Canakinumab reduces the risk of acute gouty arthritis flares during initiation of allopurinol treatment: results of a double-blind, randomised study.

Objective This study assessed the efficacy and safety of canakinumab, a fully human anti-interleukin 1 beta monoclonal antibody, for prophylaxis against acute gouty arthritis flares in patients initiating urate-lowering treatment.Methods In this double-blind, double-dummy, dose-ranging study, 432 patients with gouty arthritis initiating allopurinol treatment were randomised 1:1:1:1:1:1:2 to receive: a single dose of canakinumab, 25, 50, 100, 200, or 300 mg subcutaneously; 4 x 4-weekly doses of canakinumab (50 + 50 + 25 + 25 mg subcutaneously); or daily colchicine 0.5 mg orally for 16 weeks. Patients recorded details of flares in diaries. The study aimed to determine the canakinumab dose having equivalent efficacy to colchicine 0.5 mg at 16 weeks.Results A dose-response for canakinumab was not apparent with any of the four predefined dose-response models. The estimated canakinumab dose with equivalent efficacy to colchicine was below the range of doses tested. At 16 weeks, there was a 62% to 72% reduction in the mean number of flares per patient for canakinumab doses >= 50 mg versus colchicine based on a negative binomial model (rate ratio: 0.28-0.38, p <= 0.0083), and the percentage of patients experiencing >= 1 flare was significantly lower for all canakinumab doses (15% to 27%) versus colchicine (44%, p<0.05). There was a 64% to 72% reduction in the risk of experiencing >= 1 flare for canakinumab doses >= 50 mg versus colchicine at 16 weeks (hazard ratio (HR): 0.28-0.36, p <= 0.05). The incidence of adverse events was similar across treatment groups.Conclusions Single canakinumab doses >= 50 mg or four 4-weekly doses provided superior prophylaxis against flares compared with daily colchicine 0.5 mg.

Initiation and limitation of Ly-49A NK cell receptor acquisition by T cell factor-1.

The establishment of clonally variable expression of MHC class I-specific receptors by NK cells is not well understood. The Ly-49A receptor is used by approximately 20% of NK cells, whereby most cells express either the maternal or paternal allele and few express simultaneously both alleles. We have previously shown that NK cells expressing Ly-49A were reduced or almost absent in mice harboring a single or no functional allele of the transcription factor T cell factor-1 (TCF-1), respectively. In this study, we show that enforced expression of TCF-1 in transgenic mice yields an expanded Ly-49A subset. Even though the frequencies of Ly-49A(+) NK cells varied as a function of the TCF-1 dosage, the relative abundance of mono- and biallelic Ly-49A cells was maintained. Mono- and biallelic Ly-49A NK cells were also observed in mice expressing exclusively a transgenic TCF-1, i.e., expressing a fixed amount of TCF-1 in all NK cells. These findings suggest that Ly-49A acquisition is a stochastic event due to limiting TCF-1 availability, rather than the consequence of clonally variable expression of the endogenous TCF-1 locus. Efficient Ly-49A acquisition depended on the expression of a TCF-1 isoform, which included a domain known to associate with the TCF-1 coactivator beta-catenin. Indeed, the proximal Ly-49A promoter was beta-catenin responsive in reporter gene assays. We thus propose that Ly-49A receptor expression is induced from a single allele in occasional NK cells due to a limitation in the amount of a transcription factor complex requiring TCF-1.

HLA-Bw4 homozygosity is associated with an impaired CD4 T cell recovery after initiation of antiretroviral therapy.

We assessed the influence of human leukocyte antigen (HLA) alleles HLA-Bw4 and HLA-Bw6 on CD4 T cell recovery after starting successful combination antiretroviral therapy in 265 individuals. The median gains in the CD4 T cell count after 4 years were 258 cells/microL for HLA-Bw4 homozygotes, 321 cells/microL for HLA-Bw4/Bw6 heterozygotes, and 363 cells/microL for HLA-Bw6 homozygotes (P = .01, compared with HLA-Bw4 homozygotes). HLA-Bw4 homozygosity appears to predict an impaired CD4 T cell recovery after initiation of combination antiretroviral therapy.

A matter of time: delayed mate encounter postpones mating window initiation and reduces the strength of female choosiness

Reproductive success is determined by the presence and timing of encounter of mates. The latter depends on species-specific reproductive characteristics (e.g. initiation/duration of the mating window), season, and reproductive strategies (e.g. intensity of choosiness) that may potentially mitigate constraints imposed by mating windows. Despite their potentially crucial role for fitness and population dynamics, limited evidence exists about mating window initiation, duration and reproductive strategies. Here, we experimentally tested the mechanisms of initiation and the duration of the common lizard's Zootoca vivipara mating window, by manipulating the timing of mate encounter and analyzing its effect on (re-)mating probability. We furthermore tested treatment effects on female reproductive strategies, by measuring female choosiness. The timing of mate encounter and season did not significantly affect mating probability. However, a longer delay until mate encounter reduced female choosiness. Re-mating probability decreased with re-mating delay and was independent of mating delay. This indicates that mating window initiation depends on mate encounter, that its duration is fixed, and that plastic reproductive strategies exist. These findings contrast with previous beliefs and shows that mating windows per se may not necessarily constrain reproductive success, which is congruent with rapid range expansion and absence of positive density-effects on reproductive success (Allee effects). In summary, our results show that predicting the effect of mating windows on reproduction is complex and that experimental evidence is essential for evaluating their effect on reproduction and reproductive strategies, both being important determinants of population dynamics and the colonization of new habitats.

Decoupled evolution of floral traits and climatic preferences in a clade of Neotropical Gesneriaceae.

BACKGROUND: Major factors influencing the phenotypic diversity of a lineage can be recognized by characterizing the extent and mode of trait evolution between related species. Here, we compared the evolutionary dynamics of traits associated with floral morphology and climatic preferences in a clade composed of the genera Codonanthopsis, Codonanthe and Nematanthus (Gesneriaceae). To test the mode and specific components that lead to phenotypic diversity in this group, we performed a Bayesian phylogenetic analysis of combined nuclear and plastid DNA sequences and modeled the evolution of quantitative traits related to flower shape and size and to climatic preferences. We propose an alternative approach to display graphically the complex dynamics of trait evolution along a phylogenetic tree using a wide range of evolutionary scenarios. RESULTS: Our results demonstrated heterogeneous trait evolution. Floral shapes displaced into separate regimes selected by the different pollinator types (hummingbirds versus insects), while floral size underwent a clade-specific evolution. Rates of evolution were higher for the clade that is hummingbird pollinated and experienced flower resupination, compared with species pollinated by bees, suggesting a relevant role of plant-pollinator interactions in lowland rainforest. The evolution of temperature preferences is best explained by a model with distinct selective regimes between the Brazilian Atlantic Forest and the other biomes, whereas differentiation along the precipitation axis was characterized by higher rates, compared with temperature, and no regime or clade-specific patterns. CONCLUSIONS: Our study shows different selective regimes and clade-specific patterns in the evolution of morphological and climatic components during the diversification of Neotropical species. Our new graphical visualization tool allows the representation of trait trajectories under parameter-rich models, thus contributing to a better understanding of complex evolutionary dynamics.

Initiation of rivaroxaban in patients with nonvalvular atrial fibrillation at the primary care level: the Swiss Therapy in Atrial Fibrillation for the Regulation of Coagulation (STAR) Study.

BACKGROUND: Rivaroxaban has become an alternative to vitamin-K antagonists (VKA) for stroke prevention in non-valvular atrial fibrillation (AF) patients due to its favourable risk-benefit profile in the restrictive setting of a large randomized trial. However in the primary care setting, physician's motivation to begin with rivaroxaban, treatment satisfaction and the clinical event rate after the initiation of rivaroxaban are not known. METHODS: Prospective data collection by 115 primary care physicians in Switzerland on consecutive nonvalvular AF patients with newly established rivaroxaban anticoagulation with 3-month follow-up. RESULTS: We enrolled 537 patients (73±11years, 57% men) with mean CHADS2 and HAS-BLED-scores of 2.2±1.3 and 2.4±1.1, respectively: 301(56%) were switched from VKA to rivaroxaban (STR-group) and 236(44%) were VKA-naïve (VN-group). Absence of routine coagulation monitoring (68%) and fixed-dose once-daily treatment (58%) were the most frequent criteria for physicians to initiate rivaroxaban. In the STR-group, patient's satisfaction increased from 3.6±1.4 under VKA to 5.5±0.8 points (P<0.001), and overall physician satisfaction from 3.9±1.3 to 5.4±0.9 points (P<0.001) at 3months of rivaroxaban therapy (score from 1 to 6 with higher scores indicating greater satisfaction). In the VN-group, both patient's (5.4±0.9) and physician's satisfaction (5.5±0.7) at follow-up were comparable to the STR-group. During follow-up, 1(0.19%; 95%CI, 0.01-1.03%) ischemic stroke, 2(0.37%; 95%CI, 0.05-1.34%) major non-fatal bleeding and 11(2.05%; 95%CI, 1.03-3.64%) minor bleeding complications occurred. Rivaroxaban was stopped in 30(5.6%) patients, with side effects being the most frequent reason. CONCLUSION: Initiation of rivaroxaban for patients with nonvalvular AF by primary care physicians was associated with a low clinical event rate and with high overall patient's and physician's satisfaction.

Transgression et initiation : tendances idéologiques et développement littéraire du récit de Genèse 2-3

Several questions about the story of Gen 2-3 remain unresolved in current scholarship. For instance, the implications and manifold consequences of the transgression act - the consumption of the forbidden fruit - are much debated. Interpreters generally agree that the story is connected to several "J" / "non-P" narratives of the primeval history. Besides the use of the tetragrammaton as the designation for God, a common characteristic of these stories is the strong opposition between Yhwh as a harsh deity on one hand and disobedient and transgressing humankind on the other. This paper reconsiders several open questions as well as the aforementioned consensus. The analysis of important motifs in Gen 2-3 leads to the conclusion that this story differs in theologically important ways from the postulated "J"-narrative in Genesis. This indicates that it was not composed as an integral part of that narrative. There are, in Gen 2-3, ideological features and linguistic elements typical of the "J" stratum, but they are all found in the sections that present Yhwh God's investigation and punishment of the couple (3,8-19.24). Since these verses are in tension with or even contradict their immediate context, it should be assigned to a redactional ("J") layer. According to this analysis, the transgression in Gen 2-3 should not be considered a sin. Rather, it is an important step in human evolution towards a self-conscious and autonomous being. The plot has a structure similar to some episodes in ancient Near Eastern myths. 'Initiation' functions as a central theme. Finally, the article discusses the literary milieu of the story. Because of several linguistic and thematic similarities with Gen 1, with P-texts in general, and with the book of Ezekiel, the relationship of Gen 2-3 to these literary entities needs to be reconsidered.

Targeted cell elimination reveals an auxin-guided biphasic mode of lateral root initiation.

To sustain a lifelong ability to initiate organs, plants retain pools of undifferentiated cells with a preserved proliferation capacity. The root pericycle represents a unique tissue with conditional meristematic activity, and its tight control determines initiation of lateral organs. Here we show that the meristematic activity of the pericycle is constrained by the interaction with the adjacent endodermis. Release of these restraints by elimination of endodermal cells by single-cell ablation triggers the pericycle to re-enter the cell cycle. We found that endodermis removal substitutes for the phytohormone auxin-dependent initiation of the pericycle meristematic activity. However, auxin is indispensable to steer the cell division plane orientation of new organ-defining divisions. We propose a dual, spatiotemporally distinct role for auxin during lateral root initiation. In the endodermis, auxin releases constraints arising from cell-to-cell interactions that compromise the pericycle meristematic activity, whereas, in the pericycle, auxin defines the orientation of the cell division plane to initiate lateral roots.