Factors associated with relapses among patients treated for acute urticaria

The benefit of corticosteroids in acute urticaria is controversial. Our objective was to determine the factors associated with relapses in patients presenting with acute urticaria. A retrospective observational study, including all patients with acute urticaria who visited the angioedema reference center of Academic Public Hospitals – Saint‐Antoine in Paris between January 2015 and June 2017, was conducted. The study inclusion criterion was a diagnosis of acute urticaria in an adult patient. The urticaria was spontaneous or inducible urticaria. The primary outcome was relapse at day 7 and the secondary outcome was relapse at week 6. A total of 184 patients with a first episode of acute urticaria were included. Most of the patients were female (66%) with a mean age of 42 ± 16 years. Corticosteroid administration for treatment of acute urticaria was used in 102 (55%) patients. Overall, 85 (46%) patients had relapses after less than 7 days whereas 168 (91%) patients had relapses after more than 6 weeks. In univariate analysis, the rate of corticosteroid administration was significantly higher in cases of relapse after less than 7 days. No difference in relapse rates after more than 6 weeks appeared. In the multivariate analysis, the independent factor associated with relapses after less than 7 days was the administration of corticosteroids as treatment of acute urticaria (odds ratio, 1.93; 95% confidence interval, 1.06–3.57; P = 0.03). The prevalence of corticosteroid administration for patients with acute urticaria was high. Corticosteroid administration was an independent risk factor associated with relapses after less than 7 days.     

Computational and structural insights into the pre- and post-hydrolysis states of bovine multidrug resistance-associated protein 1

ATP-binding cassette C-family drug membrane transporters play an important role in local pharmacokinetics, that is, drug concentration in cellular compartments. From the structural point of view, only the bovine ortholog of the multidrug resistance-associated protein 1 (bMRP1) has been resolved. We here used μs-scaled molecular dynamics simulations to investigate the structure and dynamics of the bovine multidrug resistance-associated protein 1 in pre- and post-hydrolysis functional states. The present work aims to examine the slight but likely relevant structural differences between pre- and post-hydrolysis states of outward-facing conformations as well as the interactions between the multidrug resistance-associated protein 1 and the surrounding lipid bilayer. Global conformational dynamics show unfavourable extracellular opening associated with nucleotide-binding domain dimerization indicating that the post-hydrolysis state adopts a close-cleft conformation rather than an outward-open conformation. Our present simulations also highlight persistent interactions with annular cholesterol molecules and the expected active role of lipid bilayer in the allosteric communication between distant domains of the transporter.     

Detection of putative functional angiotensinogen (AGT) gene variants controlling plasma AGT levels by combined segregation-linkage analysis

Previous studies have suggested that angiotensinogen (AGT) gene variants are associated with increased plasma AGT levels, and may also contribute towards the inherited component of predisposition to essential hypertension in humans. To explore the potential functionality of several AGT polymorphisms and estimate their effects, together with other sources of familial correlations, on plasma AGT, we undertook a large study involving 545 healthy French volunteers in 130 nuclear families that include 285 offspring. Plasma AGT levels were measured in all participants, and bi-allelic AGT variants were analysed as candidate functional variants at three sites in the 5'-flanking region (C-532T, A-20C, G-6A), two sites in exon 2 (M235T, T174M) and two newly identified variant sites in the untranslated sequence of exon 5 and the 3'-flanking region (C+2054A, C+2127T) of the gene. Analysis with the class D regressive model showed significant effects influencing plasma AGT levels of all AGT polymorphisms tested, with the exception of T174M. The most significant result was found at C-532T (P=0.000001), which accounts for 4.3% of total plasma AGT variability in parents and 5.5% in offspring, with substantial residual familial correlations. Maximum likelihood estimates of haplotype frequencies and tests of linkage disequilibrium between each AGT polymorphism and a putative QTL are in agreement with a complete confounding of C-532T with the QTL, when taking into account sex and generation specific effects of the QTL. However, further combined segregation-linkage analyses showed significant evidence for additional effects of G-6A, M235T and C+2054A polymorphisms after accounting for C-532T, which supports a complex model with at least two functional variants within the AGT gene controlling AGT levels.     

Resistance of the sheep skull after a monocortical cranial graft harvest

IntroductionCranial bone grafts are commonly used for preimplant or facial reconstructive surgery. However, removing bone may weaken the parietal bone and lead to a loss of strength. This loss has never been quantified. Bone harvest site reconstruction is being carried out more frequently than in the past, but its effect on the strength of the donor site is unknown.The aim of our study is to quantify the loss of strength due to a monocortical cranial bone graft harvest in sheep.Materials and methodsThirty-four fresh sheep cadaver heads were used for the study. We performed a monocortical bone graft harvest on the posterior part of the right frontal bone. We used a surgical navigation system with optoelectronic tracking to measure bone thickness.To evaluate the resistance of the skull to an impact we developed a pendulum Charpy impact testing machine. The impact force hit a defined target frontal area.ResultsThe total thickness on both sides ranged from 3 mm to 10 mm with a mean of 6 mm (SD = 1.4 mm).The loss of strength between the intact left side and the harvested right side varied with a mean of 49% (SD = 17%) and was significant (p = 6.10^?10).ConclusionThis study has demonstrated that there is a loss of strength in the skull on the side where a bone graft has been harvested.Reconstruction of the harvested site using biomaterials reduces the poor aesthetic outcome due to depression at the site, but we do not know its effects on strength. This kind of study cannot be performed in humans for ethical reasons.Data obtained from this study will allow us to carry out a study in sheep to evaluate strength of the frontal area of a skull with a harvest site reconstructed with hydroxyapatite cement.