bluuebunny/crossref_metadata_2025 huggingface dataset:
Molecular basis of Tank-binding kinase 1 activation by transautophosphorylation
Authors: Ma Xiaolei , Helgason Elizabeth , Phung Qui T. , Quan Clifford L. , Iyer Rekha S. , Lee Michelle W. , Bowman Krista K. , Starovasnik Melissa A. , Dueber Erin C.
Published: May 2012

Tank-binding kinase (TBK)1 plays a central role in innate immunity: it serves as an integrator of multiple signals induced by receptor-mediated pathogen detection and as a modulator of IFN levels. Efforts to better understand the biology of this key immunological factor have intensified recently as growing evidence implicates aberrant TBK1 activity in a variety of autoimmune diseases and cancers. Nevertheless, key molecular details of TBK1 regulation and substrate selection remain unanswered. Here, structures of phosphorylated and unphosphorylated human TBK1 kinase and ubiquitin-like domains, combined with biochemical studies, indicate a molecular mechanism of activation via transautophosphorylation. These TBK1 structures are consistent with the tripartite architecture observed recently for the related kinase IKKβ, but domain contributions toward target recognition appear to differ for the two enzymes. In particular, both TBK1 autoactivation and substrate specificity are likely driven by signal-dependent colocalization events.
Heme-protein vibrational couplings in cytochrome
c
provide a dynamic link that connects the heme-iron and the protein surface
Authors: Galinato Mary Grace I. , Kleingardner Jesse G. , Bowman Sarah E. J. , Alp E. Ercan , Zhao Jiyong , Bren Kara L. , Lehnert Nicolai
Published: May 2012

The active site of cytochrome
c
(Cyt
c
) consists of a heme covalently linked to a pentapeptide segment (Cys-X-X-Cys-His), which provides a link between the heme and the protein surface, where the redox partners of Cyt
c
bind. To elucidate the vibrational properties of heme
c
, nuclear resonance vibrational spectroscopy (NRVS) measurements were performed on
57
Fe-labeled ferric
Hydrogenobacter thermophilus
cytochrome
c
552
, including
13
C
8
-heme–,
13
C
5
15
N-Met–, and
13
C
15
N-polypeptide (pp)–labeled samples, revealing heme-based vibrational modes in the 200- to 450-cm
−1
spectral region. Simulations of the NRVS spectra of
H. thermophilus
cytochrome
c
552
allowed for a complete assignment of the Fe vibrational spectrum of the protein-bound heme, as well as the quantitative determination of the amount of mixing between local heme vibrations and pp modes from the Cys-X-X-Cys-His motif. These results provide the basis to propose that heme-pp vibrational dynamic couplings play a role in electron transfer (ET) by coupling vibrations of the heme directly to vibrations of the pp at the protein–protein interface. This could allow for the direct transduction of the thermal (vibrational) energy from the protein surface to the heme that is released on protein/protein complex formation, or it could modulate the heme vibrations in the protein/protein complex to minimize reorganization energy. Both mechanisms lower energy barriers for ET. Notably, the conformation of the distal Met side chain is fine-tuned in the protein to localize heme-pp mixed vibrations within the 250- to 400-cm
−1
spectral region. These findings point to a particular orientation of the distal Met that maximizes ET.
Writing as resistance: Berber literature and the challenges surrounding the emergence of a Berber literary field in Morocco
Authors: Pouessel Stéphanie
Published: May 2012

This article discusses the development of Berber literature in Morocco and the connections between this literature and Moroccan national identity as well as the pan-Amazigh identity movement. Over the last 40 years, the political conjuncture in Morocco has led Berber writers to affirm an alternative definition of Moroccanness, not exclusively based on Arabness, but one in which Berberity is included. This article aims to shed light on modern Berber literature, and on the social space in which it is embedded. It argues that there is no autonomous Berber literary field, the literature being intrinsically bound up with identity issues, but a Berber literary space, located at the intermingling of several fields (the political field and the field of language production in particular). The article first reconstructs the Moroccan political context by exploring the Amazigh movement, its aspirations and its reality. It then focuses on the relationship between the language issues (alphabet, standardization, etc.) and the emergence of a Berber “neo-literature.” Lastly, it moves beyond Morocco into the wider pan-Berber world — the Maghreb and those countries to which Berbers have emigrated — to question the possibility of a transnational Berber literature.
Witt groups of Grassmann varieties
Authors: Balmer Paul , Calmès Baptiste
Published: May 2012

We compute the Witt groups of split Grassmann varieties, over any regular base XX. The answer is that the total Witt group of the Grassmannian is a free module over the total Witt ring of XX. We provide an explicit basis for this free module, which is indexed by a special class of Young diagrams, that we callevenYoung diagrams.
Morvan Syndrome
Authors: Abou-Zeid Elias , Boursoulian Lana Jeradeh , Metzer Walter S. , Gundogdu Betul
Published: May 2012

Morvan syndrome is characterized by central, autonomic, and peripheral hyperactivity. Examples of central hyperactivity include confusion, memory problems, hallucinations, insomnia, and myoclonus; examples of autonomic hyperactivity include hyperhidrosis and fluctuations in blood pressure; examples of peripheral hyperreactivity include clinical or electrophysiological evidence of painful cramps, myokymia, and neuromyotonia. We present a typical case of Morvan syndrome and the first detailed review of the clinical and therapeutic literature of all 27 cases from the English language literature. Morvan syndrome is considered to be an autoimmune disorder and antibodies against voltage-gated potassium channels are found in most cases. Oral immunomodulatory therapy, intravenous immunoglobulin, and plasmapharesis may be entertained. Thymoma is found in approximately 50% of cases and thymectomy may be curative as in our particular case.
Street lighting changes the composition of invertebrate communities
Authors: Davies Thomas W. , Bennie Jonathan , Gaston Kevin J.
Published: May 2012

Artificial lighting has been used to illuminate the nocturnal environment for centuries and continues to expand with urbanization and economic development. Yet, the potential ecological impact of the resultant light pollution has only recently emerged as a major cause for concern. While investigations have demonstrated that artificial lighting can influence organism behaviour, reproductive success and survivorship, none have addressed whether it is altering the composition of communities. We show, for the first time, that invertebrate community composition is affected by proximity to street lighting independently of the time of day. Five major invertebrate groups contributed to compositional differences, resulting in an increase in the number of predatory and scavenging individuals in brightly lit communities. Our results indicate that street lighting changes the environment at higher levels of biological organization than previously recognized, raising the potential that it can alter the structure and function of ecosystems.
Gender- and stressor-specific microRNA expression in
Tribolium castaneum
Authors: Freitak Dalial , Knorr Eileen , Vogel Heiko , Vilcinskas Andreas
Published: May 2012

MicroRNAs (miRNAs) are small non-coding RNAs mediating post-transcriptional regulation of gene expression in eukaryotes. Addressing their role in regulation of physiological adaptations to environmental stress in insects, we selected the red flour beetle
Tribolium castaneum
as a model. Beetles were fed with the bacterial entomopathogen
Pseudomonas entomophila
(to mimic natural infection), injected with peptidoglycan (experimental setting of strong immune responses) or subjected to either mild heat shock or starvation. Differential expression of selected immunity- and stress-related genes was quantified using real-time PCR, and expression and induction of 455 mature arthropod miRNAs were determined using proprietary microarrays. We found that
Tribolium
exhibits both gender- and stressor-specific adjustment of immune gene and miRNA expression. Strikingly, we discovered that the number of stressor-induced miRNAs in females is remarkably higher than in males. This observation could support the hypothesis called Bateman's principle in immunity that predicts gender-specific immune responses because females gain fitness through increased longevity, whereas males gain fitness by increasing mating rates. Our results suggest that
Tribolium
males and females display differential regulatory elements, both pre- and post-transcriptional, likely resulting from different investment strategies in life-history traits.
Radar aeroecology: exploring the movements of aerial fauna through radio-wave remote sensing
Authors: Chilson Phillip B. , Bridge Eli , Frick Winifred F. , Chapman Jason W. , Kelly Jeffrey F.
Published: May 2012

An international and interdisciplinary Radar Aeroecology Workshop was held at the National Weather Center on 5–6 March 2012 on the University of Oklahoma campus in Norman, OK, USA. The workshop brought together biologists, meteorologists, radar engineers and computer scientists from 22 institutions and four countries. A central motivation behind the Radar Aeroecology Workshop was to foster better communication and cross-disciplinary collaboration among a diverse spectrum of researchers, and promote a better understanding of the ecology of animals that move within and use the Earth's lower atmosphere (aerosphere).
Function suggests nano-structure: electrophysiology supports that granule membranes play dice
Authors: Hammel Ilan , Meilijson Isaac
Published: May 2012

Cellular communication depends on membrane fusion mechanisms. SNARE proteins play a fundamental role in all intracellular fusion reactions associated with the life cycle of secretory vesicles, such as vesicle–vesicle and vesicle plasma membrane fusion at the porosome base in the cell plasma membrane. We present growth and elimination (G&E), a birth and death model for the investigation of granule growth, its evoked and spontaneous secretion and their information content. Using a statistical mechanics approach in which SNARE components are viewed as interacting particles, the G&E model provides a simple ‘nano-machine’ of SNARE self-aggregation behind granule growth and secretion. Results from experimental work, mathematical calculations and statistical modelling suggest that for vesicle growth a minimal aggregation of three SNAREs is required, while for the evoked secretion one SNARE is enough. Furthermore, the required number of SNARE aggregates (which varies between cell types and is nearly proportional to the square root of the mean granule diameter) affects and is statistically identifiable from the size distributions of spontaneous and evoked secreted granules. The new statistical mechanics approach to granule fusion is bound to have a significant changing effect on the investigation of the pathophysiology of secretory mechanisms and methodologies for the investigation of secretion.
Metabolomics: a valuable tool for stem cell monitoring in regenerative medicine
Authors: McNamara Laura E. , Sjöström Terje , Meek R. M. Dominic , Oreffo Richard O. C. , Su Bo , Dalby Matthew J. , Burgess Karl E. V.
Published: May 2012

Metabolomics is a method for investigation of changes in the global metabolite profile of cells. This paper discusses the technical application of the approach, considering metabolite extraction, separation, mass spectrometry and data interpretation. A particular focus is on the application of metabolomics to the study of stem cell physiology in the context of biomaterials and regenerative medicine. Case studies are used to illustrate key points, focusing on the use of metabolomics in the examination of mesenchymal stem cell responses to titania-nanopillared substrata designed for orthopaedic applications.
The sensitivity of human mesenchymal stem cells to vibration and cold storage conditions representative of cold transportation
Authors: Nikolaev N. I. , Liu Y. , Hussein H. , Williams D. J.
Published: May 2012

In the current study, the mechanical and hypothermic damage induced by vibration and cold storage on human mesenchymal stem cells (hMSCs) stored at 2–8°C was quantified by measuring the total cell number and cell viability after exposure to vibration at 50 Hz (peak acceleration 140 m s
−2
and peak displacement 1.4 mm), 25 Hz (peak acceleration 140 m s
−2
, peak displacement 5.7 mm), 10 Hz (peak acceleration 20 m s
−2
, peak displacement 5.1 mm) and cold storage for several durations. To quantify the viability of the cells, in addition to the trypan blue exclusion method, the combination of annexin V-FITC and propidium iodide was applied to understand the mode of cell death. Cell granularity and a panel of cell surface markers for stemness, including CD29, CD44, CD105 and CD166, were also evaluated for each condition. It was found that hMSCs were sensitive to vibration at 25 Hz, with moderate effects at 50 Hz and no effects at 10 Hz. Vibration at 25 Hz also increased CD29 and CD44 expression. The study further showed that cold storage alone caused a decrease in cell viability, especially after 48 h, and also increased CD29 and CD44 and attenuated CD105 expressions. Cell death would most likely be the consequence of membrane rupture, owing to necrosis induced by cold storage. The sensitivity of cells to different vibrations within the mechanical system is due to a combined effect of displacement and acceleration, and hMSCs with a longer cold storage duration were more susceptible to vibration damage, indicating a coupling between the effects of vibration and cold storage.
The optimal deployment of synergistic antibiotics: a control-theoretic approach
Authors: Peña-Miller Rafael , Lähnemann David , Schulenburg Hinrich , Ackermann Martin , Beardmore Robert
Published: May 2012

Medical and pharmacological communities have long searched for antimicrobial drugs that increase their effect when used in combination, an interaction known as
synergism
. These drug combinations, however, impose selective pressures in favour of multi-drug resistance and as a result, the benefit of synergy may be lost after only a few bacterial generations. Furthermore, there is experimental evidence that antibiotic treatment can disrupt colonization resistance by shifting the balance between enteropathogenic and commensal bacteria in favour of the pathogens, with the potential to increase the risk of infections. So, we ask, what is the best way of using synergistic drugs? We pose an evolutionary model of commensal and pathogenic bacteria competing in a continuous culture device for a single limiting carbon source under the effect of two bacteriostatic and synergistic antibiotics. This model allows us to evaluate the efficacy of different drug deployment strategies and, using ideas from optimal control theory, to understand whether there are circumstances in which other types of therapy might be favoured over those based on fixed-dose multi-drug combinations. Our main result can be stated thus: the optimal deployment of synergistic antibiotics to remove a pathogen in the presence of commensal bacteria in our model system occurs not in combination, but by deploying them sequentially.
PINK1 is activated by mitochondrial membrane potential depolarization and stimulates Parkin E3 ligase activity by phosphorylating Serine 65
Authors: Kondapalli Chandana , Kazlauskaite Agne , Zhang Ning , Woodroof Helen I. , Campbell David G. , Gourlay Robert , Burchell Lynn , Walden Helen , Macartney Thomas J. , Deak Maria , Knebel Axel , Alessi Dario R. , Muqit Miratul M. K.
Published: May 2012

Missense mutations in PTEN-induced kinase 1 (PINK1) cause autosomal-recessive inherited Parkinson's disease (PD). We have exploited our recent discovery that recombinant insect PINK1 is catalytically active to test whether PINK1 directly phosphorylates 15 proteins encoded by PD-associated genes as well as proteins reported to bind PINK1. We have discovered that insect PINK1 efficiently phosphorylates only one of these proteins, namely the E3 ligase Parkin. We have mapped the phosphorylation site to a highly conserved residue within the Ubl domain of Parkin at Ser
65
. We show that human PINK1 is specifically activated by mitochondrial membrane potential (Δψm) depolarization, enabling it to phosphorylate Parkin at Ser
65
. We further show that phosphorylation of Parkin at Ser
65
leads to marked activation of its E3 ligase activity that is prevented by mutation of Ser
65
or inactivation of PINK1. We provide evidence that once activated, PINK1 autophosphorylates at several residues, including Thr
257
, which is accompanied by an electrophoretic mobility band-shift. These results provide the first evidence that PINK1 is activated following Δψm depolarization and suggest that PINK1 directly phosphorylates and activates Parkin. Our findings indicate that monitoring phosphorylation of Parkin at Ser
65
and/or PINK1 at Thr
257
represent the first biomarkers for examining activity of the PINK1-Parkin signalling pathway
in vivo
. Our findings also suggest that small molecule activators of Parkin that mimic the effect of PINK1 phosphorylation may confer therapeutic benefit for PD.
Dynamic axial crush response of circular cell honeycombs
Authors: D'Mello Royan J. , Guntupalli Sophia , Hansen Lucas R. , Waas Anthony M.
Published: May 2012

The dynamic axial crush response of circular cell polycarbonate honeycombs was studied for 3-cell and 7-cell specimens experimentally and through finite-element (FE) simulation. The experiments were conducted using two loading methods: (i) the wave loading device (WLD) method and (ii) the direct impact method (DIM). The specimens were subjected to crush velocities of about 12 000 mm s
−1
in the WLD method and 5000 mm s
−1
in the DIM. The two methods were used to obtain a fairly wide range of input velocities. The collapse sequence and displacement information of the specimens were captured using a high-speed camera. The mode of collapse was through progressive concertina-diamond fold formation over a fairly constant state of load, which is referred to as the crush load. The crushing was simulated using an explicit FE analysis using ABAQUS, with geometrically imperfect 3-cell and 7-cell honeycomb models that incorporated the rate-dependent properties of polycarbonate. The FE results were found to agree well with the experimental results in terms of overall force–displacement plots, thus providing a basis to extract energy absorption estimates from the models and to draw comparisons between the 3-cell and 7-cell response behaviour. Moreover, the dynamic crush results were compared against a quasi-static axial crush response to demonstrate the presence of rate effects.
Electrostatics of two charged conducting spheres
Authors: Lekner John
Published: May 2012

We prove that two charged conducting spheres will almost always attract each other at close approach, even when they have like charges. The one exception is when the two spheres have the same charge ratio that they would obtain by being brought into contact. In this case, they repel, and we derive an analytical expression for the force at contact, for any size ratio, generalizing a force formula for equal spheres obtained by Kelvin in 1853. We also give the electrostatic energy of two arbitrarily charged spheres, and its analytical forms at large and small separations. Expressions are derived for the surface charge densities of the two spheres. Attraction occurs between two positively charged spheres because of mutual polarization: one of the spheres obtains a negatively charged region (neighbouring the other sphere).
Physical tethering and volume exclusion determine higher-order genome organization in budding yeast
Authors: Tjong Harianto , Gong Ke , Chen Lin , Alber Frank
Published: May 2012

In this paper we show that tethering of heterochromatic regions to nuclear landmarks and random encounters of chromosomes in the confined nuclear volume are sufficient to explain the higher-order organization of the budding yeast genome. We have quantitatively characterized the contact patterns and nuclear territories that emerge when chromosomes are allowed to behave as constrained but otherwise randomly configured flexible polymer chains in the nucleus. Remarkably, this constrained random encounter model explains in a statistical manner the experimental hallmarks of the S. cerevisiae genome organization, including (1) the folding patterns of individual chromosomes; (2) the highly enriched interactions between specific chromatin regions and chromosomes; (3) the emergence, shape, and position of gene territories; (4) the mean distances between pairs of telomeres; and (5) even the co-location of functionally related gene loci, including early replication start sites and tRNA genes. Therefore, most aspects of the yeast genome organization can be explained without calling on biochemically mediated chromatin interactions. Such interactions may modulate the pre-existing propensity for co-localization but seem not to be the cause for the observed higher-order organization. The fact that geometrical constraints alone yield a highly organized genome structure, on which different functional elements are specifically distributed, has strong implications for the folding principles of the genome and the evolution of its function.
Prevalence of pathological internet use among adolescents in Europe: demographic and social factors
Authors: Durkee Tony , Kaess Michael , Carli Vladimir , Parzer Peter , Wasserman Camilla , Floderus Birgitta , Apter Alan , Balazs Judit , Barzilay Shira , Bobes Julio , Brunner Romuald , Corcoran Paul , Cosman Doina , Cotter Padraig , Despalins Romain , Graber Nadja , Guillemin Francis , Haring Christian , Kahn Jean‐Pierre , Mandelli Laura , Marusic Dragan , Mészáros Gergely , Musa George J. , Postuvan Vita , Resch Franz , Saiz Pilar A. , Sisask Merike , Varnik Airi , Sarchiapone Marco , Hoven Christina W. , Wasserman Danuta
Published: May 2012

Aims

To investigate the prevalence of pathological internet use (PIU) and maladaptive internet use (MIU) among adolescents in 11 European countries in relation to demographic, social factors and internet accessibility.

Design

Cross‐sectional survey.

Setting

The 7th Framework European Union (EU) funded project, Saving and Empowering Young Lives in Europe (SEYLE), is a randomized controlled trial (RCT) evaluating interventions for risk behaviours among adolescents in Austria, Estonia, France, Germany, Hungary, Ireland, Israel, Italy, Romania, Slovenia and Spain, with Sweden serving as the coordinating centre.

Participants

A total of 11 956 adolescents (female/male: 6731/5225; mean age: 14.9 ± 0.89) recruited from randomly selected schools within the 11 study sites.

Measurements

Internet users were classified by gender into three categories: adaptive, maladaptive and pathological, based on their score in the Young Diagnostic Questionnaire for Internet Addiction (YDQ).

Findings

The overall prevalence of PIU was 4.4%; it was higher among males than females (5.2% versus 3.8%) and differed between countries (χ2 = 309.98; d.f. = 20; P < 0.001). PIU correlated significantly with mean hours online and male gender. The highest‐ranked online activities were watching videos, frequenting chatrooms and social networking; significantly higher rates of playing single‐user games were found in males and social networking in females. Living in metropolitan areas was associated with PIU. Students not living with a biological parent, low parental involvement and parental unemployment showed the highest relative risks of both MIU and PIU.

Conclusions

Across a range of countries in Europe, using the Young Diagnostic Questionnaire for Internet Addiction yields a prevalence of ‘pathological internet use’ of 4.4% among adolescents, but varies by country and gender; adolescents lacking emotional and psychological support are at highest risk.
The safety and efficacy of antitumour necrosis factor‐alpha therapy for inflammatory bowel disease in patients post liver transplantation: a case series
Authors: Sandhu A. , Alameel T. , Dale C. H. , Levstik M. , Chande N.
Published: May 2012

Background

The role of antitumour necrosis factor‐alpha (anti‐TNF) therapy for inflammatory bowel disease (IBD) among liver transplant recipients is largely unknown given the rarity of this population and the paucity of literature on the subject.

Aim

To investigate the safety and efficacy of anti‐TNF therapy for refractory IBD in the post liver transplant population.

Methods

The liver transplant database at London Health Sciences Centre was searched to identify adult patients with IBD treated with anti‐TNF therapy post transplantation.

Results

Six patients (five men, one woman) were identified, aged 28–65. All patients had cadaveric orthotopic liver transplants. Four patients required transplantation due to primary sclerosing cholangitis, one due to autoimmune hepatitis, and one due to biliary atresia. Five patients suffered from Crohn's disease and the remaining patient from indeterminate colitis. All patients were treated with infliximab 5 mg/kg every 8 weeks after undergoing induction at weeks 0, 2 and 6, with the exception of one patient. The duration of infliximab therapy ranged from 8 weeks to 4 years. Four patients treated with infliximab experienced sustained improvement of their IBD symptoms post transplantation, as documented by Harvey–Bradshaw Index scores demonstrating clinical remission. Of the remaining two patients, neither had sustained improvement of their IBD with infliximab or subsequent adalimumab. One patient was diagnosed with systemic lupus erythematosus and another with colorectal adenocarcinoma following anti‐TNF therapy. Otherwise, no side effects were attributed to anti‐TNF therapy.

Conclusions

Based on this case series, anti‐TNF therapy appears to be safe and effective for treating refractory IBD in patients post liver transplantation. These patients respond to anti‐TNF therapy similar to those who have not been previously transplanted.
A phase 1, randomized, placebo‐controlled, dose‐escalation study of an anti‐IL‐13 monoclonal antibody in healthy subjects and mild asthmatics
Authors: Hodsman Peter , Ashman Claire , Cahn Anthony , De Boever Erika , Locantore Nicholas , Serone Adrian , Pouliquen Isabelle
Published: May 2012

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• IL‐13 can recapitulate the key pathological and clinical features of asthma.

• Exhaled NO (FeNO) concentrations are elevated under conditions of pulmonary inflammation, including asthma.

• Therapies that inhibit signalling by both IL‐13 and the functionally redundant cytokine IL‐4 have demonstrated reductions in FeNO, although relationship to dose was not reported.

WHAT THIS STUDY ADDS

• This study provides the first report of the safety and pharmacokinetics of GSK679586, a novel humanized monoclonal antibody that prevents IL‐13 from binding its two known receptors.

• This is the first report of the effects on FeNO of a therapy targeting IL‐13 alone. Inhibition of IL‐13 signalling by GSK679586 produces dose‐ and time‐dependent reductions in FeNO in mild intermittent asthmatics. Thus, FeNO appears to be a dose‐ and time‐responsive clinical biomarker of IL‐13 inhibition in mild asthma.

AIMS IL‐13 is implicated as an important mediator of the pathology of asthma. This first clinical study with GSK679586, a novel humanized anti‐IL‐13 IgG1 monoclonal antibody, evaluated the safety, pharmacokinetics and pharmacodynamics of escalating single and repeat doses of GSK679586.

METHODS In this randomized, double‐blind study, healthy subjects received single intravenous infusions of GSK679586 (0.005, 0.05, 0.5, 2.5, 10 mg kg−1) or placebo and mild intermittent asthmatics received two once monthly intravenous infusions of GSK679586 (2.5, 10, 20 mg kg−1) or placebo.

RESULTS GSK679586 displayed approximately linear pharmacokinetics (based on AUC and Cmax) with limited accumulation upon repeat administration. In mild intermittent asthmatics, treatment with GSK679586 produced an increase in serum total IL‐13 concentrations, indicative of GSK679586–IL‐13 complex formation. Additionally, mean levels of exhaled nitric oxide (FeNO), a marker of pulmonary inflammation, were reduced relative to baseline at 2.5, 10 and 20 mg kg−1 doses of GSK679586 at both 2 weeks (19%, 44% and 52% decreases) and 8 weeks (29%, 55% and 42% decreases) after the second infusion. GSK679586 was well tolerated; the incidence of AEs was comparable across all presumed biologically active doses and there were no treatment‐related SAEs.

CONCLUSIONS GSK679586 demonstrated dose‐dependent pharmacological activity in the lungs of mild intermittent asthmatics. These findings, together with the favourable safety profile and advantageous PK characteristics of a monoclonal antibody (e.g. a long half‐life supporting less frequent dosing), warrant further investigation of GSK679586 in a broader asthma patient population.
The pharmacokinetics and pharmacodynamics of single dose (R)‐ and (S)‐warfarin administered separately and together: relationship to VKORC1 genotype
Authors: Maddison John , Somogyi Andrew A. , Jensen Berit P. , James Heather M. , Gentgall Melanie , Rolan Paul E.
Published: May 2012

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• The contribution of (S)‐warfarin to the clinical effect of rac‐warfarin is well understood. The extent to which (R)‐warfarin contributes to the clinical effect of rac‐warfarin is unclear.

WHAT THIS STUDY ADDS

• Using unequivocally pure (R)‐ and (S)‐warfarin we have demonstrated that (R)‐warfarin contributes to the hypoprothrombinaemic effect of single large doses of warfarin.

• The extent of the interaction is dependent on VKORC1 genotype.

AIMS 1) To determine the pharmacokinetics and pharmacodynamics of (R)‐ and (S)‐warfarin given alone and in combination and 2) to determine whether the relative potency of (R)‐ and (S)‐warfarin is dependent on VKORC1 genotype.

METHODS A three way crossover study was conducted in which 17 healthy male subjects stratified by VKORC1 1173 C>T genotype and all CYP2C9 1*/1* received (R)‐warfarin 80 mg, (S)‐warfarin 12.5 mg and rac‐warfarin sodium 25 mg. Plasma (R)‐ and (S)‐warfarin unbound and total concentrations and prothrombin time were determined at multiple time points to 168 h.

RESULTS Pharmacokinetic parameters for (R)‐ and (S)‐warfarin were similar to the literature. (R)‐warfarin 80 mg alone resulted in a mean AUCPT (0,168 h) of 3550 s h (95% CI 3220, 3880). Rac‐warfarin sodium 25 mg containing (S)‐warfarin 11.7 mg produced a greater effect on AUCPT (0,168 h) than (S)‐warfarin 12.5 mg (mean difference 250 s.h, 95% CI 110, 380, P < 0.002) given alone. In a mixed effects model the ratio of response between (R)‐ and (S)‐warfarin (AUCPT((R)‐warfarin) : AUCPT((S)‐warfarin)) was 1.21 fold higher (95% CI 1.05, 1.41, P < 0.02) in subjects of VKORC1 TT genotype compared with the CC genotype.

CONCLUSIONS (R)‐warfarin has a clear PD effect and contributes to the hypoprothrombinaemic effect of rac‐warfarin. VKORC1 genotype is a covariate of the relative R/S potency relationship. Prediction of drug interactions with warfarin needs to consider effects on (R)‐warfarin PK and VKORC1 genotype.
Prospective parallel randomized trial of the MultiCyte™ ThinPrep® imaging system: the Scottish experience
Authors: Palmer T. J. , Nicoll S. M. , McKean M. E. , Park A. J. , Bishop D. , Baker L. , Imrie J. E. A.
Published: May 2012

T.J. Palmer, S.M. Nicoll, M.E. McKean, A.J. Park, D. Bishop, L. Baker and J.E.A. Imrie  Prospective parallel randomized trial of the MultiCyte™ ThinPrep® imaging system: the Scottish experience

Background:  Computer‐assisted screening of cervical liquid‐based cytology (LBC) preparations using the ThinPrep® Imaging System (TIS) has shown improved qualitative and quantitative gains. The use of Multicyte™ has not been described in a well‐established national screening programme with a low incidence of high‐grade dyskaryosis.

Objectives:  To assess the impact of computer‐assisted screening within the Scottish Cervical Screening Programme (SCSP).

Methods:  Two groups of three laboratories, each sharing a ThinPrep® Imager, screened 79 366 slides randomized to test and 90 551 to control arms by laboratory accession. Screeners were not blinded. Standard laboratory reporting profiles of the SCSP, sensitivity, specificity and false‐negative rates of all grades of LBC abnormalities with respect to final cytology reports, predictive value for cervical intraepithelial neoplasia grade 2 or worse (CIN2+) on histology; and screening rates were compared for both arms.

Results:  Inadequate and negative reporting rates were significantly lower and low‐grade reporting rates significantly higher in the imager arm. Imager‐assisted screening showed significantly better specificity than manual screening with respect to the final cytology result. There was no evidence of a significant difference in the detection of CIN2 +  or CIN3 + . Positive, abnormal and total predictive values (high‐grade, low‐grade and all abnormal cytology found to be CIN2 + , respectively) were similar in both arms. Productivity was significantly higher in the imager arm.

Conclusion:  Computer‐assisted screening in a well established screening programme showed significantly improved productivity without loss of quality. These findings should inform future policy for cervical screening programmes.
Proton pump inhibitors prescribing following the introduction of generic drugs
Authors: Cammarota Simona , Bruzzese Dario , Sarnelli Giovanni , Citarella Anna , Menditto Enrica , Riegler Salvatore , Savino Ivana G. , Vozzella Letizia , Piccinocchi Gaetano , Napoli Luigi , Arpino Giovanni , Cuomo Rosario
Published: May 2012

Eur J Clin Invest 2012; 42 (10): 1068–1078

Background  In many countries, the introduction of generic proton pump inhibitors (PPIs) onto the pharmaceutical market increased the phenomenon of therapeutic substitution in acid‐related disorders (ARDs).

Aim  To investigate the treatment of ARDs in an Italian primary care setting from 2005 to 2008 by verifying: (i) dynamics of PPI prescribing; (ii) predictors of PPI switching; and (iii) healthcare resource consumption costs.

Methods  This was a retrospective cohort study of 102 general practitioners (GPs) who managed an average of 150 000 inhabitants in Naples. Multilevel logistic regression was used to assess the potential predictors of both PPI switching and termination. Primary care costs were expressed as the cost of ARD management per PPI user year.

Results  The percentage of PPI users with ARD increased from 5·5% (2005) to 7·0% (2008) (P < 0·0001), especially for dyspepsia (from 9·5% to 13·7%; P < 0·0001) and chronic treatments (from 23·4% to 29·4%; P < 0·0001). PPI switching rose from 13·0% to 16·7% during the period observed (P < 0·0001). Calendar years, long‐term treatments and gastroesophageal reflux disease were positive predictors of PPI switching. Primary care costs relating to PPI switchers increased by 61·14€ compared with nonswitchers (P < 0·0001).

Conclusions  The introduction of generic PPIs onto the Italian market was associated with an increasing amount of PPI prescribing related to chronic treatments, unlicensed indications (e.g. dyspespsia) and therapeutic substitutions. Growing overall costs linked to the phenomenon of PPI switching was also found. Our data support the need to assess the effects of the introduction of generic drugs on both clinical outcomes and the cost management of ARDs.
Living a demanding life – spouses’ experiences of living with a person suffering from intermittent claudication
Authors: Egberg Louise , Andreassen Sissel , Mattiasson Anne‐Cathrine
Published: May 2012

egberg l., andreassen s. & mattiasson a‐c. (2013) Living a demanding life – spouses’ experiences of living with a person suffering from intermittent claudication. Journal of Advanced Nursing69(3), 610–618. doi: 10.1111/j.1365‐2648.2012.06043.x

Aim.  To report a study of family members’ experiences of living with a person suffering from intermittent claudication caused by peripheral arterial disease.

Background.  Intermittent claudication is a symptom caused by peripheral arterial disease. Walking ability is reduced due to pain and this also affects the family members and leads to consequences such as isolation and a restricted life.

Design.  This study has a qualitative descriptive design.

Methods.  Ten spouses living with a person suffering from intermittent claudication were interviewed between December 2009–June 2010. The interviews were then analysed using qualitative thematic analysis.

Findings.  Four themes were identified: ‘Frustrating to not meet intentions’, ‘Undergoing changes in social life’, ‘Being a person on the side of things’ and ‘Intertwining of circumstances’. The overall theme ‘Living a demanding life’ illustrates that intermittent claudication has great impact on daily life among spouses.

Conclusion.  This study gives an insight into the complexities and the difficulties of living together with someone suffering from intermittent claudication, a symptom that has great impact on both the spouses’ and the ill persons’ lives. According to the findings in this study, it is important to gain knowledge about the spouses’ experiences because an holistic perspective is essential to treat and support the ill persons and their spouses.
Using biological traits to explain ladybird distribution patterns
Authors: Comont Richard F. , Roy Helen E. , Lewis Owen T. , Harrington Richard , Shortall Christopher R. , Purse Bethan V.
Published: May 2012

Aim Determining to what extent differing distribution patterns are governed by species’ life‐history and resource‐use traits may lead to an improved understanding of the impacts of environmental change on biodiversity. We investigated the extent to which traits can explain distribution patterns in the ladybird fauna (Coleoptera: Coccinellidae) of Great Britain.

Location The British mainland and inshore islands (Anglesey, the Isle of Wight and the Inner Hebrides).

Methods The distributions of 26 ladybird species resident in Britain were characterized in terms of their range size (from 2661 10‐km grid squares across Britain) and proportional range fill (at 10‐ and 50‐km scales). These were assessed relative to five traits (body length, elytral colour pattern polymorphism, voltinism, habitat specificity and diet breadth). The role of phylogenetic autocorrelation was examined by comparing the results of phylogenetic and generalized least‐squares regressions.

Results Diet breadth was the only trait correlated with range size: species with broad diets had larger range sizes than dietary specialists. Range fill was sensitive to recording intensity (a per‐species measure of the mean number of records across occupied squares); models including both recording intensity and range size provided more explanatory power than models incorporating ecological traits alone.

Main conclusions Habitat specificity is often invoked to explain the distribution patterns of species, but here we found diet breadth to be the only ecological correlate of both range fill and range size. This highlights the importance of understanding predator–prey interactions when attempting to explain the distribution patterns of predatory species. Our results suggest that the diet breadth of predatory species is a better correlate of range size and fill than other measures, such as habitat specificity.
Fragmented esophageal smooth muscle contraction segments on high resolution manometry: a marker of esophageal hypomotility
Authors: Porter R. F. , Kumar N. , Drapekin J. E. , Gyawali C. P.
Published: May 2012

Background  Esophageal peristalsis consists of a chain of contracting striated and smooth muscle segments on high resolution manometry (HRM). We compared smooth muscle contraction segments in symptomatic subjects with reflux disease to healthy controls.

Methods  High resolution manometry Clouse plots were analyzed in 110 subjects with reflux disease (50 ± 1.4 years, 51.5% women) and 15 controls (27 ± 2.1 years, 60.0% women). Using the 30 mmHg isobaric contour tool, sequences were designated fragmented if either smooth muscle contraction segment was absent or if the two smooth muscle segments were separated by a pressure trough, and failed if both smooth muscle contraction segments were absent. The discriminative value of contraction segment analysis was assessed.

Key Results  A total of 1115 swallows were analyzed (reflux group: 965, controls: 150). Reflux subjects had lower peak and averaged contraction amplitudes compared with controls (P < 0.0001 for all comparisons). Fragmented sequences followed 18.4% wet swallows in the reflux group, compared with 7.5% in controls (P < 0.0001), and were seen more frequently than failed sequences (7.9% and 2.5%, respectively). Using a threshold of 30% in individual subjects, a composite of failed and/or fragmented sequences was effective in segregating reflux subjects from control subjects (P = 0.04).

Conclusions & Inferences  Evaluation of smooth muscle contraction segments adds value to HRM analysis. Specifically, fragmented smooth muscle contraction segments may be a marker of esophageal hypomotility.
High frequency of overlap between functional dyspepsia and overactive bladder
Authors: Matsuzaki J. , Suzuki H. , Fukushima Y. , Hirata K. , Fukuhara S. , Okada S. , Hibi T.
Published: May 2012

Background  Overactive bladder syndrome (OAB) is defined as a symptom complex comprising urgency, with or without urge incontinence, and usually frequency and nocturia. The association between irritable bowel syndrome (IBS) and bladder symptoms has been reported. This study is designed to investigate whether functional dyspepsia (FD), like IBS, is associated with OAB.

Methods  A web surveys containing questions about OAB, FD, IBS, and demographics were completed by 5494 public individuals (2302 men and 3192 women) who have no history of severe illness. The prevalence and overlap of OAB, FD, and IBS were examined.

Key Results  Among participants with FD, 20.5% could also be diagnosed with OAB (odds ratio [OR]: 2.85; 95% confidence interval [CI]: 2.21–3.67). Although concomitant FD and IBS were more strongly associated with OAB (OR: 4.34; 95% CI: 2.81–6.73), OAB was also highly prevalent among participants with FD but without IBS (OR: 3.09; 95% CI: 2.29–4.18). Among participants with FD, an overlapping OAB condition was more prevalent in those with both postprandial distress syndrome (PDS) and epigastric pain syndrome (EPS) (OR: 3.75; 95% CI: 2.48–5.67) than in those with PDS or EPS alone. Among participants with OAB, the severity of bladder symptoms was greater in participants with dyspeptic symptoms than without them.

Conclusions & Inferences  Overactive bladder syndrome is common among FD patients, even if they do not have IBS. To improve FD patients’ quality of life, it will be important to provide management for OAB.
Bilateral lung transplant for hereditary hemorrhagic telangiectasia in a pediatric patient
Authors: Misra Meghna V. , Mullen Mary P. , Vargas Sara O. , Kim Heung Bae , Boyer Debra
Published: May 2012

Misra MV, Mullen MP, Vargas SO, Kim HB, Boyer D. Bilateral lung transplant for hereditary hemorrhagic telangiectasia in a pediatric patient.

Abstract:  HHT is an autosomal dominant vascular dysplasia, in which abnormalities of endothelial cells cause patients to develop mucocutaneous telangiectasias, and AVMs of the pulmonary, hepatic, and cerebral circulations. Pulmonary AVMs occur in more than 20% of patients with HHT, and presentation varies from simple diffuse telangiectasias to large complex structures. Surgical management is usually indicated for large pulmonary AVMs. Treatment options for pulmonary AVMs include therapeutic embolization, segmental or lobar resection of the affected lung, and less commonly lung transplantation. Here we report the first successful case of a bilateral lung transplant for a four‐yr‐old girl with HHT.
Late graft failure in FA – case report and review of the literature
Authors: Ehlert Karoline , Groll Andreas H. , Rossig Claudia , Fruehwald Michael C. , Juergens Heribert
Published: May 2012

Ehlert K, Groll AH, Rossig C, Fruehwald MC, Juergens H. Late graft failure in FA – case report and review of the literature.

Abstract:  Hematological disorders in patients with FA can only be cured by allogeneic HSCT. Severe infections in primary and early secondary graft failures pose a particular risk. Whereas most graft failures occur within 100 days, those observed after day +100 are infrequent. Here, we present our analysis of a secondary graft failure more than five yr after a first allogeneic HSCT. In this patient, isolated thrombocytopenia over a period of 12 months resulted in a chimerism subset analysis revealing a considerable decrease in the CD34‐positive donor cell fraction. After a second fludarabine‐based preparative regimen, the patient received PBSC from the same donor. Chimerism returned to full donor in all subsets. This clinical course demonstrates that isolated thrombocytopenia can precede complete graft failure for several months. Our review of the literature on late graft failures in patients with FA after day +100 reveals the absence of fludarabine in the preparative regimen as a potential risk factor. Further clinical research is necessary to identify more suitable approaches for ensuring safe and stable engraftment.
Endovascular aneurysm repair: a perioperative perspective
Authors: WYLIE S. J. , WONG G. T. C. , CHAN Y. C. , IRWIN M. G.
Published: May 2012

Endovascular aneurysm repair (EVAR), has surpassed open repair as the technique of choice in many centres in response to several large studies which showed significantly improved 30‐day mortality. While several multicentre EVAR trials looked at surgical outcomes, very few have specifically investigated the effect of anaesthetic techniques or perioperative care of these patients. The purpose of this review to is to present some of the current evidence for the different aspects of perioperative management of patients undergoing EVAR. This includes surgical considerations, pre‐operative assessment, and choice of anaesthetic technique as well as pharmacological protective strategies.
Effect of current breastfeeding on sleep patterns in infants from Asia‐Pacific region
Authors: Ramamurthy Mahesh Babu , Sekartini Rini , Ruangdaraganon Nichara , Huynh Duy Houng T , Sadeh Avi , Mindell Jodi A
Published: May 2012

Aim:  The aim of this study was to assess the relationship between breastfeeding and sleep patterns in infants from Asia‐Pacific region.

Methods:  Parents of 10 321 infants (0–11 months) from Australia, China, Hong Kong, India, Indonesia, Korea, Japan, Malaysia, New Zealand, the Philippines, Singapore, Taiwan, Thailand and Vietnam completed an expanded version of the Brief Infant Sleep Questionnaire.

Results:  Overall, 4714 (45.72%) were currently being breastfed; 61.3% of those between 0 and 5 months and 36.6% of those between 6 and 11 months. Currently breastfed infants, when compared with not currently breastfed infants, had a significant increase in the number and duration of night‐time wakings and less consolidated sleep. Interestingly, currently breastfed infants less than 6 months also showed longer duration of daytime sleep and obtained more sleep overall. Of note, of those who were currently breastfed, those infants who were nursed back to sleep during night, woke up more often at night (2.41 vs. 1.67 times) and had shorter continuous night‐time sleep period (5.58 vs. 6.88 h; P < 0.001). There was no significant difference between breastfeeding and non‐breastfeeding infants in the number of night wakings, when the nursing to sleep variable was controlled for in the analysis of variance.

Conclusion:  Breastfeeding is associated with reduced sleep consolidation in infants. This relationship, however, may be moderated by parenting practices of nursing to sleep and back to sleep during the night. Thus, parents of infants with night waking problems should be encouraged to limit the association between nursing and falling to sleep, to improve sleep while maintaining breastfeeding.