumbent and the sitting position.

Conclusion

The two high-pressure zones found in this study, as a result of voluntary contractions and, even more pronounced, as a result of reflexive contractions on intravaginal stimulation, support the hypothesis that the vaginal canal has an active and passive canalicular sphincter mechanism. Further investigation of this sphincter mechanism is required to identify its role in the sexual response and genito-pelvic pain/penetration disorder.