bluuebunny/crossref_metadata_2025 huggingface dataset:
DNA double-strand break repair: a theoretical framework and its application
Authors: Murray Philip J. , Cornelissen Bart , Vallis Katherine A. , Chapman S. Jon
Published: January 2016

DNA double-strand breaks (DSBs) are formed as a result of genotoxic insults, such as exogenous ionizing radiation, and are among the most serious types of DNA damage. One of the earliest molecular responses following DSB formation is the phosphorylation of the histone H2AX, giving rise to
γ
H2AX. Many copies of
γ
H2AX are generated at DSBs and can be detected
in vitro
as foci using well-established immuno-histochemical methods. It has previously been shown that anti-
γ
H2AX antibodies, modified by the addition of the cell-penetrating peptide TAT and a fluorescent or radionuclide label, can be used to visualize and quantify DSBs
in vivo
. Moreover, when labelled with a high amount of the short-range, Auger electron-emitting radioisotope,
111
In, the amount of DNA damage within a cell can be increased, leading to cell death. In this report, we develop a mathematical model that describes how molecular processes at individual sites of DNA damage give rise to quantifiable foci. Equations that describe stochastic mean behaviours at individual DSB sites are derived and parametrized using population-scale, time-series measurements from two different cancer cell lines. The model is used to examine two case studies in which the introduction of an antibody (anti-
γ
H2AX-TAT) that targets a key component in the DSB repair pathway influences system behaviour. We investigate: (i) how the interaction between anti-
γ
H2AX-TAT and
γ
H2AX effects the kinetics of H2AX phosphorylation and DSB repair and (ii) model behaviour when the anti-
γ
H2AX antibody is labelled with Auger electron-emitting
111
In and can thus instigate additional DNA damage. This work supports the conclusion that DSB kinetics are largely unaffected by the introduction of the anti-
γ
H2AX antibody, a result that has been validated experimentally, and hence the hypothesis that the use of anti-
γ
H2AX antibody to quantify DSBs does not violate the image tracer principle. Moreover, it provides a novel model of DNA damage accumulation in the presence of Auger electron-emitting
111
In that is supported qualitatively by the available experimental data.
Dynamic growth of slip surfaces in catastrophic landslides
Authors: Germanovich Leonid N. , Kim Sihyun , Puzrin Alexander M.
Published: January 2016

This work considers a landslide caused by the shear band that emerges along the potential slip (rupture) surface. The material above the band slides downwards, causing the band to grow along the slope. This growth may first be stable (progressive), but eventually becomes dynamic (catastrophic). The landslide body acquires a finite velocity before it separates from the substrata. The corresponding initial-boundary value problem for a dynamic shear band is formulated within the framework of Palmer & Rice's (
Proc. R. Soc. Lond. A
332
, 527–548. (
doi:10.1098/rspa.1973.0040
)) approach, which is generalized to the dynamic case. We obtain the exact, closed-form solution for the band velocity and slip rate. This solution assesses when the slope fails owing to a limiting condition near the propagating tip of the shear band. Our results are applicable to both submarine and subaerial landslides of this type. It appears that neglecting dynamic (inertia) effects can lead to a significant underestimation of the slide size, and that the volumes of catastrophic slides can exceed the volumes of progressive slides by nearly a factor of 2. As examples, we consider the Gaviota and Humboldt slides offshore of California, and discuss landslides in normally consolidated sediments and sensitive clays. In particular, it is conceivable that Humboldt slide is unfinished and may still displace a large volume of sediments, which could generate a considerable tsunami. We show that in the case of submarine slides, the effect of water resistance on the shear band dynamics may frequently be limited during the slope failure stage. For a varying slope angle, we formulate a condition of slide cessation.
The evolution of sensitive periods in a model of incremental development
Authors: Panchanathan Karthik , Frankenhuis Willem E.
Published: January 2016

Sensitive periods, in which experience shapes phenotypic development to a larger extent than other periods, are widespread in nature. Despite a recent focus on neural–physiological explanation, few formal models have examined the evolutionary selection pressures that result in developmental mechanisms that produce sensitive periods. Here, we present such a model. We model development as a specialization process during which individuals incrementally adapt to local environmental conditions, while receiving a constant stream of cost-free, imperfect cues to the environmental state. We compute optimal developmental programmes across a range of ecological conditions and use these programmes to simulate developmental trajectories and obtain distributions of mature phenotypes. We highlight four main results. First, matching the empirical record, sensitive periods often result from experience or from a combination of age and experience, but rarely from age alone. Second, individual differences in sensitive periods emerge as a result of stochasticity in cues: individuals who obtain more consistent cue sets lose their plasticity at faster rates. Third, in some cases, experience shapes phenotypes only at a later life stage (lagged effects). Fourth, individuals might perseverate along developmental trajectories despite accumulating evidence suggesting the alternate trajectory is more likely to match the ecology.
Multiple rod–cone and cone–rod photoreceptor transmutations in snakes: evidence from visual opsin gene expression
Authors: Simões Bruno F. , Sampaio Filipa L. , Loew Ellis R. , Sanders Kate L. , Fisher Robert N. , Hart Nathan S. , Hunt David M. , Partridge Julian C. , Gower David J.
Published: January 2016

In 1934, Gordon Walls forwarded his radical theory of retinal photoreceptor ‘transmutation’. This proposed that rods and cones used for scotopic and photopic vision, respectively, were not fixed but could evolve into each other via a series of morphologically distinguishable intermediates. Walls' prime evidence came from series of diurnal and nocturnal geckos and snakes that appeared to have pure-cone or pure-rod retinas (in forms that Walls believed evolved from ancestors with the reverse complement) or which possessed intermediate photoreceptor cells. Walls was limited in testing his theory because the precise identity of visual pigments present in photoreceptors was then unknown. Subsequent molecular research has hitherto neglected this topic but presents new opportunities. We identify three visual opsin genes,rh1,sws1andlws, in retinal mRNA of an ecologically and taxonomically diverse sample of snakes central to Walls' theory. We conclude that photoreceptors with superficially rod- or cone-like morphology are not limited to containing scotopic or photopic opsins, respectively. Walls' theory is essentially correct, and more research is needed to identify the patterns, processes and functional implications of transmutation. Future research will help to clarify the fundamental properties and physiology of photoreceptors adapted to function in different light levels.
The effect of activation level on muscle function during locomotion: are optimal lengths and velocities always used?
Authors: Holt N. C. , Azizi E.
Published: January 2016

Skeletal muscle exhibits broad functional diversity, despite its inherent length and velocity constraints. The observed variation in morphology and physiology is assumed to have evolved to allow muscle to operate at its optimal length and velocity during locomotion. Here, we used the variation in optimum lengths and velocities that occurs with muscle activation level to experimentally test this assumption. Muscle ergometry and sonomicrometry were used to characterize force–length and power–velocity relationships, andin vivooperating lengths and velocities, at a range of activation levels. Operating lengths and velocities were mapped onto activation level specific force–length and power–velocity relationships to determine whether they tracked changing optima. Operating velocities decreased in line with decreased optimal velocities, suggesting that optimal velocities are always used. However, operating lengths did not change with changing optima. At high activation levels, fibres used an optimal range of lengths. However, at lower activation levels, fibres appeared to operate on the ascending limb of sub-maximally activated force–length relationships. This suggests that optimal lengths are only used when demand is greatest. This study provides the first mapping of operating lengths to activation level-specific optima, and as such, provides insight into our assumptions about the factors that determine muscle performance during locomotion.
Application of a pnCCD for energy-dispersive Laue diffraction with ultra-hard X-rays
Authors: Send Sebastian , Abboud Ali , Wiesner Nadja , Shokr Mohammad , Klaus Manuela , Genzel Christoph , Conka-Nurdan Tuba , Schlosser Dieter , Huth Martin , Hartmann Robert , Strüder Lothar , Pietsch Ullrich
Published: January 2016

In this work the spectroscopic performance of a pnCCD detector in the ultra-hard energy range between 40 and 140 keV is tested by means of an energy-dispersive Laue diffraction experiment on a GaAs crystal. About 100 Bragg peaks were collected in a single-shot exposure of the arbitrarily oriented sample to white synchrotron radiation provided by a wiggler at BESSY II and resolved in a large reciprocal-space volume. The positions and energies of individual Laue spots could be determined with a spatial accuracy of less than one pixel and a relative energy resolution better than 1%. In this way the unit-cell parameters of GaAs were extracted with an accuracy of 0.5%, allowing for a complete indexing of the recorded Laue pattern. Despite the low quantum efficiency of the pnCCD (below 7%), experimental structure factors could be obtained from the three-dimensional data sets, taking into account photoelectric absorption as well as Compton scattering processes inside the detector. The agreement between measured and theoretical kinematical structure factors calculated from the known crystal structure is of the order of 10%. The results of this experiment demonstrate the potential of pnCCD detectors for applications in X-ray structure analysis using the complete energy spectrum of synchrotron radiation.
CHARDI2015: charge distribution analysis of non-molecular structures
Authors: Nespolo Massimo , Guillot Benoît
Published: January 2016

The charge distribution method describes non-molecular crystal structures in a Madelung-type approach in which the formal oxidation number (`charge') of each atom is distributed among its neighbours. The sum of the distributed charges gives back the input charge when a structure is correctly refined and well balanced, so that the method can be used for structure validation and for the analysis of over- and underbonding effects. A new version of the software used to compute the charge distribution is presented, now with a CIF parser and graphical user interface.
Extension of the sasCIF format and its applications for data processing and deposition
Authors: Kachala Michael , Westbrook John , Svergun Dmitri
Published: January 2016

Recent advances in small-angle scattering (SAS) experimental facilities and data analysis methods have prompted a dramatic increase in the number of users and of projects conducted, causing an upsurge in the number of objects studied, experimental data available and structural models generated. To organize the data and models and make them accessible to the community, the Task Forces on SAS and hybrid methods for the International Union of Crystallography and the Worldwide Protein Data Bank envisage developing a federated approach to SAS data and model archiving. Within the framework of this approach, the existing databases may exchange information and provide independent but synchronized entries to users. At present, ways of exchanging information between the various SAS databases are not established, leading to possible duplication and incompatibility of entries, and limiting the opportunities for data-driven research for SAS users. In this work, a solution is developed to resolve these issues and provide a universal exchange format for the community, based on the use of the widely adopted crystallographic information framework (CIF). The previous version of the sasCIF format, implemented as an extension of the core CIF dictionary, has been available since 2000 to facilitate SAS data exchange between laboratories. The sasCIF format has now been extended to describe comprehensively the necessary experimental information, results and models, including relevant metadata for SAS data analysis and for deposition into a database. Processing tools for these files (sasCIFtools) have been developed, and these are available both as standalone open-source programs and integrated into the SAS Biological Data Bank, allowing the export and import of data entries as sasCIF files. Software modules to save the relevant information directly from beamline data-processing pipelines in sasCIF format are also developed. This update of sasCIF and the relevant tools are an important step in the standardization of the way SAS data are presented and exchanged, to make the results easily accessible to users and to promote further the application of SAS in the structural biology community.
Melanoma therapy: Check the checkpoints
Authors: Furue Masutaka , Kadono Takafumi
Published: January 2016

Recent mutational and translational studies have revealed that the Ras/Raf/mitogen‐activated protein kinase kinase (MEK)/extracellular signal‐regulated kinase (ERK) pathway plays a key role in melanomagenesis. Mutations in NRAS and BRAF are found in the majority of melanomas resulting in the formation of constitutively active NRAS and BRAF molecules, which leads to the proliferation and survival of melanoma cells through the activation of MEK/ERK signals. Inhibitors of BRAF or MEK significantly extend the progression‐free survival and overall survival of melanoma patients compared with conventional chemotherapies. Combining BRAF and MEK inhibitors further enhances the clinical effectiveness. Cytotoxic T‐lymphocyte‐associated antigen 4 (CTLA‐4) is an immune checkpoint molecule that downregulates T‐cell activation by binding to B7 (CD80/CD86) molecules on antigen‐presenting cells. Programmed death receptor ligand 1 on melanoma cells negatively regulates T‐cell function by binding to the programmed death‐1 (PD‐1) receptor on T cells. Antibodies against CTLA‐4 and PD‐1 also enhance the survival of melanoma patients. In this review, we summarize the clinical effectiveness and adverse events of the BRAF inhibitors, MEK inhibitors and anti‐immune checkpoint antibodies in melanoma treatment.
Accounting Information in Financial Contracting: The Incomplete Contract Theory Perspective
Authors: CHRISTENSEN HANS B. , NIKOLAEV VALERI V. , WITTENBERG‐MOERMAN REGINA
Published: January 2016

This paper reviews theoretical and empirical work on financial contracting that is relevant to accounting researchers. Its primary objective is to discuss how the use of accounting information in contracts enhances contracting efficiency and to suggest avenues for future research. We argue that incomplete contract theory broadens our understanding of both the role accounting information plays in contracting and the mechanisms through which efficiency gains are achieved. By discussing its rich theoretical implications, we expect incomplete contract theory to prove useful in motivating future research and in offering directions to advance our knowledge of how accounting information affects contract efficiency.
Gabapentin misuse, abuse and diversion: a systematic review
Authors: Smith Rachel V. , Havens Jennifer R. , Walsh Sharon L.
Published: January 2016

Background and Aims

Since its market release, gabapentin has been presumed to have no abuse potential and subsequently has been prescribed widely off‐label, despite increasing reports of gabapentin misuse. This review estimates and describes the prevalence and effects of, motivations behind and risk factors for gabapentin misuse, abuse and diversion.

Methods

Databases were searched for peer‐reviewed papers demonstrating gabapentin misuse, characterized by taking a larger dosage than prescribed or taking gabapentin without a prescription, and diversion. All types of studies were considered; grey literature was excluded. Thirty‐three papers met inclusion criteria, consisting of 23 case studies and 11 epidemiological reports. Published reports came from the United States, the United Kingdom, Germany, Finland, India, South Africa and France, and two analyzed websites not specific to a particular country.

Results

Prevalence of gabapentin misuse in the general population was reported to be 1%, 40–65% among individuals with prescriptions and between 15 and 22% within populations of people who abuse opioids. An array of subjective experiences reminiscent of opioids, benzodiazepines and psychedelics were reported over a range of doses, including those within clinical recommendations. Gabapentin was misused primarily for recreational purposes, self‐medication or intentional self‐harm and was misused alone or in combination with other substances, especially opioids, benzodiazepines and/or alcohol. Individuals with histories of drug abuse were most often involved in its misuse.

Conclusions

Epidemiological and case report evidence suggests that the anti‐epileptic and analgesic medication gabapentin is being misused internationally, with substance abuse populations at special risk for misuse/abuse.
Inter‐hospital variations in labor induction and outcomes for nullipara: an Australian population‐based linkage study
Authors: Nippita Tanya A. , Trevena Judy A. , Patterson Jillian A. , Ford Jane B. , Morris Jonathan M. , Roberts Christine L.
Published: January 2016

Introduction

This study aimed to describe variation in inter‐hospital induction of labor (IOL) rates, determine whether variation is explained by individual and hospital factors and examine birth outcomes.

Material and methods

Nullipara at term with a singleton cephalic birth were identified using linked hospital discharge and birth data for 66 hospitals in New South Wales, Australia, 2010–2011. Random effects multilevel logistic regression models were fitted for early term, full term, and late term births, adjusting for individual and hospital factors. Hospital intrapartum cesarean rates, and severe maternal and neonatal morbidity outcomes were determined according to hospital IOL rate.

Results

Of 69 549 nullipara, 24 673 (35%) had an IOL. For early term births, adjusted hospital IOL (aIOL) rates varied (3.3–13.9%), with 11 of 66 (17%) hospitals having aIOL rates significantly different from the average aIOL rate. For births at full term, the hospital aIOL rates varied (10.6–32.6%), with 29 hospitals (44%) having aIOL rates significantly different from the average aIOL rate. For late term births, the hospital aIOL rates varied (45.1–67.5%), with 11 hospitals (17%) having aIOL rates significantly different from the overall average aIOL rate for women with late term births. There was generally no relationship between higher or lower hospital IOL rates and intrapartum cesarean section rates, or maternal or neonatal adverse outcomes.

Conclusions

Inter‐hospital IOL rates for nullipara with a singleton cephalic term birth had high unexplained variation, with no clear association with intrapartum cesarean section rates, or maternal or neonatal adverse outcomes.
Episiotomy preferences, indication, and classification – a survey among Nordic doctors
Authors: Fodstad Kathrine , Staff Anne C. , Laine Katariina
Published: January 2016

Introduction

Episiotomy performance impacts perineal health and rates of obstetric anal sphincter injuries (OASIS). Our objective was to assess self‐reported episiotomy practice and opinions on clinical indication for episiotomy among Nordic physicians and to investigate potential misclassification.

Material and methods

A survey was conducted among doctors attending the 2012 Nordic obstetrical and gynecological conference. Participants were asked to draw an episiotomy on a photo of a perineum with a crowning fetal head similarly to their clinical practice if an episiotomy was clinically indicated, and to name the technique drawn. Differences in outcome measures were compared by country of practice and seniority.

Results

The majority of the 297 participants (47%) drew a lateral episiotomy according to our classification by incision point and angle, but as many as 64% of these 138 doctors misclassified this as mediolateral episiotomy. Only 20% drew a mediolateral episiotomy, the great majority classifying it accurately, but 8% misclassified their mediolateral cut as a lateral episiotomy. One‐third of episiotomies were nonclassifiable. In general, doctors in Finland, Sweden, and Norway more often favored lateral episiotomies compared with doctors in Denmark and Iceland. There were significant differences between Finnish and Norwegian vs. Danish and Swedish doctors in perception of clinical indications for episiotomy.

Conclusions

The great variation in self‐reported episiotomy performance between Nordic physicians and large misclassification rates indicate that educational programs are warranted. Use of uniform classification and appropriate techniques may be crucial to investigate the role of episiotomies in preventing OASIS.
Influence of Instruments Used in Root Canal Preparation on Amount of Apically Extruded Debris
Authors: Karataş Ertuğrul , Ersoy İbrahim , Gündüz Hicran Ateş , Uygun Ahmet Demirhan , Kol Elif , Çakıcı Fatih
Published: January 2016

The aim of the present study was to compare the effects of ProTaper Gold, WaveOne Gold, ProTaper Universal, and WaveOne instruments on the amount of apically extruded debris. Eighty mandibular premolar teeth with straight root canals were selected and assigned to four groups (n = 20). The root canals were instrumented using ProTaper Gold, WaveOne Gold, ProTaper Universal, and WaveOne systems. Eppendorf tubes containing apically extruded debris were weighed three times, and mean values were calculated. The net mass of the extruded debris was calculated by subtracting the initial mass from the final mass. The groups were compared using one‐way analysis of variance and Tukey's post hoc tests at a significance level of P < 0.05. The PTG group extruded less debris than the PTU group, and the WOG group extruded less debris than the WO group (P < 0.05). All the instrumentation systems tested in the present study were associated with apical extrusion of debris.
Does Implant Selection Impact Postoperative Complications Following Hip Arthroplasty for Failed Intertrochanteric Fractures? A Retrospective Comparative Study
Authors: Tsai Shang‐Wen , Chen Cheng‐Fong , Wu Po‐Kuei , Huang Ching‐Kuei , Chen Wei‐Ming , Chang Ming‐Chau
Published: January 2016

The purpose of this study is to compare postoperative complications among different acetabular and femoral components of hip arthroplasty for failed intertrochanteric fractures. A total of 79 patients were included and followed‐up for an average of 75.6 months (range, 24–244). Fifty‐five patients underwent total hip arthroplasty, and 24 had bipolar hemiarthroplasty. Cementless metaphyseal locking, cementless diaphyseal locking, and cemented standard stems were used in 41, 29, and 9 patients, respectively. Dislocation and wear rate were not different between the total hip arthroplasty and bipolar hemiarthroplasty groups. Stem subsidence or loosening was more frequently found in the cementless, metaphyseal locking stem groups. In conclusion, cemented standard stem and cementless diaphyseal locking stem might be better implant choices. With regard to dislocation rate, our results were insufficient to conclude a better implant choice of total hip arthroplasty or bipolar hemiarthroplasty than the other.
Inhibition of CaMKII Attenuates Progressing Disruption of Ca2+ Homeostasis Upon Left Ventricular Assist Device Implantation in Human Heart Failure
Authors: Fischer Thomas H. , Kleinwächter Astrid , Herting Jonas , Eiringhaus Jörg , Hartmann Nico , Renner André , Gummert Jan , Haverich Axel , Schmitto Jan D. , Sossalla Samuel
Published: January 2016

In heart failure, left ventricular assist device (LVAD) implantation is performed to ensure sufficient cardiac output. Whereas some patients are subsequently weaned from LVAD support, other patients still need heart transplantation. To elucidate underlying mechanisms, we assessed the arrhythmogenic SR‐Ca2+ leak at the time of LVAD implantation (HF‐Im) and heart transplantation (HF‐Tx) and evaluated the effects of CaMKII‐inhibition. Human left‐ventricular cardiomyocytes were isolated, paced at 1 Hz for 10 beats to ensure SR‐Ca2+ loading and scanned for diastolic Ca2+ sparks (confocal microscopy). In HF‐Im, the high diastolic spark frequency (CaSpF) of 0.76 ± 0.12 × 100 μm−1 × s−1 could be reduced to 0.48 ± 0.10 × 100 μm−1 × s−1 by CaMKII inhibition (AIP, 1 μM). The amplitude of Ca2+ sparks, width, and length was not significantly altered. In sum, CaMKII inhibition yielded a clear tendency toward a reduction of the SR‐Ca2+ leak (n cells/patients = 76/6 vs. 108/6, P = 0.08). In HF‐Tx, we detected an even higher CaSpF of 1.00 ± 0.10 100 μm−1 × s−1 and a higher SR‐Ca2+ leak compared with HF‐Im (increase by 81 ± 33%, n cells/patients = 156/7 vs. 130/7, P < 0.05), which fits to the further decreased LV function. Here, CaMKII inhibition likewise reduced CaSpF (0.35 ± 0.09 100 μm−1 × s−1, P = 0.06) and significantly reduced spark duration (n sparks/patients = 58/3 vs. 159/3, P < 0.05). Conclusively, the SR‐Ca2+ leak was reduced by 69 ± 12% in HF‐Tx upon CaMKII inhibition (n cells/patients = 53/3 vs. 91/3, P < 0.05). These data show that the SR‐Ca2+ leak correlates with the development of LV function after LVAD implantation and may represent an important pathomechanism. The fact that CaMKII inhibition reduces the SR‐Ca2+ leak in HF‐Tx suggests that CaMKII inhibition may be a promising option to beneficially influence clinical course after LVAD implantation.
Swedish children with hereditary angioedema report good overall health and quality of life despite symptoms
Authors: Nygren Anders , Nordenfelt Patrik , Lindfors Anders , Mallbris Lotus , Björkander Janne , Wahlgren Carl‐Fredrik
Published: January 2016

Aim

Few studies have been published on children with hereditary angioedema (HAE), an autosomal dominant disease caused by mutations on chromosome 11. This study explored various aspects of the disease in the Swedish paediatric population.

Methods

A retrospective questionnaire was sent to all 36 Swedish children known to have HAE, and a physician carried out follow‐up telephone interviews.

Results

Most of the questionnaires were completed by the parents of 31 (86%) children with HAE, with or without their input, at a median age of nine years (range 1–17), and the physician also interviewed 29. HAE symptoms were experienced by 23 children, including abdominal attacks (96%), skin swelling (78%) and swelling in the mouth and/or upper airways (52%). Psychological stress was the most common trigger for abdominal attacks and trauma and sports triggered skin swelling. The majority (n = 19) had access to complement‐1 esterase inhibitor concentrate at home. Current health and quality of life were generally rated as good, independent of whether the child had experienced HAE symptoms or not.

Conclusion

Most children with HAE had experienced abdominal attacks and skin swelling, but their overall health and quality of life were generally perceived to be good.
Dynamic and selective HERV RNA expression in neuroblastoma cells subjected to variation in oxygen tension and demethylation
Authors: Hu Lijuan , Uzhameckis Dmitrijs , Hedborg Fredrik , Blomberg Jonas
Published: January 2016

We studied HERV expression in cell lines after hypoxia, mitogenic stimulation, and demethylation, to better understand if hypoxia may play a role in ERV activation also within the nervous system, as represented by neuroblastoma cell lines. The level of RNA of four human ERV groups (HERVs) (HERVE, I/T, H, and W), and three housekeeping genes, of different cell lines including A549, COS‐1, Namalwa, RD‐L and Vero‐E6, as well as human neuroblastoma cell lines SH‐SY5Y, SK‐N‐DZ, and SK‐N‐AS were studied using reverse transcription and real‐time quantitative PCR (QPCR). During the course of recovery from hypoxia a pronounced and selective activation of RNA expression of HERVW‐like sequences, but not of HERVE, I/T, H, and three housekeeping genes, was found in the neuroblastoma cell lines, most pronounced in SK‐N‐DZ. In the SK‐N‐DZ cell line, we also tested the expression of HERVs after chemical treatments. HERVW‐like sequences were selectively upregulated by 5‐azacytidine, a demethylating agent. Some HERVW loci seem especially responsive to hypoxia and demethylation. HERV expression in neuroblastoma cells is selectively and profoundly influenced by some physiological and chemical stimuli.
Raw beef bones as chewing items to reduce dental calculus in Beagle dogs
Authors: Marx FR , Machado GS , Pezzali JG , Marcolla CS , Kessler AM , Ahlstrøm Ø , Trevizan L
Published: January 2016

Objective

Evaluate the effect of raw bovine cortical bone (CB) (medullary bone cross‐sectioned) and marrow or epiphyseal ‘spongy’ bone (SB) as chew items to reduce dental calculus in adult dogs.

Methods

Eight 3‐year‐old Beagle dogs were observed in two study periods. In the first study, the dogs each received a piece of bovine femur CB (122 ± 17 g) daily and in the second study, a piece of bovine femur SB (235 ± 27 g). The first study lasted 12 days and the second 20 days. Dental calculus was evaluated using image integration software.

Results

At the start of the studies, dental calculus covered 42.0% and 38.6% of the dental arcade areas, respectively. In study one, the chewing reduced the established dental calculus area to 27.1% (35.5% reduction) after 3 days and after 12 days the dental calculus covering was reduced to 12.3% (70.6% reduction). In study two, the dental calculus covered 16.8% (56.5% reduction) after 3 days, 7.1% (81.6% reduction) after 12 days and 4.7% (87.8% reduction) after 20 days. The CB remained largely intact after 24 h, but SB was reduced to smaller pieces and in some cases totally consumed after 24 h. No complications such as tooth fractures, pieces of bone stuck between teeth or intestinal obstructions were observed during the studies.

Conclusions

Chewing raw bovine bones was an effective method of removing dental calculus in dogs. The SB bones removed dental calculus more efficiently in the short term.
Anthelmintic resistance in gastrointestinal nematodes of dairy cattle in the Macalister Irrigation District of Victoria
Authors: Bullen SL , Beggs DS , Mansell PD , Runciman DJ , Malmo J , Playford MC , Pyman MF
Published: January 2016

Objective

To report anthelmintic resistance in gastrointestinal nematode parasites of cattle on commercial dairy farms in the Macalister Irrigation District of Gippsland, Victoria.

Methods

Faecal egg count reduction tests (FECRTs) were used to assess anthelmintic resistance on 20 Macalister Irrigation District dairy farms between May 2013 and June 2014. All three currently available anthelmintic classes for cattle nematodes in Australia were tested. Faecal samples were collected 10–14 days post‐treatment for individual faecal egg counts (FEC) and larval differentiation. The arithmetic mean FEC for each treatment group was compared with an untreated control post‐treatment. Resistance was defined as <95% reduction in FEC, with a lower 95% confidence interval <90% when the mean FEC of the control group, differentiated by genus, was greater than 25 eggs/g.

Results

Anthelmintic resistance was present on all 20 dairy farms involved in this study. Resistance to doramectin in at least one species was detected on 15/20 (70%) farms, fenbendazole on 16/20 (80%) farms and levamisole on 5/20 (25%) farms. On three farms, resistance by Ostertagia ostertagi to all three anthelmintic classes was detected.

Conclusion

This is the first report of anthelmintic‐resistant O. ostertagi on Australian dairy farms. Resistance to all three available anthelmintic classes is of concern, given the high pathogenicity of this species. The study highlights the need for veterinarians and dairy farmers to be aware of the risks posed by anthelmintic resistance.
CD45RA, a specific marker for leukaemia stem cell sub‐populations in acute myeloid leukaemia
Authors: Kersten Bas , Valkering Matthijs , Wouters Rolf , van Amerongen Rosa , Hanekamp Diana , Kwidama Zinia , Valk Peter , Ossenkoppele Gert , Zeijlemaker Wendelien , Kaspers Gertjan , Cloos Jacqueline , Schuurhuis Gerrit J.
Published: January 2016

Chemotherapy resistant leukaemic stem cells (LSC) are thought to be responsible for relapses after therapy in acute myeloid leukaemia (AML). Flow cytometry can discriminate CD34+CD38− LSC and normal haematopoietic stem cells (HSC) by using aberrant expression of markers and scatter properties. However, not all LSC can be identified using currently available markers, so new markers are needed. CD45RA is expressed on leukaemic cells in the majority of AML patients. We investigated the potency of CD45RA to specifically identify LSC and HSC and improve LSC quantification. Compared to our best other markers (CLL‐1, also termed CLEC12A, CD33 and CD123), CD45RA was the most reliable marker. Patients with high percentages (>90%) of CD45RA on CD34+CD38− LSC have 1·69‐fold higher scatter values compared to HSC (P < 0·001), indicating a more mature CD34+CD38− phenotype. Patients with low (<10%) or intermediate (10–90%) CD45RA expression on LSC showed no significant differences to HSC (1·12‐ and 1·15‐fold higher, P = 0·31 and P = 0·44, respectively). CD45RA‐positive LSC tended to represent more favourable cytogenetic/molecular markers. In conclusion, CD45RA contributes to more accurate LSC detection and is recommended for inclusion in stem cell tracking panels. CD45RA may contribute to define new LSC‐specific therapies and to monitor effects of anti‐LSC treatment.
Organic Matter Dynamics in a Tropical Gallery Forest in a Grassland Landscape
Authors: de Souza Rezende Renan , S. Graça Manuel A. , dos Santos Anderson M. , Medeiros Adriana O. , Santos Paola F. , Nunes Yule R. , Gonçalves Júnior José F.
Published: January 2016

The high biodiversity of tropical forest streams depends on the strong input of organic matter, yet the leaf litter decomposition dynamics in these streams are not well understood. We assessed how seasonal litterfall affects leaf litter breakdown, density and biomass of aquatic invertebrates, and the microbial biomass and sporulation of aquatic hyphomycetes in a South American grassland ‘vereda’ landscape. Although litter production in the riparian area was low, leaf litter breakdown was high compared with other South American systems, with maximum values coinciding with the rainy season. Fungal biomass in decomposing leaves was high, but spore densities in water and sporulation rates were very low. Invertebrates were not abundant in litter bags, suggesting they play a minor role in leaf litter decomposition. Chironomids accounted for ~70 percent of all invertebrates; only 10 percent of non‐Chironomidae invertebrates were shredders. Therefore, fungi appear to be the drivers of leaf litter decomposition. Our results show that despite low productivity and relatively fast litter decomposition, organic matter accumulated in the stream and riparian area. This pattern was attributed to the wet/dry cycles in which leaves falling in the flat riparian zone remain undecomposed (during the dry period) and are massively transported to the riverbed (rainy season).
Disablement as inveterate condition: Living with habitual ableism in Prince George, British Columbia
Authors: Blewett Jessica , Hanlon Neil
Published: January 2016

Key Messages

Disablement is an inveterate condition of Prince George that has played a large role in the creation of a disabling environment.

The most important factor in the construction of a disabling environment is ableism, as expressed through social attitudes, practices, and interactions.

The lived experience of (dis)Ability in Prince George is reinforced by the ways in which local decision‐makers respond to conditions of resource‐dependence and seasonality.
Serum NT‐proCNP levels increased after initiation of GH treatment in patients with achondroplasia/hypochondroplasia
Authors: Kubota Takuo , Wang Wei , Miura Kohji , Nakayama Hirofumi , Yamamoto Keiko , Fujiwara Makoto , Ohata Yasuhisa , Tachibana Makiko , Kitaoka Taichi , Takakuwa Satoshi , Miyoshi Yoko , Namba Noriyuki , Ozono Keiichi
Published: January 2016

Objective

Serum amino‐terminal propeptide of C‐type natriuretic peptide (NT‐proCNP) levels have been proposed as a biomarker of linear growth in healthy children. The usefulness of NT‐proCNP in patients with achondroplasia (ACH)/hypochondroplasia (HCH) remains to be elucidated. The objective was to study whether serum NT‐proCNP level is a good biomarker for growth in ACH/HCH and other patients of short stature.

Design

This was a longitudinal cohort study.

Patients

Sixteen children with ACH (aged 0·4–4·3 years), six children with HCH (2·7–6·3 years), 23 children with idiopathic short stature (ISS) (2·2–9·0 years), eight short children with GH deficiency (GHD) (2·9–6·8 years) and five short children born small for gestational age (SGA) (2·0–6·6 years). Patients with ACH/HCH received GH treatment for 1 year.

Measurements

Serum NT‐proCNP levels and height were measured.

Results

NT‐proCNP levels positively correlated with height velocity in these short children (P < 0·05, r = 0·27). NT‐proCNP levels inversely correlated with age in children with ISS alone (P < 0·01, r = −0·55). Serum NT‐proCNP levels in patients with ACH/HCH were increased 3 months following the initiation of GH treatment (P < 0·05). Height SDS gain during GH treatment for 1 year was positively correlated with the changes in NT‐proCNP levels after the initiation of GH (P < 0·01, r = 0·72).

Conclusion

Serum NT‐proCNP levels may be a good biomarker to indicate the effect of GH treatment on growth in patients with ACH/HCH at least in the first year and height velocity in short stature patients.
ST09, a Novel Thioester Derivative of Tacrine, Alleviates Cognitive Deficits and Enhances Glucose Metabolism in Vascular Dementia Rats
Authors: Liu Jian‐Min , Wu Peng‐Fei , Rao Jing , Zhou Jun , Shen Zu‐Cheng , Luo Han , Huang Jian‐Geng , Liang Xiao , Long Li‐Hong , Xie Qing‐Guo , Jiang Feng‐Chao , Wang Fang , Chen Jian‐Guo
Published: January 2016

Aims

Chemical entities containing mercapto group have been increasingly attractive in the therapy of central nerve system (CNS) diseases. In the recent study, we screened a series of mercapto‐tacrine derivatives with synergistic neuropharmacological profiles in vitro.

Methods

We investigated the effect and mechanism of ST09, a thioester derivative of tacrine containing a potential mercapto group, on the vascular dementia (VaD) model of rat induced by bilateral common carotid arteries occlusion (2‐VO).

Results

ST09 and its active metabolite ST10 retained excellent inhibition on acetylcholinesterase (AChE) activity. ST09 significantly attenuated the 2‐VO‐induced impairment in spatial acquisition performance and inhibited the 2‐VO‐induced rise of AChE activity. In the VaD model, ST09 attenuated the oxidative stress and decreased the apoptosis in the cortex and hippocampus. Compared with donepezil, ST09 exhibited a better effect on the regeneration of free thiols in 2‐VO rats. Interestingly, ST09, not donepezil, greatly improved glucose metabolism in various brain regions of 2‐VO rats using functional imaging of 18F‐labeled fluoro‐deoxyglucose (FDG) positron emission tomography (PET).

Conclusions

ST09 may serve as a more promising agent for the therapy of VaD than tacrine owing to the introduction of a potential mercapto group into the parent skeleton.
Satisfaction and attrition in paediatric weight management
Authors: Skelton J. A. , Martin S. , Irby M. B.
Published: January 2016

Paediatric obesity treatment experiences unacceptably high rates of attrition. Few studies have explored parent and child perspectives on dropout. This study sought to capture child and parent experience in treatment and expressed contributors to attrition. Children and parents enrolled in a single family‐based weight management programme participated in semi‐structured interviews, conducted either upon completion of the first intensive phase of treatment or program dropout. Interviews were recorded, transcribed and coded using a multistage inductive approach. Interviews were obtained from 57 parents and 30 children, nearly equal between ‘completers’ or ‘dropouts’. Five themes emerged: overall positive experience with programme; logistical challenges of participation; improved health; discrepancies between child and parent experience and perception, and importance of structure and expectations of weight loss. Primary reasons given for dropout were time commitment; distance from clinic; missed school and work; lack of dedicated adolescent programme; clinic hours; and stress. Few parents or children expressed dissatisfaction. Children reportedly enjoyed ‘having someone to talk to’ about weight, and spending increased time with family. Children and parents overall reported positive experiences in this weight management programme. Attrition appears more related to logistical issues than low satisfaction. Innovative approaches to help overcome logistical challenges and preserve positive aspects may help in decreasing programme attrition.
Non‐ECG‐gated CT pulmonary angiography and the prediction of right ventricular dysfunction in patients suspected of pulmonary embolism
Authors: Gutte Henrik , Mortensen Jann , Mørk Mette Louise , Kristoffersen Ulrik Sloth , Jensen Claus Verner , Petersen Claus Leth , von der Recke Peter , Kjær Andreas
Published: January 2016

Purpose

Right ventricular dysfunction (RVD) is an important prognostic factor of 30‐day mortality in patients with acute pulmonary embolism (PE). The aim of our study was to evaluate whether non‐electrocardiogram (ECG)‐gated cardiovascular parameters attained during computed tomography pulmonary angiography (CTPA) could predict RVD in patients suspected of PE using ECG‐gated cardiac CT angiography as reference.

Methods

Consecutive patients suspected of PE were referred to a ventilation/perfusion single‐photon emission tomography (V/Q‐SPECT) as first‐line imaging procedure. Patients had a V/Q‐SPECT/CT, a CTPA and an ECG‐gated cardiac CT angiography performed the same day.

Results

A total of 71 patients were available for analysis. Seventeen patients (24%) had RVD. The non‐ECG‐gated dimensions of left and right ventricle and the major vessels were correlated with ECG‐gated cardiac dimensions. The size of the pulmonary trunk could identify patients with RVD: AUC (0·67, 95% confidence intervals (CIs) 0·52–0·82) as seen in the ROC curve (P<0·05). With a cut‐off value of the pulmonary trunk of 29 mm, the sensitivity and specificity were 70·6% and 55·5%, respectively. The positive predictive and negative predictive values for detection of RVD were 59·1% and 85·7%, respectively.

Conclusion

In the present study, we demonstrated correlation between ECG‐gated cardiac dimensions and non‐ECG‐gated cardiovascular parameters, however with only moderate diagnostic accuracies. We demonstrated that the dimension of the pulmonary trunk might be of value in detection of patients with RVD. We suggest further studies on the potential value of non‐ECG‐gated cardiac dimensions in patients suspected of PE.
Effect of antibiotics on gut microbiota, glucose metabolism and body weight regulation: a review of the literature
Authors: Mikkelsen K. H. , Allin K. H. , Knop F. K.
Published: January 2016

Gut bacteria are involved in a number of host metabolic processes and have been implicated in the development of obesity and type 2 diabetes in humans. The use of antibiotics changes the composition of the gut microbiota and there is accumulating evidence from observational studies for an association between exposure to antibiotics and development of obesity and type 2 diabetes. In the present paper, we review human studies examining the effects of antibiotics on body weight regulation and glucose metabolism and discuss whether the observed findings may relate to alterations in the composition and function of the gut microbiota.
Seizures as presenting and prominent symptom in chorea‐acanthocytosis with c.2343del VPS13A gene mutation
Authors: Benninger Felix , Afawi Zaid , Korczyn Amos D. , Oliver Karen L. , Pendziwiat Manuela , Nakamura Masayuki , Sano Akira , Helbig Ingo , Berkovic Samuel F. , Blatt Ilan
Published: January 2016

Objective

The aim of the study was to characterize the clinical features of nine patients in three families with chorea‐acanthocytosis (ChAc) sharing the same rare c.2343del mutation in the VPS13A gene.

Methods

Genetic test results, clinical description, magnetic resonance imaging (MRI), and electroencephalography (EEG), as well as laboratory results are summarized.

Results

ChAc is a rare genetic disorder characterized by hyperkinetic movements, seizures, cognitive decline, neuropsychiatric symptoms, and acanthocytes on peripheral blood smear. This unique cohort of nine patients is characterized by seizures as a first and prominent symptom. In our patients, other features of ChAc appeared later, including tics, other movement disorders, dysarthria, and mild to moderate cognitive decline.

Significance

Patients with chorea‐acanthocytosis carrying the described rare mutation can present with focal, treatment‐resistant seizures.
Caveolin‐1‐dependent activation of the metalloprotease TACE/ADAM17 by TGF‐β in hepatocytes requires activation of Src and the NADPH oxidase NOX1
Authors: Moreno‐Càceres Joaquim , Mainez Jèssica , Mayoral Rafael , Martín‐Sanz Paloma , Egea Gustavo , Fabregat Isabel
Published: January 2016

Transforming growth factor‐β (TGF‐β) plays a dual role in hepatocytes, inducing both pro‐ and anti‐apoptotic responses, the balance between which decides cell fate. Survival signals are mediated by the epidermal growth factor receptor (EGFR) pathway, which is activated by TGF‐β. We have previously shown that caveolin‐1 (CAV1) is required for activation of the metalloprotease tumour necrosis factor (TNF)‐α‐converting enzyme/a disintegrin and metalloproteinase 17 (TACE/ADAM17), and hence transactivation of the EGFR pathway. The specific mechanism by which TACE/ADAM17 is activated has not yet been determined. Here we show that TGF‐β induces phosphorylation of sarcoma kinase (Src) in hepatocytes, a process that is impaired in Cav1−/− hepatocytes, coincident with a decrease in phosphorylated Src in detergent‐resistant membrane fractions. TGF‐β‐induced activation of TACE/ADAM17 and EGFR phosphorylation were blocked using the Src inhibitor PP2. Cav1+/+ hepatocytes showed early production of reactive oxygen species (ROS) induced by TGF‐β, which was not seen in Cav1−/− cells. Production of ROS was inhibited by both the NADPH oxidase 1 (NOX1) inhibitor STK301831 and NOX1 knock‐down, which also impaired TACE/ADAM17 activation and thus EGFR phosphorylation. Finally, neither STK301831 nor NOX1 silencing impaired Src phosphorylation, but PP2 blocked early ROS production, showing that Src is involved in NOX1 activation. As expected, inhibition of Src or NOX1 increased TGF‐β‐induced cell death in Cav1+/+ cells. In conclusion, CAV1 is required for TGF‐β‐mediated activation of TACE/ADAM17 through a mechanism that involves phosphorylation of Src and NOX1‐mediated ROS production.