bluuebunny/crossref_metadata_2025 huggingface dataset:
Kinship, inbreeding and fine‐scale spatial structure influence gut microbiota in a hindgut‐fermenting tortoise
Authors: Yuan Michael L. , Dean Samantha H. , Longo Ana V. , Rothermel Betsie B. , Tuberville Tracey D. , Zamudio Kelly R.
Published: March 2015

Herbivorous vertebrates rely on complex communities of mutualistic gut bacteria to facilitate the digestion of celluloses and hemicelluloses. Gut microbes are often convergent based on diet and gut morphology across a phylogenetically diverse group of mammals. However, little is known about microbial communities of herbivorous hindgut‐fermenting reptiles. Here, we investigate how factors at the individual level might constrain the composition of gut microbes in an obligate herbivorous reptile. Using multiplexed 16S rRNA gene sequencing, we characterized the faecal microbial community of a population of gopher tortoises (Gopherus polyphemus) and examined how age, genetic diversity, spatial structure and kinship influence differences among individuals. We recovered phylotypes associated with known cellulolytic function, including candidate phylum Termite Group 3, suggesting their importance for gopher tortoise digestion. Although host genetic structure did not explain variation in microbial composition and community structure, we found that fine‐scale spatial structure, inbreeding, degree of relatedness and possibly ontogeny shaped patterns of diversity in faecal microbiomes of gopher tortoises. Our findings corroborate widespread convergence of faecal‐associated microbes based on gut morphology and diet and demonstrate the role of spatial and demographic structure in driving differentiation of gut microbiota in natural populations.
Genetic divergence between the sympatric queen morphs of the antMyrmica rubra
Authors: Leppänen Jenni , Seppä Perttu , Vepsäläinen Kari , Savolainen Riitta
Published: March 2015

Pairs of obligate social parasites and their hosts, where some of the parasites have recently diverged from their host through intraspecific social parasitism, provide intriguing systems for studying the modes and processes of speciation. Such speciation, probably in sympatry, has also been propounded in the antMyrmica rubraand its intraspecific social parasite. In this species, parasitism is associated with queen size dimorphism, and the small microgyne has become a social parasite of the large macrogyne. Here, we investigated the genetic divergence of the host and the parasite queen morphs in 11 localities in southern Finland, using nuclear and mitochondrial markers of queens and workers. We formulated and tested four speciation‐related hypotheses that differed in the degree of genetic divergence between the morphs. The queen morphs were genetically distinct from each other with little hybridization. In the nuclear data, when localities were nested within queen morphs in the hierarchicalamova, 39% of the genetic variation was explained by the queen morph (standardizedF'CT = 0.63, uncorrectedFCT = 0.39), whereas 18% was explained by the locality (F'SC = 0.39,FSC = 0.29). This result corroborated thehypothesis of advanced sympatric speciation. In contrast, the mitochondrialDNAcould not settle between the hierarchical levels of locality and queen morph, thus substantiating equally thehypotheses of incipientandadvanced sympatric speciation. Together, our results support the view that the microgynous parasite has genetically diverged from its macrogynous host to the level of a nascent species.
PfSR1 controls alternative splicing and steady‐state RNA levels in Plasmodium falciparum through preferential recognition of specific RNA motifs
Authors: Eshar Shiri , Altenhofen Lindsey , Rabner Alona , Ross Phil , Fastman Yair , Mandel‐Gutfreund Yael , Karni Rotem , Llinás Manuel , Dzikowski Ron
Published: March 2015

Plasmodium species have evolved complex biology to adapt to different hosts and changing environments throughout their life cycle. Remarkably, these adaptations are achieved by a relatively small genome. One way by which the parasite expands its proteome is through alternative splicing (AS). We recently identified PfSR1 as a bona fide Ser/Arg‐rich (SR) protein that shuttles between the nucleus and cytoplasm and regulates AS in Plasmodium falciparum. Here we show that PfSR1 is localized adjacent to the Nuclear Pore Complex (NPC) clusters in the nucleus of early stage parasites. To identify the endogenous RNA targets of PfSR1, we adapted an inducible overexpression system for tagged PfSR1 and performed RNA immunoprecipitation followed by microarray analysis (RIP‐chip) to recover and identify the endogenous RNA targets that bind PfSR1. Bioinformatic analysis of these RNAs revealed common sequence motifs potentially recognized by PfSR1. RNA‐EMSAs show that PfSR1 preferentially binds RNA molecules containing these motifs. Interestingly, we find that PfSR1 not only regulates AS but also the steady‐state levels of mRNAs containing these motifs in vivo.
Basal glucosuria is ubiquitous in critically ill patients
Authors: Brunner Richard , Kurz Annabella , Adelsmayr Gabriel , Holzinger Ulrike
Published: March 2015

The ‘renal threshold for glucose’ has never been evaluated in critically ill patients. Therefore, we aimed to investigate the renal glucose threshold in this patient group using high‐sensitivity urine glucose assays. In this retrospective analysis of prospectively collected data, we analysed 100 consecutive critically ill patients from a medical intensive care unit (ICU). Arterial blood glucose and spot urine glucose were simultaneously quantified daily during the first week after ICU admission. Three hundred seventy‐three pairs of blood/urine glucose were plotted in five pre‐defined categories of blood glucose (<80, 80–109, 110–139, 140–179 and ≥180 mg/dL). Urine glucose values of the five categories were compared using the Kruskal–Wallis test to assess the relation with blood glucose. Urine glucose was detected in virtually all of the urine samples. Urine glucose showed a positive nonlinear correlation with blood glucose and was significantly elevated at blood glucose levels of 140–179 and ≥180 mg/dL compared with lower blood glucose ranges. Basal glucosuria is ubiquitous in critically ill patients. A ‘soft’ renal threshold for glucose is present at blood glucose levels in the range of 140–179 mg/dL.
Results after sacral nerve stimulation for chronic constipation
Authors: Graf W. , Sonesson A.‐C. , Lindberg B. , Åkerud P. , Karlbom U.
Published: March 2015

Background

Sacral nerve stimulation is an established treatment for fecal incontinence and initial reports describe successful results also in subjects with chronic constipation.

Methods

Consecutive patients with slow transit or outlet obstruction type constipation were offered external stimulation through a test electrode inserted in a sacral foramen during a 3‐week period. The symptomatic evaluation was based on the number of bowel movements and a validated obstructed defecation score (ODS). A permanent implant was performed provided an overall 50% decrease in symptoms was observed.

Key Results

In total, 44 patients with chronic constipation were treated with a 3‐week test stimulation. Fifteen experienced a 50% reduction of symptoms and received a permanent implant. Four of the 15 with permanent implants were explanted during the course of the study. Five subjects (11% of original group) reported sustained symptom relief at final follow‐up after a mean of 24 months (range 4–81). Mean ODS score did not change during the treatment. Patients with predominantly slow transit constipation or outlet obstruction did not differ concerning success rate.

Conclusions & Inferences

Sacral nerve stimulation has limited efficacy in unselected patients with chronic constipation and cannot be recommended for treatment on routine basis.
Acute sacral nerve stimulation reduces visceral mechanosensitivity in Rat through spinal opioid pathway
Authors: Langlois L. , Meleine M. , Ouelaa W. , Caremel R. , Bridoux V. , Benard M. , Dechelotte P. , Ducrotte P. , Grise P. , Leroi A. M. , Gourcerol G.
Published: March 2015

Background

Sacral nerve stimulation (SNS) is an alternative surgical treatment of refractory urge incontinence and/or fecal incontinence. Despite its clinical efficacy, the mechanisms of action of SNS remain poorly understood. The aim of this experimental study was to evaluate the effect of SNS on visceral mechanosensitivity in rats.

Methods

Anesthetized Sprague–Dawley rats were treated with SNS or sham stimulation. SNS was performed by implanting an electrode close to the sacral nerve root S1. Rats were administered either a non‐selective opioid receptor antagonist (naloxone) or a nitric oxide synthase inhibitor (L‐NAME). Colonic mechanosensitivity was evaluated using the variation of arterial blood pressure as a spino‐bulbar reflex in response to graded isobaric colorectal distension (CRD). C‐fos immunoreactive neurons were quantified in spinal and supraspinal sites. μ‐opioid receptor (MOR) internalization was counted in the sacral spinal cord with sham or effective SNS in response to CRD.

Key Results

SNS reduced visceral mechanosensitivity in response to CRD. This effect was reversed by intrathecal and intraveinous naloxone administration. In both models, CRD induced increased c‐fos immunoreactivity in the dorsal horn neurons of the sacral spinal cord and supraspinal areas. This increase was prevented by SNS. MOR internalization was significantly higher in stimulated group.

Conclusions & Inferences

SNS impacts on visceral mechanosensitivity by decreasing the spino‐bulbar reflex in response to CRD. Spinal opioid receptors are likely involved in this effect.
Defensive secretions of larvae of a carabid beetle
Authors: Holliday Alison E. , Mattingly Travis M. , Holliday Neil J.
Published: March 2015

Secretions of an eversible gland on the metathorax of larvae of Chlaenius cordicollis Kirby (Coleoptera: Carabidae) are investigated by headspace analysis using solid phase microextraction followed by gas chromatography‐mass spectrometry (GC‐MS). Larvae from Manitoba, Canada and Pennsylvania, U.S.A., are sampled. Nine presumed defensive compounds are detected when the gland is everted, and this represents the first characterization of defensive secretions of larvae of a carabid beetle. With the exception of a single component (2‐methoxy‐4‐methylphenol), these compounds are distinct from those found in the defensive secretion of adult C. cordicollis. However, seven are more oxidized versions of the alkylphenolic compounds secreted by adult beetles: three hydroquinones (hydroquinone, methylhydroquinone and 2,3‐dimethylhydroquinone) and four quinones (p‐benzoquinone, toluquinone, 2,3‐dimethylquinone and ethyl‐p‐benzoquinone). An additional alkoxyphenol (2‐methoxy‐4‐ethylphenol) is also detected. Two patterns of composition are observed: in one, p‐benzoquinone and hydroquinone are undetectable and the ratio of toluquinone : 2,3‐dimethylquinone is 1 : 4.6 ± 0.6 (mean ± SE); in the other, all nine compounds are detectable and the ratio of toluquinone : 2,3‐dimethylquinone is 1 : 1.0 ± 0.2. These differences in pattern do not appear to be related to geographical source, sex or age of the larvae.
Involvement of endothelins in deoxycorticosterone acetate–salt hypertension through the modulation of noradrenergic transmission in the rat posterior hypothalamus
Authors: Abramoff Tamara , Guil María J. , Morales Vanina P. , Hope Sandra I. , Höcht Christian , Bianciotti Liliana G. , Vatta Marcelo S.
Published: March 2015

New Findings

What is the central question of this study?

Does ex vivo administration of endothelin‐1 and endothelin‐3 regulate noradrenergic transmission in the posterior hypothalamus of deoxycorticosterone acetate–salt hypertensive rats compared with normotensive rats?

What is the main finding and its importance?

Endothelin‐1 and endothelin‐3 enhanced diverse mechanisms leading to increased noradrenergic transmission in the posterior hypothalamus of deoxycorticosterone acetate–salt hypertensive rats. Unveiling the role of brain endothelins in hypertension would probably favour the development of new therapeutic targets for the treatment of essential hypertension, which still represents a challenging disease with high mortality.

Brain catecholamines participate in diverse biological functions regulated by the hypothalamus. We have previously reported that endothelin‐1 and endothelin‐3 (ET‐1 and ET‐3) modulate catecholaminergic activity in the anterior and posterior hypothalamus of normotensive rats. The aim of the present study was to evaluate the interaction between endothelins and noradrenergic transmission in the posterior hypothalamus of deoxycorticosterone acetate (DOCA)–salt hypertensive rats. We assessed the effects of ET‐1 and ET‐3 on tyrosine hydroxylase activity and expression, neuronal noradrenaline (NA) release, neuronal NA transporter (NAT) activity and expression, monoamine oxidase activity and NA endogenous content and utilization (as a marker of turnover) in the posterior hypothalamus of DOCA–salt hypertensive rats. In addition, levels of ETA and ETB receptors were assayed in normotensive and hypertensive rats. Results showed that tyrosine hydroxylase activity and total and phosphorylated levels, NAT activity and content, NA release, monoamine oxidase activity and NA utilization were increased in DOCA–salt rats. Both ET‐1 and ET‐3 further enhanced all noradrenergic parameters except for total tyrosine hydroxylase level and NA endogenous content and utilization. The expression of ETA receptors was increased in the posterior hypothalamus of DOCA–salt rats, but ETB receptors showed no changes. These results show that ET‐1 and ET‐3 upregulate noradrenergic activity in the posterior hypothalamus of DOCA–salt hypertensive rats. Our findings suggest that the interaction between noradrenergic transmission and the endothelinergic system in the posterior hypothalamus may be involved in the development and/or maintenance of hypertension in this animal model.
Contractile properties and sarcoplasmic reticulum calcium content in type I and type II skeletal muscle fibres in active aged humans
Authors: Lamboley C. R. , Wyckelsma V. L. , Dutka T. L. , McKenna M. J. , Murphy R. M. , Lamb G. D.
Published: March 2015

Key points

Muscle weakness in old age is due in large part to an overall loss of skeletal muscle tissue, but it remains uncertain how much also stems from alterations in the properties of the individual muscle fibres.

This study examined the contractile properties and amount of stored intracellular calcium in single muscle fibres of Old (70 ± 4 years) and Young (22 ± 3 years) adults.

The maximum level of force production (per unit cross‐sectional area) in fast twitch fibres in Old subjects was lower than in Young subjects, and the fibres were also less sensitive to activation by calcium.

The amount of calcium stored inside muscle fibres and available to trigger contraction was also lower in both fast‐ and slow‐twitch muscle fibres in the Old subjects.

These findings indicate that muscle weakness in old age stems in part from an impaired capacity for force production in the individual muscle fibres.

This study examined the contractile properties and sarcoplasmic reticulum (SR) Ca2+ content in mechanically skinned vastus lateralis muscle fibres of Old (70 ± 4 years) and Young (22 ± 3 years) humans to investigate whether changes in muscle fibre properties contribute to muscle weakness in old age. In type II fibres of Old subjects, specific force was reduced by ∼17% and Ca2+ sensitivity was also reduced (pCa50 decreased ∼0.05 pCa units) relative to that in Young. S‐Glutathionylation of fast troponin I (TnIf) markedly increased Ca2+ sensitivity in type II fibres, but the increase was significantly smaller in Old versus Young (+0.136 and +0.164 pCa unit increases, respectively). Endogenous and maximal SR Ca2+ content were significantly smaller in both type I and type II fibres in Old subjects. In fibres of Young, the SR could be nearly fully depleted of Ca2+ by a combined caffeine and low Mg2+ stimulus, whereas in fibres of Old the amount of non‐releasable Ca2+ was significantly increased (by > 12% of endogenous Ca2+ content). Western blotting showed an increased proportion of type I fibres in Old subjects, and increased amounts of calsequestrin‐2 and calsequestrin‐like protein. The findings suggest that muscle weakness in old age is probably attributable in part to (i) an increased proportion of type I fibres, (ii) a reduction in both maximum specific force and Ca2+ sensitivity in type II fibres, and also a decreased ability of S‐glutathionylation of TnIf to counter the fatiguing effects of metabolites on Ca2+ sensitivity, and (iii) a reduction in the amount of releasable SR Ca2+ in both fibre types.
Extensor motoneurone properties are altered immediately before and during fictive locomotion in the adult decerebrate rat
Authors: MacDonell C. W. , Power K. E. , Chopek J. W. , Gardiner K. R. , Gardiner P. F.
Published: March 2015

Key points

This is the first report, in adult decerebrate rats, to examine intracellular hindlimb motoneurone properties during quiescence, fictive locomotion and a tonic period immediately before fictive locomotion that is characterized by increased peripheral nerve activity.

It is shown for the first time during fictive locomotion that motoneurones become more responsive in the tonic period, suggesting that the motoneurone pool becomes primed before patterned motor output commences.

Spike frequency adaptation exists in quiescence and during fictive locomotion during constant excitation with injected current but not during centrally driven fictive locomotion.

Motoneurones within the extensor motor pool show changes in excitability even when they are not directly involved in locomotion.

The data show increased responsiveness of motoneurones during locomotion via a lowered threshold for spike initiation and decreased rheobase.

This study examined motoneurone properties during fictive locomotion in the adult rat for the first time. Fictive locomotion was induced via electrical stimulation of the mesencephalic locomotor region in decerebrate adult rats under neuromuscular blockade to compare basic and rhythmic motoneurone properties in antidromically identified extensor motoneurones during: (1) quiescence, before and after fictive locomotion; (2) the ‘tonic’ period immediately preceding locomotor‐like activity, whereby the amplitude of peripheral flexor (peroneal) and extensor (tibial) nerves are increased but alternation has not yet occurred; and (3) locomotor‐like episodes. Locomotion was identified by alternating flexor–extensor nerve activity, where the motoneurone either produced membrane oscillations consistent with a locomotor drive potential (LDP) or did not display membrane oscillation during alternating nerve activity. Cells producing LDPs were referred to as such, while those that did not were referred to as ‘idle’ motoneurones. LDP and idle motoneurones during locomotion had hyperpolarized spike threshold (Vth; LDP: 3.8 mV; idle: 5.8 mV), decreased rheobase and an increased discharge rate (LDP: 64%; idle: 41%) during triangular ramp current injection even though the frequency–current slope was reduced by 70% and 55%, respectively. Modulation began in the tonic period immediately preceding locomotion, with a hyperpolarized Vth and reduced rheobase. Spike frequency adaptation did not occur in spiking LDPs or firing generated from sinusoidal current injection, but occurred during a sustained current pulse during locomotion. Input conductance showed no change. Results suggest motoneurone modulation occurs across the pool and is not restricted to motoneurones engaged in locomotion.
Calculations and Measurements of Pressure Vessel Thermal Neutron Fluxes in the VVER-1000 Mock-Up in the LR-0 Research Reactor
Authors: Košťál Michal , Juříček Vlastimil , Milčák Ján , Rypar Vojtěch , Kolros Antonín
Published: March 2015

This paper deals with measured as well as calculated parameters of thermal neutron transport in the reactor pressure vessel model, located behind the LR-0 reactor vessel. A VVER-1000 mock-up core placed in the LR-0 reactor is the source of neutrons, whose transport through heavy steel structures surrounding the core (i.e., the side reflector up to the area behind LR-0 vessel), is studied. The change of neutron distribution due to the variable thickness of the steel reactor pressure vessel (RPV) layers was measured and calculated using MCNPX code. The experimental results are compared with calculations performed with CENDL 3.1 and ENDF/B VII using both the thermal scattering law sublibrary with the S(α,β) model and the free gas transport model. When steel thickness increases, the measured reaction rate attenuation coefficients show a considerable decrease in thermal neutron flux, while measured Cd ratios show a faster decrease in the thermal part of the neutron spectra than the epithermal part. The calculation to experiment (C/E) for the Cd ratio shows in most cases better correspondence when the thermal neutron transport is described by means of a free gas transport model than with the thermal scattering law (TSL) model. Significantly better agreement of reaction rates is observed for the epithermal reaction rate attenuation coefficients than for thermal ones. The results are similar for both the free gas and TSL models at these energies.
A Quantitative Interpretation of the Response of Articular Cartilage to Atomic Force Microscopy-Based Dynamic Nanoindentation Tests
Authors: Taffetani Matteo , Raiteri Roberto , Gottardi Riccardo , Gastaldi Dario , Vena Pasquale
Published: March 2015

In this paper, a quantitative interpretation for atomic force microscopy-based dynamic nanoindentation (AFM-DN) tests on the superficial layers of bovine articular cartilage (AC) is provided. The relevant constitutive parameters of the tissue are estimated by fitting experimental results with a finite element model in the frequency domain. Such model comprises a poroelastic stress–strain relationship for a fibril reinforced tissue constitution, assuming a continuous distribution of the collagen network orientations. The identification procedure was first validated using a simplified transversely isotropic constitutive relationship; then, the experimental data were manually fitted by using the continuous distribution fibril model. Tissue permeability is derived from the maximum value of the phase shift between the input harmonic loading and the harmonic tissue response. Tissue parameters related to the stiffness are obtained from the frequency response of the experimental storage modulus and phase shift. With this procedure, an axial to transverse stiffness ratio (anisotropy ratio) of about 0.15 is estimated.
Probabilistic Analysis of Local Ice Loads on a Lifeboat Measured in Full-Scale Field Trials
Authors: Rahman Md Samsur , Taylor Rocky S. , Kennedy Allison , Simões Ré António , Veitch Brian
Published: March 2015

This paper presents an analysis of local ice loads measured during full-scale field trials conducted in 2014 with a totally enclosed motor propelled survival craft (TEMPSC) in controlled pack ice conditions. These data were collected as part of an ongoing research program that aims to identify the limitations of conventional TEMPSC operating in sea ice environments and to provide insight as to how these limitations might be extended. During the 2014 trials, local ice loads were measured at two locations on the TEMPSC's bow area. These loads were the most severe measured to date and corresponded to an average ice floe mass that was approximately 1.25 times the mass of the fully loaded TEMPSC. The event-maximum method of local ice pressure analysis was used to analyze these field data to improve understanding of the nature of ice loads for such interactions and to evaluate the suitability of this approach for design load estimation for TEMPSCs (i.e., lifeboats) in ice. The event-maximum method was adapted for the present application, so as to link exceedance probabilities with design load levels for a given scenario. Comparison of the 2014 results with a previous analysis of 2013 field trials data supports earlier conclusions that these interactions are highly influenced by kinetic energy, since more massive ice floes are observed to impart significantly higher loads on the lifeboats. Illustrative examples examining the influence of ice concentration and sail-away distance have also been provided. The work establishes links between extreme loads and the exposure of the lifeboat to ice for different operating conditions. Based on this work it is concluded that the event-maximum method provides a promising approach for establishing risk-based design criteria for lifeboats if field data are available which adequately represent ice conditions encountered during the design life of the lifeboat.
Dose domain regularization of MLC leaf patterns for highly complex IMRT plans
Authors: Nguyen Dan , O'Connor Daniel , Yu Victoria Y. , Ruan Dan , Cao Minsong , Low Daniel A. , Sheng Ke
Published: March 2015

Purpose:

The advent of automated beam orientation and fluence optimization enables more complex intensity modulated radiation therapy (IMRT) planning using an increasing number of fields to exploit the expanded solution space. This has created a challenge in converting complex fluences to robust multileaf collimator (MLC) segments for delivery. A novel method to regularize the fluence map and simplify MLC segments is introduced to maximize delivery efficiency, accuracy, and plan quality.

Methods:

In this work, we implemented a novel approach to regularize optimized fluences in the dose domain. The treatment planning problem was formulated in an optimization framework to minimize the segmentation‐induced dose distribution degradation subject to a total variation regularization to encourage piecewise smoothness in fluence maps. The optimization problem was solved using a first‐order primal‐dual algorithm known as the Chambolle‐Pock algorithm. Plans for 2 GBM, 2 head and neck, and 2 lung patients were created using 20 automatically selected and optimized noncoplanar beams. The fluence was first regularized using Chambolle‐Pock and then stratified into equal steps, and the MLC segments were calculated using a previously described level reducing method. Isolated apertures with sizes smaller than preset thresholds of 1–3 bixels, which are square units of an IMRT fluence map from MLC discretization, were removed from the MLC segments. Performance of the dose domain regularized (DDR) fluences was compared to direct stratification and direct MLC segmentation (DMS) of the fluences using level reduction without dose domain fluence regularization.

Results:

For all six cases, the DDR method increased the average planning target volume dose homogeneity (D95/D5) from 0.814 to 0.878 while maintaining equivalent dose to organs at risk (OARs). Regularized fluences were more robust to MLC sequencing, particularly to the stratification and small aperture removal. The maximum and mean aperture sizes using the DDR were consistently larger than those from DMS for all tested number of segments.

Conclusions:

The fluence map to MLC segmentation conversion problem was formulated as a secondary optimization problem in the dose domain to minimize the smoothness‐regularized dose discrepancy. The large scale optimization problem was solved using a primal‐dual algorithm that transformed complicated fluences into maps that were more robust to the MLC segmentation and sequencing, affording fewer and larger segments with minimal degradation to dose distribution.
Dose ratio proton radiography using the proximal side of the Bragg peak
Authors: Doolan P. J. , Royle G. , Gibson A. , Lu H.‐M. , Prieels D. , Bentefour E. H.
Published: March 2015

Purpose:

In recent years, there has been a movement toward single‐detector proton radiography, due to its potential ease of implementation within the clinical environment. One such single‐detector technique is the dose ratio method in which the dose maps from two pristine Bragg peaks are recorded beyond the patient. To date, this has only been investigated on the distal side of the lower energy Bragg peak, due to the sharp falloff. The authors investigate the limits and applicability of the dose ratio method on the proximal side of the lower energy Bragg peak, which has the potential to allow a much wider range of water‐equivalent thicknesses (WET) to be imaged. Comparisons are made with the use of the distal side of the Bragg peak.

Methods:

Using the analytical approximation for the Bragg peak, the authors generated theoretical dose ratio curves for a range of energy pairs, and then determined how an uncertainty in the dose ratio would translate to a spread in the WET estimate. By defining this spread as the accuracy one could achieve in the WET estimate, the authors were able to generate lookup graphs of the range on the proximal side of the Bragg peak that one could reliably use. These were dependent on the energy pair, noise level in the dose ratio image and the required accuracy in the WET. Using these lookup graphs, the authors investigated the applicability of the technique for a range of patient treatment sites. The authors validated the theoretical approach with experimental measurements using a complementary metal oxide semiconductor active pixel sensor (CMOS APS), by imaging a small sapphire sphere in a high energy proton beam.

Results:

Provided the noise level in the dose ratio image was 1% or less, a larger spread of WETs could be imaged using the proximal side of the Bragg peak (max 5.31 cm) compared to the distal side (max 2.42 cm). In simulation, it was found that, for a pediatric brain, it is possible to use the technique to image a region with a square field equivalent size of 7.6 cm2, for a required accuracy in the WET of 3 mm and a 1% noise level in the dose ratio image. The technique showed limited applicability for other patient sites. The CMOS APS demonstrated a good accuracy, with a root‐mean‐square‐error of 1.6 mm WET. The noise in the measured images was found to be σ = 1.2% (standard deviation) and theoretical predictions with a 1.96σ noise level showed good agreement with the measured errors.

Conclusions:

After validating the theoretical approach with measurements, the authors have shown that the use of the proximal side of the Bragg peak when performing dose ratio imaging is feasible, and allows for a wider dynamic range than when using the distal side. The dynamic range available increases as the demand on the accuracy of the WET decreases. The technique can only be applied to clinical sites with small maximum WETs such as for pediatric brains.
Adaptation: A Two-Perception Probabilistic Conceptual Framework
Authors: Tenenbaum Gershon , Lane Andrew , Razon Selen , Lidor Ronnie , Schinke Robert
Published: March 2015

We introduce a two-perception probabilistic concept of adaptation (TPPCA), which accounts for fast and slow adaptation processes. The outcome of both processes depends on the perceptual difference (termed herein a quantum) of how an individual perceives his or her abilities, skills, and capacities (βv) to interact, cope, and perform a given task (δi). Thus, the adaptation process is determined by (βv – δi). Fast adaptation processes target aspects that require immediate responses while slow adaptation processes involve ongoing adaptation to long-term demands. We introduce the TPPCA in several domains of inquiry, which rely on fast adaptation processes (perceptual–cognitive–action coupling, performance routines, psychological crisis, reversal states), slow adaptation processes (i.e., career aspirations, burnout), and processes that can be either fast or slow (i.e., flow, affect and mood changes, emotion regulation).
On being less tolerant: Enhanced cancer immunosurveillance enabled by targeting checkpoints and agonists of T cell activation
Authors: Lesokhin Alexander M. , Callahan Margaret K. , Postow Michael A. , Wolchok Jedd D.
Published: March 2015

This Review presents the state of research and future outlook on cancer immunotherapy approaches such as immune checkpoint inhibitors.
Personalized cancer medicines
Authors: Bhardwaj Anshu
Published: March 2015

An in silico prescription strategy targets genes driving tumorigenesis.
Malaria Parasites Produce Volatile Mosquito Attractants
Authors: Kelly Megan , Su Chih-Ying , Schaber Chad , Crowley Jan R. , Hsu Fong-Fu , Carlson John R. , Odom Audrey R.
Published: March 2015

The malaria parasite
Plasmodium falciparum
contains a nonphotosynthetic plastid organelle that possesses plant-like metabolic pathways. Plants use the plastidial isoprenoid biosynthesis pathway to produce volatile odorants, known as terpenes. In this work, we describe the volatile chemical profile of cultured malaria parasites. Among the identified compounds are several plant-like terpenes and terpene derivatives, including known mosquito attractants. We establish the molecular identity of the odorant receptors of the malaria mosquito vector
Anopheles gambiae
, which responds to these compounds. The malaria parasite produces volatile signals that are recognized by mosquitoes and may thereby mediate host attraction and facilitate transmission.

IMPORTANCE
Malaria is a key global health concern. Mosquitoes that transmit malaria are more attracted to malaria parasite-infected mammalian hosts. These studies aimed to understand the chemical signals produced by malaria parasites; such an understanding may lead to new transmission-blocking strategies or noninvasive malaria diagnostics.
Manganese Homeostasis in Group A Streptococcus Is Critical for Resistance to Oxidative Stress and Virulence
Authors: Turner Andrew G. , Ong Cheryl-lynn Y. , Gillen Christine M. , Davies Mark R. , West Nicholas P. , McEwan Alastair G. , Walker Mark J.
Published: March 2015

Streptococcus pyogenes(group A Streptococcus [GAS]) is an obligate human pathogen responsible for a spectrum of human disease states. Metallobiology of human pathogens is revealing the fundamental role of metals in both nutritional immunity leading to pathogen starvation and metal poisoning of pathogens by innate immune cells. Spy0980 (MntE) is a paralog of the GAS zinc efflux pump CzcD. Through use of an isogenicmntEdeletion mutant in the GAS serotype M1T1 strain 5448, we have elucidated that MntE is a manganese-specific efflux pump required for GAS virulence. The 5448ΔmntEmutant had significantly lower survival following infection of human neutrophils than did the 5448 wild type and the complemented mutant (5448ΔmntE::mntE). Manganese homeostasis may provide protection against oxidative stress, explaining the observedex vivoreduction in virulence. In the presence of manganese and hydrogen peroxide, 5448ΔmntEmutant exhibits significantly lower survival than wild-type 5448 and the complemented mutant. We hypothesize that MntE, by maintaining homeostatic control of cytoplasmic manganese, ensures that the peroxide response repressor PerR is optimally poised to respond to hydrogen peroxide stress. Creation of a 5448ΔmntE-ΔperRdouble mutant rescued the oxidative stress resistance of the double mutant to wild-type levels in the presence of manganese and hydrogen peroxide. This work elucidates the mechanism for manganese toxicity within GAS and the crucial role of manganese homeostasis in maintaining GAS virulence.

IMPORTANCEManganese is traditionally viewed as a beneficial metal ion to bacteria, and it is also established that most bacteria can tolerate high concentrations of this transition metal. In this work, we show that in group A Streptococcus, mutation of themntElocus, which encodes a transport protein of the cation diffusion facilitator (CDF) family, results in accumulation of manganese and sensitivity to this transition metal ion. The toxicity of manganese is indirect and is the result of a failure of the PerR regulator to respond to oxidative stress in the presence of high intracellular manganese concentrations. These results highlight the importance of MntE in manganese homeostasis and maintenance of an optimal manganese/iron ratio in GAS and the impact of manganese on resistance to oxidative stress and virulence.
Contribution of Resistance-Nodulation-Cell Division Efflux Systems to Antibiotic Resistance and Biofilm Formation in Acinetobacter baumannii
Authors: Yoon Eun-Jeong , Nait Chabane Yassine , Goussard Sylvie , Snesrud Erik , Courvalin Patrice , Dé Emmanuelle , Grillot-Courvalin Catherine
Published: March 2015

Acinetobacter baumannii
is a nosocomial pathogen of increasing importance due to its multiple resistance to antibiotics and ability to survive in the hospital environment linked to its capacity to form biofilms. To fully characterize the contribution of AdeABC, AdeFGH, and AdeIJK resistance-nodulation-cell division (RND)-type efflux systems to acquired and intrinsic resistance, we constructed, from an entirely sequenced susceptible
A. baumannii
strain, a set of isogenic mutants overexpressing each system following introduction of a point mutation in their cognate regulator or a deletion for the pump by allelic replacement. Pairwise comparison of every derivative with the parental strain indicated that AdeABC and AdeFGH are tightly regulated and contribute to acquisition of antibiotic resistance when overproduced. AdeABC had a broad substrate range, including β-lactams, fluoroquinolones, tetracyclines-tigecycline, macrolides-lincosamides, and chloramphenicol, and conferred clinical resistance to aminoglycosides. Importantly, when combined with enzymatic resistance to carbapenems and aminoglycosides, this pump contributed in a synergistic fashion to the level of resistance of the host. In contrast, AdeIJK was expressed constitutively and was responsible for intrinsic resistance to the same major drug classes as AdeABC as well as antifolates and fusidic acid. Surprisingly, overproduction of AdeABC and AdeIJK altered bacterial membrane composition, resulting in decreased biofilm formation but not motility. Natural transformation and plasmid transfer were diminished in recipients overproducing AdeABC. It thus appears that alteration in the expression of efflux systems leads to multiple changes in the relationship between the host and its environment, in addition to antibiotic resistance.

IMPORTANCE
Increased expression of chromosomal genes for RND-type efflux systems plays a major role in bacterial multidrug resistance.
Acinetobacter baumannii
has recently emerged as an important human pathogen responsible for epidemics of hospital-acquired infections. Besides its remarkable ability to horizontally acquire resistance determinants, it has a broad intrinsic resistance due to low membrane permeability, endogenous resistance genes, and antibiotic efflux. The study of isogenic mutants from a susceptible
A. baumannii
clinical isolate overproducing or deleted for each of the three major RND-type pumps demonstrated their major contribution to intrinsic resistance and to the synergism between overproduction of an efflux system and acquisition of a resistance gene. We have also shown that modulation of expression of the structural genes for the efflux systems results in numerous alterations in membrane-associated cellular functions, in particular, in a decrease in biofilm formation and resistance gene acquisition.
Parotid epithelial–myoepithelial carcinoma: an unexpected intraoperative finding
Authors: Davidoss Nishant Hemanth , Khaleel Ziyad , Low Tsu-Hui (Hubert)
Published: March 2015

We present a case of a 72-year-old man with a parotid mass which was initially diagnosed as a pleomorphic adenoma. Intraoperatively, the tumour was found to be invading the facial nerve. It was later found to be an epithelial–myoepithelial carcinoma, a rare salivary gland tumour. Despite invasion of the facial nerve, function of the nerve remained intact.
Management of the sodium hypochlorite accident: a rare but significant complication of root canal treatment
Authors: Hatton Jonathan , Walsh Stephen , Wilson Alan
Published: March 2015

A 66-year-old female patient presented to the accident and emergency department, 3 h following a dental appointment. Significant right-sided facial swelling, bruising and pain were present. The patient had been sent by her general dental practitioner with a covering letter explaining that a hypochlorite accident had occurred during root canal treatment of the upper right first premolar tooth. An iatrogenic perforation was suspected. The patient was admitted under the care of the maxillofacial team and intravenous antibiotics, analgesia and steroids were administered. The patient was prepared for the possibility of requiring surgical intervention under a general anaesthetic. No nerve injury was encountered and the periorbital tissues were spared. A full recovery was made by the patient with no surgical intervention required but significant bruising and swelling were present up to 4 weeks following the incident.
Flucloxacillin and fusidic acid-associated neutropenia in a patient with periaortic abscess: rare side effects of commonly used antibiotics
Authors: Damali Amiri Negin , Wijenaike Nishan
Published: March 2015

The use of long-term antibiotics for deep-seated infections is very common, and is associated with many clinically significant side effects. In this report we describe the history of a 48-year-old man who attended West Suffolk Hospital with nausea and vomiting, and was subsequently found to have a deep-seated infection following his repeat aortic valve replacement. He completed a 7-week course of intravenous flucloxacillin and oral fusidic acid, however, prior to finishing this course a random blood test revealed a neutrophil count of zero. He was re-admitted to hospital with fever, and was treated accordingly as per the trust's neutropenic sepsis protocol with the addition of growth colony stimulating factor (GCSF). His neutrophil count recovered after 3 days and has remained within the normal range ever since.
Complete recovery after severe myxoedema coma complicated by status epilepticus
Authors: Fjølner Jesper , Søndergaard Esben , Kampmann Ulla , Nielsen Søren
Published: March 2015

We report a case of life-threatening myxoedema presenting with hypothermia, hypotension, bradycardia, pericardial effusion and deep coma. The condition was complicated by prolonged status epilepticus. The optimal treatment strategy has been debated over the years and the literature is briefly reviewed. Treatment withl-thyroxine (LT4) monotherapy without initial loading dose and with nol-triiodothyronine (LT3) treatment was successful with full recovery after hospitalisation for more than a month. Myxoedema coma is a rare, reversible condition with a high mortality and should be considered as a differential diagnosis in medical emergencies.
Conservative management of a post-traumatic pseudoaneurysm of the artery of cervical enlargement–anterior spinal artery junction
Authors: Boeris Davide , Mortimer Alex , Sakthithasan Mathuri , Evins Alexander Ian , Sandeman David , Renowden Shelly
Published: March 2015

A 22-year-old man suffered severe sudden onset head and neck pain after being pushed from behind during an assault. Physical examination was normal. Cervical MRI demonstrated an intradural hematoma, anterior to the cord, between C2–4. Subsequent contrast enhanced MR angiography and digital subtraction vertebral angiography confirmed that the cause of the hemorrhage was a fusiform (presumed dissecting) pseudoaneurysm of the artery of the cervical enlargement at its junction with the anterior spinal artery. The aneurysm was managed conservatively. Follow-up angiography demonstrated that the aneurysm had spontaneously thrombosed within 10 days and remained occluded at 2 months. The patient remained occluded at 6 months following the initial injury. Anterior spinal aneurysms represent a management dilemma and options are discussed.
Acupuncture for erectile dysfunction: a systematic review protocol
Authors: Cui Xiaoming , Li Xiaoli , Peng Weina , Zhou Jing , Yu Jinna , Ye Yongming , Liu Zhishun
Published: March 2015

Introduction

This systematic review protocol aims to provide a protocol for assessing the safety and effectiveness of acupuncture for the treatment of erectile dysfunction(ED). Previous systematic reviews did not draw convincing conclusions owing to high heterogeneity and few included randomised controlled trials, so it is necessary to reassess the efficacy and safety of acupuncture for ED.

Methods and analysis

Eight electronic databases will be searched: the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, PubMed, EMBASE, PsycInfo, the Chinese Biomedical Literature Database (CBM), the Chinese Medical Current Content (CMCC) and the China National Knowledge Infrastructure (CNKI). Related Chinese literature will be searched in other Chinese databases. All relevant randomised controlled trials in English or Chinese without any restrictions of publication type will be included. The main outcome measure will be improvements in sexual activity assessed by validated questionnaires. Assessment of risk of bias, data synthesis and subgroup analysis will be carried out using Review Manager 5.3.

Ethics and dissemination

The results of the systematic review will be disseminated via publication in a peer-reviewed journal and presented at a relevant conference. The data we will use do not include individual patient data, so ethical approval is not required.

Trial registration number

PROSPERO CRD42014013575.
The prevalence, risk factors and short-term outcomes of delirium in Thai elderly emergency department patients
Authors: Sri-on Jiraporn , Tirrell Gregory Philip , Vanichkulbodee Alissala , Niruntarai Supa , Liu Shan W
Published: March 2015

Background

We sought to determine the prevalence of delirium in a Thai emergency department (ED). The secondary objective was to identify risk factors and short-term outcomes in delirious elderly ED patients.

Methods

This was a prospective cross-sectional study in the ED of an urban tertiary care hospital. Patients aged ≥65 years who presented to the ED were included. We excluded patients who had severe dementia, were not responsive to verbal stimuli, had severe trauma and were blind, deaf, aphasic or unable to speak Thai. Delirium was determined using the Confusion Assessment Method for the Intensive Care Unit. We collected 30-day mortality rate, hospital length of stay and revisit rate as short-term outcomes.

Results

We had a final sample size of 232 patients; 27 (12%) were delirious in the ED, of which 16 (59%) were not recognised to be delirious by the emergency physician. Multivariable logistic regression analysis showed dementia (adjusted OR (AOR) 13.1; 95% CI 2.9 to 59.6), auditory impairment (AOR 4.8; 95% CI 1.6 to 13.8) and ED diagnosis of metabolic derangement (AOR 6.5; 95% CI 1.6 to 26.8) were associated with delirium in the ED. Delirium was associated with a higher mortality rate than those without delirium (15% vs 2%, p=0.004).

Conclusions

In one middle-income country, elderly ED patients were delirious >10% of the time. Delirium was underdiagnosed and was associated with an increased 30-day mortality rate. Delirium screening needs to be improved, potentially focusing on high-risk patients.
The Study Team for Early Life Asthma Research (STELAR) consortium ‘Asthma e-lab’: team science bringing data, methods and investigators together
Authors: Custovic Adnan , Ainsworth John , Arshad Hasan , Bishop Christopher , Buchan Iain , Cullinan Paul , Devereux Graham , Henderson John , Holloway John , Roberts Graham , Turner Steve , Woodcock Ashley , Simpson Angela
Published: March 2015

We created Asthma e-Lab, a secure web-based research environment to support consistent recording, description and sharing of data, computational/statistical methods and emerging findings across the five UK birth cohorts. The e-Lab serves as a data repository for our unified dataset and provides the computational resources and a scientific social network to support collaborative research. All activities are transparent, and emerging findings are shared via the e-Lab, linked to explanations of analytical methods, thus enabling knowledge transfer. eLab facilitates the iterative interdisciplinary dialogue between clinicians, statisticians, computer scientists, mathematicians, geneticists and basic scientists, capturing collective thought behind the interpretations of findings.