Prescription of non-steroidal anti-inflammatory drugs for patients with inflammatory arthritis decreases with the initiation of tumour necrosis factor inhibitor therapy: results from the ICEBIO registry.

Objective: To study the impact of tumour necrosis factor-α inhibitor (TNFi) therapy on the use of non-steroidal anti inflammatory drugs (NSAIDs) in patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA), and axial spondyloarthritis (axSpA) in Iceland.

Method: This registry cohort study used data from the nationwide database on biologics in Iceland (ICEBIO) and the Icelandic Prescription Medicines Register on disease activity, and filled prescriptions for NSAIDs, to study the period from 2 years before to 2 years after initiation of a first TNFi. Five randomly selected individuals from the general population matched on age, sex, and calendar time for each patient served as comparators.

Predicting evolutionary outcomes through the probability of accessing sequence variants.

Natural selection can only operate on available genetic variation. Thus, determining the probability of accessing different sequence variants from a starting sequence can help predict evolutionary trajectories and outcomes. We define the concept of "variant accessibility" as the probability that a set of genotypes encoding a particular protein function will arise through mutations before subject to natural selection.

Outpatient Use of Antimicrobials in Patients With Rheumatoid Arthritis Before and After Treatment With Tumor Necrosis Factor Inhibitors: A Nationwide Retrospective Cohort Study.

Objective: The objective of this study was to investigate the effect of tumor necrosis factor α inhibitor (TNFi) initiation on the use of antimicrobials among biologic-naïve patients with rheumatoid arthritis (RA).

Methods: Information on all biologic-naïve patients with RA was extracted from ICEBIO, a nationwide registry. Each patient was matched on age, sex, and calendar time to five randomly selected individuals from the general population.

Children may need higher vancomycin doses to achieve therapeutic levels.

Aim: Vancomycin is frequently used in paediatric hospitals. Data suggest trough levels of 10-20 mg/L are needed to achieve bacterial killing. This study aimed to evaluate if commonly used dosing regimens are efficient in reaching these levels and if therapeutic drug monitoring (TDM) was appropriately used.

Estimation of a whole plant Q10 to assess seagrass productivity during temperature shifts.

Through respiration and photosynthesis, seagrass meadows contribute greatly to carbon and oxygen fluxes in shallow coastal waters. There is increasing concern about how shallow-water primary producers will react to a near-future climate scenario with increased temperature variation. When modelling primary productivity under high temperature variability, Q10 values are commonly used to predict rate changes depending on biophysical factors.

Patients with psoriatic arthritis who are not eligible for randomised controlled trials for TNF inhibitors have treatment response and drug survival similar to those who are eligible.

Objectives: To determine in a retrospective cohort whether patients with psoriatic arthritis (PsA) who would not have fulfilled the inclusion criteria for randomised controlled trials (RCTs) for the TNF inhibitor (TNFi) chosen for their treatment (excl) have similar benefits and drug survival as those patients who would have (incl).

Methods: All patients with rheumatic disorders who are treated with biological disease-modifying antirheumatic drugs in Iceland are registered in ICEBIO. On 1 February 2016, 329 individuals with PsA were registered in ICEBIO, of whom 231 had data available for their first start of TNFi and could be evaluated according to the inclusion criteria of the respective RCTs.

The majority of patients with psoriatic arthritis are not eligible for randomised clinical trials.

Objectives: To identify the proportion of patients with psoriatic arthritis (PsA) who would meet inclusion criteria of the randomised clinical trials that were performed leading up to registration of the tumour necrosis factor inhibitors (TNFi).

Methods: Data from 329 patients with PsA were obtained from an Icelandic database, ICEBIO, medical records at the University Hospital of Iceland, and the private out-patient clinic Laeknasetrid Ltd. The patients were classified according to whether they met the inclusion criteria of the clinical trials that were performed ahead of the registration of each respective TNFi.

The genetics of speciation: Insights from Fisher's geometric model.

Research in speciation genetics has uncovered many robust patterns in intrinsic reproductive isolation, and fitness landscape models have been useful in interpreting these patterns. Here, we examine fitness landscapes based on Fisher's geometric model. Such landscapes are analogous to models of optimizing selection acting on quantitative traits, and have been widely used to study adaptation and the distribution of mutational effects.

Fiix-prothrombin time versus standard prothrombin time for monitoring of warfarin anticoagulation: a single centre, double-blind, randomised, non-inferiority trial.

Background: Rapid fluctuations in factor VII during warfarin anticoagulation change the international normalised ratio (INR) but contribute little to the antithrombotic effect. We aimed to assess non-inferiority of anticoagulation stabilisation with a warfarin monitoring method affected only by factors II and X (Fiix-prothrombin time [Fiix-PT]) compared with standard PT-INR monitoring that includes factor VII measurement as well.

Methods: The Fiix trial was a single centre, double-blind, prospective, non-inferiority, randomised controlled clinical trial.

Protease-activated receptor 1 (PAR1) signalling desensitization is counteracted via PAR4 signalling in human platelets.

PARs (protease-activated receptors) 1 and 4 belong to the family of G-protein-coupled receptors which induce both G(α12/13) and G(αq) signalling. By applying the specific PAR1- and PAR4-activating hexapeptides, SFLLRN and AYPGKF respectively, we found that aggregation of isolated human platelets mediated via PAR1, but not via PAR4, is abolished upon homologous receptor activation in a concentration- and time-dependent fashion. This effect was not due to receptor internalization, but to a decrease in Ca²⁺ mobilization, PKC (protein kinase C) signalling and α-granule secretion, as well as to a complete lack of dense granule secretion.

Reducing vasomotor symptoms with acupuncture in breast cancer patients treated with adjuvant tamoxifen: a randomized controlled trial.

To evaluate true acupuncture to control acupuncture (CTRL) (non-insertive stimulation at non-acupuncture points) in breast cancer patients treated with adjuvant tamoxifen suffering from hot flushes and sweatings. Eighty-four patients were randomized to receive either true acupuncture or CTRL twice a week for 5 weeks. Seventy-four patients were treated according to the protocol.

alpha(1)-acid glycoprotein (AGP)-induced platelet shape change involves the Rho/Rho kinase signalling pathway.

alpha(1)-acid glycoprotein (AGP) is an acute-phase protein that contributes to inflammation processes. The role of AGP in platelet activation and thrombosis is, however, largely unknown. Therefore, we thoroughly investigated the effects of AGP on human platelets.

Sialic acid residues play a pivotal role in alpha(1)-acid glycoprotein (AGP)-induced generation of reactive oxygen species in chemotactic peptide pre-activated neutrophil granulocytes.

Objective: We have recently shown that terminal sialic acid residues are essential for alpha(1)-acid glycoprotein (AGP)-induced Ca(2+) mobilization in neutrophils. The aim of the present study was to establish the importance of sialic acid residues on AGP in modulating human neutrophil functions, with emphasis on the generation of reactive oxygen species (ROS).

Materials And Methods: ROS were measured by luminol-enhanced chemiluminescence in isolated human neutrophils.

Effects of alpha1-acid glycoprotein fucosylation on its Ca2+ mobilizing capacity in neutrophils.

We recently showed that the acute-phase protein alpha(1)-acid glycoprotein (AGP) induces rises in cytosolic calcium concentration, [Ca(2+)](i,) in neutrophils through sialic acid dependent interactions with the neutrophil receptors siglec-5 and/or siglec-14. Whereas both siglec-5 and siglec-14 have a relatively broad specificity for sialylated oligosaccharide structures, including both structures with terminal alpha2-3 or alpha2-6 linked sialic acid, there is a markedly reduced affinity to the fucosylated epitope sialyl Lewis x (SLe(x)). Increased fucosylation, leading to increased expression of SLe(x) on AGP is commonly associated with inflammatory conditions.

Increased degradation rate of nitrososureas in media containing carbonate.

The stability of two nitrosoureas, tauromustine and lomustine, has been investigated in different media and buffers. All media tested, except Leibovitz's L-15 medium, significantly increased the degradation rate of the investigated nitrosoureas at pH 7.4.

The periodontal pathogen Porphyromonas gingivalis cleaves apoB-100 and increases the expression of apoM in LDL in whole blood leading to cell proliferation.

Objective: Several studies support an association between periodontal disease and atherosclerosis with a crucial role for the pathogen Porphyromonas gingivalis. This study aims at investigating the proteolytic and oxidative activity of P. gingivalis on LDL in a whole blood system using a proteomic approach and analysing the effects of P.

The acute-phase protein alpha 1-acid glycoprotein (AGP) induces rises in cytosolic Ca2+ in neutrophil granulocytes via sialic acid binding immunoglobulin-like lectins (siglecs).

We studied whether the acute-phase protein alpha1-acid glycoprotein (AGP) induces rises in [Ca2+]i in neutrophils and sought to identify the corresponding AGP receptor (or receptors). We found that AGP elicited a minimal rise in [Ca2+]i in Fura-2-loaded neutrophils, and this response was markedly enhanced by pretreatment with anti-L-selectin antibodies. (The EC50 value of the AGP-induced Ca2+ response was 9 microg/ml.

Determination of the immunomodulator laquinimod in human plasma by liquid chromatography/tandem mass spectrometry; development, validation and application of two methods in clinical pharmacokinetic profiling.

Laquinimod (ABR-215062) is a synthetic compound currently undergoing clinical development for oral treatment of multiple sclerosis. The present paper describes the development, validation and clinical application of two rapid and sensitive methods for the determination of ABR-215062 in human plasma. Both methods use liquid chromatography/tandem mass spectrometry (LC/MS/MS) with electrospray ionization in positive mode and a stable isotope (13C6)-labeled ABR-215062 as internal standard for calibration.

Glucose-induced incretin hormone release and inactivation are differently modulated by oral fat and protein in mice.

Monounsaturated fatty acids, such as oleic acid (OA), and certain milk proteins, especially whey protein (WP), have insulinotropic effects and can reduce postprandial glycemia. This effect may involve the incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). To explore this, we examined the release and inactivation of GIP and GLP-1 after administration of glucose with or without OA or WP through gastric gavage in anesthetized C57BL/6J mice.

Dual actions of dephostatin on the nitric oxide/cGMP-signalling pathway in porcine iliac arteries.

We examined the effects of the nitrosoamine dephostatin on the nitric oxide (NO)/cyclic guanosine 3',5'-monophosphate (cGMP)-signalling in porcine iliac arteries. Dephostatin has been characterised as a tyrosine phosphatase inhibitor, but Western blot analyses showed that dephostatin did not augment tyrosine phosphorylation of arterial proteins. However, dephostatin relaxed pre-contracted arteries, and this effect was antagonised by the soluble guanylyl cyclase inhibitor 1H[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ).

In vitro metabolism and in vivo pharmacokinetics of quinoline 3-carboxamide derivatives in various species.

The metabolism of a group of quinoline 3-carboxamide derivatives was evaluated in liver microsomes from various species. In addition, metabolism data were compared with in vivo pharmacokinetics in the mouse. The studied compounds were metabolized by cytochrome P450 enzymes.

Cytochrome P450 3A4 is the major enzyme responsible for the metabolism of laquinimod, a novel immunomodulator.

In the present study, the involvement of cytochrome P450 enzyme(s) in the primary metabolism of laquinimod, a new orally active immunomodulator, has been investigated in human liver microsomes. Hydroxylated and dealkylated metabolites were formed. The metabolite formation exhibited single enzyme Michaelis-Menten kinetics with apparent KM in the range of 0.