bluuebunny/crossref_metadata_2025 huggingface dataset:
Structure-guided design of an invariant natural killer T cell agonist for optimum protection from type 1 diabetes in non-obese diabetic mice
Authors: Blumenfeld H J , Tohn R , Haeryfar S M M , Liu Y , Savage P B , Delovitch T L
Published: July 2011

Because invariant natural killer T (iNK T) cells link innate and adaptive immunity, the structure-dependent design of iNK T cell agonists may have therapeutic value as vaccines for many indications, including autoimmune disease. Previously, we showed that treatment of non-obese diabetic (NOD) mice with the iNK T cell activating prototypic glycolipid α-galactosylceramide (α-GalCer) protects them from type 1 diabetes (T1D). However, α-GalCer is a strong agonist that can hyperactivate iNK T cells, elicit several side effects and has shown only limited success in clinical trials. Here, we used a structure-guided design approach to identify an iNK T cell agonist that optimally protects from T1D with minimal side effects. Analyses of the kinetics and function of a panel of synthetic α-GalCer fatty acyl chain derivatives (C8:0-C16:0) were performed in NOD mice. C16:0 elicited the highest protection from insulitis and T1D, which was associated with a higher frequency and survival of iNK T cells and enhanced activity of tolerogenic dendritic cells (DCs) in draining pancreatic lymph nodes (PLN), inability to transactivate NK cells and a more rapid kinetics of induction and recovery of iNK T cells from anergy. We conclude that the length and structure of the acyl chain of α-GalCer regulates the level of protection against T1D in mice, and propose that the extent of this protection depends on the relative capacity of the acyl chain to accommodate an endogenous spacer lipid of appropriate length and structure. Thus, our findings with the α-GalCer C16:0 derivative suggest strongly that it be considered as a lead glycolipid candidate in clinical trials of T1D.
Stochastic inversion of a gravity field on multiple scale parameters using surface and borehole data
Authors: Shamsipour Pejman , Marcotte Denis , Chouteau Michel , Allard Michel
Published: July 2011

A 3D stochastic inversion method based on a geostatistical approach is presented for three‐dimensional inversion of gravity on multiple scale parameters using borehole density and gravity and surface gravity. The algorithm has the capability of inverting data on multiple supports. The method involves four main steps: i) upscaling of borehole densities to block densities, ii) selection of block densities to use as constraints, iii) inversion of gravity data with selected block densities as constraints and iv) downscaling of inverted densities to small prisms. Two modes of application are presented: estimation and simulation. The method is first applied to a synthetic stochastic model. The results show the ability of the method to invert surface and borehole data simultaneously on multiple scale parameters. The results show the usefulness of borehole data to improve depth resolution. Finally, a case study using gravity measurements at the Perseverance mine (Quebec, Canada) is presented. The recovered 3D density model identifies well three known deposits and it provides beneficial information to analyse the geology of massive sulfide for the domain under study.
Spatial variability of the plankton trophic interaction in the North Sea: a new feature after the early 1970s
Authors: Llope Marcos , Licandro Priscilla , Chan Kung‐Sik , Stenseth Nils Chr.
Published: July 2011

Traditionally, marine ecosystem structure was thought to be bottom‐up controlled. In recent years, a number of studies have highlighted the importance of top‐down regulation. Evidence is accumulating that the type of trophic forcing varies temporally and spatially, and an integrated view – considering the interplay of both types of control – is emerging. Correlations between time series spanning several decades of the abundances of adjacent trophic levels are conventionally used to assess the type of control: bottom‐up if positive or top‐down if this is negative. This approach implies averaging periods which might show time‐varying dynamics and therefore can hide part of this temporal variability. Using spatially referenced plankton information extracted from the Continuous Plankton Recorder, this study addresses the potential dynamic character of the trophic structure at the planktonic level in the North Sea by assessing its variation over both temporal and spatial scales. Our results show that until the early‐1970s a bottom‐up control characterized the base of the food web across the whole North Sea, with diatoms having a positive and homogeneous effect on zooplankton filter‐feeders. Afterwards, different regional trophic dynamics were observed, in particular a negative relationship between total phytoplankton and zooplankton was detected off the west coast of Norway and the Skagerrak as opposed to a positive one in the southern reaches. Our results suggest that after the early 1970s diatoms remained the main food source for zooplankton filter‐feeders east of Orkney–Shetland and off Scotland, while in the east, from the Norwegian Trench to the German Bight, filter‐feeders were mainly sustained by dinoflagellates.
Nitrogen deposition enhances moss growth, but leads to an overall decline in habitat condition of mountain moss‐sedge heath
Authors: Armitage Heather F. , Britton Andrea J. , van der Wal René , Pearce Imogen S. K. , Thompson Des B. A. , Woodin Sarah J.
Published: July 2011

Ecosystems are subject to multiple, natural and anthropogenic environmental influences, including nitrogen (N) deposition, land use and climate. Assessment of the relative importance of these influences on biodiversity and ecosystem functioning is crucial for guiding policy and management decisions to mitigate global change; yet, few studies consider multiple drivers. In the UK, ongoing loss of the internationally important arctic/alpine moss‐sedge community, Racomitrium heath, has been linked to elevated N deposition, high grazing pressures and their combination; however, the relative importance of these drivers remains unclear. We used environmental gradients across the habitat's European distribution (UK, Faroes, Norway and Iceland) to investigate the relative impact of N deposition and grazing pressure, as well as climate, on the condition of the dominant moss species, Racomitrium lanuginosum. Key variables including tissue chemistry, growth and cover were measured at 36 sites, and multiple linear regressions were used to examine the relative importance of the drivers across sites. Our results clearly show that regional variation in the condition of R. lanuginosum across Europe is primarily associated with the impacts of N deposition, with climate (air temperature) and grazing pressure playing secondary roles. In contrast to previous experimental studies, we found moss growth to be stimulated by elevated N deposition; this apparent discrepancy may result from the use of artificially high N concentrations in many experiments. Despite increased growth rates, we found that moss mat depth and cover declined in response to N deposition. Our results suggest that this is due to increased decomposition of material in the moss mat, which ultimately leads to loss of moss cover and habitat degradation. This study clearly demonstrates both the key role of N deposition in degradation of Racomitrium heath and the importance of observational studies along natural gradients for testing predictions from experimental studies in the real world.
Modeling methane emissions from irrigated rice cultivation inChina from 1960 to 2050
Authors: Zhang Wen , Yu Yongqiang , Huang Yao , Li Tingting , Wang Ping
Published: July 2011

Rice paddy is a major source of anthropogenic terrestrial methane (CH4).China has the second‐largest area of rice cultivation in the world, accounting for ca. 19% of the world's rice‐producing area. Recognizing the significance ofChina's rice cultivation in the globalCH4budget, we estimated theCH4emissions resulting from irrigated rice cultivation inChina from 1960 to 2050 using aCH4MODmodel. The model estimates suggest that the annualCH4emissions decreased from 5.62 Tg yr−1in 1960 to 4.13 Tg yr−1in 1970, and this decrease was attributed to changes in water management from continuous flooding to mid‐season drainage irrigation. Since the early 1970s, the amount ofCH4emissions gradually increased to 6.85 Tg yr−1by 2009 because of significant improvements in crop production that led to high‐crop residue retention. Higher levels ofCH4emissions occurred in southernChina, where double rice cropping systems are most common. For theA1BandB1scenarios of theIPCCSpecial Report on Emissions Scenarios (SRES), the amount ofCH4emissions from 2010 to 2050 is predicted to increase at an average rate of 1.2 kg ha−1 yr−1in response to global warming. Compared to 2009, theCH4flux is predicted to increase by ca. 14% by the late 2040s, and the increase in these emissions in northeasternChina is estimated to become more significant than in the other rice‐growing regions of the country. Under the assumptions that the rice‐producing land area will remain the same, decrease by 25% or increase by 38% by the late 2040s, theCH4emissions are projected to be 7.8, 5.6 or 11.7 Tg yr−1, respectively.
Repeated infusions of VWF/FVIII concentrate: impact of VWF:FVIII ratio on FVIII trough and peak levels in a rabbit model
Authors: RAQUET E. , STOCKSCHLÄDER M. , DICKNEITE G.
Published: July 2011

Summary.  The ratio of von Willebrand factor (VWF) to FVIII differs among available VWF/FVIII concentrates. Repeated infusions of concentrates with a low VWF:FVIII ratio may expose patients with von Willebrand disease to supranormal FVIII levels. The aim of this study was to determine the effects of repeated infusions with two VWF/FVIII concentrates differing in VWF:FVIII ratio on attained FVIII trough and peak levels as well as other pharmacokinetic parameters. Rabbits were randomized to receive multiple 150 IU kg−1 VWF:RCo infusions at 4 h intervals with VWF/FVIII concentrates of a high (Haemate® P/Humate‐P®) or low (Wilate®) VWF:FVIII ratio. Trough plasma FVIII and VWF levels were measured after each infusion. Pharmacokinetic analysis was performed using samples collected frequently after infusion. Mean FVIII trough level after the first Wilate infusion was 50.6 IU dL−1 with a 95% confidence interval (CI) of 43.1–58.2 IU dL−1, compared with 31.8 IU dL−1 (CI, 24.4–39.1 IU dL−1) for Haemate P (P < 0.001). Trough levels progressively increased over the 24 h treatment period in both groups. After the final infusion, mean trough FVIII remained significantly higher (P = 0.002) in recipients of Wilate. Mean peak FVIII concentration after infusion was 67% higher in the Wilate group (167 vs. 100 IU dL−1, respectively; P = 0.002). Mean cumulative exposure to FVIII, as measured by area under the curve, was 84% greater in Wilate‐treated animals. Half‐life did not differ between the two concentrates. Animal model data suggest that exposure to elevated FVIII levels can be reduced through use of VWF/FVIII concentrates with higher VWF:FVIII ratios.
Influence of class I and II HLA alleles on inhibitor development in severe haemophilia A patients from the South of Brazil
Authors: DE BARROS M. F. , HERRERO J. C. M. , SELL A. M. , De MELO F. C. , BRAGA M. A. , PELISSARI C. B. , MACHADO J. , De SOUZA SCHILLER S. , De SOUZA HIRLE L. , VISENTAINER J. E. L.
Published: July 2011

Summary.  Congenital haemophilia A is a chromosome‐linked recessive disorder caused by the deficiency or reduction of factor VIII (FVIII) pro‐coagulant activity. During treatment, some patients develop alloantibodies (FVIII inhibitors) that neutralize the action of exogenously administered FVIII. Currently, the presence of these inhibitors is the most serious adverse event found in replacement therapy. Some studies have suggested that genetic factors influence the development of the FVIII coagulation inhibitors. To identify the class I and II alleles that may be influencing the formation of inhibitors in severe haemophilic patients. Genotyping of the class I (HLA‐A, ‐B and ‐C) and class II (HLA‐DRB1, ‐DQA1 and ‐DQB1) alleles of 122 patients with severe haemophilia A, including 36 who had developed antibodies to factor VIII, was performed. After the comparison of the group without inhibitors and the group with inhibitors, HLA‐C*16 [Odds ratio (OR) = 7.73; P = 0.0092] and HLA‐DRB1*14 (OR = 4.52; P = 0.0174) were found to be positively associated with the formation of the inhibitors. These results confirm that HLA alleles are involved in inhibitor production and could be used as a tool for recognition of groups at high risk of possible inhibitor development in Southern Brazilian haemophilic patients.
A Bayesian hierarchical occupancy model for track surveys conducted in a series of linear, spatially correlated, sites
Authors: Aing Chrisna , Halls Sarah , Oken Kiva , Dobrow Robert , Fieberg John
Published: July 2011

1. Natural resource agencies often rely on surveys of animal sign (e.g. scat, scent marks, tracks) for population assessment, with repeat surveys required to model and account for uncertain detection. Using river otter Lontra canadensis snow‐track survey data as a motivating example, we develop a 3‐level occupancy model with parameters that describe (i) site‐level occupancy probabilities, (ii) otter movement (and thus, track availability) and (iii) recorded presence–absence of tracks (conditional on the availability of tracks for detection).

2. We incorporated several recent developments in occupancy modelling, including the presence of both false negatives and false positives, spatial and temporal correlation and repeated sampling across distinct observers.

3. We investigated optimal allocation of sampling effort (e.g. within and among snowfall events) using simulations. We also compared models that allowed site‐level occupancy and track‐laying processes to be spatially correlated with models that assumed independence among sites.

4. Both types of models (independence and spatial) performed well across a range of simulated parameter values, but the spatial model resulted in more accurate point estimates for detection parameters and credibility intervals with better coverage rates when data were spatially correlated. When applied to real data, the spatial model resulted in a higher estimate of the occupancy rate than the baseline model (0·82 vs. 0·59). A minimum of 15–20 helicopter flights, distributed among at least three unique snow events, were needed to meet precision goals (standard error ).

5.
Synthesis and applications. We describe a flexible and robust occupancy modelling framework that accounts for heterogeneous detection rates in surveys of animal sign. The method allows for spatially correlated sites and should have broad relevance to surveys conducted by many natural resource agencies.
A literature review of the impact of a diagnosis of cancer of the vulva and surgical treatment
Authors: Jefferies Hilary , Clifford Collette
Published: July 2011

Aims and objectives.  This paper examines the evidence available regarding the physical, psychological and sexual consequences for women following a diagnosis and treatment for cancer of the vulva.

Background.  Cancer of the vulva is a rare condition affecting approximately 1000 women in the UK each year. However, little is known about the impact of the condition as there is a limited research base to inform clinical practice.

Design.  Review.

Method.  This paper critiques the 15 studies identified in the English language literature relating to carcinoma of the vulva from 1983 to the present. Collectively these involved less than 400 women with this condition.

Results.  The review highlighted a paucity of published studies on this patient group. There are weaknesses in the design and analytical methods of the studies and a lack of clarity in the analysis of the published data. However, the review has enabled a picture to be built up of the challenges these women face postoperatively. The lack of recent evidence to support care practices offers limited help in contemporary health care today.

Conclusion.  There is a clear need for further research to explore the issues for women facing treatment for carcinoma vulva.

Relevance to clinical practice.  An awareness of the issues facing women following a diagnosis and subsequent treatment, usually surgery, for cancer of the vulva will allow nurses and other health care professionals to have a greater understanding of the needs of these women and thus impact on care planning.
Stress tolerance in closely related species and their first‐generation hybrids: a case study ofSilene
Authors: Favre Adrien , Karrenberg Sophie
Published: July 2011

1. Hybridization is common in natural plant populations. Trait expression and ecological performance of hybrids determine the consequences of hybridization such as the degree and direction of gene flow or the generation of phenotypic novelty.

2. We investigated responses to shade and drought stress in crosses within the naturally hybridizing campionsSilene dioica and S. latifoliaand reciprocal crosses between them. We collected data on fitness proxies and on leaf and root traits in a 2‐year greenhouse experiment.

3. Responses to drought stress did not differ between cross types. Shade stress, in contrast, led to a reduced flowering incidence inS. dioicabut not inS. latifolia. Rapid flowering under stress conditions inS. latifoliacould be an adaptation to disturbance in its habitat, whereas a delay of reproduction might be adaptive in the more predictable environment ofS. dioica.

4. Hybrids exhibited intermediate, parental‐like and transgressive trait expression. Both hybrid cross types were similar toS. latifoliain terms of biomass production possibly because of dominance ofS. latifoliaalleles or heterosis. Hybrids further had a strongly reduced flowering incidence under shade stress as didS. dioica, suggesting dominance ofS. dioicaalleles for flower induction. Under shade stress, both hybrid cross types produced much larger leaves than either of the two species suggesting that epigenetic interactions are disturbed. Reciprocal hybrids did not differ in fitness; however, maternal effects were observed for root cross‐sectional area and mass per male flower, possibly supporting asymmetric gene flow in natural populations.

5. Synthesis. Silene latifoliaandS. dioicaresponded to stress with differences in life history rather than in growth. Our results further suggest that different modes of gene action are responsible for the specific combination of intermediate, parental‐like and transgressive traits observed in first‐generation hybrids that may limit their performance and thus gene flow between the species.
Seed dispersal distance is more strongly correlated with plant height than with seed mass
Authors: Thomson Fiona J. , Moles Angela T. , Auld Tony D. , Kingsford Richard T.
Published: July 2011

1. It is often assumed that there is a trade‐off between maternal provisioning and dispersal capacity, leading small‐seeded species to disperse further than large‐seeded species. However, this relationship between dispersal distance and seed mass has only been quantified for species from particular sites or with particular dispersal syndromes.

2. We provided the first large‐scale, cross‐species quantification of the correlations between dispersal distance and both seed mass and plant height. Seed mass was positively related to mean dispersal distance, with a 100‐fold increase in seed mass being associated with a 4.5‐fold increase in mean dispersal distance (R2 = 0.16; n = 210 species; P < 0.001). However, plant height had substantially stronger explanatory power than did seed mass, and we found a 5‐fold increase in height was associated with a 4.6‐fold increase in mean dispersal distance (R2 = 0.54; n = 211 species; P < 0.001).

3. Once plant height was accounted for, we found that small‐seeded species dispersed further than did large‐seeded species (R2 = 0.54; n = 181 species; slope = −0.130; P < 0.001); however, seed mass only added 2% to the R2 of the model. Within dispersal syndromes, tall species dispersed further than did short species, while seed mass had little influence on dispersal distance.

4. Synthesis. These findings enhance our understanding of plant life‐history strategies and improve our ability to predict which species are best at colonizing new environments.
Reducing interrater variability and improving health care: a meta‐analytical review
Authors: Tuijn Saskia , Janssens Frans , Robben Paul , van den Bergh Huub
Published: July 2011

Objectives  In the scientific literature about reliability, the main approach to increasing reliability seems to involve increasing the number of observers and improving the instrument used. Other aspects for improving reliability – like the training of raters – seem to receive less notice. It is worth asking whether this technical approach could be complemented by training the user of the instrument. A systematic meta‐analytical review of the research literature was performed to answer this question and examine the effectiveness of planned interventions for improving interrater reliability of health care professionals.

Method  The databases of PubMed (MEDLINE), Embase, Omega and PsycINFO were searched. The inclusion criteria were met by 57 studies. Details extracted from the studies included the study design, the number of observers and the number of observed cases, the intervention, the type of instrument (whether or not it was highly technical), and statistical information about the agreement before and after the intervention. Interventions were categorized into three groups: training of professionals, improving the diagnostic instrument and a combination of training and improving the instrument. A meta‐analysis was performed by means of linear regression.

Results  The interventions were arranged according to their effectiveness in improving the diagnostic instrument (mean change: β = 0.13), training combined with improving the instrument (mean change: β = 0.10) and training (mean change: β = 0.09).

Conclusion  On average, although all types of interventions are effective, improving the diagnostic instrument seems to be the most effective. Especially when highly technical instruments were concerned, improvement proved to be very effective (β = 0.52). Because instrumental variables constitute a major source of error, improving the instrument is an important approach. However, this review offers solid arguments that can complement the literature and practice, with a focus on training the user of the instrument.
The impact of living arrangements and deinstitutionalisation in the health status of persons with intellectual disability in Europe
Authors: Martínez‐Leal R. , Salvador‐Carulla L. , Linehan C. , Walsh P. , Weber G. , Van Hove G. , Määttä T. , Azema B. , Haveman M. , Buono S. , Germanavicius A. , van Schrojenstein Lantman‐de Valk H. , Tossebro J. , Carmen‐Câra A. , Moravec Berger D. , Perry J. , Kerr M.
Published: July 2011

Background  Despite progress in the process of deinstitutionalisation, very little is known about the health conditions of people with intellectual disability (PWID) who live in large institutions and PWID living in small residential services, family homes or independent living within the community. Furthermore, there are no international comparison studies at European level of the health status and health risk factors of PWID living in fully staffed residential services with formal support and care compared with those living in unstaffed family homes or independent houses with no formal support.

Methods  A total of 1269 persons with ID and/or their proxy respondents were recruited and face‐to‐face interviewed in 14 EU countries with the P15, a multinational assessment battery for collecting data on health indicators relevant to PWID. Participants were grouped according to their living arrangements, availability of formal support and stage of deinstitutionalisation.

Results  Obesity and sedentary lifestyle along with a number of illnesses such as epilepsy, mental disorders, allergies or constipation were highly prevalent among PWID. A significantly higher presence of myocardial infarctions, chronic bronchitis, osteoporosis and gastric or duodenal ulcers was found among participants in countries considered to be at the early stage of deinstitutionalisation. Regardless of deinstitutionalisation stage, important deficits in variables related to such medical health promotion measures as vaccinations, cancer screenings and medical checks were found in family homes and independent living arrangements. Age, number of people living in the same home or number of places in residential services, presence of affective symptoms and obesity require further attention as they seem to be related to an increase in the number of illnesses suffered by PWID.

Discussion  Particular illnesses were found to be highly prevalent in PWID. There were important differences between different living arrangements depending on the level of formal support available and the stage of deinstitutionalisation. PWID are in need of tailored primary health programs that guarantee their access to quality health and health promotion and the preventative health actions of vaccination programs, systematic health checks, specific screenings and nutritional controls. Extensive national health surveys and epidemiological studies of PWID in the EC member states are urgently needed in order to reduce increased morbidity rates among this population.
Variability of self‐regulatory strategies in children with intellectual disability and typically developing children in pretend play situations
Authors: Nader‐Grosbois N. , Vieillevoye S.
Published: July 2011

Objective This study has examined whether or not self‐regulatory strategies vary depending on pretend play situations in 40 children with intellectual disability and 40 typically developing children.

Method Their cognitive, linguistic and individual symbolic play levels were assessed in order to match the children of the two groups. During two dyadic pretend play sessions (Itinerary, Creativity), their abilities in dyadic pretend play and in self‐regulation were assessed by coding their behaviour via two validated grids.

Results The results showed similar overall levels in dyadic pretend play in both groups but a lower involvement was observed in disabled children. Some specific deficits and strengths in self‐regulatory strategies were highlighted in children with intellectual disability. In both groups, non‐structured Creativity situation induced weaker abilities in pretend play, and better self‐evaluation strategy than in the structured Itinerary situation. In both groups, positive links between specific self‐regulation strategies (identification of objective, planning, self‐regulated attention, self‐motivation, self‐evaluation) and specific dyadic pretend play abilities (involvement, roles, actions, objects, social participation) are more numerous and higher in the structured Itinerary situation than in the Creativity situation.
The prevalence of low self‐esteem in an intellectually disabled forensic population
Authors: Johnson P.
Published: July 2011

Background  This was a quantitative study to measure the prevalence low self‐esteem in an intellectually disabled forensic population. The dependent variables used were the adapted six‐item Rosenberg Self‐Esteem Scale and the adapted Evaluative Beliefs Scale. It had a repeated measures design with independent variables including consideration of differences between the low and medium secure parts of the service, the influences of types of offences and the effects of disrupted childhood attachments.

Methods  Forty‐four male clients, with mild to borderline intellectual disabilities, were recruited. Data were collected by one key researcher during individual research interviews using the two structured instruments to measure self‐esteem. Further data were then obtained from routinely recorded clinical information held on the hospital computer system.

Results  Unexpectedly, the majority of clients scored as having moderate or high self‐esteem on both self‐esteem measures. There was a statistically significant positive correlation between the two scales. In all, 64% of the population studied had committed either sexual offences or fire setting offences. Contrary to expectation, those who had evidence of disrupted attachments had slightly higher self‐esteem than those who had not experienced disrupted attachments.

Conclusions  Self‐esteem is a complex personal concept with many influencing factors. Cognitive behaviour therapy has a unique role in realising and overcoming negative core beliefs and feelings of low self‐worth. The offence types concurred with previously noted patterns of offending within the intellectually disabled forensic population.
Combined clopidogrel and proton pump inhibitor therapy is associated with higher cardiovascular event rates after percutaneous coronary intervention: a report from the BASKET trial
Authors: Burkard T. , Kaiser C. A. , Brunner‐La Rocca H. , Osswald S. , Pfisterer M. E. , Jeger R. V. ,   for the BASKET Investigators
Published: July 2011

Abstract.  Burkard T, Kaiser CA, Brunner‐La Rocca H, Osswald S, Pfisterer ME, Jeger RV for the BASKET Investigators (Cardiology, University Hospital; and Cardiology, Maastricht University Hospital Center, Maastricht, the Netherlands). Combined clopidogrel and proton pump inhibitor therapy is associated with higher cardiovascular event rates after percutaneous coronary intervention: a report from the BASKET trial. J Intern Med 2012; 271: 257–263.

Objective.  To investigate whether there is an increased risk of cardiac events with a combined therapy of clopidogrel and proton pump inhibitors (PPIs) after percutaneous coronary intervention (PCI).

Design.  In the BAsel Stent Kosten Effektivitäts Trial (BASKET), all patients undergoing PCI received 6 months of clopidogrel and were analysed for the use of PPI therapy. Endpoints were major adverse cardiac events (MACE), myocardial infarction (MI), death and target vessel revascularization (TVR) after 36 months.

Results.  Of 801 patients with available discharge medication data, 109 (14%) received PPIs. Patients who received PPIs were older (66.5 ± 10.5 vs. 63.3 ± 11.3 years, P = 0.006), more likely to be woman (80% vs. 69%, P = 0.009) and have a history of diabetes (29.6% vs. 17.3%, P = 0.002) or gastrointestinal ulcer disease (8.3% vs. 3.3%, P = 0.015) and more often received nonsteroidal anti‐inflammatory drugs (7.3% vs. 2.2%, P = 0.003) and corticosteroids (11% vs. 3.6%, P = 0.001) but not aspirin (91.7% vs. 97%, P = 0.008) compared with those who did not receive PPIs. Patients who received PPI therapy had higher rates of MACE (30.3% vs. 20.8%, P = 0.027) and MI (14.7% vs. 7.4%, P = 0.01) but similar rates of death (9.2% vs. 7.4%, P = 0.51) and TVR (20.2% vs. 15.3%, P = 0.2) compared with those who did not. By multivariate analysis, diabetes (hazard ratio 1.83, 95% confidence interval 1.07–3.15) and PPI use (hazard ratio 1.88, 95% confidence interval 1.05–3.37) were the only independent risk factors for MI.

Conclusion.  In a real‐world PCI population, the combination of PPIs and clopidogrel was associated with a doubling of MI rates after 3 years. Even after correction for confounding factors, concomitant PPI use remained an independent predictor of outcome emphasizing the clinical importance of this drug–drug interaction.
Effects of enrofloxacin on cytochromes P4501A and P4503A in Carassius auratus gibelio (crucian carp)
Authors: HU X. , LI X.‐C. , SUN B.‐B. , FANG W.‐H. , ZHOU S. , HU L.‐L. , ZHOU J.‐F.
Published: July 2011

Hu, X., Li, X.‐C., Sun, B.‐B., Fang, W.‐H., Zhou, S., Hu, L.‐L., Zhou, J.‐F. Effects of enrofloxacin on cytochromes P4501A and P4503A in Carassius auratus gibelio (crucian carp). J. vet. Pharmacol. Therap. 35, 216–223.

Currently, although enrofloxacin (EF) as a widely used veterinary medicine has begun to apply to treating fish bacterial infections, the researches on the effects of EF on their main drug metabolic enzymes are limited. To investigate the effects of EF on fish cytochromes P450 (CYPs) 1A and 3A, the enzymatic activities and expressions (mRNA and protein) of crucian carp CYP1A and CYP3A after EF administration were examined. For CYP1A, in the in vivo experiments, EF exhibited potent inhibition on the CYP1A‐related ethoxyresorufin‐O‐deethylase (EROD) activity, as well as CYP1A expressions at both protein and mRNA levels, at 24 h after administration with different EF dosages (3, 10, 30, and 60 mg/kg); Furthermore, CYP1A enzymatic activity and expressions at both protein and mRNA levels decreased more with increasing EF dosages. Additionally, the in vitro experimental results showed that, after incubated with microsomes, EF did not change the EROD activity through interacting directly with CYP1A. For CYP3A, the in vitro and in vivo experimental results demonstrated that EF could inhibit the CYP3A‐related erythromycin N‐demethylase activity in a time‐ and dose‐dependent manner, while it did not suppress CYP3A expressions at both protein and mRNA levels after administration with EF for a short period (no more than 24 h); however, after injection with EF at a high dose (10 mg/kg) for a long period, the CYP3A protein and mRNA reached their lowest levels at 96 and 48 h, respectively. These results indicate that EF can suppress CYP1A expressions in a dose‐dependent manner, thereby inhibiting further its catalytic activity; meanwhile, both the interactions of EF with CYP3A and the expressions decrease (protein and mRNA) caused by EF contribute to the CYP3A inhibition.
Fungal defences against animal antagonists – lectins & more
Authors: KEMPKEN FRANK
Published: July 2011

Unlike in the laboratory, in nature fungi are exposed to antagonists including competitors, pathogens, parasites and predators. In this issue of Molecular Ecology, an exciting paper by Bleuler‐Martínez et al. (2011) has unearthed on one of the processes used by fungi to protect themselves against animal antagonists. The authors from Markus Künzler′s group at the ETH Zürich, Switzerland present direct evidence that filamentous fungi possess an inducible resistance mechanism against predators and parasites. This is based on cytoplasmic lectins, which specifically bind to glycans of these predators and parasites, and thus provide toxicity against them. These lectins are expressed at high levels in fruiting bodies and sclerotia of these fungi (Fig. 1). While there have been previous suggestions and efforts to implicate mycotoxins such as sterigmatocystin into fungal defence mechanisms and as an evolutionary force (see Kempken & Rohlfs 2010), the data presented by Markus Künzler′s group highlight the ecological relevance of lectins in defending fungi from parasites and fungivorous animals. As such this paper provides important ecological clues and suggests that secondary metabolites are not the sole player in fungal–animal competition. It rather appears that fungi have evolved several lines of defence against antagonistic organisms.

 Fungi protect their fruiting bodies by the use of lectin (picture of Aleuria aurantia provided by Taylor F. Lockwood).

image
Interleukin 4, interleukin 4 receptor‐α and interleukin 10 gene polymorphisms in Chagas disease
Authors: FLÓREZ O. , MARTÍN J. , GONZÁLEZ C. I.
Published: July 2011

In this study, we investigated the association between single‐nucleotide polymorphisms (SNPs) of the interleukin‐4 (IL4), interleukin‐4 receptor‐α (IL4RA) and interleukin‐10 (IL10) genes with the development of chagasic heart disease. This study included 260 patients from Colombia who were serologically positive for Trypanosoma cruzi antigens (cardiomyopathic, n = 130; asymptomatic, n = 130). Genotypes were determined by polymerase chain reaction (PCR)–restriction fragment length polymorphism or sequence‐specific primer methods. We found statistically significant differences in the distribution of the IL4RA +148 AA (P = 0·025, OR = 1·89, CI = 1·04–3·43) genotype when comparing asymptomatic and symptomatic patients. No statistically significant differences in the genotype and allele frequency of IL4 and IL10 gene polymorphisms between symptomatic and asymptomatic patients were observed. Our experimental evidence suggests that the IL4RA +148 AA genotype has a weak association with the development of chagasic cardiomyopathy in the population under study.
High concentration of adenosine in human visceral leishmaniasis despite increased ADA and decreased CD73
Authors: RAI A. K. , THAKUR C. P. , VELPANDIAN T. , SHARMA S. K. , GHOSH B. , MITRA D. K.
Published: July 2011

Absence of an effective Th‐1 response has been demonstrated as a major cause for the disease pathology among patients with visceral leishmaniasis (VL). Defining strategies to prevent the development of Th‐2 response and/or initiate/activate effective Th‐1 response may be of help to reduce the growing incidence of drug unresponsiveness. Adenosine, which is considered as an endogenous anti‐inflammatory agent is generated in injured/inflamed tissues by the enzymatic catabolism of adenosine triphosphate (ATP), and it suppresses inflammatory responses of essentially all immune cells. The extracellular adenosine‐producing pathway comprises two major enzymes CD39 (ATP→ADP→AMP) and CD73 (AMP→Adenosine). In contrast, the adenosine‐degrading pathway contains only one major enzyme adenosine deaminase (ADA). Our study shows high concentration of adenosine in diseased condition, varying expression of enzyme involved in adenosine‐producing (CD73↓) and adenosine‐degrading (ADA↑) pathways. These are less studied in infections like VL but are very important in terms of endogenous regulation of immune response among patients.
Safeners recruit multiple signalling pathways for the orchestrated induction of the cellular xenobiotic detoxification machinery in Arabidopsis
Authors: BEHRINGER CARINA , BARTSCH KLAUS , SCHALLER ANDREAS
Published: July 2011

Safeners enhance herbicide tolerance in crop plants but not in target weeds, thus improving herbicide selectivity. The safeners isoxadifen‐ethyl and mefenpyr‐diethyl protect cereal crops from sulfonyl urea herbicides in postemergence application. The two safeners were shown here to induce the cellular xenobiotic detoxification machinery in Arabidopsis thaliana when applied to leaves in a way mimicking field application. Gene expression profiling revealed the induction of 446 genes potentially involved in the detoxification process. Transgenic Arabidopsis plants expressing a reporter gene under control of a safener‐responsive maize promoter were used as a model system to study the safener signalling pathway. Reporter gene analysis in the tga2/3/5/6, sid2‐2 and npr1 mutants as compared with the wild‐type background showed that safener inducibility required TGA transcription factors and salicylic acid (SA) in a NON‐EXPRESSOR of PR‐1 (NPR1)‐independent pathway converging on two as‐1 promoter elements. For the majority of the safener‐responsive Arabidopsis genes, a similar dependence on TGA transcription factors and/or SA was shown by gene expression profiling in wild‐type plants as compared with the tga2/3/5/6 and sid2‐2 mutants. Thirty‐eight percent of the genes, however, were induced by safeners in a TGA/SA‐independent manner. These genes are likely to be controlled by WRKY transcription factors and cognate W‐boxes in their promoters.
Do treatment preferences for patients with angina change? An 18‐month follow‐up study
Authors: Bowling Ann , Reeves Barnaby C , Rowe Gene
Published: July 2011

Objectives  To assess whether preferences for patients with angina changed at 18‐month follow‐up using the Patient Preferences Questionnaire for Angina treatment (PPQA).

Background  Evidence suggests that patients want information about treatment options. Reliable measurement of patient preferences for treatment is important for empowering patients.

Design  Postal self‐administered questionnaire survey at baseline and follow‐up. The preference questionnaire comprised 18 items about the main treatments for angina: medication, angioplasty and coronary artery bypass grafting (CABG).

Setting and participants  Patients with diagnosed angina from seven participating general practices across England. The sample comprised 222 patients with angina who responded to both baseline and follow‐up treatment preference questionnaires.

Results  Most patients’ condition and preferences scores for treatment remained stable over 18 months. An exception was angioplasty preference scores, which indicated more negative attitudes towards this procedure over time. People aged over 75 years least preferred angioplasty. There were no associations between any changes in condition and changes in preferences. However, within‐subject agreement could vary by ±5 to 7 points between baseline and follow‐up, with stability apparently worst for the medication and best for surgery sub‐scales, raising the question of what represents reasonable stability.

Conclusion  These results suggest preferences are relatively stable, even where there are changes in health, and provide further evidence of the utility (in particular, reliability) of the PPQA. However, this stability in scores did mask some movement in scale scores and in patients’ first‐ranked treatment choices, showing changing preferences largely from angioplasty to CABG and vice versa, indicating the complexity of preferences.
What Australian women want and when they want it: cervical screening testing preferences, decision‐making styles and information needs
Authors: Dieng Mbathio , Trevena Lyndal , Turner Robin M. , Wadolowski Monika , McCaffery Kirsten
Published: July 2011

Background  New testing technologies and human papillomavirus (HPV) vaccines have recently brought changes to cervical cancer screening. In 2006, the Australian government also changed the protocol for managing abnormal Pap smears. Australian women’s attitudes and preferences to these changes are largely unknown. Quantitative data on information needs and community attitudes to informed decision making in screening in Australia are also limited.

Objective  This national study measures women’s preferences for testing and management of abnormal screening results, preferred decision‐making styles and information needs for cervical cancer screening.

Design  A randomly selected sample of Australian women aged 18–70 participated in a structured telephone questionnaire, exploring testing preferences, information and decision‐making needs.

Results  A total of 1279, of 1571 eligible women, participated in the study with an overall response rate of 81.4%. Half of the women (n = 637) preferred having their Pap smears at least annually, and 85% wanted concurrent HPV testing. A large proportion of women preferred to be involved in decision making for both routine Pap smears (87%) and follow‐up for abnormal results (89%). The majority of women wanted information on screening risks (70%) and benefits (77%); of these 81 (85%) wanted this information before screening. However, 63% of women only wanted information about follow‐up examinations if they had an abnormal Pap test result.

Conclusion  Australian women want to be involved in decision making for cervical cancer screening and require information on the risks and benefits of Pap testing prior to undergoing any screening.
A novel HLA‐DRB1 allele: DRB1*15:02:08
Authors: Sun Y. , Ji Y. , Xie J. , Liu Y. , Du K.
Published: July 2011

The HLA‐DRB1*15:02:08 allele differs from the closest allele HLA‐DRB1*15:02:01 by a single synonymous nucleotide change at position 116 in exon 2 from C to T.
Natural killer cell subsets in man and rodents
Authors: Inngjerdingen M. , Kveberg L. , Naper C. , Vaage J. T.
Published: July 2011

NK cells are important contributors to the early immune defence against infected or transformed cells. They are rapidly activated in response to cytokines, whereby they exert their effector functions. NK cell responses are controlled by a multitude of receptors, which are expressed by subpopulations of NK cells with distinct phenotypes and functionalities. Direct comparisons between species are often difficult because of differences in the expression of NK cell receptors and other markers. In addition, NK cells change their phenotype and effector functions during differentiation, by tissue‐specific factors, or upon activation, complicating interpretations. We will here review the similarities and differences between the major NK cell subsets in man and two well‐characterized rodent models.
Plasma soluble HLA‐G is a potential biomarker for diagnosis of colorectal, gastric, esophageal and lung cancer
Authors: Cao M. , Yie S.‐M. , Liu J. , Ye S. R. , Xia D. , Gao E.
Published: July 2011

Human leukocyte antigen‐G (HLA‐G) is a novel tumor marker and its soluble isoforms produce secretory proteins. Increased soluble HLA‐G (sHLA‐G) levels have been reported in patients with melanoma, neuroblastoma, lymphoproliferative disorders, breast, ovarian and colorectal carcinoma when compared to healthy controls or subjects with benign neoplasms. The aim of this study is to investigate whether or not plasma sHLA‐G can be used as a potential biomarker for cancer diagnosis. We measured plasma sHLA‐G levels in 166 patients with early stages of colorectal cancer (CRC, n = 37), gastric cancer (GC, n = 28), esophageal squamous cell carcinoma (ESCC, n = 58) and non‐small cell lung cancer (NSCLC, n = 43), and compared them to healthy controls (n = 260) by using a specific HLA‐G enzyme‐linked immunosorbent assay (ELISA). We found that plasma sHLA‐G levels were significantly higher in cancer patients than in healthy controls (all P < 0.0001). The areas under the receiver‐operating characteristic (ROC) curves for sHLA‐G were 0.97, 0.91, 0.98 and 0.80 for healthy controls vs CRC, GC, ESCC and NSCLC, respectively. At 100% specificity, the highest sensitivity achieved to detect CRC, GC, ESCC and NSCLC was 94% [95% confidence interval (CI), 89–99], 85% (95% CI, 76–94), 91% (95% CI, 88–94) and 51% (95% CI, 43–59) at a cutoff value of 49 U/ml, respectively. These findings suggest that plasma sHLA‐G may be a useful molecule in the differential diagnosis of these malignancies against healthy controls.
KIR/HLA gene combinations influence susceptibility to B‐cell chronic lymphocytic leukemia and the clinical course of disease
Authors: Karabon L. , Jedynak A. , Giebel S. , Wołowiec D. , Kielbinski M. , Woszczyk D. , Kapelko‐Slowik K. , Kuliczkowski K. , Frydecka I.
Published: July 2011

The aim of this study was to analyze the association between gene polymorphisms of killer‐cell immunoglobulin‐like receptors (KIRs) and their human leukocyte antigen (HLA) ligands and susceptibility to B‐cell chronic lymphocytic leukemia (B‐CLL) and the clinical course of disease. The distribution of individual KIR genes in 197 B‐CLL patients and 200 controls was similar, except for a tendency for lower frequencies of the KIR2DS3 and KIR2DL5 genes among B‐CLL patients (26.9% vs 35.5%, P = 0.06, 46.2% vs 55.5%, P = 0.06). The associations between KIR2DS3 and B‐CLL reached statistical significance in women (P = 0.05). Moreover, we found a trend toward a lower frequency of genotypes with the presence of five or six activating KIR genes in B‐CLL patients compared to controls (20.8% vs 29.0%, P = 0.06), and a significantly higher frequency of individuals possessing genotypes with a prevalence of inhibitory over activating KIR genes (ratio < 0.71) among B‐CLL patients (P = 0.04). The HLA‐Bw4 specificity was significantly reduced among B‐CLL patients (48.7% vs 63.0%, P = 0.005), which resulted from a decreased frequency of HLA‐Bw4(Thr80) (21.6% vs 32.0%, P = 0.02). Moreover, among HLA‐Bw4‐positive individuals, progression‐free survival (PFS) tended to be higher in the presence of KIR3DS1 (77% ± 9% vs 39% ± 13%, P = 0.07). However, in B‐CLL patients, the presence of HLA‐C2 was associated with decreased PFS (49% ± 9% vs 75% ± 7%, P = 0.02), and among HLA‐C2‐positive patients, the probability of PFS was significantly reduced in the absence of KIR2DS1 (34% ± 11% vs 77% ± 7%, P = 0.007). Our results indicate that the pattern of inhibitory/activating KIR genes, together with their HLA ligands, is associated with susceptibility to B‐CLL and affects the clinical course of this disease.