bluuebunny/crossref_metadata_2025 huggingface dataset:
The Effect of the Secret Ballot on Party System Fragmentation: A Test of Three Competing Arguments
Authors: Raymond Christopher D.
Published: April 2014

Few studies have examined the impact that the adoption of the secret ballot had on party system fragmentation outside the United States. This article tests arguments maintaining that the adoption of the secret ballot had a negative, positive or nil effect on party system fragmentation. Using time-series cross-sectional data from several countries adopting the secret ballot around the turn of the twentieth century the results demonstrate that the adoption of the secret ballot did not hinder – though did not favour, either – the development of multiparty systems.
British Think-Tanks and Their Collaborative and Communicative Networks
Authors: Pautz Hartwig
Published: April 2014

This article looks at UK-based think-tanks and their communicative and cooperative networks with other actors in Britain and beyond. Which institutions and people do British think-tanks talk to most to exert influence on domestic public policy? What forms do such communications take? What are British think-tanks' objectives for cooperation with non-UK organisations? This article is based on a survey with analysts at British think-tanks that was conducted in 2012. The data suggests that while British think-tanks communicate and co-operate intensively with some actors within Britain, contacts and cooperation with organisations outside the UK are rather lacklustre. Particular actors are more important for advocacy think-tanks than they are for academic think-tanks; some actors have very little importance for either type.
Antioxidant potential of herbs and spices during deep frying of ghee
Authors: Patel Shriyesh , Shende Sneha , Arora Sumit , Singh Ram Ran Bijoy , Rastogi Subha , Singh Rawat Ajay Kumar
Published: April 2014

The present study was carried out to evaluate antioxidant potential of ashwagandha, clove, coriander, green tea, shatavari and vidarikand extracts as compared to BHA. Clove, coriander and green tea extracts showed significantly higher antioxidant activity than vidarikand, shatavari and ashwagandha extracts. Radical‐scavenging activity by DPPH model system revealed that clove and green tea extracts were superior to other extracts. All the natural antioxidants significantly reduced the formation of peroxides, FFA, thiobarbituric acid value and conjugated dienes. Ghee with added clove, green tea and coriander extracts showed higher induction period as compared to ghee containing vidarikand, ashwagandha, shatavari or BHA.
Antihypertensive and antithrombotic activities of a commercial fermented milk product made with Lactobacillus casei Shirota and Streptococcus thermophilus
Authors: Domínguez‐González Karina N , Cruz‐Guerrero Alma , González‐Márquez Humberto , Gómez‐Ruiz Lorena , García‐Garibay Mariano , Jiménez‐Guzmán Judith , Rodríguez‐Serrano Gabriela
Published: April 2014

Peptides which inhibit the human angiotensin‐converting enzyme (ACE) may be released during milk fermentation, and the micro‐organisms or fermentation conditions influence the specific peptides produced. The aim of this study was to evaluate the ACE inhibitory and antithrombotic activities of a fermented milk product commercially available in Mexico. Viable cell numbers, protein hydrolysis and the pH remained constant during refrigerated storage. The IC50 of ACE inhibitory activity was 31.38 mg/mL. Eight peptide fractions exhibited ACE inhibitory activity and six showed antithrombotic activity. Two fractions showed both. This is the first time that both activities have been reported in a commercial probiotic product.
Gram‐negative bacteria can also form pellicles
Authors: Armitano Joshua , Méjean Vincent , Jourlin‐Castelli Cécile
Published: April 2014

There is a growing interest in the bacterial pellicle, a biofilm floating at the air–liquid interface. Pellicles have been well studied in the Gram‐positive bacterium Bacillus subtilis, but far less in Gram‐negative bacteria, where pellicle studies have mostly focused on matrix components rather than on the regulatory cascades involved. Several Gram‐negative bacteria, including pathogenic bacteria, have been shown to be able to form a pellicle under static conditions. Here, we summarize the growing body of knowledge about pellicle formation in Gram‐negative bacteria, especially about the components of the pellicle matrix. We also propose that the pellicle is a specific biofilm, and that its formation involves particular processes. Since this lifestyle concerns a growing number of bacteria, its properties undoubtedly deserve further investigation.
Fluorescence in situ hybridization probes targeting members of the phylum Candidatus Saccharibacteria falsely target Eikelboom type 1851 filaments and other Chloroflexi members
Authors: Nittami Tadashi , Speirs Lachlan B. M. , Fukuda Junji , Watanabe Masatoshi , Seviour Robert J.
Published: April 2014

The FISH probe TM7‐305 is thought to target the filamentous Eikelboom morphotype 0041 as a member of the Candidatus ‘Saccharibacteria’ (formerly TM7) phylum. However, with activated sludge samples in both Japan and Australia, this probe hybridized consistently with filamentous bacteria fitting the description of the morphotype 1851, which also responded positively to the CHL1851 FISH probe designed to target Chloroflexi members of this morphotype. 16S rRNA clone libraries from samples containing type 1851 TM7‐305‐positive filaments yielded Chloroflexi clones with high sequence similarity to Kouleothrix aurantiaca. These contained a variant TM7‐305 probe target site possessing weakly destabilizing mismatches insufficient to prevent probe hybridization. Furthermore, the TM7‐905 FISH probe, designed to target members of the entire Candidatus ‘Saccharibacteria’ phylum, also hybridized with the filament morphotypes 0041/0675, which responded also to the phylum level Chloroflexi probes. Many Chloroflexi sequences have only a single base mismatch to the TM7‐905 probe target sequence. When competitor probes for both the TM7‐305 and TM7‐905 Chloroflexi non‐target sites were applied, no fluorescent signal was seen in any of the filamentous organisms also hybridizing with the aforementioned Chloroflexi probes. These data indicate that these competitor probes must be included in hybridizations when both the TM7‐905 and TM7‐305 FISH probes are applied, to minimize potential false positive FISH results.
Bioinformatics analysis and expression study of fumarate hydratase in lung cancer
Authors: Ming Zongjuan , Jiang Meihua , Li Wei , Fan Na , Deng Wenjing , Zhong Yujie , Zhang Yuping , Zhang Qiuhong , Yang Shuanying
Published: April 2014

Background

As its etiology and pathogenesis is obscure, illustrating the molecular mechanism of lung cancer has become a serious and urgent task. Studies have shown that fumarate hydratase (FH) is a tumor suppressor related to tumorigenesis, development, and invasion. Our aim was to analyze the biological information of FH, and detect the messenger ribonucleic acid (mRNA) and protein expression of FH in lung cancer cells to explore its role in tumorigenesis and in the development of lung cancer.

Method

We analyzed the biological characteristics of FH, then utilized reverse transcription‐polymerase chain reaction (RT‐PCR) to study FH mRNA expression in A549 and 16 human bronchial epithelial (HBE) cell lines. The protein expression of FH was detected in 57 cases of human lung cancer tissues and 19 cases of normal lung tissues by immunohistochemistry.

Results

1. Bioinformatic analysis: FH mainly exist in the mitochondria; the common structural elements of FH are mainly α‐helix, random coil, β‐turn, and extended strand; there are five possible transmembrane domains in the entire polypeptide chain; FH is a hydrophilic and soluble protein. 2. RT‐PCR result: FH mRNA expression was downregulated in A549 cells compared with 16HBE cells. 3. Immunohistochemistry: FH protein expression was significantly lower in lung cancer cells than in normal lung tissues (P < 0.05), but was not correlated with the patients' age, gender, tumor size, pathological type, or lymph node, distant, or tumor node metastasis stage.

Conclusion

FH was under‐expressed in lung cancer, suggesting that it may be an indicator of tumorigenesis and could be a potential target for therapies against lung cancer in the future.
Clinical characteristics of the mixed form of neuroendocrine tumor in the lung: A retrospective study in 2501 lung cancer cases
Authors: Li Dong‐Hai , Wang Chun , Chen Hui‐Jiao , Huang Hui , Ding Zhen‐Yu
Published: April 2014

Background

A neuroendocrine tumor (NET) is a special kind of epithelial tumor with predominant neuroendocrine differentiation, which arises throughout the body, including the lung. A subpopulation of lung cancer patients suffer from the mixed (combined) form of NET with components of non‐neuroendocrine carcinoma. However, the clinical characteristics of the mixed form of NET are not well established.

Methods

We analyzed 2501 consecutive cases of primary lung cancer from 2009 to 2011. The diagnosis, histology, therapy, and outcome were collected.

Results

A total of 22 patients were enrolled. The occurrence rate of lung cancer was 0.9%. Neither gender (1.2% and 0.3% for male and female, respectively, P = 0.35) nor age (0.6% and 1.3% for patients aged ≤60 and >60, respectively, P = 0.13) was associated with the onset of this disease; however it has become more frequent in recent years (0.6% and 1.6% at the time ≤ and >2010 respectively, P = 0.03). This cohort of 22 patients had a median survival of 60.0 months (95% confidence interval: 14.3–105.6 months). Patients with metastatic disease (60 months and not reached [NR], P = 0.18) or a small‐cell lung cancer component tended to have a shorter survival (35 months and NR, P = 0.16). Patients who underwent surgery had a significantly longer survival period (NR and 17.0 months, P = 0.001).

Conclusions

A mixed form of NET in the lung is a rare disease. While stage and histology might influence prognosis, surgery is the critical factor for long‐term survival.
A simple measure of the strength of convergent evolution
Authors: Arbuckle Kevin , Bennett Cheryl M. , Speed Michael P.
Published: April 2014

Convergent evolution, the independent occurrence of phenotypic similarity, is a widespread and common phenomenon. Methods have been developed to identify instances of convergence, but there is a lack of techniques for quantifying the strength of convergence. We therefore investigated whether convergent evolution can be quantified in a meaningful way.

We have developed a simple metric (the Wheatsheaf index) that provides an index of the strength of convergent evolution incorporating both phenotypic similarity and phylogenetic relatedness. The index is comparable across any quantitative or semiquantitative traits and thus will enable the testing of various hypotheses relating to convergence.

The index performs well over a range of conditions. We apply it to an empirical example using Anolis lizard ecomorphs to demonstrate how it can be used.

The Wheatsheaf index provides an additional tool that complements methods aimed at identifying cases of convergent evolution. It will enable cases of convergence to be analysed in more detail, test hypotheses about its mechanics as an evolutionary process and, more generally, the predictability of evolution (how often do we see strong convergence and does this mean evolutionary solutions are limited?).
Continuous‐time spatially explicit capture–recapture models, with an application to a jaguar camera‐trap survey
Authors: Borchers David , Distiller Greg , Foster Rebecca , Harmsen Bart , Milazzo Lorenzo
Published: April 2014

Many capture–recapture surveys of wildlife populations operate in continuous time, but detections are typically aggregated into occasions for analysis, even when exact detection times are available. This discards information and introduces subjectivity, in the form of decisions about occasion definition.

We develop a spatiotemporal Poisson process model for spatially explicit capture–recapture (SECR) surveys that operate continuously and record exact detection times. We show that, except in some special cases (including the case in which detection probability does not change within occasion), temporally aggregated data do not provide sufficient statistics for density and related parameters, and that when detection probability is constant over time, our continuous‐time (CT) model is equivalent to an existing model based on detection frequencies. We use the model to estimate jaguar density from a camera‐trap survey and conduct a simulation study to investigate the properties of a CT estimator and discrete‐occasion estimators with various levels of temporal aggregation. This includes investigation of the effect on the estimators of spatiotemporal correlation induced by animal movement.

The CT estimator is found to be unbiased and more precise than discrete‐occasion estimators based on binary capture data (rather than detection frequencies) when there is no spatiotemporal correlation. It is also found to be only slightly biased when there is correlation induced by animal movement, and to be more robust to inadequate detector spacing, while discrete‐occasion estimators with binary data can be sensitive to occasion length, particularly in the presence of inadequate detector spacing.

Our model includes as a special case a discrete‐occasion estimator based on detection frequencies, and at the same time lays a foundation for the development of more sophisticated CT models and estimators. It allows modelling within‐occasion changes in detectability, readily accommodates variation in detector effort, removes subjectivity associated with user‐defined occasions and fully utilizes CT data. We identify a need for developing CT methods that incorporate spatiotemporal dependence in detections and see potential for CT models being combined with telemetry‐based animal movement models to provide a richer inference framework.
Landscape connectivity for wildlife: development and validation of multispecies linkage maps
Authors: Koen Erin L. , Bowman Jeff , Sadowski Carrie , Walpole Aaron A.
Published: April 2014

The ability to identify regions of high functional connectivity for multiple wildlife species is of conservation interest with respect to habitat management and corridor planning. We present a method that does not require independent, field‐collected data, is insensitive to the placement of source and destination sites (nodes) for modeling connectivity, and does not require the selection of a focal species.

In the first step of our approach, we created a cost surface that represented permeability of the landscape to movement for a suite of species. We randomly selected nodes around the perimeter of the buffered study area and used circuit theory to connect pairs of nodes. When the buffer was removed, the resulting current density map represented, for each grid cell, the probability of use by moving animals.

We found that using nodes that were randomly located around the perimeter of the buffered study area was less biased by node placement than randomly selecting nodes within the study area. We also found that a buffer of ≥ 20% of the study area width was sufficient to remove the effects of node placement on current density. We tested our method by creating a map of connectivity in the Algonquin to Adirondack region in eastern North America, and we validated the map with independently collected data. We found that amphibians and reptiles were more likely to cross roads in areas of high current density, and fishers (Pekania [Martes] pennanti) used areas with high current density within their home ranges.

Our approach provides an efficient and cost effective method of predicting areas with relatively high landscape connectivity for multiple species..
Allergens on desktop surfaces in preschools and elementary schools of urban children with asthma
Authors: Kanchongkittiphon W. , Sheehan W. J. , Friedlander J. , Chapman M. D. , King E.‐M. , Martirosyan K. , Baxi S. N. , Permaul P. , Gaffin J. M. , Kopel L. , Bailey A. , Fu C. , Petty C. R. , Gold D. R. , Phipatanakul W.
Published: April 2014

Desktop dust has been studied as a source of food allergen, but not as a source of potential aeroallergen exposure. Thirty‐six wiped samples from desktop surfaces were collected from preschools and schools. Samples were analyzed for detectable levels of common aeroallergens including Alternaria, cockroach, dog, dust mite, cat, mouse, and rat allergens by immunoassay. Mouse allergen was the most prevalent, detectable in 97.2% of samples. Cat allergen was detectable in 80.6% of samples, and dog allergen was detectable in 77.8% of samples. Other allergens were not as prevalent. Mouse was the only allergen that was highly correlated with settled floor dust collected from the same rooms (r = 0.721, P < 0.001). This is the first study to detect aeroallergens on desktop surfaces by using moist wipes. Allergens for mouse, cat, and dog were highly detectable in wipes with mouse desktop surface levels correlating with levels in vacuumed floor dust.
Transforming growth factor‐beta 1 pathways in inflammatory airway diseases
Authors: Yang Y. , Zhang N. , Lan F. , Van Crombruggen K. , Fang L. , Hu G. , Hong S. , Bachert C.
Published: April 2014

Transforming growth factor‐beta 1 (TGF‐β1) has been reported being involved in the remodeling and immunosuppression processes of inflammatory airway diseases; understanding the regulation of TGF‐β1 is therefore a key to unravel the pathomechanisms of these diseases. This review briefly summarizes the current knowledge on the influencing factors for driving TGF‐β1 and its regulatory pathways in inflammatory airway diseases and discusses possible therapeutic approaches to TGF‐β1 control. The factors include smoking and oxidative stress, prostaglandins (PGs), leukotrienes (LTs), bradykinin (BK), and microRNAs (miRs). Based on the summary, new innovative treatment strategies may be developed for inflammatory airway diseases with an impaired expression of TGF‐β1.
Postoperative morphine concentration in infants with or without biliary atresia and its association with hepatic blood flow
Authors: Wang X. , Qiao Z. W. , Zhou Z. J. , Zhuang P. J. , Zheng S.
Published: April 2014

We measured pre‐operative hepatic blood flow and postoperative morphine concentration in infants with or without biliary atresia. Thirty‐four infants (0–3 months) with biliary atresia undergoing portoenterostomy (Kasai operation) were included and hepatic blood flow was assessed by magnetic resonance imaging before surgery in 12 of them. Sixteen subjects (0–3 months) without liver disease undergoing abdominal or pelvic surgery acted as controls and six of them had hepatic blood flow assessed. Intravenous morphine (8 μg.kg−1.h−1) was administered to all patients postoperatively. The median (IQR [range]) relative hepatic blood flow was 3.51 (2.72–3.88 [1.68–4.43]) with and 3.15 (2.66–4.42 [2.30–5.01]) without biliary atresia (p = 0.851). The median (IQR [range]) morphine concentration after 24 h infusion was 5.9 (4.5–16.4 [2.9–42.2]) ng.ml−1and 6.4 (3.2–12.0 [1.9–48.6]) ng.ml−1, respectively (p = 0.460). An inverse regression relation was found between the morphine concentration and the hepatic perfusion index (R2 = 0.519, p = 0.001). Compensatory increases in hepatic arterial blood flow maintain the total hepatic blood flow in infants with biliary atresia.
Psychometric evaluation of a direct observation of procedural skills assessment tool for ultrasound‐guided regional anaesthesia
Authors: Watson M. J. , Wong D. M. , Kluger R. , Chuan A. , Herrick M. D. , Ng I. , Castanelli D. J. , Lin L. , Lansdown A. K. , Barrington M. J.
Published: April 2014

Assessment tools must be investigated for reliability, validity and feasibility before being implemented. In 2013, the Australian and New Zealand College of Anaesthetists introduced workplace‐based assessments, including a direct observation of a procedural skills assessment tool. The objective of this study was to evaluate the psychometric properties of this assessment tool for ultrasound‐guided regional anaesthesia. Six experts assessed 30 video‐recorded trainee performances of ultrasound‐guided regional anaesthesia. Inter‐rater reliability, assessed using absolute agreement intraclass correlation coefficients, varied from 0.10 to 0.49 for the nine individual nine‐point scale items, and was 0.25 for a ‘total score’ of all items. Internal consistency was measured by correlation between ‘total score’ and ‘overall performance’ scale item (r = 0.68, p < 0.001). Construct validity was demonstrated by the ‘total score’ correlating with trainee experience (r = 0.51, p = 0.004). The mean time taken to complete assessments was 6 min 35 s.
The use of a nasogastric tube to facilitate nasotracheal intubation: a randomised controlled trial
Authors: Lim C.‐W. , Min S.‐W. , Kim C.‐S. , Chang J.‐E. , Park J.‐E. , Hwang J.‐Y.
Published: April 2014

During nasotracheal intubation, the tracheal tube passes through either the upper or lower pathway in the nasal cavity, and it has been reported to be safer that the tracheal tube passes though the lower pathway, just below the inferior turbinate. We evaluated the use of a nasogastric tube as a guide to facilitate tracheal tube passage through the lower pathway, compared with the ‘conventional’ technique (blind insertion of the tracheal tube into the nasal cavity). A total of 60 adult patients undergoing oral and maxillofacial surgery were included in the study. In 20 out of 30 patients (66.7%) with the nasogastric tube‐guided technique, the tracheal tube passed through the lower pathway, compared with 8 out of 30 patients (26.7%) with the ‘conventional’ technique (p = 0.004). Use of the nasogastric tube‐guided technique reduced the incidence and severity of epistaxis (p = 0.027), improved navigability (p = 0.034) and required fewer manipulations (p = 0.001) than the ‘conventional’ technique.
Bacterial contamination of surgical scrub suits worn outside the operating theatre: a randomised crossover study
Authors: Hee H. I. , Lee S. , Chia S. N. , Lu Q. S. , Liew A. P. Q. , Ng A.
Published: April 2014

In this study, we aimed to evaluate the bacterial contamination of surgical scrub suits worn outside the operating theatre. We randomised 16 anaesthetists on separate occasions into one of 3 groups: restricted to the operating theatre only; theatre and surgical wards; and theatre and departmental office. For each group, sample fabric pieces attached to the chest, waist and hip areas of each suit were removed at 150 min intervals between 08:30 and 16:00 on the day of study, and sent for microbiological assessment. Mean bacterial counts increased significantly over the course of the working day (p = 0.036), and were lower in the chest compared to the hip (p = 0.007) and waist areas (p = 0.016). The mean (SD) bacterial counts, expressed as colony‐forming units per cm2 at 16:00 on the day of study, were 25.2 (43.5) for those restricted to theatre and 18.5 (25.9) and 17.9 (31.0) for those allowed out to visit the ward and office, respectively (p = 0.370). We conclude that visits to ward and office did not significantly increase bacterial contamination of scrub suits.
Undermining Optimistic Denial Reactions to Domestic and Campus Emergency Warning Messages
Authors: Thompson Suzanne C. , Schlehofer Michele M.
Published: April 2014

Background: Individuals who prepare for public emergencies can mitigate the effects of an incident, but denial of personal susceptibility may reduce the likelihood of preparation. Some denial may be due to a positive self‐image that is at odds with being “at risk”. The potential for an enhanced warning message that included a positive image of a protector to circumvent this denial was tested in two studies. Methods: Optimistic denial threat orientation was measured. Then participants received either a traditional or a positive protector warning message about terrorism (Study 1; nationally representative sample of US adults; N = 587) or campus emergency preparation (Study 2; US college students; N = 179). Results: As predicted, in the enhanced image condition optimistic denial was no longer related to stronger denial reactions and lower intentions to protect oneself. In addition, Study 2 tested explanatory mediators and found that negative perceptions of and low similarity to a protector partially explained the denial of those higher in optimistic denial and why their denial was dampened in the positive image condition. Conclusions: An enhanced message including a positive image of protector may be an effective way to encourage protection for those prone to optimistic denial.
Epigallocatechin Gallate Promotes the Development of Mouse 2‐Cell Embryos In Vitro by Regulating Mitochondrial Activity and Expression of Genes Related to p53 Signalling Pathway
Authors: Zhang Weiyu , Lv Junjie , Zhang Yanqin , Jiang Yufei , Chu Chenfeng , Wang Shie
Published: April 2014

Preliminary studies have found that the epigallocatechin gallate (EGCG) at proper concentration could promote development of pre‐implantation mouse embryos in vitro. However, the underlying mechanisms have not been well understood. In this study, we collected 1‐cell embryos from Kunming (KM) mice, cultured them in M16 medium or M16 medium supplemented with 10 μg/mL EGCG and investigated the effects of EGCG on mitochondrial activity and reactive oxygen species (ROS) level of 2‐cell embryos. Furthermore, we explored expression differences of genes related to p53 signalling pathway in 2‐cell embryos using a PCR array. The results showed that ROS level and mitochondrial membrane potential were significantly lower in embryos cultured in the EGCG group than in the M16 group (p < 0.05), while the adenosine triphosphate content was slightly lower than in the M16 group (p > 0.05). PCR array test results showed that 18 genes were differentially expressed, among which eight genes involving cell growth, cell cycle regulation and mRNA transcription were up‐regulated and 10 genes involving apoptosis, cell cycle arrest and DNA repair were down‐regulated in the EGCG groups. It is concluded that EGCG could promote the development of 1‐cell embryos in vitro possibly due to its ability to scavenge ROS and regulate mitochondrial activity. In addition, EGCG could influence expression of genes related to p53 signalling pathway in 2‐cell embryos and promote cell cycle progression.
Pre‐clinical and Clinical Safety Studies of CMX‐2043: A Cytoprotective Lipoic Acid Analogue for Ischaemia–Reperfusion Injury
Authors: Kates Steven A. , Lader Alan S. , Casale Ralph , Beeuwkes Reinier
Published: April 2014

CMX‐2043 is an α‐lipoic acid analogue targeted to reduction of cellular injury and organ damage due to ischaemia–reperfusion injury (IRI). It has been shown to be effective in a rat model of cardiac IRI. The studies here reported evaluate its safety and pharmacokinetic profile in preparation for human clinical studies in procedures associated with IRI. Safety and tolerability were tested in standard pre‐clinical in vitro and animal models and in a Phase 1 human clinical trial. CMX‐2043 did not bind to a wide range of receptors and specific targets at approximately 4 μg/mL (10 μM). It was not mutagenic by Ames assay, did not produce chromosome aberrations in Chinese hamster ovary (CHO) cells, and was negative for clastogenic potential. Toxicological studies in rats including both single and 14‐day repeat intravenous doses and in dogs (single intravenous dose) with a 2‐week recovery period were conducted. The NOAEL in rats and dogs was 30 and >10 mg/kg, respectively. No serious adverse events were reported in a placebo‐controlled, sequential dose escalation Phase 1 clinical trial. The low toxicity in the pre‐clinical studies and the absence of adverse events in the Phase 1 trial have supported investigation of CMX‐2043 in a human efficacy trial.
Reperfusion Therapy with Low‐Dose Insulin or Insulin‐Like Growth Factor 2; Myocardial Function and Infarct Size in a Porcine Model of Ischaemia and Reperfusion
Authors: Salminen Pirjo‐Riitta , Dahle Geir Olav , Moen Christian Arvei , Wergeland Anita , Jonassen Anne Kristin , Haaverstad Rune , Matre Knut , Grong Ketil
Published: April 2014

In an open‐chest porcine model, we examined whether myocardial pharmacological conditioning at the time of reperfusion with low‐dose insulin or insulin‐like growth factor 2 (IGF2), not affecting serum glucose levels, could reduce infarct size and improve functional recovery. Two groups of anaesthetized pigs with either 60 or 40 min. of left anterior descending artery occlusion (total n = 42) were randomized to receive either 0.9% saline, insulin or IGF2 infusion for 15 min., starting 5 min. before a 180‐min. reperfusion period. Repeated fluorescent microsphere injections were used to confirm ischaemia and reperfusion. Area at risk and infarct size was determined with Evans blue and triphenyltetrazolium chloride staining. Local myocardial function was evaluated with multi‐layer radial tissue Doppler strain and speckle‐tracking strain from epicardial echocardiography. Western blotting and TUNEL staining were performed to explore apoptosis. Infarct size did not differ between treatment groups and was 56.7 ± 6.8%, 49.7 ± 9.6%, 56.2 ± 8.0% of area at risk for control, insulin and IGF2 group, respectively, in the 60‐min. occlusion series. Corresponding values were 45.6 ± 6.0%, 48.4 ± 7.2% and 34.1 ± 5.8% after 40‐min. occlusion. Global and local cardiac function did not differ between treatment groups. No differences related to treatment could be found in myocardial tissue cleaved caspase‐3 content or the degree of TUNEL staining. Reperfusion therapy with low‐dose insulin or with IGF2 neither reduced infarct size nor improved function in reperfused myocardium in this in vivo porcine model.
Bayesian estimation of the phylogeography of African gorillas with genome‐differentiated population trees
Authors: Kim Joungyoun , Larget Bret
Published: April 2014

Phylogeography investigates the historical process that is responsible for the contemporary geographic distributions of populations in a species. The inference is made on the basis of molecular sequence data sampled from modern‐day populations. The estimates, however, may fluctuate depending on the relevant genomic regions, because the evolution mechanism of each genome is unique, even within the same individual. In this article, we propose a genome‐differentiated population tree model that allows the existence of separate population trees for each homologous genome. In each population tree, the unique evolutionary characteristics account for each genome, along with their homologous relationship; therefore, the approach can distinguish the evolutionary history of one genome from that of another. In addition to the separate divergence times, the new model can estimate separate effective population sizes, gene‐genealogies and other mutation parameters. For Bayesian inference, we developed a Markov chain Monte Carlo (MCMC) methodology with a novel MCMC algorithm which can mix over a complicated state space. The stability of the new estimator is demonstrated through comparison with the Monte Carlo samples and other methods, as well as MCMC convergence diagnostics. The analysis of African gorilla data from two homologous loci reveals discordant divergence times between loci, and this discrepancy is explained by male‐mediated gene flows until the end of the last ice age.
Combined estimating equation approaches for semiparametric transformation models with length‐biased survival data
Authors: Cheng Yu‐Jen , Huang Chiung‐Yu
Published: April 2014

Survival data are subject to length‐biased sampling when the survival times are left‐truncated and the underlying truncation time random variable is uniformly distributed. Substantial efficiency gains can be achieved by incorporating the information about the truncation time distribution in the estimation procedure [Wang (1989)Journal of the American Statistical Association84, 742–748; Wang (1996)Biometrika83, 343–354]. Under the semiparametric transformation models, the maximum likelihood method is expected to be fully efficient, yet it is difficult to implement because the full likelihood depends on the nonparametric component in a complicated way. Moreover, its asymptotic properties have not been established. In this article, we extend the martingale estimating equation approach [Chen et al. (2002)Biometrika89, 659–668; Kim et al. (2013)Journal of the American Statistical Association108, 217–227] and the pseudo‐partial likelihood approach [Severini and Wong (1992)The Annals of Statistics4, 1768–1802; Zucker (2005)Journal of the American Statistical Association100, 1264–1277] for semiparametric transformation models with right‐censored data to handle left‐truncated and right‐censored data. In the same spirit of the composite likelihood method [Huang and Qin (2012)Journal of the American Statistical Association107, 946–957], we further construct another set of unbiased estimating equations by exploiting the special probability structure of length‐biased sampling. Thus the number of estimating equations exceeds the number of parameters, and efficiency gains can be achieved by solving a simple combination of these estimating equations. The proposed methods are easy to implement as they do not require additional programming efforts. Moreover, they are shown to be consistent and asymptotically normally distributed. A data analysis of a dementia study illustrates the methods.
TEL@work: Toward integration of theory and practice
Authors: Tynjälä Päivi , Häkkinen Päivi , Hämäläinen Raija
Published: April 2014

This paper examines technology‐enhanced learning at work in the context of the integrative pedagogy model. The basic idea behind this model is to create learning environments whereby the four basic elements of professional expertise (ie, theoretical, practical, self‐regulative and sociocultural knowledge) can be integrated. The paper illustrates two basic ways of applying the model in technology‐enhanced learning at work. First, examples of how to make use of existing technologies, especially social media, to empower learning at work is presented, and second, an instance of the way the model is used in the design of specific technologies for enhancing collaborative learning in the work context is described. The paper concludes that the integrative pedagogy model has the potential to serve both as a principle for designing technologies and for applying existing technologies for workplace learning.
MBD5 regulates iron metabolism via methylation‐independent genomic targeting of Fth1 through KAT2A in mice
Authors: Tao Yunlong , Wu Qian , Guo Xin , Zhang Zhuzhen , Shen Yuanyuan , Wang Fudi
Published: April 2014

Ferritin plays important roles in iron metabolism and controls iron absorption in the intestine. The ferritin subunits ferritin heavy chain (Fth1) and ferritin light chain (Ftl1) are tightly regulated at both the transcriptional and post‐transcriptional levels. However, mechanisms of maintaining stable, basal expression of Fth1 are poorly understood. Here, we show that global deletion of Mbd5 in mice induces an iron overload phenotype. Liver and serum iron levels in Mbd5−/− mice were 3·2‐fold and 1·5‐fold higher respectively, than wild‐type littermates; moreover, serum ferritin was increased >5‐fold in the Mbd5−/− mice. Mbd5 encodes a member of the methyl‐CpG binding domain family; however, the precise function of this gene is poorly understood. Here, we found that intestinal Fth1 mRNA levels were decreased in Mbd5−/− mice. Loss of Fth1 expression in the intestine could lead to iron over‐absorption. Furthermore, deleting Mbd5 specifically in the intestine resulted in a phenotype similar to that of conditional deletion of Fth1 mice. An Fth1 promoter‐report luciferase assay indicated that overexpression of Mbd5 enhanced Fth1 transcription in a dose‐dependent manner. Histone H4 acetylation of the Fth1 promoter was reduced in the intestine of Mbd5−/− mice and further analysis showed that histone acetyltransferase KAT2A was essential for MBD5‐induced Fth1 transcription.
Management of the acute painful crisis in sickle cell disease‐ a re‐evaluation of the use of opioids in adult patients
Authors: Telfer Paul , Bahal Nawal , Lo Alice , Challands Joanne
Published: April 2014

Management of the acute painful crisis (APC) of sickle cell disease (SCD) remains unsatisfactory despite advances in the understanding and management of acute pain in other clinical settings. One reason for this is an unsophisticated approach to the use of opioid analgesics for pain management. This applies to haematologists who are responsible for developing acute sickle pain management protocols for their patients, and to health care staff in the acute care setting. The objective of this article is to evaluate the evidence for use of opioids in APC management. We have highlighted the possibilities for improving management by using alternatives to morphine, and intranasal (IN) or transmucosal routes of administration for rapid onset of analgesia in the emergency department (ED). We suggest how experience gained in managing acute sickle pain in children could be extrapolated to adolescents and young adults. We have also questioned whether patients given strong opioids in the acute setting are being safely monitored and what resources are required to ensure efficacy, safety and patient satisfaction. We also identify aspects of care where there are significant differences of opinion, which require further study by randomized controlled trial.
Persistence of recipient human leucocyte antigen (HLA) antibodies and production of donor HLA antibodies following reduced intensity allogeneic haematopoietic stem cell transplantation
Authors: Fasano Ross M. , Mamcarz Ewelina , Adams Sharon , Donohue Jerussi Theresa , Sugimoto Kyoko , Tian Xin , Flegel Willy A. , Childs Richard W.
Published: April 2014

The effects of reduced intensity conditioning (RIC) on human leucocyte antigen (HLA)‐alloimmunization and platelet transfusion refractoriness (PTR) following allogeneic haematopoietic stem cell transplantation (Allo‐HSCT) are unknown. We studied HLA‐alloantibodies in a cohort of 16 patients (eight HLA‐alloimmunized with pre‐transplant histories of PTR and eight non‐alloimmunized controls) undergoing Allo‐HSCT using fludarabine/cyclophosphamide‐based RIC. Pre‐ and post‐transplant serum samples were analysed for HLA‐antibodies and compared to myeloid, T‐cell and bone marrow plasma cell chimaerism. Among alloimmunized patients, the duration that HLA‐antibodies persisted post‐transplant correlated strongly with pre‐transplant HLA‐antibody mean fluorescence intensity (MFI) and PRA levels (Spearman's rank correlation = 0·954 (P = 0·0048) and 0·865 (P = 0·0083) respectively). Pre‐transplant MFI >10 000 was associated with post‐transplant HLA antibody persistence >100 d (P = 0·029). HLA‐antibodies persisted ≥100 d in 3/8 patients despite recipient chimaerism being undetectable in all lympho‐haematopoietic lineages including plasma cells. Post‐transplant de‐novo HLA‐antibodies developed in three control patients with two developing PTR; the donors for two of these patients demonstrated pre‐existing HLA‐antibodies of equivalent specificity to those in the patient, confirming donor origin. These data show HLA‐antibodies may persist for prolonged periods following RIC. Further study is needed to determine the incidence of post‐transplant PTR as a consequence of donor–derived HLA alloimmunization before recommendations on donor HLA‐antibody screening can be made.
Breaking good: the inexorable rise of BTK inhibitors in the treatment of chronic lymphocytic leukaemia
Authors: Hutchinson Claire V. , Dyer Martin J. S.
Published: April 2014

Although expressed in several haematological lineages and involved in multiple different signalling pathways, Bruton tyrosine kinase (BTK) plays an indispensible role in B cells in signalling from the B cell receptor (BCR) for antigen. Many B cell malignancies remain dependent on constitutive BCR signalling, making BTK a functional therapeutic target. Several BTK inhibitors (BTKi) with different kinomes and modes of action are being assessed clinically. This review documents the efficacy and toxicity of BTKi in chronic lymphocytic leukaemia (CLL). Clinically, the furthest in development is ibrutinib (trade name, Imbruvica), an irreversible BTKi, which has shown spectacular preliminary efficacy, with rapid reductions in lymph nodes accompanied by peripheral blood lymphocytosis. The lymphocytosis resolves slowly and most patients do not enter a complete remission. Nevertheless, it is possible to maintain many CLL patients, even those with adverse cytogenetic features, on drug for many months with minimal toxicities, thus potentially transforming the therapeutic paradigms for CLL. The efficacy, lack of toxicity and oral administration of BTKi will ensure their adoption in a wide range of B cell malignancies. An outstanding challenge is to incorporate BTKi with other precision medicines in a mechanism‐based manner in order to dispense with conventional chemotherapy.
Current status of antifungal resistance and its impact on clinical practice
Authors: Alcazar‐Fuoli Laura , Mellado Emilia
Published: April 2014

Mortality linked to invasive fungal diseases remains very high despite the availability of novel antifungals and new therapeutic strategies. Candida albicans and Aspergillus fumigatus account for most invasive mycosis produced by yeast or moulds, respectively. Other Candida non‐albicans are increasingly being reported and newly emerging, as well as cryptic, filamentous fungi often cause disseminated infections in immunocompromised hosts. Management of invasive fungal infections is becoming a challenge as emerging fungal pathogens generally show poor response to many antifungals. The ability of reference antifungal susceptibility testing methods to detect emerging resistance patterns, together with the molecular characterization of antifungal resistance mechanisms, are providing useful information to optimize the effectiveness of antifungal therapy. The current status of antifungal resistance epidemiology with special emphasis on the molecular resistant mechanisms that have been described in the main pathogenic fungal species are reviewed.
Whole exome sequencing to estimate alloreactivity potential between donors and recipients in stem cell transplantation
Authors: Sampson Juliana K. , Sheth Nihar U. , Koparde Vishal N. , Scalora Allison F. , Serrano Myrna G. , Lee Vladimir , Roberts Catherine H. , Jameson‐Lee Max , Ferreira‐Gonzalez Andrea , Manjili Masoud H. , Buck Gregory A. , Neale Michael C. , Toor Amir A.
Published: April 2014

Whole exome sequencing (WES) was performed on stem cell transplant donor‐recipient (D‐R) pairs to determine the extent of potential antigenic variation at a molecular level. In a small cohort of D‐R pairs, a high frequency of sequence variation was observed between the donor and recipient exomes independent of human leucocyte antigen (HLA) matching. Nonsynonymous, nonconservative single nucleotide polymorphisms were approximately twice as frequent in HLA‐matched unrelated, compared with related D‐R pairs. When mapped to individual chromosomes, these polymorphic nucleotides were uniformly distributed across the entire exome. In conclusion, WES reveals extensive nucleotide sequence variation in the exomes of HLA‐matched donors and recipients.
Outpatient bendamustine and idarubicin for upfront therapy of elderly acute myeloid leukaemia/myelodysplastic syndrome: a phase I/II study using an innovative statistical design
Authors: Lionberger Jack M. , Pagel John M. , Sandhu Vicky K. , Xie Hu , Shadman Mazyar , Mawad Raya , Boehm Alexandra , Dean Carol , Shannon‐Dorcy Kathleen , Scott Bart L. , Deeg Hans Joachim , Becker Pamela S. , Hendrie Paul C. , Walter Roland B. , Ostronoff Fabiana , Appelbaum Frederick R. , Estey Elihu H.
Published: April 2014

Combinations of agents may improve outcomes among elderly acute myeloid leukaemia (AML) and high‐risk myelodysplastic syndrome (MDS) patients. We performed an adaptive phase I/II trial for newly‐diagnosed AML or high‐risk MDS patients aged ≥50 years using a Bayesian approach to determine whether 1 of 3 doses of bendamustine (45, 60, 75 mg/m2 days 1–3), together with idarubicin (12 mg/m2 days 1–2), might provide a complete response (CR) rate ≥40% with <30% grade 3–4 non‐haematological toxicity. We treated 39 patients (34 AML; five MDS with >10% marrow blasts; median age 73 years). None of the three bendamustine doses in combination with idarubicin met the required CR and toxicity rates; the 75 mg/m2 dose because of excess toxicity (two of three patients) and the 60 mg/m2 dose because of low efficacy (CR rate 10/33), although no grade 3–4 non‐haematological toxicity was seen at this dose. Median survival was 7·2 months. All patients began treatment as outpatients but hospitalization was required in 90% (35/39). Although we did not find a dose of bendamustine combined with idarubicin that would provide a CR rate of >40% with acceptable toxicity, bendamustine may have activity in AML/MDS patients, suggesting its addition to other regimens may be warranted.
R‐CHOPwith iodine‐131 tositumomab consolidation for advanced stage diffuse largeB‐cell lymphoma (DLBCL):SWOG S0433
Authors: Friedberg Jonathan W. , Unger Joseph M. , Burack W. Richard , Gopal Ajay K. , Raju Robert N. , Nademanee Auayporn P. , Kaminski Mark S. , Li Hongli , Press Oliver W. , Miller Thomas P. , Fisher Richard I.
Published: April 2014

Radiolabelled antiCD‐20 antibodies have demonstrated single agent activity in relapsed diffuse large B‐cell lymphoma (DLBCL). The S0433 clinical trial enrolled patients with newly diagnosed, advanced stage or bulky stageII, histologically confirmedDLBCL. Patients received six cycles of R‐CHOP(rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone), two cycles ofCHOP, then iodine‐131 tositumomab radioimmunotherapy consolidation 30–60 d after completion of chemotherapy. The primary endpoint was 2‐year progression‐free survival (PFS). Eighty‐four eligible patients were enrolled, and 56 patients completed the entire course of protocol treatment. Of the 84 patients evaluable for treatment response, 72 [86%, 95% confidence interval (CI): 76–92%] achieved a partial response (n = 21) or a confirmed (n = 41) or unconfirmed (n = 10) complete response to therapy. With a median follow‐up of 3·9 years, the 2‐yearPFSestimate is 69% and the 2‐year overall survival estimate is 77%. Rituximab levels at time of radioimmunotherapy did not correlate with toxicity or outcome. Twenty percent of patients had double hit features (MYC+;BCL2+) by immunohistochemistry, and had inferior outcome. These current results suggest that the incorporation of novel agents earlier in therapy may ultimately have greater impact inDLBCL, as early progressions, deaths and declining performance status duringCHOPchemotherapy limited the number of patients who ultimately could benefit from radioimmunotherapy consolidation.