Can an app supporting psoriasis patients improve adherence to topical treatment? A single-blind randomized controlled trial.

BACKGROUND: Topical corticosteroid or corticosteroid/calcipotriol preparations are recommended first-line topical treatments of psoriasis, but a main cause for the lack of efficacy of topical treatments is considered low rates of adherence to topical drugs. Patient support by the use of applications (apps) for smartphones is suggested to improve medical adherence. METHODS/DESIGN: Design: An investigator-initiated, single-center, single-blind, parallel-group, phase-4 clinical superiority randomized controlled trial (RCT). PARTICIPANTS: 134 patients 18 to 75 years of age with mild-to-moderate psoriasis, who are capable of reading English language, own a smartphone, and are candidates for the study drug calcipotriol and betamethasone dipropionate (Cal/BD) cutaneous foam once daily prn (pro re nata). INTERVENTION: A 28-day adherence-supporting app providing compulsory daily treatment reminders that pop-up on the smartphone screen with a short alert sound. The app synchronizes through Bluetooth® to an electronic monitor (EM) attached to the medication canister. The EM contains a chip registering the amount of foam, day and time the patient use the foam dispenser. The information is displayed in a diary that shows the amount of Cal/BD cutaneous foam used and the number of applied treatment sessions. The app has an optional diary with the patient's rating of symptoms. Non-intervention: Use of Cal/BD cutaneous foam and EM without the app. All participants are prescribed Cal/BD cutaneous foam prn for the entire study period. Primary outcome obtained in week 4: rates of adherence measured by patient report, weight of medication canisters, and number of treatment sessions measured by the EM. Secondary outcomes obtained at baseline, weeks 4, 8, and 26: Lattice System Physician's Global Assessment (LS-PGA) and Dermatology Quality of Life Index (DLQI). DISCUSSION: This trial tests of whether an app can improve rates of adherence to a topical antipsoriatic drug. If the app improves rates of adherence and reduces the burden of psoriasis in a clinically significant way, the app could easily be implemented as a standard routine of care in the clinic. TRIAL REGISTRATION: NCT02858713 , registered on August 3, 2016. EudraCT number 2016-002143-42.

Dielectric Genome of van der Waals Heterostructures.

Vertical stacking of two-dimensional (2D) crystals, such as graphene and hexagonal boron nitride, has recently lead to a new class of materials known as van der Waals heterostructures (vdWHs) with unique and highly tunable electronic properties. Ab initio calculations should in principle provide a powerful tool for modeling and guiding the design of vdWHs, but in their traditional form such calculations are only feasible for commensurable structures with a few layers. Here we show that the dielectric properties of realistic, incommensurable vdWHs comprising hundreds of layers can be efficiently calculated using a multiscale approach where the dielectric functions of the individual layers (the dielectric building blocks) are computed ab initio and coupled together via the long-range Coulomb interaction. We use the method to illustrate the 2D-3D transition of the dielectric function of multilayer MoS2 crystals, the hybridization of quantum plasmons in thick graphene/hBN heterostructures, and to demonstrate the intricate effect of substrate screening on the non-Rydberg exciton series in supported WS2. The dielectric building blocks for a variety of 2D crystals are available in an open database together with the software for solving the coupled electrodynamic equations.

Reduced content of chloroatranol and atranol in oak moss absolute significantly reduces the elicitation potential of this fragrance material.

BACKGROUND: Oak moss absolute, an extract from the lichen Evernia prunastri, is a valued perfume ingredient but contains extreme allergens. OBJECTIVES: To compare the elicitation properties of two preparations of oak moss absolute: 'classic oak moss', the historically used preparation, and 'new oak moss', with reduced contents of the major allergens atranol and chloroatranol. PATIENTS/MATERIALS/METHODS: The two preparations were compared in randomized double-blinded repeated open application tests and serial dilution patch tests in 30 oak moss-sensitive volunteers and 30 non-allergic control subjects. RESULTS: In both test models, new oak moss elicited significantly less allergic contact dermatitis in oak moss-sensitive subjects than classic oak moss. The control subjects did not react to either of the preparations. CONCLUSIONS: New oak moss is still a fragrance allergen, but elicits less allergic contact dermatitis in previously oak moss-sensitized individuals, suggesting that new oak moss is less allergenic to non-sensitized individuals.

Computer-aided discovery of aromatic l-α-amino acids as agonists of the orphan G protein-coupled receptor GPR139.

GPR139 is an orphan G protein-coupled receptor expressed mainly in the central nervous system. We developed a pharmacophore model based on known GPR139 surrogate agonists which led us to propose aromatic-containing dipeptides as potential ligands. Upon testing, the dipeptides demonstrated agonism in the Gq pathway. Next, in testing all 20 proteinogenic l-α-amino acids, L-tryptophan and l-phenylalanine were found to have EC50 values of 220 and 320 µM, respectively, making them the first putative endogenous agonists for GPR139.

The role of flagella and chemotaxis genes in host pathogen interaction of the host adapted Salmonella enterica serovar Dublin compared to the broad host range serovar S. Typhimurium.

BACKGROUND: The importance of flagella and chemotaxis genes in host pathogen interaction in Salmonella enterica is mainly based on studies of the broad host range serovar, S. Typhimurium, while little is known on the importance in host specific and host adapted serovars, such as S. Dublin. In the current study we have used previously characterized insertion mutants in flagella and chemotaxis genes to investigate this and possible differences in the importance between the two serovars. RESULTS: fliC (encoding the structural protein of the flagella) was essential for adhesion and fliC and cheB (CheB restores the chemotaxis system to pre-stimulus conformation) were essential for invasion of S. Dublin into epithelial Int407 cells. In S. Typhimurium, both lack of flagella (fliC/fljB double mutant) and cheB influenced adhesion, and invasion was influenced by lack of both cheA (the histidine-kinase of the chemotaxis system), fliC/fljB and cheB mutation. Uptake in J774A.1 macrophage cells was significantly reduced in cheA, cheB and fliC mutants of S. Dublin, while cheA was dispensable in S. Typhimurium. Removal of flagella in both serotypes caused an increased ability to propagate intracellular in J774 macrophage cells and decreased cytotoxicity toward these cells. Flagella and chemotaxis genes were found not to influence the oxidative response. The induction of IL-6 from J774A-1 cells depended on the presence of flagella in S. Typhimurium, whilst this was not the case following challenge with S. Dublin. Addition of fliC from S. Typhimurium in trans to a fliC mutant of S. Dublin increased cytotoxicity but it did not increase the IL-6 production. Flagella were demonstrated to contribute to the outcome of infection following oral challenge of mice in S. Dublin, while an S. Typhimurium fliC/fljB mutant showed increased virulence following intra peritoneal challenge. CONCLUSIONS: The results showed that flagella and chemotaxis genes differed in their role in host pathogen interaction between S. Dublin and S. Typhimurium. Notably, lack of flagella conferred a more virulent phenotype in S. Typhimurium at systemic sites, while this was not the case in S. Dublin. In vitro assays suggested that this could be related to flagella-induced induction of the IL-6 pro-inflammatory response, but further in vivo studies are needed to confirm this.

Gender differences in anxiety and concerns about the cardioverter defibrillator.

BACKGROUND: Little is known about gender differences in the response to implantable cardioverter defibrillator (ICD) therapy. We compared female and male ICD patients on anxiety, depression, health-related quality of life (HRQL), ICD concerns, and ICD acceptance. METHODS: A cohort of consecutive, surviving patients (n = 535; mean age = 61.5 +/- 14.4, 81.9% male) implanted with an ICD between 1989 and 2006 completed the Hospital Anxiety and Depression Scale, the Short-Form Health Survey (SF-36), the ICD concerns questionnaire, and the Florida Patient Acceptance Survey. RESULTS: High levels of anxiety (52% vs 34%, P < 0.001) and ICD concerns (34% vs 16%, P = 0.001) were more prevalent in women than men, whereas no significant differences were found on depression and device acceptance (Ps > 0.05). Women were more anxious (odds ratio [OR]: 2.60 [95% confidence interval (CI): 1.46-4.64], P < 0.01) and had more ICD concerns (OR: 1.81 [95% CI: 1.09-3.00], P < 0.05) than men, adjusting for demographic and clinical characteristics. Those ICD patients experiencing shocks were also more anxious (OR: 2.02 [95% CI: 1.20-3.42], P < 0.01) and had higher levels of ICD concerns (OR: 2.70 [95% CI: 1.76-4.16], P < 0.01). In multivariable analysis of variance, significant gender differences were found for only three of the eight subscales of the SF-36 (the physical social functioning and the mental health subscale), with women reporting poorer HRQL on all three subscales. CONCLUSIONS: Women were more prone to experience anxiety and ICD concerns compared to men regardless of whether they had experienced shocks. In clinical practice, female ICD patients should be closely monitored, and if warranted offered psychosocial intervention, as increased anxiety has been shown to precipitate arrhythmic events in defibrillator patients.

Simple preimplant identification of optimum VV timing before cardiac resynchronization therapy: tissue Doppler imaging versus conventional 2D echocardiography.

AIMS: Optimum interventricular (VV) timing may potentially reduce the number of nonresponders to cardiac resynchronization therapy (CRT). We investigated whether optimum VV-timing interval could be determined before CRT implantation by means of tissue Doppler imaging (TDI) analysis and from visual assessment of conventional 2D echocardiography. METHODS AND RESULTS: Thirty consecutive patients prospectively underwent 2D, 3D, and TDI echocardiographic evaluation before and 1 month after CRT. By using 3D echocardiography, LVEF was found to be increased from 23.8 +/- 6% to 35.7 +/- 9% 1 month after CRT (P < 0.001). NYHA class improved from 3.0 +/- 0.6 to 1.8 +/- 0.6 (P < 0.001). In 93% (77-99% with 95% confidence limits) of the patients optimum VV timing was correctly predicted based on preimplant TDI identification of the region with delayed myocardial contraction. A similar result could be obtained in 83% (65-94%) of the patients simply by visual assessment of conventional black and white 2D echocardiography (ns). CONCLUSION: Preimplant TDI evaluation seems to be convenient for the determination of optimum VV timing. Further postimplant adjustment guided by TDI is hardly necessary unless patients do not experience clinical benefit. TDI may seem superior to visual assessment of dyssynchrony by means of conventional 2D echocardiography. However, this simple technique indicated optimum VV timing in the majority of cases in this study.

Symptomatic heart failure is the most important clinical correlate of impaired quality of life, anxiety, and depression in implantable cardioverter-defibrillator patients: a single-centre, cross-sectional study in 610 patients.

AIMS: To identify correlates of impaired quality of life (QOL), anxiety, and depression in patients with an implantable cardioverter-defibrillator (ICD). METHODS AND RESULTS: Surviving patients (n = 610) who received an ICD in our institution since 1989 completed the Short Form Health Survey (SF-36) and the Hospital Anxiety and Depression Scale. Mean age was 62.4 years with 18% females. In a multivariate logistic regression analysis, symptomatic heart failure was the most important correlate of impaired QOL (SF-36) across all eight subscales [odds ratios (ORs) ranging from 5.21 to 22.53)], whereas psychotropic medication, age, comorbidity, amiodarone, and ICD shocks all correlated to a lesser extent. Symptomatic heart failure was also the most dominant correlate of anxiety [OR 5.15 (3.08-8.63), P < 0.001] and depression [OR 6.82 (3.77-12.39), P < 0.001]. Implantable cardioverter-defibrillator shocks correlated less yet significantly with anxiety [OR 2.21 (1.32-3.72) P < 0.01] and depression [OR 2.00 (1.06-3.80), P < 0.05]. CONCLUSION: Symptomatic heart failure was the single most important clinical correlate of impaired QOL, anxiety, and depression, with ICD shocks playing only a secondary role. This suggests that comorbidity rather than ICD therapy per se influences patients' device acceptance, supporting the increasing use of prophylactic ICD implantation.

The GPR139 reference agonists 1a and 7c, and tryptophan and phenylalanine share a common binding site.

GPR139 is an orphan G protein-coupled receptor expressed in the brain, in particular in the habenula, hypothalamus and striatum. It has therefore been suggested that GPR139 is a possible target for metabolic disorders and Parkinson's disease. Several surrogate agonist series have been published for GPR139. Two series published by Shi et al. and Dvorak et al. included agonists 1a and 7c respectively, with potencies in the ten-nanomolar range. Furthermore, Isberg et al. and Liu et al. have previously shown that tryptophan (Trp) and phenylalanine (Phe) can activate GPR139 in the hundred-micromolar range. In this study, we produced a mutagenesis-guided model of the GPR139 binding site to form a foundation for future structure-based ligand optimization. Receptor mutants studied in a Ca2+ assay demonstrated that residues F1093×33, H1875×43, W2416×48 and N2717×38, but not E1083×32, are highly important for the activation of GPR139 as predicted by the receptor model. The initial ligand-receptor complex was optimized through free energy perturbation simulations, generating a refined GPR139 model in agreement with experimental data. In summary, the GPR139 reference surrogate agonists 1a and 7c, and the endogenous amino acids L-Trp and L-Phe share a common binding site, as demonstrated by mutagenesis, ligand docking and free energy calculations.

The orphan G protein-coupled receptor GPR139 is activated by the peptides: Adrenocorticotropic hormone (ACTH), α-, and ß-melanocyte stimulating hormone (α-MSH, and ß-MSH), and the conserved core motif HFRW.

GPR139 is an orphan G protein-coupled receptor that is expressed primarily in the brain. Not much is known regarding the function of GPR139. Recently we have shown that GPR139 is activated by the amino acids l-tryptophan and l-phenylalanine (EC50 values of 220 µM and 320 µM, respectively), as well as di-peptides comprised of aromatic amino acids. This led us to hypothesize that GPR139 may be activated by peptides. Sequence alignment of the binding cavities of all class A GPCRs, revealed that the binding pocket of the melanocortin 4 receptor is similar to that of GPR139. Based on the chemogenomics principle "similar targets bind similar ligands", we tested three known endogenous melanocortin 4 receptor agonists; adrenocorticotropic hormone (ACTH) and α- and ß-melanocyte stimulating hormone (α-MSH and ß-MSH) on CHO-k1 cells stably expressing the human GPR139 in a Fluo-4 Ca2+-assay. All three peptides, as well as their conserved core motif HFRW, were found to activate GPR139 in the low micromolar range. Moreover, we found that peptides consisting of nine or ten N-terminal residues of α-MSH activate GPR139 in the submicromolar range. α-MSH1-9 was found to correspond to the product of a predicted cleavage site in the pre-pro-protein pro-opiomelanocortin (POMC). Our results demonstrate that GPR139 is a peptide receptor, activated by ACTH, α-MSH, ß-MSH, the conserved core motif HFRW as well as a potential endogenous peptide α-MSH1-9. Further studies are needed to determine the functional relevance of GPR139 mediated signaling by these peptides.

Protection of Primary Dopaminergic Midbrain Neurons by GPR139 Agonists Supports Different Mechanisms of MPP(+) and Rotenone Toxicity.

The G-protein coupled receptor 139 (GPR139) is expressed specifically in the brain in areas of relevance for motor control. GPR139 function and signal transduction pathways are elusive, and results in the literature are even contradictory. Here, we examined the potential neuroprotective effect of GPR139 agonism in primary culture models of dopaminergic (DA) neuronal degeneration. We find that in vitro GPR139 agonists protected primary mesencephalic DA neurons against 1-methyl-4-phenylpyridinium (MPP(+))-mediated degeneration. Protection was concentration-dependent and could be blocked by a GPR139 antagonist. However, the protection of DA neurons was not found against rotenone or 6-hydroxydopamine (6-OHDA) mediated degeneration. Our results support differential mechanisms of toxicity for those substances commonly used in Parkinson's disease (PD) models and potential for GPR139 agonists in neuroprotection.

Novel Agonist Bioisosteres and Common Structure-Activity Relationships for The Orphan G Protein-Coupled Receptor GPR139.

GPR139 is an orphan class A G protein-coupled receptor found mainly in the central nervous system. It has its highest expression levels in the hypothalamus and striatum, regions regulating metabolism and locomotion, respectively, and has therefore been suggested as a potential target for obesity and Parkinson's disease. The two aromatic amino acids L-Trp and L-Phe have been proposed as putative endogenous agonists, and three structurally related benzohydrazide, glycine benzamide, and benzotriazine surrogate agonist series have been published. Herein, we assayed 158 new analogues selected from a pharmacophore model, and identified 12 new GPR139 agonists, containing previously untested bioisosteres. Furthermore, we present the first combined structure-activity relationships, and a refined pharmacophore model to serve as a rationale for future ligand identification and optimization.

The Inhibitory Effect of Natural Products on Protein Fibrillation May Be Caused by Degradation Products--A Study Using Aloin and Insulin.

Protein fibrillation is the pathological hallmark of several neurodegenerative diseases and also complicates the manufacturing and use of protein drugs. As a case study, the inhibitory activity of the natural compound aloin against insulin fibrillation was investigated. Based on Thioflavin T assays, high-performance liquid chromatography and transmission electron microscopy it was found that a degradation product of aloin, formed over weeks of storage, was able to significantly inhibit insulin fibrillation. The activity of the stored aloin was significantly reduced in the presence of small amounts of sodium azide or ascorbic acid, suggesting the active compound to be an oxidation product. A high-performance liquid chromatography method and a liquid chromatography-mass spectrometry method were developed to investigate the degradation products in the aged aloin solution. We found that the major compounds in the solution were aloin A and aloin B. In addition, 10-hydroxy aloin and elgonica dimers were detected in smaller amounts. The identified compounds were isolated and tested for activity by means of Thioflavin T assays, but no activity was observed. Thus, the actual fibrillation inhibitor is an as yet unidentified and potentially metastable degradation product of aloin. These results suggest that degradation products, and in particular oxidation products, are to be considered thoroughly when natural products are investigated for activity against protein fibrillation.

The RNA splicing factor ASF/SF2 inhibits human topoisomerase I mediated DNA relaxation.

Human topoisomerase I interacts with and phosphorylates the SR-family of RNA splicing factors, including ASF/SF2, and has been suggested to play an important role in the regulation of RNA splicing. Here we present evidence to support the theory that the regulation can go the other way around with the SR-proteins controlling topoisomerase I DNA activity. We demonstrate that the splicing factor ASF/SF2 inhibits relaxation by interfering with the DNA cleavage and/or DNA binding steps of human topoisomerase I catalysis. The inhibition of relaxation correlated with the ability of various deletion mutants of the two proteins to interact directly, suggesting that an interaction between the RS-domain of ASF/SF2 and a region between amino acid residues 208-735 on topoisomerase I accounts for the observed effect. Consistently, phosphorylation of the RS-domain with either topoisomerase I or a human cell extract reduced the inhibition of relaxation activity. Taken together with the previously published studies of the topoisomerase I kinase activity, these observations suggest that topoisomerase I activity is shifted from relaxation to kinasing by specific interaction with SR-splicing factors.

Recombinogenic flap ligation mediated by human topoisomerase I.

Aberration of eukaryotic topoisomerase I catalysis leads to potentially recombinogenic pathways by allowing the joining of heterologous DNA strands. Recently, a new ligation pathway (flap ligation) was presented for vaccinia virus topoisomerase I, in which blunt end cleavage complexes ligate the recessed end of duplex acceptors having a single-stranded 3'-tail. This reaction was suggested to play an important role in the repair of topoisomerase I-induced DNA double-strand breaks. Here, we characterize flap ligation mediated by human topoisomerase I. We demonstrate that cleavage complexes containing the enzyme at a blunt end allow invasion of a 3'-acceptor tail matching the scissile strand of the donor, which facilitates ligation of the recessed 5'-hydroxyl end. However, the reaction was strictly dependent on the length of double-stranded DNA of the donor complexes, and longer stretches of base-pairing inhibited strand invasion. The stabilization of the DNA helix was most probably provided by the covalently bound enzyme itself, since deleting the N-terminal domain of human topoisomerase I stimulated flap ligation. We suggest that stabilization of the DNA duplex upon enzyme binding may play an important role during normal topoisomerase I catalysis by preventing undesired strand transfer reactions. For flap ligation to function in a repair pathway, factors other than topoisomerase I, such as helicases, would be necessary to unwind the DNA duplex and allow strand invasion.

Intestinal invasion of Salmonella enterica serovar Typhimurium in the avian host is dose dependent and does not depend on motility and chemotaxis.

Salmonella enterica serotype Typhimurium (S. Typhimurium) can invade in the intestine of the avian host, and knowledge on the mechanisms that govern this is potentially important for prevention of disease. This study investigated the invasion of S. Typhimurium in the avian host and to which extent it depended on motility and chemotaxis. Wild type and previously well-characterized transposon mutants in flagella genes fliC and fljB and in chemotaxis genes cheA, cheB and cheR were used as challenge strains in intestinal loop experiments. Invasion was shown to be dose dependent, but did not require functional flagella or chemotaxis genes. In support of the results from intestinal loop experiments, flagella and chemotaxis genes were not significantly important to the outcome of an oral infection. The results showed that S. Typhimurium invasion in the avian host was dose dependent and was not affected by the loss of flagella and chemotaxis genes.

Haematoma after coronary angiography and percutaneous coronary intervention via the femoral artery frequency and risk factors.

BACKGROUND: The most common complication after coronary angiography (CA) and percutaneous coronary intervention (PCI) is the development of haematoma. Several changes in procedures regarding CA and PCI have been made in our department in recent years. The aim of this audit is to establish how many patients develop haematoma after CA/PCI via the femoral artery and subsequently to find predictors that increase the risk of developing haematoma. METHODS: We initially included 474 consecutive patients-322 patients undergoing CA and 141 patients undergoing PCI. Eleven patients were later excluded due to the absence of complete data. Thirty-three variables were registered in order to find predictors, which might increase the haematoma frequency. A univariate as well as a multivariate logistic regression analysis was performed. RESULTS: Of the 463 patients, 6 patients developed a haematoma >10 cm (1.3%) and 41 patients developed a haematoma >5 cm (8.9%). The following factors were found to be associated with the generation of haematoma: Women, systolic blood pressure >160 mm Hg, artery puncture >1, sheath time >16 min, ACT > or = 175 s, Glycoprotein (GP) IIB/IIIa inhibitors, Low Molecular Weight Heparin before procedure, personnel change during compression, and anti-coagulant-treatment before procedure. CONCLUSIONS: The frequency of haematoma was 1.3% (>10 cm) and 8.9% (>5 cm), which corresponds with reports from similar studies and departments. The factors found to increase the risk of haematoma development can provide background for procedural changes and increase the focus on patients at increased risk in order to minimize the development of haematomas.