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Identifying subjects with cystic fibrosis (CF) who may benefit from cystic fibrosis transmembrane conductance regulator (CFTR)-modulating drugs is time-consuming, costly, and especially challenging for individuals with rare uncharacterized CFTR mutations. We studied CFTR function and responses to two drugs-the prototypical CFTR potentiator VX-770 (ivacaftor/KALYDECO) and the CFTR corrector VX-809 (lumacaftor)-in organoid cultures derived from the rectal epithelia of subjects with CF, who expressed a broad range of CFTR mutations. We observed that CFTR residual function and responses to drug therapy depended on both the CFTR mutation and the genetic background of the subjects. In vitro drug responses in rectal organoids positively correlated with published outcome data from clinical trials with VX-809 and VX-770, allowing us to predict from preclinical data the potential for CF patients carrying rare CFTR mutations to respond to drug therapy. We demonstrated proof of principle by selecting two subjects expressing an uncharacterized rare CFTR genotype (G1249R/F508del) who showed clinical responses to treatment with ivacaftor and one subject (F508del/R347P) who showed a limited response to drug therapy both in vitro and in vivo. These data suggest that in vitro measurements of CFTR function in patient-derived rectal organoids may be useful for identifying subjects who would benefit from CFTR-correcting treatment, independent of their CFTR mutation.

Small-molecule therapies that restore defects in cystic fibrosis transmembrane conductance regulator (CFTR) gating (potentiators) or trafficking (correctors) are being developed for cystic fibrosis (CF) in a mutation-specific fashion. Options for pharmacological correction of CFTR-p.Phe508del (F508del) are being extensively studied but correction of other trafficking mutants that may also benefit from corrector treatment remains largely unknown.We studied correction of the folding mutants CFTR-p.Phe508del, -p.Ala455Glu (A455E) and -p.Asn1303Lys (N1303K) by VX-809 and 18 other correctors (C1–C18) using a functional CFTR assay in human intestinal CF organoids.Function of both CFTR-p.Phe508del and -p.Ala455Glu was enhanced by a variety of correctors but no residual or corrector-induced activity was associated with CFTR-p.Asn1303Lys. Importantly, VX-809-induced correction was most dominant for CFTR-p.Phe508del, while correction of CFTR-p.Ala455Glu was highest by a subgroup of compounds called bithiazoles (C4, C13, C14 and C17) and C5.These data support the development of mutation-specific correctors for optimal treatment of different CFTR trafficking mutants, and identify C5 and bithiazoles as the most promising compounds for correction of CFTR-p.Ala455Glu.

Rheumatoid arthritis (RA) is the world’s most common autoimmune disease mainly characterized by a chronic inflammation of multiple synovial joints. Rheumatologists now have a whole range of treatment options including glucocorticoids (GCs), classical synthetic and biological disease-modifying antirheumatic drugs (cs- and bDMARDS), resulting in a tremendous improvement in treatment outcomes for RA patients over the last two decades. Despite this progress, the choice of treatment regimen to achieve stable remission at the individual patient level still largely depends on trial and error. In this review, the need for novel theranostic markers that can predict a patient’s response to methotrexate, the standard first-line csDMARD treatment, is discussed. Like in many autoimmune diseases, the majority of RA patients form a whole range of autoantibodies. We aim to find novel theranostic autoantibody markers using serological antigen selection, a high-throughput technique that uses cDNA phage display to identify novel antigen targets. We have constructed a barcoded cDNA phage display library from the synovial tissue of three RA patients by fusing cDNA products to the filamentous phage minor coat protein VI. This library contains a large proportion of full-length genes and gene fragments that are cloned in frame with the phage gene VI. By screening this library for antibody reactivity in serum samples of patients from the CareRA trial, which compared different intensive treatment strategies based on csDMARDs and a step-down GC schedule, our cDNA phage display library has great potential for the discovery of novel theranostic autoantibody biomarkers. This study is supported by Hasselt University, Transnationale Universiteit Limburg and KULeuven. We thank all members of the CareRA study group, Veerle Stouten and Johan Joly, and show our gratitude to all participating patients.

{#article-title-2} To the Editor: I have dedicated my professional career to caring for patients with chronic and debilitating neurologic diseases and have come to appreciate and respect the meaning of the Hippocratic Oath statement “First do no harm.” The American Academy of Neurology (AAN) guideline update on plasmapheresis in neurologic disorders1 is inaccurate and may cause harm to patients. I have successfully treated more than 100 patients with myasthenia gravis (MG) with therapeutic plasma exchange (TPE) not only for myasthenic crises but also on an ongoing basis (maintenance plasmapheresis) to prevent further worsening. This has allowed me to drastically reduce the use of long-term immunosuppressive drugs in such patients. Insurance companies will now cite these guidelines to deny TPE for such patients. Just as it is unnecessary to conduct a double-blind, placebo-controlled study to justify ongoing insulin therapy for diabetic patients, there should be no need to do such a study in MG. The pathogenesis of MG2 itself lends support to the use of long-term TPE, which unequivocally removes pathogenic circulating antibodies. With reference to secondary or chronic progressive multiple sclerosis (MS), the authors' interpretation of our trial study is erroneous.3 This study, heralded by Dr. George Ellison4 as “an exemplary study for others to match or exceed,” showed a significant ( p < 0.007) improvement in disability in the TPE group over the placebo group. A long-term follow-up study5 in 200 chronic progressive patients confirmed the earlier report and further identified the clinical characteristics of those who should respond to TPE. In light of this report, it would be impossible to provide TPE to patients with secondary progressive MS, in whom there are data to show efficacy when conventional therapies have failed. As the organization that represents those who care for patients with chronic and debilitating …

Focused ion beam-scanning electron microscope (FIB-SEM) tomography is a powerful application in obtaining three-dimensional (3D) information. The FIB creates a cross section and subsequently removes thin slices. The SEM takes images using secondary or backscattered electrons, or maps every slice using X-rays and/or electron backscatter diffraction patterns. The objective of this study is to assess the possibilities of combining FIB-SEM tomography with cathodoluminescence (CL) imaging. The intensity of CL emission is related to variations in defect or impurity concentrations. A potential problem with FIB-SEM CL tomography is that ion milling may change the defect state of the material and the CL emission. In addition the conventional tilted sample geometry used in FIB-SEM tomography is not compatible with conventional CL detectors. Here we examine the influence of the FIB on CL emission in natural diamond and the feasibility of FIB-SEM CL tomography. A systematic investigation establishes that the ion beam influences CL emission of diamond, with a dependency on both the ion beam and electron beam acceleration voltage. CL emission in natural diamond is enhanced particularly at low ion beam and electron beam voltages. This enhancement of the CL emission can be partly explained by an increase in surface defects induced by ion milling. CL emission enhancement could be used to improve the CL image quality. To conduct FIB-SEM CL tomography, a recently developed novel specimen geometry is adopted to enable sequential ion milling and CL imaging on an untilted sample. We show that CL imaging can be manually combined with FIB-SEM tomography with a modified protocol for 3D microstructure reconstruction. In principle, automated FIB-SEM CL tomography should be feasible, provided that dedicated CL detectors are developed that allow subsequent milling and CL imaging without manual intervention, as the current CL detector needs to be manually retracted before a slice can be milled. Due to the required high electron beam acceleration voltage for CL emission, the resolution for FIB-SEM CL tomography is currently limited to several hundreds of nm in XY and up to 650 nm in Z for diamonds. Opaque materials are likely to have an improved Z resolution, as CL emission generated deeper in the material is not able to escape from it.

Background and objectives Mycophenolate mofetil (MMF) is an immunosuppressive drug used in renal transplant patients. Upon oral administration it is hydrolyzed to the active agent mycophenolic acid (MPA). In renal transplant recipients, MMF therapy is optimal when the area under the curve of MPA is 30 to 60 mg.h/L. When MMF doses are adjusted, a linear relationship between dose and MPA exposure is assumed. In this study, the linearity of MMF pharmacokinetics was investigated. Design, setting, participants, & measurements MPA concentration-time profiles from renal transplant recipients cotreated with cyclosporine (n = 140) or tacrolimus (n = 101) were analyzed retrospectively using nonlinear mixed-effects modeling. The correlation between the MMF dose and the pharmacokinetics parameters was evaluated. Results In the developed population pharmacokinetics model MPA clearance and the central volume of distribution were correlated with cyclosporine coadministration and time posttransplantation. The pharmacokinetics of MPA were not linear. Bioavailability decreased with increasing MMF doses. Compared with an MMF dose of 1000 mg (=100%), relative bioavailability was 123%, 111%, 94%, and 90% in patients receiving MMF doses of 250, 500, 1500, and 2000 mg in combination with cyclosporine (P

Naturally deformed ice contains subgrains with characteristic geometries that have recently been identified in etched surfaces using high-resolution light microscopy (LM). The probable slip systems responsible for these subgrain boundary types can be determined using electron backscattered diffraction (EBSD), providing the etch features imaged with reflected LM can be retained during EBSD data acquisition in a scanning electron microscope (SEM). Retention of the etch features requires that the ice surface is stable. Depending on the pressure and temperature, sublimation of ice can occur. The equilibrium temperature for a low pressure SEM operating at 1 × 10^−6 hPa is about −112°C and operating at higher temperatures causes sublimation. Although charging of uncoated ice samples is reduced by sublimation, important information contained in the etch features are removed as the surface sublimes. We developed a method for collecting EBSD data on stable ice surfaces in a low pressure SEM. We found that operating at temperatures of

Two new companions to the Pluto-Charon binary system have been detected in 2005 by Weaver et al. These small satellites, named Nix and Hydra, are located beyond Charon's orbit. Although they are small when compared to Charon, their gravitational perturbations can decrease the stability of the external region (beyond Charon's orbit). The dynamical structure of this external region is analysed by numerically simulating a sample of particles under the gravitational effects of Pluto, Charon, Nix and Hydra. As expected the effects of Nix and Hydra decrease the external stable region. Agglomerates of particles can survive even after 10 5 orbital periods of the binary in some regions, such as coorbital to Nix and Hydra and between their orbits. We also analysed the effects of hypothetical satellites on the orbital evolution of Nix and Hydra in order to constrain an upper limit size. Some hypothetical satellites can be coorbital to Nix or Hydra without provoking any significant gravitational effects on them.

BackgroundAirways of cystic fibrosis (CF) patients are colonised with bacteria early in life. We aimed to analyse differences between results of simultaneously taken upper airway (UAW) and lower airway (LAW) cultures, to describe clinical characteristics of patients with positive versus negative cultures and to follow up the patients with P. aeruginosa positive UAW cultures.MethodsBacteriological and clinical data from 157 children were collected during annual check up. The number of positive UAW and LAW cultures and correspondence between these results and clinical characteristics were analysed.ResultsPositive LAW and UAW cultures were found in 79.6% and 43.9% of patients respectively (p

Background Organoid technology enables the cultivation of human tissues in a dish. Its precision medicine potential could revolutionize the Cystic Fibrosis (CF) field. We provide a first thematic exploration of the patient perspective on organoid technology to set the further research agenda, which is necessary for responsible development of this ethically challenging technology. Methods 23 semi-structured qualitative interviews with 14 Dutch adult CF patients and 12 parents of young CF patients to examine their experiences, opinions, and attitudes regarding organoid technology. Results Four themes emerged: (1) Respondents express a close as well as a distant relationship to organoids; (2) the open-endedness of organoid technology sparks hopes and concerns, (3) commercial use evokes cautiousness. (4) Respondents mention the importance of sound consent procedures, long-term patient engagement, responsible stewardship, and stringent conditions for commercial use. Conclusions The precision medicine potential of organoid technology can only be realized if the patient perspective is taken adequately into account.

Summary Atherogenesis is a pathological condition in which changes in the ultrastructure and in the localization of proteins occur within the vasculature during all stages of the disease. To gain insight in those changes, high-resolution imaging is necessary. Some of these changes will only be present in a small number of cells, positioned in a ‘sea’ of non-affected cells. To localize this relatively small number of cells, there is a need to first navigate through a large area of the sample and subsequently zoom in onto the area of interest. This approach enables the study of specific cells within their in vivo environment and enables the study of (possible) interactions of these cells with their surrounding cells/environment. The study of a sample in a correlative way using light and electron microscopy is a promising approach to achieve this; however, it is very laborious and additional ultrastructural techniques might be very valuable to find the places of interest. In this report we show that the focused ion beam-scanning electron microscope is a powerful tool to study biological specimens in a correlative way. With this microscope one can scan for the area of interest at low magnification, in this case the atherosclerotic plaque, and subsequently zoom in, for further analysis on an ultrastructural level, rendering valuable and detailed two- and three-dimensional information of, in this case, the endothelial cells and the vessel wall. Moreover, in combination with pre-embedment labelling of surface exposed antigens, the method allows insight into the 3D distribution of these markers.

This review focuses on the heart and vascular system in patients with Down syndrome. A clear knowledge on the wide spectrum of various abnormalities associated with this syndrome is essential for skillful management of cardiac problems in patients with Down syndrome. Epidemiology of congenital heart defects, cardiovascular aspects and thyroid-related cardiac impairment in patients with Down syndrome will be discussed.

Mycophenolic acid (MPA), the active compound of mycophenolate mofetil (MMF), is used to prevent graft rejection in renal transplant recipients. MPA is glucuronidated to the metabolite MPAG, which exhibits enterohepatic recirculation (EHC). MPA binds for 97% and MPAG binds for 82% to plasma proteins. Low plasma albumin concentrations, impaired renal function and coadministration of cyclosporine have been reported to be associated with increased clearance of MPA. The aim of the study was to develop a population pharmacokinetic model describing the relationship between MMF dose and total MPA (tMPA), unbound MPA (fMPA), total MPAG (tMPAG) and unbound MPAG (fMPAG). In this model the correlation between pharmacokinetic parameters and renal function, plasma albumin concentrations and cotreatment with cyclosporine was quantified. tMPA, fMPA, tMPAG and fMPAG concentration-time profiles of renal transplant recipients cotreated with cyclosporine (n = 48) and tacrolimus (n = 45) were analyzed using NONMEM. A 2- and 1-compartment model were used to describe the pharmacokinetics of fMPA and fMPAG. The central compartments of fMPA and fMPAG were connected with an albumin compartment allowing competitive binding (bMPA and bMPAG). tMPA and tMPAG were modeled as the sum of the bound and unbound concentrations. EHC was modeled by transport of fMPAG to a separate gallbladder compartment. This transport was decreased in case of cyclosporine cotreatment (P < 0.001). In the model, clearance of fMPAG decreased when creatinine clearance (CrCL) was reduced (P < 0.001), and albumin concentration was correlated with the maximum number of binding sites available for MPA and MPAG (P < 0.001). In patients with impaired renal function cotreated with cyclosporine the model adequately described that increasing fMPAG concentrations decreased tMPA AUC due to displacement of MPA from its binding sites. The accumulated MPAG could also be reconverted to MPA by the EHC, which caused increased tMPA AUC in patients cotreated with tacrolimus. Changes in CrCL had hardly any effect on fMPA exposure. A decrease in plasma albumin concentration from 0.6 to 0.4 mmol/l resulted in ca. 38% reduction of tMPA AUC, whereas no reduction in fMPA AUC was seen. In conclusion, a pharmacokinetic model has been developed which describes the relationship between dose and both total and free MPA exposure. The model adequately describes the influence of renal function, plasma albumin and cyclosporine co-medication on MPA exposure. Changes in protein binding due to altered renal function or plasma albumin concentrations influence tMPA exposure, whereas fMPA exposure is hardly affected.

Electron-beam-induced deposition of platinum from methylcyclopentadienyl-platinum-trimethyl was performed with a focused electron beam at low landing energies, down to 10?eV. The deposition growth rate is maximal at 140?eV, with the process being over ten times more efficient than at 20?kV. No significant dependence of composition with landing energy was found in the deposits performed at energies between 40 and 1000?eV. This study provides further evidence for the dissociation process being primarily driven by the sub-20-eV secondary electrons.

Different lines of cell suspension cultures of Taxus × media Rehd. and Taxus floridana Nutt. were cryopreserved with a two-step freezing method using a simple and inexpensive freezing container instead of a programmable freezer. Four to seven days old suspension cell cultures were precultured in growth medium supplemented with 0.5 M mannitol for 2 d. The medium was then replaced with cryoprotectant solution (1 M sucrose, 0.5 M glycerol and 0.5 M dimethylsulfoxide) and the cells incubated on ice for 1 h. Before being plunged into liquid nitrogen, cells were frozen with a cooling rate of approximately −1 °C per min to −80 °C. The highest post-thaw cell viability was 90 %. The recovery was line dependent. The cryopreservation procedure did not alter the nuclear DNA content of the cell lines. The results indicate that cryopreservation of Taxus cell suspension cultures using inexpensive freezing container is possible.

Around 48 million used tyres are generated in the UK each year and their disposal, no longer permissible via landfill due to the provisions of the European Union Landfill Directive, is thus a considerable problem. By no means restricted to the UK and other parts of Europe, this problem has a truly international complexion as other regions seek to address the problem of used tyre disposal. The compression of whole tyres into rectilinear tyre bales for use in construction is one possible means of addressing the problem. This paper assesses the recently published British Standards publicly available specification (PAS) 108 for the production of tyre bales for use in construction. Issues with respect to input materials (tyres), the production of tyre bales and the use of tyre bales are covered. Information on the properties and behaviours of tyre bales are described, as are suggested methods of measurement. General construction considerations and specific applications for tyre bales are highlighted along with end of service life options.

Since the Voyager flybys, embedded moonlets have been proposed to explain some of the surprising structures observed in Saturn's narrow F ring. Experiments conducted with the Cassini spacecraft support this suggestion. Images of the F ring show bright compact spots, and seven occultations of stars by the F ring, monitored by ultraviolet and infrared experiments, revealed nine events of high optical depth. These results point to a large number of such objects, but it is not clear whether they are solid moonlets or rather loose particle aggregates. Subsequent images suggested an irregular motion of these objects so that a determination of their orbits consistent with the F ring failed. Some of these features seem to cross the whole ring. Here we show that these observations are explained by chaos in the F ring driven mainly by the ‘shepherd’ moons Prometheus and Pandora. It is characterized by a rather short Lyapunov time of about a few hundred orbital periods. Despite this chaotic diffusion, more than 93 per cent of the F-ring bodies remain confined within the F ring because of the shepherding, but also because of a weak radial mobility contrasted by an effective longitudinal diffusion. This chaotic stirring of all bodies involved prevents the formation of ‘propellers’ typical of moonlets, but their frequent ring crossings explain the multiple radial ‘streaks’ seen in the F ring. The related ‘thermal’ motion causes more frequent collisions between all bodies which steadily replenish F-ring dust and allow for ongoing fragmentation and re-accretion processes (ring recycling).

Mycophenolate mofetil (MMF), a prodrug of mycophenolic acid (MPA), is increasingly used in the prophylaxis of graft-versus-host disease (GVHD) after hematopoietic stem cell transplantation (HCT). Few pharmacokinetic data are available about the use of MMF for this indication. This case series aimed at analyzing the pharmacokinetics of MMF in a population of HCT recipients representative for everyday practice. From 15 HCT recipients, serial plasma samples were taken after twice-daily oral intake of MMF. Plasma concentrations of total MPA and its glucuronide metabolites, as well as free MPA, were quantified. Median apparent oral MPA clearance (CL/F), apparent half-life, and total MPA area under the curve for hours 0 to 12 (AUC0-12, normalized to 1000 mg MMF) were, respectively, 56 L/h (range: 29-98 L/h), 2.3 hours (range: 0.8-5.7 hours), and 18.0 mg*h/L (range: 10-35 mg*h/L). Total MPA concentrations were below 2 mg/L 8 hours after MMF administration, indicating reduced enterohepatic recirculation. Median free MPA AUC0-12 (normalized to 1000 mg MMF) was 224 microg*h/L (range: 56-411 microg*h/L). Because of high CL/F, total MPA exposure in HCT recipients is low and apparent half-life is short in comparison with reference values from renal transplantation. Exposure may be improved in HCT recipients by higher or more frequent MMF dosing.

Focused ion beam systems are applied for the creation of nano-scale structures by patterned milling into a substrate. For a given material, the local dose (nC) determines the amount of material (@mm^3) removed by the beam: this volume per dose is referred to as the milling yield. In practice the milling yield is dependent on the material type and can be predicted from modelling calculations such as applied in SRIM. Ion channelling effects however, will induce a local variation of the yield. For common construction materials such as aluminium, brass, phosphor bronze, titanium, lead, stainless steel and silicon the milling yield has been measured with averaging of channelling and compared to predicted values. Overall, the predicted values are higher than the measured values. This effect is attributed to inaccuracies in the modelling calculations as well as to re-deposition of released material during the milling process.

In the present work we analyse the behaviour of a particle under the gravitational influence of two massive bodies and a particular dissipative force. The circular restricted three body problem, which describes the motion of this particle, has five equilibrium points in the frame which rotates with the same angular velocity as the massive bodies: two equilateral stable points ( L 4 , L 5 ) and three colinear unstable points ( L 1 , L 2 , L 3 ). A particular solution for this problem is a stable orbital libration, called a tadpole orbit, around the equilateral points. The inclusion of a particular dissipative force can alter this configuration. We investigated the orbital behaviour of a particle initially located near L 4 or L 5 under the perturbation of a satellite and the Poynting–Robertson drag. This is an example of breakdown of quasi-periodic motion about an elliptic point of an area-preserving map under the action of dissipation. Our results show that the effect of this dissipative force is more pronounced when the mass of the satellite and/or the size of the particle decrease, leading to chaotic, although confined, orbits. From the maximum Lyapunov Characteristic Exponent a final value of γ was computed after a time span of 106 orbital periods of the satellite. This result enables us to obtain a critical value of log γ beyond which the orbit of the particle will be unstable, leaving the tadpole behaviour. For particles initially located near L 4 , the critical value of log γ is −4.07 and for those particles located near L 5 the critical value of log γ is −3.96.

Treatment with the immunosuppressive agent mycophenolate mofetil (MMF) decreases the risk of rejection after renal transplantation and improves graft survival compared with azathioprine. The exposure to the active metabolite mycophenolic acid (MPA) is correlated to the risk of developing acute rejection. The interpatient variability in exposure of MPA is wide relative to the proposed therapeutic window of the MPA AUC(0 12) (30 - 60 mg.h/l). The pharmacokinetics of MPA are influenced by patient characteristics such as gender, time after transplantation, serum albumin concentration, renal function, comedication and pharmacogenetic factors. Therapeutic drug monitoring is likely to reduce inter-patient variability. Limited sampling strategies are used to predict the full AUC(0 12). Three prospective randomised studies compared concentration controlled MMF therapy to a fixed-dose regimen. Preliminary outcomes of these studies showed conflicting results and longer follow up is needed to further clarify the role of therapeutic drug monitoring in increasing the therapeutic potential of MMF.

The potentiator VX-770 (ivacaftor/KALYDECO™) targets defective gating of CFTR and has been approved for treatment of cystic fibrosis (CF) subjects carrying G551D, S1251N or one of 8 other mutations. Still, the current potentiator treatment does not normalize CFTR-dependent biomarkers, indicating the need for development of more effective potentiator strategies. We have recently pioneered a functional CFTR assay in primary rectal organoids and used this model to characterize interactions between VX-770, genistein and curcumin, the latter 2 being natural food components with established CFTR potentiation capacities. Results indicated that all possible combinations of VX-770, genistein and curcumin synergistically repaired CFTR-dependent forskolin-induced swelling of organoids with CFTR-S1251N or CFTR-G551D, even under suboptimal CFTR activation and compounds concentrations, conditions that may predominate in vivo. Genistein and curcumin also enhanced forskolin-induced swelling of F508del homozygous organoids that were treated with VX-770 and the prototypical CFTR corrector VX-809. These results indicate that VX-770, genistein and curcumin in double or triple combinations can synergize in restoring CFTR-dependent fluid secretion in primary CF cells and support the use of multiple potentiators for treatment of CF.

Real-time medication monitoring (RTMM) is a promising tool for improving adherence to inhaled corticosteroids (ICS), but has not been sufficiently tested in children with asthma. We aimed to study the effects of RTMM with short message service (SMS) reminders on adherence to ICS, asthma control, asthma-specific quality of life and asthma exacerbation rate; and to study the associated cost-effectiveness.In a multicentre, randomised controlled trial, children (aged 4–11 years) using ICS were recruited from five outpatient clinics and were given an RTMM device for 12 months. The intervention group also received tailored SMS reminders, sent only when a dose was at risk of omission. Outcome measures were adherence to ICS (RTMM data), asthma control (childhood asthma control test questionnaire), quality of life (paediatric asthma quality of life questionnaire) and asthma exacerbations. Costs were calculated from a healthcare and societal perspective.We included 209 children. Mean adherence was higher in the intervention group: 69.3%versus57.3% (difference 12.0%, 95% CI 6.7%–17.7%). No differences were found for asthma control, quality of life or asthma exacerbations. Costs were higher in the intervention group, but this difference was not statistically significant.RTMM with tailored SMS reminders improved adherence to ICS, but not asthma control, quality of life or exacerbations in children using ICS for asthma.

Background: Poor adherence to inhaled corticosteroids (ICS) is a risk factor for asthma exacerbations in children. Reminding systems are a promising tool for improving adherence, but have not been tested in children with asthma. Aims and objectives: Main aim is to study the effect of Real Time Medication Monitoring (RTMM) with SMS reminders on adherence to ICS. Secondary aim is to study the effects on asthma control (AC), asthma-specific quality of life (QoL) and the frequency of exacerbations. Final aim was to study whether the intervention is cost-effective. Methods: In a multicenter, randomized controlled trial in children (4-11 years) using ICS for asthma, all children received an RTMM-device for 12 months. The intervention group also received tailored SMS reminders, sent only when a dose was at risk of omission. Outcome measures: adherence to ICS (RTMM data), AC (c-ACT questionnaire), QoL (PAQLQ questionnaire) and asthma exacerbations. Costs were calculated from a healthcare and from a societal perspective. Results: 209 children were included. Mean adherence was 69.0% in the intervention group and 57.3% in the control group (difference 11.8%; 95%CI 6.9%-17.5%). The difference gradually declined from 15.2% in the first 6 months, but remained stable at 8.3% over the last 6 months. No differences were found for AC (mean ACT score 21.1 vs 22.2), QoL (mean PAQLQ score 6.2 vs 6.3) or asthma exacerbations (yearly rate 0.23 vs 0.37). Costs were higher in the intervention group: €719 versus €615 from the healthcare perspective and €1030 versus €743 from a societal perspective. Conclusions: RTMM with tailored SMS reminders effectively improves adherence to ICS, but not AC, QoL or exacerbations in this population.

Dominant mutations in TPM3, encoding α-tropomyosinslow, cause a congenital myopathy characterized by generalized muscle weakness. Here, we used a multidisciplinary approach to investigate the mechanism of muscle dysfunction in 12 TPM3-myopathy patients. We confirm that slow myofibre hypotrophy is a diagnostic hallmark of TPM3-myopathy, and is commonly accompanied by skewing of fibre-type ratios (either slow or fast fibre predominance). Patient muscle contained normal ratios of the three tropomyosin isoforms and normal fibre-type expression of myosins and troponins. Using 2D-PAGE, we demonstrate that mutant α-tropomyosinslow was expressed, suggesting muscle dysfunction is due to a dominant-negative effect of mutant protein on muscle contraction. Molecular modelling suggested mutant α-tropomyosinslow likely impacts actin-tropomyosin interactions and, indeed, co-sedimentation assays showed reduced binding of mutant α-tropomyosinslow (R168C) to filamentous actin. Single fibre contractility studies of patient myofibres revealed marked slow myofibre specific abnormalities. At saturating [Ca(2+)] (pCa 4.5), patient slow fibres produced only 63% of the contractile force produced in control slow fibres and had reduced acto-myosin cross-bridge cycling kinetics. Importantly, due to reduced Ca(2+)-sensitivity, at sub-saturating [Ca(2+)] (pCa 6, levels typically released during in vivo contraction) patient slow fibres produced only 26% of the force generated by control slow fibres. Thus, weakness in TPM3-myopathy patients can be directly attributed to reduced slow fibre force at physiological [Ca(2+)], and impaired acto-myosin cross-bridge cycling kinetics. Fast myofibres are spared; however, they appear to be unable to compensate for slow fibre dysfunction. Abnormal Ca(2+)-sensitivity in TPM3-myopathy patients suggests Ca(2+)-sensitizing drugs may represent a useful treatment for this condition.

Background Nemaline myopathy (NM), the most common non-dystrophic congenital myopathy, is characterized by generalized skeletal muscle weakness, often from birth. To date, no therapy exists that enhances the contractile strength of muscles of NM patients. Mutations in NEB, encoding the giant protein nebulin, are the most common cause of NM. The pathophysiology of muscle weakness in NM patients with NEB mutations (NEB-NM) includes a lower calcium-sensitivity of force generation. We propose that the lower calcium-sensitivity of force generation in NEB-NM offers a therapeutic target. Levosimendan is a calcium sensitizer that is approved for use in humans and has been developed to target cardiac muscle fibers. It exerts its effect through binding to slow skeletal/cardiac troponin C. As slow skeletal/cardiac troponin C is also the dominant troponin C isoform in slow-twitch skeletal muscle fibers, we hypothesized that levosimendan improves slow-twitch muscle fiber strength at submaximal levels of activation in patients with NEB-NM. Methods To test whether levosimendan affects force production, permeabilized slow-twitch muscle fibers isolated from biopsies of NEB-NM patients and controls were exposed to levosimendan and the force response was measured. Results No effect of levosimendan on muscle fiber force in NEB-NM and control skeletal muscle fibers was found, both at a submaximal calcium level using incremental levosimendan concentrations, and at incremental calcium concentrations in the presence of levosimendan. In contrast, levosimendan did significantly increase the calcium-sensitivity of force in human single cardiomyocytes. Protein analysis confirmed that the slow skeletal/cardiac troponin C isoform was present in the skeletal muscle fibers tested. Conclusions These findings indicate that levosimendan does not improve the contractility in human skeletal muscle fibers, and do not provide rationale for using levosimendan as a therapeutic to restore muscle weakness in NEB-NM patients. We stress the importance of searching for compounds that improve the calcium-sensitivity of force generation of slow-twitch muscle fibers. Such compounds provide an appealing approach to restore muscle force in patients with NEB-NM, and also in patients with other neuromuscular disorders. Electronic supplementary material The online version of this article (doi:10.1186/s13395-015-0037-7) contains supplementary material, which is available to authorized users.

Introduction: An increased risk of vertebral fracture (VF) is one of the extra-articular manifestations of spondyloarthropathy (SpA). The prevalence of moderate to severe VFs visualized by radiography (Rx) in patients with SpA in daily practice is unknown until imaging of the full spine is available, as most VFs do not present with clinical signs and symptoms of an acute fracture. Methods: We evaluated the prevalence of VFs (>25 % loss in height) on available Rx and dual-energy X-ray absorptiometry (DXA) images in 390 consecutive patients with SpA in daily practice. We assessed their association with disease characteristics, bone mineral density, the modified Stoke Ankylosing Spondylitis Spinal Score, and history of trauma. Results: Forty-six patients (11.8 %) had Rx VF (56.4 % men, 93.5 % in the thoracic spine), and 44.5 % had multiple VFs. Compared with patients without VF, patients with VF were older (52.2 vs. 47.3 years, p < 0.01; range 25-84 years), had lower femoral neck T-scores (-1.1 vs. -0.7; p < 0.05), and had a marginally higher modified Stoke Ankylosing Spondylitis Spinal Score (11.7 vs. 7.0; p = 0.06). Among patients with VFs, 15.2 % had a history of trauma with acute back pain (p < 0.001 vs. no VF). The reliability of DXA for diagnosing radiographic VFs was high (kappa 0.90). Conclusions: Moderate to severe VFs are found in more than 10 % of patients with SpA before the age of 40 years in 5 % of women and 9 % in men. Most VFs are located in the thoracic region, are related to low femoral neck bonemineral density and to stiffening of the spine, and are only rarely related to trauma history. DXA is a useful alternative for diagnosing VFs. This study was supported by Hasselt University and Transnationale Universiteit Limburg, Maastricht University Medical Centre. It was also supported by an unrestricted grant from AbbVie for a non-interventional study survey.

Starting doses of tacrolimus and ciclosporin are typically chosen on a calculated mg/kg bodyweight basis. After initiation of treatment, doses are adjusted with therapeutic drug monitoring (TDM). This trial-and-error approach has been accepted by most physicians and pharmacists involved in the care of transplanted patients.Dosing algorithms have only fairly recently been proposed to better individualize the starting dose. This review provides an overview of all the currently available dosing algorithms in adult and children for the starting dose of ciclosporin, tacrolimus and mycophenolic acid. In these algorithms, multiple other covariates influencing the starting dose, such as age, hematocrit, comedication and genotype are taken into account. After selecting the starting dose with an algorithm and after initiation of treatment, TDM will, however, remain necessary. Whether or not implementation of such algorithms will improve clinical outcome remains to be demonstrated.First of all an algorithm needs to be validated, against an independent dataset. Second, in a prospective study the algorithm should prove to reduce the time to reach the target concentration, and to reduce the number of patients with drug concentrations (far) outside the therapeutic window. Finally, a clinical trial demonstrating a benefit on clinical outcome will be crucial in achieving broad acceptance of calculating starting dose using individualized dosing algorithms.

The Cassini-Huygens arrival into the Saturnian system brought a large amount of data about the satellites and rings. Two diffuse rings were found in the region between the A ring and Prometheus. R/2004 S1 is coorbital to Atlas and R/2004 S2 is close to Prometheus. In this work we analysed the closest approach between Prometheus and both rings. As a result we found that the satellite removes particles from R/2004 S2 ring. Long-term numerical simulations showed that some particles can cross the F ring region . The well known region of the F ring, where small satellites are present and particles are being taking from the ring, gains a new insight with the presence of particles from R/2004 S2 ring. The computation of the Lyapunov Characteristic Exponent reveled that the R/2004 S2 ring lies in a chaotic region while R/2004 S1 ring and Atlas are in a stable region. Atlas is responsible for the formation of three regimes in the R/2004 S1 ring, as expected for a satellite embedded in a ring.

Some Voyager images showed that the F ring of Saturn is composed of at least four separate, non-intersecting, strands covering about 45° in longitude. According to Murray et al. [Murray, C.D., Gordon, M., Giuliatti Winter, S.M. Unraveling the strands of Saturn’s F ring. Icarus 129, 304, 1997.] this structure may be caused by undetected satellites embedded in the gaps. Due to precession, the satellites Prometheus and Pandora and the ring particles can experience periodic close encounters. Giuliatti Winter et al. [Giuliatti Winter, S.M, Murray, C.D., Gordon, M. Perturbations to Saturn’s F-ring strands at their closest approach to Prometheus. Plan. Space Sciences, 48, 817, 2000.] analysed the behaviour of these four strands at closest approach with the satellite Prometheus. Their work suggests that Prometheus can induce the ring particles to scatter in the direction of the planet, thus increasing the population of small bodies in this region. In this work we analysed the effects of Prometheus on the radial structure of Saturn’s F ring during the Voyager and early Cassini epochs. Our results show that at Voyager epoch Prometheus, and also Pandora, had a negligible influence in the strands. However, during the Cassini encounter Prometheus could affect the strands significantly, scattering particles of the inner strand in the direction of the planet. This process can contribute to the replenishment of material in the region between the F ring and the A ring, where two rings have recently been discovered [Porco, C. et al. Cassini imaging science. Initial results on Saturn’s rings and small Satellites. Science, 307, 1226, 2005]. We also analyse the behaviour of undetected satellites under the effects of these two satellites by computing the Lyapunov Characteristic Exponent. Our results show that these satellites have a chaotic behaviour which leads to a much more complex scenario. The new satellite S/2004 S6 also presents a chaotic behaviour with can alter the dynamic of the system, since this satellite crosses the orbit of the strands.

Soybean cyst nematode (SCN) is the primary pest responsible for yield losses of Glycine max. Management of SCN remains difficult in commercial soybean production due to the length of its biological cycle, frequent changes in population virulence, and ease of spread via infested soil. Effective management relies on crop rotation in combination with resistant cultivars, which have been derived from a limited germplasm base. Breeding for SCN resistance in soybean is difficult due to the quantitative nature of the trait, genetic variation within SCN populations, time required for phenotyping experimental soybean lines, and environmental factors affecting SCN reproduction. Quantitative trait loci associated with SCN resistance have been identified on 17 of the 20 soybean linkage groups, explaining 1–91% of the total phenotypic variation. Two major resistance genes, rhg 1 and Rhg 4, have been identified on linkage groups G and A2, respectively. Several minor resistance genes have been identified, but their importance varies with germplasm source and nematode race. Enhancement of SCN resistance in G. max may be achieved by interspecific hybridization with G. soja, the wild ancestor, or by engineering plants with candidate resistance genes such as Hs1pro-1. Key words: Genetic engineering, Glycine soja, soybean cyst nematode, molecular markers, resistance

The system formed by the F ring and two close satellites, Prometheus and Pandora, has been analysed since the time that Voyager visited the planet Saturn. During the ring plane crossing in 1995 the satellites were found in different positions as predicted by the Voyager data. Besides the mutual effects of Prometheus and Pandora, they are also disturbed by a massive F ring. Showalter et al. [Icarus 100 (1992) 394] proposed that, the core of the ring has a mass which corresponds to a moonlet varying in size from 15 to 70 km in radius which can prevent the ring from spreading due to dissipative forces, such as Poynting–Robertson drag and collisions. We have divided this work into two parts. Firstly we analysed the secular interactions between Prometheus–Pandora and a massive F ring using the secular theory. Our results show the variation in eccentricity and inclination of the satellites and the F ring taking into account a massive ring corresponding to a moonlet of different sizes. There is also a population of dust particles in the ring in the company of moonlets at different sizes [Icarus 109 (1997) 304]. We also analysed the behaviour of these particles under the effects of the Poynting–Robertson drag and radiation pressure. Our results show that the time scale proposed for a dust particle to leave the ring is much shorter than predicted before even in the presence of a coorbital moonlet. This result does not agree with the confinement model proposed by Dermott et al. [Nature 284 (1980) 309]. In 2004, Cassini mission will perform repeated observations of the whole system, including observations of the satellites and the F ring environment. These data will help us to better understand this system.

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Neutral B meson oscillations in the B-s(0) - , and B-d(0) - systems were studied using a sample of about 4.0 million hadronic Z decays recorded by the DELPHI detector between 1992 and 2000. Events with a high transverse momentum lepton were removed and a sample of 770 k events with an inclusively reconstructed vertex was selected. The mass difference between the two physical states in the B-d(0) - system was measured to be: Deltam(d) = (0.531 +/- 0.025(stat.) +/- 0.007(syst.))ps(-1). The following limit on the width difference of these states was also obtained: DeltaGamma(Bd)/Gamma(Bd) oscillations was found, a limit on the mass difference of the two physical states was given:, Deltam(s) > 5.0 ps(-1) at 95% CL. The corresponding sensitivity of this analysis is equal to 6.6 ps(-1).

Pericardial diseases have multiple clinical presentations with acute and chronic complications. Early diagnosis and prompt treatment markedly enhance the chance of complete resolution of the hemodynamic complications of pericardial disease. The treatment of patients with acute idiopathic pericarditis is mainly to alleviate symtoms of chest pain. A nonsteroidal anti-inflammatory agent such as indomethacin is our first drug of choice. Therapy is effective and symptoms resolve within 24 to 48 hours. In patients with chronic recurrent idiopathic pericarditis, we advise the use of colchicine at 1 mg/d. Constrictive pericarditis is a progressive disease and surgical pericardiectomy is the only definite treatment. It should be performed early in the disease process before myocardial fibrosis occurs. Cardiac tamponade is a cardiac emergency and patients should be treated promptly. We often start with volume expansion with intravenous fluid in preparation for transcutaneous pericardiocentesis. Echocardiographically guided, transcutaneous pericardiocentesis is the procedure of choice. Patients with asymptomatic pericardial effusion are followed with serial echocardiography, and reserve drainage for enlarging effusions if there are signs of cardiac compression.

The Summitville Mine was a high-elevation (3500 m) gold mine in southwestern Colorado. The mine was abandoned in 1992, leaving approximately 200 ha of disturbance comprised partially of an open pit, a cyanide heap leach pad, and two large waste rock piles. Reclamation of these mine facilities is challenging due to extreme climatic conditions in conjunction with high acid-production potential and low organic matter content of waste materials on site. In addition, stockpiled topsoil at the site is acidic and biologically inactive due to long-term storage, and may not be suitable for plant growth. The purpose of this study was to evaluate the effects of organic amendments (mushroom compost vs. biosolids) and topsoil (stockpiled vs. nonstockpiled) on aboveground biomass and plant trace element uptake. An on-site field study was established in 1995 to identify the most effective combination of treatments for successful reclamation of on-site waste rock materials. Incorporation of organic matter significantly increased aboveground biomass, with mushroom compost being more effective than biosolids, but did not significantly influence trace element uptake. Conversely, the use of topsoil did not affect aboveground biomass, but did influence trace element uptake. Treatments that received topsoil supported plant growth with significantly higher trace element tissue concentrations than treatments that did not receive topsoil. In general, it was found that waste rock could be directly revegetated when properly neutralized, fertilized, and amended with organic matter. Additionally, stockpiled topsoil, when neutralized with lime, supported plant growth equivalent to that on nonstockpiled topsoil.

Most fills when compacted in layers will, to some degree, experience variations in density with depth. When measured using a nuclear density gauge in direct transmission mode, such variations in density through the layer will lead to unrepresentative density–depth profiles. This is because each measurement used to generate the profile is the mean density between the surface and the depth of measurement, and no correction for this is currently made. Uniform sands and silts, and pulverised fuel ash (PFA), often go through a process of over-stressing during compaction, leading to significantly lower densities in the upper part of a compacted layer. Under these circumstances the errors recorded in nuclear density gauge determinations of the density–depth profile may become significant. In extreme cases the usual guidance is to remove the upper part of the compacted layer prior to density testing. This paper describes numerical techniques to determine the mean density between successive measurement depths for the cases of both equal and unequal depth increments, thus giving a density–depth profile that is much closer to reality.

A conceptual framework for the understanding of recycled aggregate applications is presented. The framework is described in terms of the environmental and economic utility (or value) of the application, and the utility relative to the original application. The determination of utility considers production factors (energy consumption, financial cost, amount of pollution and waste generated) and factors such as the market value of the product and ‘renewability’ of the primary resource. Examples for each category of utility and relative utility are given. Estimates of the level of aggregate recycling at each level of environmental and economic utility in Scotland are given for 1999. These illustrate the use of the framework as an aid to the interpretation of data for the quantities of aggregates recycled. Although the framework was developed specifically for recycled aggregates it is equally applicable to other material categories and examples are given where appropriate, particularly in relation to relative utility. The concept of utility is considered suitable for both project-level comparisons of different applications for recycled aggregates and also for strategic evaluations at a national level. The concept of relative utility is considered suitable for project-level evaluations of recycled aggregate applications, but not for strategic evaluations.

Low doses of the acetylcholinesterase-inhibiting carbamate nematicides disrupt chemoreception in plant-parasitic nematodes. Fluorescein isothiocyanate (FITC)/dextran conjugates up to 12 kDa are taken up from the external medium by certain chemosensory neurons in Caenorhabditis elegans. Similar chemoreceptive neurons of the non-feeding infective stage of Heterodera glycines (soybean cyst nematode) fill with FITC and the nuclei of their cell bodies selectively stain with bisbenzimide. The widely used nematicide aldicarb disrupts the chemoreceptive response of H. glycines with 50% inhibition at very low concentrations (ca 1 pM), some 10−6-fold lower than required to affect locomotion. Similarly, the anthelmintic levamisole had this effect at 1 nM. Peptides selected as mimetics of aldicarb and levamisole also disrupt chemoreception in H. glycines and Globodera pallida at 10−3-fold or lower concentration than required to inhibit locomotion. We propose an uptake pathway for aldicarb, levamisole, peptide mimetics and other soluble molecules by retrograde transport along dendrites of chemoreceptive neurons to the cell bodies and synapses where they act. This may prove to be a general mechanism for the low-dose effects of some nematicides and anthelmintics.

In the UK, the introduction of a tax on landfill and the tightening of planning consents for disposal provided powerful incentives for the use of industrial by-products such as pulverised fuel ash (PFA) in construction. PFA (known as fly ash in some parts of the world) has a long history of successful use as general fill, including applications in environmentally sensitive locations. However, the current commonly used Specification for Highway Works treats PFA as a manufactured material, and applies an end-product specification for compaction. This form of specification is restrictive as it requires that the maximum dry density and optimum moisture content be determined for each consignment of PFA delivered to site, a process that can take up to two days. In addition, the Specification requires testing to determine effective shear strength parameters under fully saturated conditions for embankment design. No guidance is given on whether peak or post-peak parameters are to be selected for design purposes or, indeed, on appropriate factors of safety. As a result, most engineers test PFA in the fully saturated condition, select post-peak effective shear strength parameters for design, and apply a conservative factor of safety. As the testing protocol represents a worst-case scenario the application of such a conservative approach can be questioned. A method specification is more commonly applied to natural fill materials used as general fill. Historical evidence shows that PFA has been placed using a method specification, and that those fills still function as designed. Thus the introduction of a method-based specification for the use of PFA as general fill would make possible its greater use and thus reduce the UK-wide need for landfill.

Excavations for a new service installation in Lindsay Road, Edinburgh, revealed that the ferritic stainless steel reinforcements of the supporting reinforced earth retaining wall were, in parts, severely corroded. This paper presents the findings of an investigation into the cause of the deterioration of the wall. The results of chemical tests undertaken on the backfill indicate that the material was most likely unsuitable for the construction of reinforced earth structures with any of the types of metallic, reinforcement that are, or have been, commonly used. Ferritic stainless steels are now generally considered to be unsuitable for use in reinforced earth structures regardless of backfill type. Indeed, the use of the materials for reinforcements ceased within a few years of the construction of the wall at Lindsay Road. Surveys of the alignments of the wall have also been conducted. The surveys of the wall indicated that there was no measurable movement prior to demolition.

Even in the absence of serious injuries and fatalities, rainfall-induced debris flow events can have significant socio-economic impacts when roads are affected. These include the cost of clean-up and repair, and of diversion. Costs also include those associated with the severance of access to/from remote communities for services and markets for goods; employment, health and educational opportunities; and social activities. The extent of such impacts depends upon the vulnerability shadow cast, which can be extensive and its geographical extent may be determined by the road network rather than the small footprint of the event itself. Indeed, such small events may (at most) directly affect a few tens of metres of road but cast a vulnerability shadow amounting to thousands of square kilometres.

The diagnostic work-up in patients with carcinoma of unknown primary (CUP) syndrome is extensive, highly time-consuming and cost-intensive and ultimately often fails to detect a primary site.In this context chest X-ray and computed tomography (CT) have been used as standard imaging modalities in CUP syndrome.Since the introduction of positron emission tomography (PET) evaluation of tumor vitality has become possible. Furthermore, PET-CT hybrid scanners allow the combination of functional and morphological imaging.Several meta-analyses have reported an additional overall detection rate between 24.5 % and 44 % by either PET or PET-CT. Metastatic localization (cervical versus extracervical) did not influence the performance. The sensitivity was usually high ( 80 %) but specificity was moderate ranging from 68 % to 88 % at best. If mentioned, the results obtained by fluorodeoxyglucose (FDG)-PET significantly changed the clinical management in approximately one third of the patients studied. In a direct comparison with PET alone, PET-CT did not depict significantly more primary tumors but was able to reduce false positive findings.To determine the real additional value of PET-CT in the diagnosis of CUP syndrome large prospective studies with more uniform inclusion criteria are needed. Despite the capabilities of FDG-PET-CT there is as yet no evidence that a potentially improved diagnostic algorithm is translated into a better patient outcome.Nevertheless, FDG-PET-CT should be performed in all CUP patients where conventional imaging failed to detect a primary site or the results are equivocal. In CUP patients with cervical lymph node metastases PET-CT should be carried out prior to panendoscopy to reduce the number of false negative biopsies.

Opalinus Clay is one of the fine-grained sedimentary formations investigated as a possible geological repository for the long-term storage of radioactive waste. Porosity, pore size, pore shape and connectivity of pores will help to define sealing capacities of a host rock. Here a combination of FIB-SEM, BIB-SEM and µ-CT has been used in order to investigate the nm-mm scale microstructure of the Shaly facies of Opalinus Clay in 2D and 3D. The µ-CT measurements gave a 3D overview of the microstructure of a 2 mm core down to a 2.6 µm voxel size. Which showed cracks, larger bivalve fragments and pyrite nodules embedded in a matrix, which was investigated down to the nm scale (enabling to image the pores) in 2D using the BIB-SEM method. FIB-SEM measurements were afterwards performed on selected areas to investigate the pore shape and connectivity in 3D down to the nm scale.

The strange morphology of the F ring of Saturn is thought to be caused by the perturbing effects of two close satellites, Prometheus and Pandora. The F ring and the satellites also experience periodic close encounters as a result of differential precession arising from Saturn’s oblateness. Using the orbits of the F-ring strands derived by Murray et al. (1997, Icarus 129, 304–316) the behaviour of the ring particles at their closest approach to Prometheus is analysed using numerical simulations. The results show that a gap and a wave are formed in the ring at each encounter with the satellite. However, the gap is expected to have a short lifetime due to keplerian shear.