bluuebunny/crossref_metadata_2025 huggingface dataset:
Detection and Classification of SPLCV Isolates in the U.S. Sweetpotato Germplasm Collection via a Real-Time PCR Assay and Phylogenetic Analysis
Authors: Barkley N. A. , Pinnow D. L. , Wang M. L. , Ling K. S. , Jarret R. L.
Published: June 2011

The United States Department of Agriculture–Agricultural Research Service sweetpotato (Ipomoea batatas) germplasm collection contains accessions that were initially collected from various countries worldwide. These materials have been maintained and distributed as in vitro plantlets since the mid-1980s. The status of viral infection by the emerging Sweet potato leaf curl virus (SPLCV) and other Begomovirus spp. in this germplasm has yet to be determined. In order to minimize the potential distribution of virus-infected clones, all accessions in the collection were tested for SPLCV using a real-time polymerase chain reaction assay. In total, 47 of 701 accessions of in vitro plantlets tested positive for SPLCV. The presence of SPLCV detected in these materials was confirmed via biological indexing using the indicator plants I. nil and I. muricata. Symptoms appeared more rapidly on I. muricata than on I. nil. Nucleotide polymorphisms among the isolates were evaluated by sequencing the AV1 coat protein gene from 24 SPLCV-infected accessions. The results revealed that the SPLCV isolates shared high sequence identity. Ten nucleotide substitutions were identified, most of which were synonymous changes. Phylogenetic analysis was conducted on those 24 SPLCV isolates in combination with six described SPLCV species and various SPLCV strains from GenBank to evaluate the relationships among viral species or strains. The results from this analysis indicated that most of the AV1 genes derived from previously classified SPLCV species clustered together, some of which formed well-supported monophyletic clades, further supporting the current taxonomy. Overall, identification of SPLCV-infected germplasm will allow approaches to be employed to eliminate the virus from the collection and limit the distribution of infected materials.
Activation of Opioid μ-Receptors in the Commissural Subdivision of the Nucleus Tractus Solitarius Abolishes the Ventilatory Response to Hypoxia in Anesthetized Rats
Authors: Zhang Zhenxiong , Zhuang Jianguo , Zhang Cancan , Xu Fadi
Published: June 2011

Background

: The commissural subnucleus of the nucleus tractus solitarius (comNTS) is a key region in the brainstem responsible for the hypoxic ventilatory response (HVR) because it contains the input terminals of the carotid chemoreceptor. Because opioids inhibit the HVR via activating central μ-receptors that are expressed abundantly in the comNTS, the authors of the current study asked whether activating local μ-receptors attenuated the carotid body-mediated HVR.

Methods

: To primarily stimulate the carotid body, brief hypoxia (100% N2) and hypercapnia (15% CO2) for 10 s and/or intracarotid injection of NaCN (10 μg/100 μl) were performed in anesthetized and spontaneously breathing rats. These stimulations were repeated after: (1) microinjecting three doses of μ-receptor agonist [d-Ala2, N-Me-Phe4, Gly-ol]-Enkephalin (DAMGO) (approximately 3.5 nl) into the comNTS; (2) carotid body denervation; and (3) systemic administration of DAMGO (300 μg/kg) without and with previous intracomNTS injection of d-Phe-Cys-Tyr-d-Trp-Arg-Thr-Pen-Thr-NH2, a μ-receptor antagonist.

Results

: Study results showed that DAMGO at 0.25 and 2.5, but not 0.025 mM, caused a similar decrease in baseline ventilation (approximately 12%). DAMGO at 0.25 mM largely reduced (64%) the HVR, whereas DAMGO at 2.5 mM abolished the HVR (and the VE response to NaCN) and moderately attenuated (31%) the hypercapnic ventilatory response. Interestingly, similar HVR abolition and depression of the hypercapnic ventilatory response were observed after carotid body denervation. Blocking comNTS μ-receptors by d-Phe-Cys-Tyr-d-Trp-Arg-Thr-Pen-Thr-NH2 significantly attenuated the HVR depression by systemic DAMGO with little change in the DAMGO modulatory effects on baseline ventilation and the hypercapnic ventilatory response.

Conclusion

: The data suggest that opioids within the comNTS, via acting on μ-receptors, are able to abolish the HVR by affecting the afferent pathway of the carotid chemoreceptor.
Quantum control in spintronics
Authors: Ardavan A. , Briggs G. A. D.
Published: July 2011

Superposition and entanglement are uniquely quantum phenomena. Superposition incorporates a phase that contains information surpassing any classical mixture. Entanglement offers correlations between measurements in quantum systems that are stronger than any that would be possible classically. These give quantum computing its spectacular potential, but the implications extend far beyond quantum information processing. Early applications may be found in entanglement-enhanced sensing and metrology. Quantum spins in condensed matter offer promising candidates for investigating and exploiting superposition and entanglement, and enormous progress is being made in quantum control of such systems. In gallium arsenide (GaAs), individual electron spins can be manipulated and measured, and singlet–triplet states can be controlled in double-dot structures. In silicon, individual electron spins can be detected by ionization of phosphorus donors, and information can be transferred from electron spins to nuclear spins to provide long memory times. Electron and nuclear spins can be manipulated in nitrogen atoms incarcerated in fullerene molecules, which in turn can be assembled in ordered arrays. Spin states of charged nitrogen vacancy centres in diamond can be manipulated and read optically. Collective spin states in a range of materials systems offer scope for holographic storage of information. Conditions are now excellent for implementing superposition and entanglement in spintronic devices, thereby opening up a new era of quantum technologies.
Organic spintronics
Authors: Bergenti I. , Dediu V. , Prezioso M. , Riminucci A.
Published: July 2011

Organic semiconductors are emerging materials in the field of spintronics. Successful achievements include their use as a tunnel barrier in magnetoresistive tunnelling devices and as a medium for spin-polarized current in transport devices. In this paper, we give an overview of the basic concepts of spin transport in organic semiconductors and present the results obtained in the field, highlighting the open questions that have to be addressed in order to improve devices performance and reproducibility. The most challenging perspectives will be discussed and a possible evolution of organic spin devices featuring multi-functional operation is presented.
New directions in spintronics
Authors: Marrows C. H. , Hickey B. J.
Published: July 2011

Conventional microelectronics exploits only the charge degree of freedom of the electron. Bringing the spin degree of freedom to bear on sensing, radio frequency, memory and logic applications opens up new possibilities for ‘more than Moore’ devices incorporating magnetic components that can couple to an external field, store a bit of data or represent a Boolean state. Moreover, the electron spin is an archetypal two-state quantum system that is an excellent candidate for a solid-state realization of a qubit.
Using heterokaryons to understand pluripotency and reprogramming
Authors: Piccolo Francesco M. , Pereira Carlos F. , Cantone Irene , Brown Karen , Tsubouchi Tomomi , Soza-Ried Jorge , Merkenschlager Matthias , Fisher Amanda G.
Published: July 2011

Reprogramming differentiated cells towards pluripotency can be achieved by different experimental strategies including the forced expression of specific ‘inducers’ and nuclear transfer. While these offer unparalleled opportunities to generate stem cells and advance disease modelling, the relatively low levels of successful reprogramming achieved (1–2%) makes a direct analysis of the molecular events associated with productive reprogramming very challenging. The generation of transient heterokaryons between human differentiated cells (such as lymphocytes or fibroblasts) and mouse pluripotent stem cell lines results in a much higher frequency of successful conversion (15% SSEA4 expressing cells) and provides an alternative approach to study early events during reprogramming. Under these conditions, differentiated nuclei undergo a series of remodelling events before initiating human pluripotent gene expression and silencing differentiation-associated genes. When combined with genetic or RNAi-based approaches and high-throughput screens, heterokaryon studies can provide important new insights into the factors and mechanisms required to reprogramme unipotent cells towards pluripotency.
Using stem cells to study and possibly treat type 1 diabetes
Authors: Melton D. A.
Published: July 2011

Stem cells with the potential to form many different cell types are actively studied for their possible use in cell replacement therapies for several diseases. In addition, the differentiated derivatives of stem cells are being used as reagents to test for drugs that slow or correct disease phenotypes found in several degenerative diseases. This paper explores these approaches in the context of type 1 or juvenile diabetes, pointing to recent successes as well as the technical and theoretical challenges that lie ahead in the path to new treatments and cures.
Modelling familial dysautonomia in human induced pluripotent stem cells
Authors: Lee Gabsang , Studer Lorenz
Published: July 2011

Induced pluripotent stem (iPS) cells have considerable promise as a novel tool for modelling human disease and for drug discovery. While the generation of disease-specific iPS cells has become routine, realizing the potential of iPS cells in disease modelling poses challenges at multiple fronts. Such challenges include selecting a suitable disease target, directing the fate of iPS cells into symptom-relevant cell populations, identifying disease-related phenotypes and showing reversibility of such phenotypes using genetic or pharmacological approaches. Finally, the system needs to be scalable for use in modern drug discovery. Here, we will discuss these points in the context of modelling familial dysautonomia (FD, Riley–Day syndrome, hereditary sensory and autonomic neuropathy III (HSAN-III)), a rare genetic disorder in the peripheral nervous system. We have demonstrated three disease-specific phenotypes in FD-iPS-derived cells that can be partially rescued by treating cells with the plant hormone kinetin. Here, we will discuss how to use FD-iPS cells further in high throughput drug discovery assays, in modelling disease severity and in performing mechanistic studies aimed at understanding disease pathogenesis. FD is a rare disease but represents an important testing ground for exploring the potential of iPS cell technology in modelling and treating human disease.
Epigenetic reprogramming in the germline: towards the ground state of the epigenome
Authors: Hajkova Petra
Published: July 2011

Epigenetic reprogramming in the germline provides a developmental model to study the erasure of epigenetic memory as it occurs naturallyin vivoin the course of normal embryonic development. Our data show that germline reprogramming comprises both active DNA demethylation and extensive chromatin remodelling that are mechanistically linked through the activation of the base excision DNA repair pathway involved in the DNA demethylation process. The observed molecular hallmarks of the germline reprogramming exhibit intriguing similarities to other dedifferentiation or regeneration systems, pointing towards the existence of unifying molecular pathways underlying cell fate reversal. Elucidation of molecular processes involved in the resetting of epigenetic informationin vivowill thus add to our ability to manipulate cell fate and to restore pluripotency inin vitrosettings.
Transcription factor heterogeneity and epiblast pluripotency
Authors: Osorno Rodrigo , Chambers Ian
Published: July 2011

Stem cells are defined by the simultaneous possession of the seemingly incongruent properties of self-renewal and multi-lineage differentiation potential. To maintain a stem cell population, these opposing forces must be balanced. Transcription factors that function to direct pluripotent cell identity are not all equally distributed throughout the pluripotent cell population. While Oct4 levels are relatively homogeneous, other transcription factors, such as Nanog, are more heterogeneously expressed. Moreover, Oct4 positive cells fluctuate between states of high Nanog expression associated with a high probability of self-renewal and low Nanog expression associated with an increased propensity to differentiate. As embryonic stem (ES) cells transit to the more developmentally advanced epiblast stem cell (EpiSC) state, the levels of pluripotency transcription factors are modulated. Such modulations are blunted in cells that overexpress Nanog and this may underlie the resistance of Nanog-overexpressing cells to transit to an EpiSC state. Interestingly, increasing the levels of Nanog in EpiSC can facilitate reversion to the ES cell state. Together these observations suggest that Nanog lies close to the top of the hierarchy of pluripotent transcription factor regulation.
The evolving biology of cell reprogramming
Authors: Wilmut Ian , Sullivan Gareth , Chambers Ian
Published: July 2011

Modern stem cell biology has achieved a transformation that was thought by many to be every bit as unattainable as the ancient alchemists' dream of transforming base metals into gold. Exciting opportunities arise from the process known as ‘cellular reprogramming’ in which cells can be reliably changed from one tissue type to another. This is enabling novel approaches to more deeply investigate the fundamental basis of cell identity. In addition, new opportunities have also been created to study (perhaps even to treat) human genetic and degenerative diseases. Specific cell types that are affected in inherited disease can now be generated from easily accessible cells from the patient and compared with equivalent cells from healthy donors. The differences in cellular phenotype between the two may then be identified, and assays developed to establish therapies that prevent the development or progression of disease symptoms. Cellular reprogramming also has the potential to create new cells to replace those whose death or dysfunction causes disease symptoms. For patients suffering from inherited cases of degenerative diseases like Parkinson's disease or amyotrophic lateral sclerosis (also known as motor neuron disease), the future realization of such cell-based therapies would truly be worth its weight in gold. However, before this enormous potential can become a reality, several significant biological and technical challenges must be overcome. Furthermore, to maintain the credibility of the scientific community with the general public, it is important that hope-inspiring advances are not over-hyped. The papers in this issue of the
Philosophical Transactions of the Royal Society B
:
Biological Sciences
cover many areas relevant to this topic. In this
Introduction
, we provide an overall context in which to consider these individual papers.
The vaccinia virus A56 protein: a multifunctional transmembrane glycoprotein that anchors two secreted viral proteins
Authors: DeHaven Brian C. , Gupta Kushol , Isaacs Stuart N.
Published: June 2011

The vaccinia virus A56 protein was one of the earliest-described poxvirus proteins with an identifiable activity. While originally characterized as a haemagglutinin protein, A56 has other functions as well. The A56 protein is capable of binding two viral proteins, a serine protease inhibitor (K2) and the vaccinia virus complement control protein (VCP), and anchoring them to the surface of infected cells. This is important; while both proteins have biologically relevant functions at the cell surface, neither one can locate there on its own. The A56–K2 complex reduces the amount of virus superinfecting an infected cell and also prevents the formation of syncytia by infected cells; the A56–VCP complex can protect infected cells from complement attack. Deletion of theA56Rgene results in varying effects on vaccinia virus virulence. In addition, since the gene encoding the A56 protein is non-essential, it can be used as an insertion point for foreign genes and has been deleted in some viruses that are in clinical development as oncolytic agents.
Inoculation of young horses with bovine papillomavirus type 1 virions leads to early infection of PBMCs prior to pseudo-sarcoid formation
Authors: Hartl Bettina , Hainisch Edmund K. , Shafti-Keramat Saeed , Kirnbauer Reinhard , Corteggio Annunziata , Borzacchiello Giuseppe , Tober Reinhard , Kainzbauer Christina , Pratscher Barbara , Brandt Sabine
Published: June 2011

Bovine papillomavirus types 1 and 2 (BPV-1 and BPV-2) are known to induce common equine skin tumours, termed sarcoids. Recently, it was demonstrated that vaccination with BPV-1 virus-like particles (VLPs) is safe and highly immunogenic in horses. To establish a BPV-1 challenge model for evaluation of the protective potential of BPV-1 VLPs, four foals were injected intradermally with infectious BPV-1 virions and with viral genome-based and control inocula, and monitored daily for tumour development. Blood was taken before inoculation and at weekly intervals. BPV-1-specific serum antibodies were detected by a pseudo-virion neutralization assay. Total nucleic acids extracted from tumours, intact skin and PBMCs were tested for the presence of BPV-1 DNA and mRNA using PCR and RT-PCR, respectively. Intralesional E5 oncoprotein expression was determined by immunofluorescence. Pseudo-sarcoids developed exclusively at sites inoculated with virions. Tumours became palpable 11–32 days after virion challenge, reached a size of ≤20 mm in diameter and then resolved in ≤6 months. No neutralizing anti-BPV-1 serum antibodies were detectable pre- or post-challenge. BPV-1 DNA was present in lesions but not in intact skin. In PBMCs, viral DNA was already detectable before lesions were first palpable, in concentrations correlating directly with tumour growth kinetics. PBMCs from two of two foals also harboured E5 mRNA. Immunofluorescence revealed the presence of the E5 protein in tumour fibroblasts, but not in the apparently normal epidermis overlying the lesions. Together with previous findings obtained in horses and cows, these data suggest that papillomavirus infection may include a viraemic phase.
Complement‐mediated tumor‐specific cell lysis by antibody combinations targeting epidermal growth factor receptor (EGFR) and its variant III (EGFRvIII)
Authors: Klausz Katja , Berger Sven , Lammerts van Bueren Jeroen J. , Derer Stefanie , Lohse Stefan , Dechant Michael , van de Winkel Jan G. J. , Peipp Matthias , Parren Paul W. H. I. , Valerius Thomas
Published: June 2011

Monoclonal antibodies (mAb) against variant III of epidermal growth factor receptor (EGFRvIII) hold promise for improving tumor selectivity of EGFR‐targeted therapy. Here, we compared Fc‐mediated effector functions of three mAb against EGFRvIII (MR1‐1, ch806, 13.1.2) with those of zalutumumab, a high affinity EGFR mAb in advanced clinical trials. MR1‐1 and ch806 demonstrated preferential and 13.1.2 exclusive binding to EGFRvIII, in contrast to zalutumumab, which bound both wild‐type and EGFRvIII. All four human IgG1κ mAb mediated antibody‐dependent cellular cytotoxicity (ADCC) of EGFRvIII‐expressing cells with mononuclear cells and isolated monocytes, while only zalutumumab in addition triggered ADCC by polymorphonuclear cells. Interestingly, combinations of zalutumumab and EGFRvIII mAb specifically mediated complement‐dependent cytotoxicity (CDC) of EGFRvIII‐transfected but not wild‐type cells. Moreover, EGFRvIII‐specific CDC was significantly enhanced when zalutumumab was combined with a Fc‐engineered variant of MR1‐1 (K326A/E333A). These observations confirm the immunotherapeutic potential of antibody combinations against EGFR, and demonstrate that tumor selectivity can be improved by combining therapeutic EGFR mAb with an antibody against EGFRvIII. (Cancer Sci 2011; 102: 1761–1768)
Roles of AKT1 and AKT2 in non‐small cell lung cancer cell survival, growth, and migration
Authors: Lee Myoung W. , Kim Dae S. , Lee Joo H. , Lee Bum S. , Lee Soo H. , Jung Hye L. , Sung Ki W. , Kim Heung T. , Yoo Keon H. , Koo Hong H.
Published: July 2011

Although AKT/protein kinase B is constitutively active in non‐small cell lung cancer (NSCLC) cells and is an attractive target for enhancing the cytotoxicity of therapeutic agents, the distinct roles of the AKT isoforms in NSCLC are largely unknown. In the present study, we investigated the roles of AKT1 and AKT2 in NSCLC cells using RNAi. The siRNA targeting of AKT1 or AKT2 effectively decreased protein levels of AKT1 and AKT2, respectively, in A549 and H460 cells. Cisplatin treatment of these cells increased apoptotic cell death compared with control. The siRNA‐induced knockdown of AKT1 in H460 cells significantly decreased basal MEK/ERK1/2 activity, resulting in nuclear factor‐κB activation, whereas knockdown of AKT2 resulted in anti‐apoptotic Bcl‐2 family protein MCL‐1 (MCL‐1) cleavage, the collapse of mitochondrial membrane potential, cytochrome c release, and activation of the caspase cascade. Consequently, both siRNA treatments enhanced the chemosensitivity of H460 cells to cisplatin. However, neither AKT1 nor AKT2 siRNA treatment had any effect of p27 expression, and although both treatments tended to induced G2/M phase arrest, the effect was not statistically significant. Treatment with AKT1 siRNA markedly decreased colony formation growth and migration, but AKT2 siRNA had no significant effects on these parameters. These data suggest that AKT1 and AKT2 both contribute to cell survival, albeit via different mechanisms, and that the effects on cell growth and migration are predominantly regulated by AKT1. These findings may aid in refining targeted strategies for the inhibition of AKT isoforms towards the sensitization of NSCLC cells to therapeutic agents. (Cancer Sci 2011; 102: 1822–1828)
The effect of transoesophageal echocardiography probe insertion on tracheal cuff pressure
Authors: Tan P.‐H. , Lin V.‐C. , Chen H.‐S. , Hung K.‐C.
Published: June 2011

Increased tracheal cuff pressure during mechanical ventilation is associated with reduced mucosal blood flow and ischaemia, as well as postoperative sore throat. We assessed the potential effects of transoesophageal echocardiography probe insertion on the tracheal cuff pressure in patients undergoing cardiac surgery. Using a manometer, the cuff pressure of a high‐volume, low‐pressure tracheal tube (inner diameter 7.0 mm for women and 7.5 mm for men) was adjusted to 25–30 cmH2O before blind insertion of a transoesophageal echocardiography probe. The pressure changes were then recorded for 1 min. After probe insertion, the mean (SD) intra‐cuff pressure increased from 27.7 (1.5) to 36.2 (6.4) cmH2O (p < 0.001) and was > 35 cmH20 in 17/38 patients (45%). Our results suggest that transoesophageal echocardiography probe insertion may increase the tracheal cuff pressure more than that is generally recommended and therefore the latter should be routinely monitored under such circumstances.
Single dose pharmacokinetics of the transdermal rotigotine patch in patients with impaired renal function
Authors: Cawello Willi , Ahrweiler Sascha , Sulowicz Wladyslaw , Szymczakiewicz‐Multanowska Agnieszka , Braun Marina
Published: June 2011

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• The transdermal dopamine agonist rotigotine has been shown to be an efficacious and well tolerated treatment for Parkinson's disease and restless legs syndrome in clinical trials.

• The prevalence of Parkinson's disease and restless legs syndrome increases with age.

• Renal function deteriorates with age and can influence drug treatment.

• Many patients with end‐stage renal disease experience restless legs syndrome.

WHAT THIS STUDY ADDS

• The pharmacokinetic profiles of the active substance, unconjugated rotigotine, were similar in healthy subjects and subjects with renal impairment.

• The results suggest that no dose adjustments are required for transdermal rotigotine in subjects with different stages of chronic renal insufficiency including patients on haemodialysis.

AIM

To evaluate the influence of different stages of chronic renal insufficiency on the pharmacokinetics and safety/tolerability of the transdermally applied dopamine agonist rotigotine in an open label group comparison including 32 subjects (healthy, mild, moderate or severe impairment of renal function and patients with end‐stage renal insufficiency requiring haemodialysis).

METHODS All subjects received a single transdermal 10 cm2 patch (24 h patch‐on period) containing 4.5 mg rotigotine (nominal drug release 2 mg 24 h−1). Main evaluations included relative bioavailability and renal elimination of rotigotine and its metabolites.

RESULTS

Point estimates for the ratios between the groups with moderate to severe renal impairment and healthy subjects for the pharmacokinetic parameters AUC(0,tlast) and Cmax for the active substance unconjugated rotigotine were near 1:0.88 for AUC and 0.93 for Cmax for moderate renal impairment, 1.14 and 1.18 for severe renal impairment and 1.05 and 1.25 for end‐stage renal insufficiency requiring haemodialysis. There was no correlation of these parameters with creatinine clearance. The amount of unconjugated rotigotine excreted into urine and renal clearance decreased with increasing severity of renal insufficiency but had no observable effect on total clearance as the amounts excreted were below 1% of the administered dose. Occurrence of adverse events did not increase with the degree of renal insufficiency.

CONCLUSIONS

The pharmacokinetic profiles of unconjugated rotigotine were similar in healthy subjects and subjects with impaired renal function indicating that no dose adjustments are required for transdermal rotigotine in patients with different stages of chronic renal insufficiency including patients on haemodialysis.
microRNA-mediated keratinocyte hyperproliferation in psoriasis vulgaris
Authors: Ichihara A. , Jinnin M. , Yamane K. , Fujisawa A. , Sakai K. , Masuguchi S. , Fukushima S. , Maruo K. , Ihn H.
Published: June 2011

Background Psoriasis is a chronic inflammatory skin disease characterized by intense proliferation and abnormal differentiation of keratinocytes, although the pathogenesis is still not completely clarified.

Objectives We investigated the mechanism of keratinocyte proliferation seen in psoriasis, focusing on microRNA (miRNA).

Materials and methods miRNAs were extracted from tissues and sera of psoriasis, atopic dermatitis and healthy control. To determine pathogenic miRNAs, we performed miRNA polymerase chain reaction (PCR) array analysis. The results were confirmed with quantitative real-time PCR, in situ hybridization, immunohistochemistry, transient transfection of siRNA and inhibitor in cultured keratinocytes and Western blotting.

Results PCR array analysis using tissue miRNA demonstrated miR-424 level was markedly decreased in psoriasis skin in vivo. Protein expression of mitogen-activated protein kinase kinase 1 (MEK1) or cyclin E1, predicted target genes of miR-424, was increased in psoriatic skin, although their mRNA levels were not. The transfection of specific inhibitor of miR-424 in normal human keratinocytes led to upregulation of MEK1 or cyclin E1 protein, and resulted in increased cell proliferation. On the other hand, cell number was significantly decreased when cells were transfected with siRNA for MEK1 or cyclin E1. Furthermore, we first investigated serum miRNA levels in psoriasis. Although not significant, serum miR-424 concentration tended to be decreased in patients with psoriasis compared with healthy controls.

Conclusions Decreased miR-424 expression and subsequently increased MEK1 or cyclin E1 may play a key role in the pathogenesis of psoriasis. Investigation of the regulatory mechanisms of keratinocyte proliferation by miRNA may lead to new treatments and a disease activity marker.
Haemophilia: provision of factors and novel therapies: World Federation of Hemophilia goals and achievements
Authors: Skinner Mark W.
Published: June 2011

For nearly 50 years, the goal of the World Federation of Hemophilia (WFH) has been to achieve ‘Treatment for All’ patients with inherited bleeding disorders, regardless of where they live. With proper diagnosis, management and care, people with bleeding disorders can live perfectly healthy lives. Without treatment, the reality is that many will die young or, if they survive, suffer joint damage that leaves them with permanent disabilities. Only about 25% of the estimated 400 000 people with haemophilia worldwide receive adequate treatment. The percentage is far lower for those with von Willebrand Disease (VWD) and the rarer bleeding disorders. The achievements of the WFH to close the gap in care for people with bleeding disorders are measureable over time by using three key indicators; the difference in the estimated and actual number of people known with bleeding disorders, the amount of treatment products needed versus that available, and the number of people born with bleeding disorders and the number who reach adulthood. There are five essential elements to achieve a sustainable national care programme: ensuring accurate laboratory diagnosis, achieving government support, improving the care delivery system, increasing the availability of treatment products, and building a strong national patient organization.
The relationship between motor competence, physical fitness and self‐perception in children
Authors: Vedul‐Kjelsås V. , Sigmundsson H. , Stensdotter A.‐K. , Haga M.
Published: June 2011

Aim  The aim of the current research was to explore the relationship between motor competence, physical fitness and self‐perception, and to study to which extent this relationship may vary by gender.

Methods  A sample of 67 children (mean age 11.46 years, SD 0.27) completed Harter's Self‐Perception Profile for Children (SPPC), the Movement Assessment Battery for Children (MABC) and the Test of Physical Fitness (TPF) to assess self‐perception, motor competence and physical fitness.

Results  The SPPC was stronger related to total score on TPF than to total score on MABC. However, when looking at boys and girls separately, this result was found for the boys only. In the group in general, total scores on both TPF and MABC correlated significantly with three of the domains of SPPC (social acceptance, athletic competence and physical appearance) and general self‐worth. This relationship varied by gender. Interestingly, TPF was highest correlated with perception of athletic competence in boys but with perception of social acceptance in girls. A high and significant correlation was found between physical fitness and motor competence for both genders.

Conclusion  The results indicated a strong relationship between physical fitness, motor competence and self‐perception in children that varied by gender. This implies that all these factors are essential contributions in order to facilitate participation in physical activity in children.
Accidental injuries are more common in children with attention deficit hyperactivity disorder compared with their non‐affected siblings
Authors: Shilon Y. , Pollak Y. , Aran A. , Shaked S. , Gross‐Tsur V.
Published: July 2011

Background  Accidental injuries are a leading cause of paediatric morbidity and mortality. We hypothesized that attention deficit hyperactivity disorder (ADHD), a common childhood disorder characterized by behaviours such as hyperactivity and impulsivity, is a risk factor for accidental injuries. Previous retrospective studies suggested that children with ADHD have an increased injury rate, but controlled prospective studies are lacking.

Methods  We conducted a prospective case–control study of 29 school‐aged children with ADHD and their same‐sex, similarly aged, non‐ADHD‐affected siblings. All diagnoses were made by a paediatric neurologist according to DSM‐IV criteria and the children and their parents underwent a structured psychiatric interview and a battery of complementary assessments including: Child Behavior Checklist (CBCL), ADHD Rating scale and Developmental Coordination Disorder Questionnaire (DCDQ). The parents were contacted by telephone every 3 months during a 9‐month follow‐up period and all injuries requiring medical attention were recorded. Incidence of injuries was compared between the pairs of siblings.

Results  During the follow‐up period, a total of 13 injuries in 13 children with ADHD were reported, compared with six injuries in six children from the control group (Z=−2.11, P < 0.05). ADHD severity and subtype, CBCL, DCDQ and IQ scores were not predictive of injury risk.

Conclusions  School‐aged children with ADHD are at higher risk of accidental injuries than their non‐ADHD siblings, regardless of ADHD subtype, co‐morbid psychiatric conditions, developmental co‐ordination problems and environmental/familial conditions. Awareness and adequate education of parents and caregivers of children with ADHD concerning the increased injury risks are thus warranted.
How do children with a chronic or long‐term illness perceive their school re‐entry after a period of homebound instruction?
Authors: Boonen H. , Petry K.
Published: July 2011

Background  A considerable number of children are confronted with a chronic or long‐term illness in their lives. For these children, absenteeism is problematic, because education plays a major role in stimulating their cognitive development and in promoting a sense of normalcy and psychosocial well‐being. In the literature, a great deal of attention has been paid to school reintegration programmes, which try to counter the barriers that these children may face when they return to school. Another way of surmounting these barriers is through the use of homebound instruction, in which the educational process for the child is continued during the period of absence. Despite the growing awareness of the necessity of education for these children, there is still little empirical research available addressing programmes that facilitate school re‐entry.

Methods  The major goal of this study is to investigate how parents and their children with a chronic or long‐term illness perceive school re‐entry after a period of homebound instruction, by using a descriptive–explorative, multi‐informant research design. Participants were 60 children and their parents who filled in a self‐constructed questionnaire.

Results  Both parents and children perceived the period of homebound instruction, as well as their school re‐entry, predominantly positively. Most of the children stated that they had been able to keep up with their subjects, and that they had good contact with their peers when they returned to school. According to parents, homebound instruction made a positive contribution to the school re‐entry of their child.

Conclusions  The current study is one of the first to explore the school re‐entry of children with a chronic or long‐term illness. According to both parents and children, the school re‐entry process passed off positively. However, more research is needed with regard to the quality of education and the programmes aimed at facilitating school re‐entry.
Molecular characterization of Der p 10: a diagnostic marker for broad sensitization in house dust mite allergy
Authors: Resch Y. , Weghofer M. , Seiberler S. , Horak F. , Scheiblhofer S. , Linhart B. , Swoboda I. , Thomas W. R. , Thalhamer J. , Valenta R. , Vrtala S.
Published: June 2011

Background Tropomyosins represent clinically relevant seafood allergens but the role of mite tropomyosin, Der p 10, in house dust mite (HDM) allergy has not been studied in detail.

Objective To express and purify a recombinant Der p 10 with equivalent IgE reactivity as natural Der p 10 and to evaluate its IgE reactivity and allergenic activity in HDM‐allergic patients.

Methods rDer p 10 was expressed in Escherichia coli, purified and characterized by mass spectrometry and circular dichroism. It was tested for IgE reactivity in 1322 HDM‐allergic patients. Detailed IgE‐reactivity profiles to six HDM allergens (Der p 1, 2, 5, 7, 10, 21) were established for subgroups of Der p 10‐positive and ‐negative patients. The allergenic activity of rDer p 10 was evaluated in basophil degranulation experiments.

Results rDer p 10 is an α‐helical protein sharing IgE epitopes with nDer p 10. It is recognized by 15.2% of HDM‐allergic patients. Der p 10‐negative patients were primarily sensitized to Der p 1 and/or Der p 2, whereas Der p 10‐positive patients reacted to several other HDM allergens besides the major allergens (Der p 1, Der p 2) or showed a rather selective Der p 10 reactivity. The allergenic activity of Der p 10 was generally low but patients could be identified who suffered from clinically relevant HDM allergy due to Der p 10 sensitization.

Conclusion and Clinical Relevance Der p 10 may be a diagnostic marker for HDM‐allergic patients with additional sensitization to allergens other than Der p 1 and Der p 2. Such patients may require attention when allergen‐specific immunotherapy is considered.

Cite this as: Y. Resch, M. Weghofer, S. Seiberler, F. Horak, S. Scheiblhofer, B. Linhart, I. Swoboda, W. R. Thomas, J. Thalhamer, R. Valenta and S. Vrtala, Clinical & Experimental Allergy, 2011 (41) 1468–1477.
Reciprocal expression of IL‐25 and IL‐17A is important for allergic airways hyperreactivity
Authors: Barlow J. L. , Flynn R. J. , Ballantyne S. J. , McKenzie A. N. J.
Published: July 2011

Background Interleukin (IL)‐25 (IL‐17E) is a potent inducer of the type‐2 immune effector response. Previously we have demonstrated that a neutralizing anti‐IL‐25 antibody, given during the establishment of ovalbumin‐specific lung allergy, abrogates airways hyperreactivity.

Objective Blocking IL‐25 results in the suppression of IL‐13, a cytokine known to exacerbate pulmonary inflammation, and an unexpected reciprocal increase in IL‐17A. The role of IL‐17A in asthma is complex with reports of both pro‐inflammatory and anti‐inflammatory functions. Our aim was to determine the influence of IL‐17A in regulating IL‐25‐dependent lung allergy.

Method Neutralizing antibodies to IL‐25 and/or IL‐17A were administered during an experimental model of allergic asthma. Bronchoalveolar cell infiltrates and lung cytokine production were determined to assess lung inflammation. Invasive plethysmography was undertaken to measure lung function.

Results Neutralization of IL‐25 correlated with a decrease in IL‐13 levels and an increase in IL‐17A production, and an accompanying prevention of airway hyperresponsiveness (AHR). Notably, the blocking of IL‐17A reversed the protective effects of treating with anti‐IL‐25 antibodies, resulting in the re‐expression of several facets of the lung inflammatory response, including IL‐13 and eotaxin production, eosinophilia and AHR. Using mice over‐expressing IL‐13 we demonstrate that treatment of these mice with anti‐IL‐25 fails to suppress IL‐13 levels and in turn IL‐17A levels remain suppressed.

Conclusions and Clinical Relevance IL‐13 is known to be an important inducer of lung inflammation, causing goblet cell hyperplasia and promoting airways hyperreactivity. Our data now demonstrate that IL‐13 also plays an important role in the genesis of lung inflammation downstream of IL‐25 by suppressing a protective IL‐17A response. These findings also highlight the important reciprocal interplay of the IL‐17 family members, IL‐25 and IL‐17A, in regulating allergic lung responses and suggest that the balance of IL‐17A, together with IL‐25, will be an important consideration in the treatment of allergic asthma.

Cite this as: J. L. Barlow, R. J. Flynn, S. J. Ballantyne and A. N. J. McKenzie, Clinical & Experimental Allergy, 2011 (41) 1447–1455.
Altered phenotype of regulatory T cells associated with lack of human immunodeficiency virus (HIV)-1-specific suppressive function
Authors: Burton C T , Westrop S J , Eccles-James I , Boasso A , Nelson M R , Bower M , Imami N
Published: June 2011

Mechanisms by which CD4+ regulatory T cells (Tregs) mediate suppression of virus-specific responses remain poorly defined. Adenosine, mediated via CD39 and CD73, has been shown to play a role in the action of murine Tregs. In this study we investigate the phenotype of Tregs in the context of human immunodeficiency virus (HIV)-1 infection, and the function of these cells in response to HIV-1-Gag and cytomegalovirus (CMV) peptides. Phenotypic data demonstrate a decrease in forkhead box transcription factor 3 (FoxP3+) Treg numbers in the peripheral blood of HIV-1+ individuals compared to healthy controls, which is most pronounced in those with high HIV-1 RNA plasma load. Due to aberrant expression of CD27 and CD127 during HIV-1 disease, these markers are unreliable for Treg identification. The CD3+CD4+CD25hiCD45RO+ phenotype correlated well with FoxP3 expression in both the HIV-1+ and seronegative control cohorts. We observed expression of CD39 but not CD73 on Tregs from HIV-1+ and healthy control cohorts. We demonstrate, through Treg depletion, the suppressive potential of Tregs over anti-CMV responses in the context of HIV-1 infection; however, no recovery of the HIV-1-specific T cell response was observed indicating a preferential loss of HIV-1-specific Treg function. We propose that before immunotherapeutic manipulation of Tregs is considered, the immunoregulatory profile and distribution kinetics of this population in chronic HIV-1 infection must be elucidated fully.
Identification of a novel mutation in the exon 2 splice donor site of the POU1F1/PIT‐1 gene in Japanese identical twins with mild combined pituitary hormone deficiency
Authors: Inoue Hiroshi , Mukai Tokuo , Sakamoto Yukiko , Kimura Chizuko , Kangawa Natsumi , Itakura Mitsuo , Ogata Tsutomu , Ito Yoshiya , Fujieda Kenji ,   on behalf of the Japan Growth Genome Consortium
Published: July 2011

Context  To date, approximately 35 different POU1F1 mutations have been described in patients with familial and sporadic combined pituitary hormone deficiency (CPHD) from different ethnic backgrounds. The majority are missense mutations clustered within the conserved POU‐specific and POU‐homeo domains, encoded by exons 4 and 6, respectively.

Objectives  This study aimed to identify the molecular basis and clinical characteristics of a Japanese CPHD family with a novel POU1F1 mutation.

Design  The POU1F1 gene was sequenced in identical twin brothers with mild CPHD. The mutation identified was also evaluated in family members as well as 188 Japanese controls and then examined in functional studies.

Results  A novel heterozygous splice site mutation (Ex2 + 1G>T; c.214 + 1G>T) was detected. This mutation was also present in their undiagnosed mother, but not in any of the controls. In vitro splicing studies suggested this mutation to result in an in‐frame skipping of exon 2, thus producing an internally deleted protein lacking most of the R2 transactivation subdomain (TAD‐R2). Heterologous expression studies of the mutated POU1F1 protein showed only modest reductions in its transactivation activities in HEK293T cells, while acting as a dominant‐negative inhibitor of the endogenous activities of POU1F1 in pituitary GH3 cells.

Conclusions  This is the first report of a mutation at the exon 2 donor splice site of POU1F1, affecting TAD‐R2. The addition of this mutation to the growing list of pathological POU1F1 mutations may provide deeper insights into clinical heterogeneity in the expressions of individual mutations and a better understanding of the structure–function relationships of POU1F1.
Estimation and application of near‐surface full waveform redatuming operators
Authors: Haffinger Peter , Verschuur Eric
Published: July 2011

Land seismic data quality can be severely affected by near‐surface anomalies. The imprint of a complex near‐surface can be removed by redatuming the data to a level below the surface, from where the subsurface structures are assumed to be relatively smooth. However, to derive a velocity‐depth model that explains the propagation effects of the near‐surface is a non‐trivial task. Therefore, an alternative approach has been proposed, where the redatuming operators are obtained in a data‐driven manner from the reflection event related to the datum. In the current implementation, the estimation of these redatuming operators is done in terms of traveltimes only, based on a high‐frequency approximation. The accompanying amplitudes are usually derived from a local homogeneous medium, which is obviously a simplification of reality. Such parametrization has produced encouraging results in the past but cannot completely remove the near‐surface complexities, leaving artefacts in the redatumed results. In this paper we propose a method that estimates the redatuming operators directly from the data, i.e., without using a velocity model, in a full waveform manner, such that detailed amplitude and phase variations are included. The method directly outputs the inverse propagation operators that are needed for true‐amplitude redatuming. Based on 2D synthetic data it is demonstrated that the resulting redatuming quality is improved and artefacts are reduced.
Gene expression profiling in male genital lichen sclerosus
Authors: Edmonds Emma , Barton Geraint , Buisson Sandrine , Francis Nick , Gotch Frances , Game Laurence , Haddad Munther , Dinneen Michael , Bunker Chris
Published: June 2011

Male genital lichen sclerosus (MGLSc) has a bimodal distribution in boys and men. It is associated with squamous cell carcinoma (SCC). The pathogenesis of MGLSc is unknown. HPV and autoimmune mechanisms have been mooted. Anti extracellular matrix protein (ECM)1 antibodies have been identified in women with GLSc. The gene expression pattern of LSc is unknown. Using DNA microarrays we studied differences in gene expression in healthy and diseased prepuces obtained at circumcision in adult males with MGLSc (n = 4), paediatric LSc (n = 2) and normal healthy paediatric foreskin (n = 4). In adult samples 51 genes with significantly increased expression and 87 genes with significantly reduced expression were identified; paediatric samples revealed 190 genes with significantly increased expression and 148 genes with significantly reduced expression. Concordance of expression profiles between adult and paediatric samples indicates the same disease process. Functional analysis revealed increased expression in the adult and child MGSLc samples in the immune response/cellular defence gene ontology (GO) category and reduced expression in other categories including genes related to squamous cancer. No specific HPV, autoimmune or squamous carcinogenesis‐associated gene expression patterns were found. ECM1 and CABLES1 expression were significantly reduced in paediatric and adult samples respectively.
Chemical and microstructural evaluation of ‘hard‐to‐cook’ phenomenon in legumes (pinto bean and small‐type lentil)
Authors: Pirhayati Mansoureh , Soltanizadeh Nafiseh , Kadivar Mahdi
Published: June 2011

Some physicochemical and microstructural characteristics of hard‐to‐cook (HTC) and easy‐to‐cook (ETC) pinto beans and small‐type lentils were compared. The development of HTC seeds was monitored over 6 months for changes in physicochemical properties. Results indicated that hardness, extent of water absorption and solid loss of HTC legumes were, respectively, 21–97%, 7–72% and 62–236% higher than those of ETC legumes. In addition, darkening of HTC beans and lentils was significantly higher than those of ETC ones. Scanning electron microscope observations indicated deteriorations in cytoplasmic contents of cotyledon cells of hard seeds. Phytic acid and total phenolic contents were, respectively, decreased 36–61% and 43–61% during storage, whereas hardness of seeds was increased 3–6 times. The soaking of hard seeds in sodium solutions resulted in the improvement in legume texture.