1,913 research outputs found
Ataluren and similar compounds (specific therapies for premature termination codon class I mutations) for cystic fibrosis.
Cystic fibrosis is a common life-shortening genetic disorder in the Caucasian population (less common in other ethnic groups) caused by the mutation of a single gene that codes for the production of the cystic fibrosis transmembrane conductance regulator protein. This protein coordinates the transport of salt (and bicarbonate) across cell surfaces and the mutation most notably affects the airways. In the lungs of people with cystic fibrosis, defective protein results in a dehydrated surface liquid and compromised mucociliary clearance. The resulting thick mucus makes the airway prone to chronic infection and inflammation, which consequently damages the structure of the airways, eventually leading to respiratory failure. Additionally, abnormalities in the cystic fibrosis transmembrane conductance regulator protein lead to other systemic complications including malnutrition, diabetes and subfertility.Five classes of mutation have been described, depending on the impact of the mutation on the processing of the cystic fibrosis transmembrane conductance regulator protein in the cell. In class I mutations, the presence of premature termination codons prevents the production of any functional protein resulting in a severe cystic fibrosis phenotype. Advances in the understanding of the molecular genetics of cystic fibrosis has led to the development of novel mutation-specific therapies. Therapies targeting class I mutations (premature termination codons) aim to mask the abnormal gene sequence and enable the normal cellular mechanism to read through the mutation, potentially restoring the production of the cystic fibrosis transmembrane conductance regulator protein. This could in turn make salt transport in the cells function more normally and may decrease the chronic infection and inflammation that characterises lung disease in people with cystic fibrosis.To evaluate the benefits and harms of ataluren and similar compounds on clinically important outcomes in people with cystic fibrosis with class I mutations (premature termination codons).We searched the Cochrane Cystic Fibrosis Trials Register which is compiled from electronic database searches and handsearching of journals and conference abstract books. We also searched the reference lists of relevant articles. Last search of Group's register: 24 October 2016.We searched clinical trial registries maintained by the European Medicines Agency, the US National Institutes of Health and the WHO. Last search of clinical trials registries: 28 November 2016.Randomised controlled trials of parallel design comparing ataluren and similar compounds (specific therapies for class I mutations) with placebo in people with cystic fibrosis who have at least one class I mutation. Cross-over trials were reviewed individually to evaluate whether data from the first treatment arm could be included. We excluded trials that combined therapies for premature termination codon class I mutations with other mutation-specific therapies.The authors independently assessed the risk of bias and extracted data from the included trial; they contacted trial authors for additional data.Our searches identified 28 references to eight trials; five trials were excluded (three were cross-over and one was not randomised and one did not have relevant outcomes), one cross-over trial is awaiting classification pending provision of data and one trial is ongoing. The included parallel randomised controlled trial compared ataluren to placebo for a duration of 48 weeks in 238 participants (age range 6 to 53 years) with cystic fibrosis who had at least one nonsense mutation (a type of class I mutation).The quality of evidence and risk of bias assessments for the trial were moderate overall. Random sequence generation, allocation concealment and blinding of trial personnel were well-documented; participant blinding was less clear. Some participant data were excluded from the analysis. The trial was assessed as high risk of bias for selective outcome reporting, especially when reporting on the trial's post hoc subgroup of participants by chronic inhaled antibiotic use.The trial was sponsored by PTC Therapeutics Incorporated with grant support by the Cystic Fibrosis Foundation, the Food and Drug Administration's Office of Orphan Products Development and the National Institutes of Health (NIH).The trial reported no significant difference between treatment groups in quality of life, assessed by the Cystic Fibrosis Questionnaire-Revised respiratory domain score and no improvement in respiratory function measures (mean difference of relative change in forced expiratory volume at one second 2.97% (95% confidence interval -0.58 to 6.52)). Ataluren was associated with a significantly higher rate of episodes of renal impairment, risk ratio 17.70 (99% confidence interval 1.28 to 244.40). The trial reported no significant treatment effect for ataluren for the review's secondary outcomes: pulmonary exacerbation; computerised tomography score; weight; body mass index; and sweat chloride. No deaths were reported in the trial.A post hoc subgroup analysis of participants not receiving chronic inhaled tobramycin (n = 146) demonstrated favourable results for ataluren (n = 72) for relative change in % predicted forced expiratory volume at one second and pulmonary exacerbation rate. Participants receiving chronic inhaled tobramycin appeared to have a reduced rate of pulmonary exacerbation compared to those not receiving chronic inhaled tobramycin. This drug interaction was not anticipated and may affect the interpretation of the trial results.There is currently insufficient evidence to determine the effect of ataluren as a therapy for people with cystic fibrosis with class I mutations. Future trials should carefully assess for adverse events, notably renal impairment and consider the possibility of drug interactions. Cross-over trials should be avoided given the potential for the treatment to change the natural history of cystic fibrosis
I2PA, U-prove, and Idemix: An Evaluation of Memory Usage and Computing Time Efficiency in an IoT Context
The Internet of Things (IoT), in spite of its innumerable advantages, brings
many challenges namely issues about users' privacy preservation and constraints
about lightweight cryptography. Lightweight cryptography is of capital
importance since IoT devices are qualified to be resource-constrained. To
address these challenges, several Attribute-Based Credentials (ABC) schemes
have been designed including I2PA, U-prove, and Idemix. Even though these
schemes have very strong cryptographic bases, their performance in
resource-constrained devices is a question that deserves special attention.
This paper aims to conduct a performance evaluation of these schemes on
issuance and verification protocols regarding memory usage and computing time.
Recorded results show that both I2PA and U-prove present very interesting
results regarding memory usage and computing time while Idemix presents very
low performance with regard to computing time
Rheology of High-Capillary Number Two-Phase Flow in Porous Media
Flow of immiscible fluids in porous media at high capillary numbers may be characterized by an effective viscosity. We demonstrate that the effective viscosity is well-described by the Lichtenecker-Rother equation. Depending on the pore geometry, wettability, and viscosity of the fluids, the exponent α in this equation can have different values. We find α = 1 when fluids are well-mixed with small bubbles, α = 0.6 in two- and 0.5 in three-dimensional systems when there is less mixing with the appearance of big bubbles, and α = −0.5 when lubrication layers are formed along the pore walls. Our arguments are based on analytical and numerical methods
Generalised massive gravity one-loop partition function and AdS/(L)CFT
The graviton 1-loop partition function is calculated for Euclidean
generalised massive gravity (GMG) using AdS heat kernel techniques. We find
that the results fit perfectly into the AdS/(L)CFT picture. Conformal
Chern-Simons gravity, a singular limit of GMG, leads to an additional
contribution in the 1-loop determinant from the conformal ghost. We show that
this contribution has a nice interpretation on the conformal field theory side
in terms of a semi-classical null vector at level two descending from a primary
with conformal weights (3/2,-1/2).Comment: 25 p., 2 jpg figs, v2: added 6 lines of clarifying text after Eq.
(2.38
Three-Dimensional Myocardial Perfusion Maps by Contrast Echocardiography
We evaluated the clinical applicability of a system for three-dimensional (3-D) display of a perfusion map following myocardial contrast echocardiography (MCE). The system was used in 12 patients (9 males and 3 females, mean age 52 ± 10 years) undergoing interventional treatment of chronic total coronary occlusion. In each patient three standard apical views were acquired at baseline with sonicated IopamidolR injections into the left coronary artery (LCA) and into the right coronary artery (RCA). Following successful recanalization of the occluded artery MCE was repeated. The patients tolerated the procedure well. Acquisition of three standard apical views provided sufficient information for the reconstruction of 3-D perfusion maps containing the 16 standard left ventricular (LV) segments. Side-by-side display of the perfusion maps obtained following LCA and RCA echocontrast injections allowed us to classify the myocardial segments (192) into three groups: (1) those supplied by one major artery (124); (2) those supplied by collaterals from contralateral or both major arteries (58); and (3) segments supplied by none of the major arteries (10). Decreased opacification was observed in 50 segme
RTL551 Treatment of EAE Reduces CD226 and T-bet+ CD4 T Cells in Periphery and Prevents Infiltration of T-bet+ IL-17, IFN-γ Producing T Cells into CNS
Recombinant T cell receptor ligands (RTLs) that target encephalitogenic T-cells can reverse clinical and histological signs of EAE, and are currently in clinical trials for treatment of multiple sclerosis. To evaluate possible regulatory mechanisms, we tested effects of RTL therapy on expression of pathogenic and effector T-cell maturation markers, CD226, T-bet and CD44, by CD4+ Th1 cells early after treatment of MOG-35-55 peptide-induced EAE in C57BL/6 mice. We showed that 1–5 daily injections of RTL551 (two-domain I-Ab covalently linked to MOG-35-55 peptide), but not the control RTL550 (“empty” two-domain I-Ab without a bound peptide) or Vehicle, reduced clinical signs of EAE, prevented trafficking of cells outside the spleen, significantly reduced the frequency of CD226 and T-bet expressing CD4+ T-cells in blood and inhibited expansion of CD44 expressing CD4+ T-cells in blood and spleen. Concomitantly, RTL551 selectively reduced CNS inflammatory lesions, absolute numbers of CNS infiltrating T-bet expressing CD4+ T-cells and IL-17 and IFN-γ secretion by CNS derived MOG-35-55 reactive cells cultured ex vivo. These novel results demonstrate that a major effect of RTL therapy is to attenuate Th1 specific changes in CD4+ T-cells during EAE and prevent expansion of effector T-cells that mediate clinical signs and CNS inflammation in EAE
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Carbon and nitrogen isotopic ratios of urine and faeces as novel nutritional biomarkers of meat and fish intake
Purpose
Meat and fish consumption are associated with changes in the risk of chronic diseases. Intake is mainly assessed using self-reporting, as no true quantitative nutritional biomarker is available. The measurement of plasma fatty acids, often used as an alternative, is expensive and time-consuming. As meat and fish differ in their stable isotope ratios, δ13C and δ15N have been proposed as biomarkers. However, they have never been investigated in controlled human dietary intervention studies.
Objective
In a short-term feeding study, we investigated the suitability of δ13C and δ15N in blood, urine and faeces as biomarkers of meat and fish intake.
Methods
The dietary intervention study (n = 14) followed a randomised cross-over design with three eight-day dietary periods (meat, fish and half-meat–half-fish). In addition, 4 participants completed a vegetarian control period. At the end of each period, 24-h urine, fasting venous blood and faeces were collected and their δ13C and δ15N analysed.
Results
There was a significant difference between diets in isotope ratios in faeces and urine samples, but not in blood samples (Kruskal–Wallis test, p < 0.0001). In pairwise comparisons, δ13C and δ15N were significantly higher in urine and faecal samples following a fish diet when compared with all other diets, and significantly lower following a vegetarian diet. There was no significant difference in isotope ratio between meat and half-meat–half-fish diets for blood, urine or faecal samples.
Conclusions
The results of this study show that urinary and faecal δ13C and δ15N are suitable candidate biomarkers for short-term meat and fish intake
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