Background The efficacy and safety of a 5-grass-pollen sublingual immunotherapy (SLIT) tablet (Stallergènes SA, Antony, France) have been evaluated in clinical studies during the pollen season. The ...allergen challenge chamber (ACC) has been developed as a pharmacodynamic assessment tool to control the environmental allergens and to avoid all problems associated with unpredictable pollen seasons. Objective We sought to evaluate the onset of action and efficacy of 300-IR (index of reactivity) SLIT tablets by using an ACC. Methods Patients with grass pollen–induced rhinoconjunctivitis were randomized into the active or placebo groups. A standardized allergen challenge with grass pollen and symptom evaluation every 15 minutes was performed at baseline, 1 week, and 1, 2, and 4 months of treatment. The primary end point was the average rhinoconjunctivitis total symptom score (ARTSS). Allergen-specific basophil activation, T-cell proliferation, and plasmatic IgE and IgG responses were assessed before and after treatment. Results In the intention-to-treat population (n = 89) a significant treatment effect was achieved after the first month ( P = .0042) and second month ( P = .0203) and was maintained through to the fourth month ( P = .0007). In the active group the ARTSS (means ± SDs) decreased at each challenge: week 1, 7.40 ± 2.682; month 1, 5.89 ± 2.431; month 2, 5.09 ± 2.088; and month 4, 4.85 ± 1.999. An improvement (vs placebo) of 29.3% for the mean ARTSS (median, 33.3%) was observed at end point. Furthermore, the induction of grass pollen allergen–specific IgGs was associated with clinical response. The most frequent adverse reactions were local: oral pruritus, ear pruritus, and throat irritation. Conclusions In this ACC study the 300-IR 5-grass-pollen SLIT tablets had a significant effect on rhinoconjunctivitis symptoms (vs placebo) from the first month of treatment onward.
Summary Background Generalised convulsive status epilepticus (GCSE) should be treated quickly. Benzodiazepines are the only drug treatment available so far that is effective before admission to ...hospital. We assessed whether addition of the antiepileptic drug levetiracetam to the benzodiazepine clonazepam would improve prehospital treatment of GCSE. Methods We did a prehospital, randomised, double-blind, phase 3, placebo-controlled, superiority trial to determine the efficacy of adding intravenous levetiracetam (2·5 g) to clonazepam (1 mg) in treatment of GCSE in 13 emergency medical service centres and 26 hospital departments in France. Randomisation was done at the Paris Descartes Clinical Research Unit with a list of random numbers generated by computer. Adults with convulsions lasting longer than 5 min were randomly assigned (1:1) by prehospital physicians to receive levetiracetam or placebo in combination with clonazepam. All physicians and paramedics were masked to group assignments. If the status epilepticus lasted beyond 5 min after drug injection, a second dose of 1 mg clonazepam was given. The primary outcome was cessation of convulsions within 15 min of drug injection. We analysed the modified intention-to-treat population that had received at least one injection of clonazepam and levetiracetam or placebo, excluding patients without valid consent and those randomised more than once. The trial is registered at EudraCT, number 2007-005782-35. Findings Between July 20, 2009, and Dec 15, 2012, 107 patients were randomly assigned to receive placebo and 96 were assigned to receive levetiracetam. The trial was discontinued on Dec 15, 2012 when interim analysis showed no evidence of a treatment difference, and 68 patients in each group were included in the modified intention-to-treat analysis. Convulsions stopped at 15 min of drug injection in 57 of 68 patients (84%) receiving clonazepam and placebo and in 50 of 68 patients (74%) receiving clonazepam and levetiracetam (percentage difference −10·3%, 95% CI −24·0 to 3·4). Three deaths, 19 of 47 (40 %) serious adverse events, and 90 of 197 (46%) non-serious events were reported in the levetiracetam group, and four deaths, 28 of 47 (60%) serious events, and 107 of 197 (54%) non-serious events were reported in the placebo group. Interpretation The addition of levetiracetam to clonazepam treatment presented no advantage over clonazepam treatment alone in the control of GCSE before admission to hospital. Future prehospital trials could assess the efficacy of clonazepam alone as a first-line treatment in status epilepticus and the efficacy of a second injection of clonazepam with another antiepileptic drug as second-line treatment. Funding UCB Pharma.
Objective Radial-cephalic fistulas (RCFs) perianastomotic stenoses (PASs) are on and around the fistula anastomosis. This group of lesions encompasses juxta-anastomotic stenosis (stenosis located on ...the venous side within 3 cm away from the anastomosis), anastomotic, and arterial stenosis. The purpose of our study was to assess the postintervention primary patency and assisted postintervention primary patency (APP) rates for surgery and angioplasty when treating these stenoses. The secondary endpoint was to identify factors that might influence the procedure's patency rates. Materials and Methods This retrospective study included 73 consecutive patients treated for lack of maturation PASs between January 1999 and December 2005 in two interventional centers. Patients' mean age was 65 years old. Stenoses were treated by surgery (n = 21) or percutaneous transluminal angioplasty (PTA; n = 52). Surgery meant creation of a new anastomosis excluding the area of stenosis. Preoperative characteristics including the patient's age, gender, comorbidities, stenosis location, and length were not statistically different between the two groups. The mean follow-up was 39 months for PTA and 49 months for surgery. Results Anatomical and clinical success rates were 86% and 90% for surgery, and 75% and 92% for PTA. At 1 year, the primary patency rates were 71 ± 10% for surgery and 41 ± 6% for PTA, respectively ( P < .02). There was no significant difference between the two groups with respect to assisted primary patency (95% vs 92%). In the PTA group, stenosis location at the anastomosis itself was a risk factor of early recurrence ( P = .047). The complication rate was similar between surgery and PTA. Conclusion Our results suggest that the treatment of anastomotic stenoses should be surgical rather than endovascular. Angioplasty and surgery have shown similar results when used to treat other perianastomotic stenoses, but repeat procedures were more frequent with angioplasty.
Autoantibodies directed against various cardiac receptors have been implicated in cardiomyopathy and heart rhythm disturbances. In a previous study among patients with dilated cardiomyopathy, ...autoantibodies targeting the cardiac voltage-gated KCNQ1 K(+) channel were associated with shortened corrected QT intervals (QTc). However, the electrophysiologic actions of KCNQ1 autoimmunity have not been assessed experimentally in a direct fashion.
The purpose of this study was to investigate the cardiac electrophysiologic effects of KCNQ1 autoantibody production induced by vaccination in a rabbit model.
Rabbits were immunized with KCNQ1 channel peptide. ECG recordings were obtained during a 1-month follow-up period. Rabbits then underwent in vivo electrophysiologic study, after which cardiomyocytes were isolated for analysis of slow delayed rectifier current (IKs) and action potential properties via patch-clamp.
KCNQ1-immunized rabbits exhibited shortening of QTc compared to sham-immunized controls. Reduced ventricular effective refractory periods and increased susceptibility to ventricular tachyarrhythmia induction were noted in KCNQ1-immunized rabbits upon programmed ventricular stimulation. Action potential durations were shortened in cardiomyocytes isolated from KCNQ1-immunized rabbits compared to the sham group. IKs step and tail current densities were enhanced after KCNQ1 immunization. Functional and structural changes of the heart were not observed. The potential therapeutic significance of KCNQ1 immunization was then explored in a dofetilide-induced long QT rabbit model. KCNQ1 immunization prevented dofetilide-induced QTc prolongation and attenuated long QT-related arrhythmias.
Induction of KCNQ1 autoimmunity accelerates cardiac repolarization and increases susceptibility to ventricular tachyarrhythmia induction through IKs enhancement. On the other hand, vaccination against KCNQ1 ameliorates drug-induced QTc prolongation and might be useful therapeutically to enhance repolarization reserve in long QT syndrome.
There is equivocal evidence of in utero nucleoside reverse transcriptase inhibitor (NRTI) exposure and the occurrence of mitochondrial dysfunction (MD) in HIV-uninfected children born of HIV-infected ...women.
The primary analysis included 1037 HIV-uninfected children born in 1991-2002 and enrolled in Pediatric AIDS Clinical Trials Group protocols 219/219C. Possible cases with unexplained signs of MD according to the Enquête Périnatale Française criteria were identified through retrospective review. Associations between overall in utero NRTI exposure, and trimester of first in utero NRTI exposure and possible MD were estimated with exact logistic regression.
Cases (n = 20) were significantly more likely to be male and to be born in earlier years than non-cases (n = 1017). There was no association between overall in utero NRTI exposure and MD. In unadjusted models there were higher odds of first in utero exposure in the third trimester to lamivudine (3TC) odds ratio (OR), 3.76 versus 3TC unexposed; 95% confidence interval (CI), 1.09-11.78 and to zidovudine (ZDV) and 3TC in combination (ZDV/3TC) (OR, 3.29 vs. ZDV/3TC unexposed; 95% CI, 0.96-10.25) among cases than noncases. When adjusted for year of birth the odds of first exposure in the third trimester to 3TC (OR, 10.57; 95% CI, 1.93-75.61) and ZDV/3TC (OR, 9.84; 95% CI, 1.77-71.68) were significantly higher among cases than non-cases. Incomplete data precluded control of possible confounding by maternal viral load and psychoactive drug use.
Our study suggests that first exposure to 3TC or ZDV/3TC in the third trimester may be associated with the occurrence of possible MD. Further studies that rigorously assess MD and better control confounding are needed.
According to World Health Organization recommendations, opioids prescription is a key aspect of improvement in cancer pain relief. However, studies on opioids prescription in France are scarce. This ...study aimed principally to investigate the impact of cancer on opioids prescription and then to identify factors associated with this prescription, focusing on patients& characteristics impact.
We matched the following two cohorts: cancer survivors (N = 6,760) and individuals without cancer (N = 6,760). Using French health insurance databases, we compared the prevalence of prescribed opioids in 2009-2015 in people with and without cancer and we applied afterwards conditional Poisson regressions to estimate relative risks for monthly opioids prescription. For cancer survivors only (N = 3,055), multivariate negative binomial regressions were performed to identify factors associated with opioids prescription.
Cancer was associated with a higher analgesics prescription in the cancer population. While Step II and III opioids prescription decreased over time, the latter remained marginal and tended to stabilize. Older people were most adversely affected by underprescription of opioids, especially Step III opioids. Furthermore, although the matched case/control study suggested that men were prescribed opioids more often than women, multivariate analysis did not support this finding.
The inconsistency between our findings and existing literature regarding both opioids prescription trends and postdiagnosis pain chronicity in cancer survivors over the medium term suggests possible changes in pain perception and the evolution of cancer pain management strategies. Further research should explore these hypotheses and investigate patient characteristics& effect in cancer pain management.
Abstract Background context Adolescent idiopathic scoliosis (AIS) causes a spine and rib cage three-dimensional (3D) deformity previously treated by bracing. Whatever the manufacturing process, this ...rigid system acts biomechanically on the patient through the “three-point bending” mechanical principle. It applies corrective forces to a limited area and acts especially in the frontal plane. It seemed to us that a nonrigid system, called “Cbrace,” with 3D action allowing distribution of forces could increase compliance and provide better long-term correction prospects. Purpose The aim of this study was to design a nonrigid brace by numerically testing in a finite-element model developed here. Study design A finite-element model has been developed to simulate brace effect on AIS right thoracic deformation of a 10-year-old patient. Methods A two-step method was needed; first, the reliability of our model is evaluated, and then, the ability to use distributed forces to correct scoliosis deformation is tested. To obtain a 3D correction, several treatments are experimented, leading to a comparison test between the best combination to the “three-point bending” principle. Results The numerical model developed here shows good qualitative answers for the treatment of brace forces. The first results demonstrate numerically that distributed forces may be of interest in brace treatment design. Overall force of 40 N above cartilage of the last nonfloating ribs associated to two posterior asymmetrical areas appears to be the best way to correct scoliosis deformation with nonrigid action. Conclusion The results show numerical efficacy of distributed forces to correct spinal deformities and raises the prospect that a new numerical brace, called “Cbrace,” could be a starting point in the search for a nonrigid system.
Microsporidia are obligate intracellular parasites infesting many animal groups. Lacking mitochondria and peroxysomes, these unicellular eukaryotes were first considered a deeply branching protist ...lineage that diverged before the endosymbiotic event that led to mitochondria. The discovery of a gene for a mitochondrial-type chaperone combined with molecular phylogenetic data later implied that microsporidia are atypical fungi that lost mitochondria during evolution. Here we report the DNA sequences of the 11 chromosomes of the ∼2.9-megabase (Mb) genome of Encephalitozoon cuniculi (1,997 potential protein-coding genes). Genome compaction is reflected by reduced intergenic spacers and by the shortness of most putative proteins relative to their eukaryote orthologues. The strong host dependence is illustrated by the lack of genes for some biosynthetic pathways and for the tricarboxylic acid cycle. Phylogenetic analysis lends substantial credit to the fungal affiliation of microsporidia. Because the E. cuniculi genome contains genes related to some mitochondrial functions (for example, Fe-S cluster assembly), we hypothesize that microsporidia have retained a mitochondrion-derived organelle.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Objectives Because systemic vasculitis (SV) predisposes to atherosclerosis, and high-density lipoprotein (HDL) prevents atherosclerosis by “reverse cholesterol transport” and by inhibiting ...low-density lipoprotein (LDL) oxidation thanks to apolipoprotein A-I (Apo-AI) and paraoxonase 1 (PON1), we assessed whether LDL oxidation was increased in SV and associated with less PON1 activity. Methods The sera of 33 patients with active SV (ASV), 32 in full remission of SV (RSV) and 20 healthy subjects (HS) were analyzed for C-reactive protein (CRP), high-sensitivity-CRP, lipids, lipoproteins, apolipoproteins, PON1 activity, LDL-immune complexes (LDL-IC), and auto-antibodies to oxidized-LDL (ox-LDL), and anticardiolipin antibodies. Results CRP was higher in ASV than RSV and HS, and negatively correlated with HDL-cholesterol and Apo-AI. Autoantibodies to ox-LDL and highly oxidized malondialdehyde-LDL were higher in RSV than ASV and HS ( P < 0.05). LDL-IC titers were higher in ASV than RSV and HS ( P < 0.05). PON1 activity was lower in ASV and RSV than HS ( P = 0.02). A trend toward a negative correlation between basal PON1 activity and anti-MDA-LDL antibodies ( P = 0.06) was observed. Conclusion Inflammatory markers in SV were associated with a modified lipoprotein profile, which could lower PON1 activity and contribute to increased ox-LDL titers and accelerated atherosclerosis development.
To initiate a system-level analysis of
C. elegans DAF-7/TGF-β signaling, we combined interactome mapping with single and double genetic perturbations. Yeast two-hybrid (Y2H) screens starting with ...known DAF-7/TGF-β pathway components defined a network of 71 interactions among 59 proteins. Coaffinity purification (co-AP) assays in mammalian cells confirmed the overall quality of this network. Systematic perturbations of the network using RNAi, both in wild-type and
daf-7/TGF-β pathway mutant animals, identified nine DAF-7/TGF-β signaling modifiers, seven of which are conserved in humans. We show that one of these has functional homology to human SNO/SKI oncoproteins and that mutations at the corresponding genetic locus
daf-5 confer defects in DAF-7/TGF-β signaling. Our results reveal substantial molecular complexity in DAF-7/TGF-β signal transduction. Integrating interactome maps with systematic genetic perturbations may be useful for developing a systems biology approach to this and other signaling modules.
PDF
