We report the final measurement of the neutrino oscillation parameters Δm322 and sin2 θ23 using all data from the MINOS and MINOS+ experiments. These data were collected using a total exposure of ...23.76 × 1020 protons on target producing νμ and νμ beams and 60.75 kt yr exposure to atmospheric neutrinos. The measurement of the disappearance of νμ and the appearance of νe events between the Near and Far detectors yields ... and ... at 68% C.L. for normal (inverted) hierarchy. (ProQuest: ... denotes formulae omited.).
Background Component resolution recently identified distinct sensitization profiles in honey bee venom (HBV) allergy, some of which were dominated by specific IgE to Api m 3 and/or Api m 10, which ...have been reported to be underrepresented in therapeutic HBV preparations. Objective We performed a retrospective analysis of component-resolved sensitization profiles in HBV-allergic patients and association with treatment outcome. Methods HBV-allergic patients who had undergone controlled honey bee sting challenge after at least 6 months of HBV immunotherapy (n = 115) were included and classified as responder (n = 79) or treatment failure (n = 36) on the basis of absence or presence of systemic allergic reactions upon sting challenge. IgE reactivity to a panel of HBV allergens was analyzed in sera obtained before immunotherapy and before sting challenge. Results No differences were observed between responders and nonresponders regarding levels of IgE sensitization to Api m 1, Api m 2, Api m 3, and Api m 5. In contrast, Api m 10 specific IgE was moderately but significantly increased in nonresponders. Predominant Api m 10 sensitization (>50% of specific IgE to HBV) was the best discriminator (specificity, 95%; sensitivity, 25%) with an odds ratio of 8.444 (2.127-33.53; P = .0013) for treatment failure. Some but not all therapeutic HBV preparations displayed a lack of Api m 10, whereas Api m 1 and Api m 3 immunoreactivity was comparable to that of crude HBV. In line with this, significant Api m 10 sIgG4 induction was observed only in those patients who were treated with HBV in which Api m 10 was detectable. Conclusions Component-resolved sensitization profiles in HBV allergy suggest predominant IgE sensitization to Api m 10 as a risk factor for treatment failure in HBV immunotherapy.
Nuclear physics began with the discovery of radioactivity. Several different forms of nuclear disintegration have been identified very early, starting with the familiar alpha, beta, and gamma decays. ...In 1938, nuclear fission joined the elite club of nuclear decays. The exotic, short lived nuclei, accessible experimentally during the last decades, have demonstrated quite a bit of skill and ingenuity in releasing its binding energy by spitting various particles out. This review is devoted to the traditional and unusual forms of nuclear radioactivity observed at the limits of nuclear stability.
Background
The anti‐IgE antibody omalizumab has been approved for the treatment of chronic spontaneous urticaria (CSU) in patients insufficiently responding to antihistamines. However, its mode of ...action in CSU is not clearly understood.
Objectives
The aim of this study was to get a better insight in the immune mechanisms involved in clinical improvement of CSU patients treated with omalizumab.
Methods
Chronic spontaneous urticaria patients (n = 15) were followed for 5 months after initiation of omalizumab treatment. Clinical symptoms were assessed by UCT and CU‐Q2oL. Cell‐bound IgE was quantified on both FcεRI‐ and FcεRII‐expressing cell populations in peripheral blood. In addition, IgE and IgG as well as their receptors were measured on basophils, and basophil activation was assessed with different concentrations of anti‐FcεRI and fMLP. Furthermore, the frequencies of different T‐cell subsets secreting IL‐5, IL‐10, IL‐31 or IFN‐γ were analysed by ELISpot assay.
Results
Seven patients showed a full, five a partial and three no clinical response to omalizumab. Cell‐bound IgE was reduced on FcεRI‐bearing cells, but not on FcεRII‐expressing cells. Likewise, the expression of FcεRI declined. Basophil activation increased upon FcεRI‐stimulation while their sensitivity was not affected. Both basophil and T‐cell frequencies remained unchanged. However, when comparing the individual response to omalizumab treatment with distinct T‐cell subsets, a significant correlation was found between improved UCT and decreased frequencies of IL‐10‐, IL‐31‐ and IFN‐γ‐secreting T cells.
Conclusions
We here show that besides addressing IgE‐dependent immune mechanisms, omalizumab treatment of CSU patients has effects on distinct T‐cell subsets, which correlate with clinical improvement.
Background
Chronic urticaria (CU) is a frequent skin disease characterized by relapsing appearance of pruritic hives. While clinical symptoms are due to the release of histamine by cutaneous mast ...cells, the underlying pathophysiology is still unknown. However, previous studies indicate that basophils might be of relevance. Besides, the occurrence of autoantibodies against IgE or its receptor, FcεRI, and the therapeutic efficacy of anti‐IgE antibodies imply that IgE‐mediated mechanisms also play an important role in CU.
Methods
Reactivity of CU patients’ peripheral blood basophils (n=60) to specific anti‐FcεRI and IgE‐independent fMLP stimulation was determined by basophil activation test in comparison with patients suffering from IgE‐mediated allergic rhinitis (n=10) and healthy controls (n=10). In addition, immunoglobulin receptor (FcεRI, FcγRII) expression and surface bound antibodies (IgE, IgG) were quantified on basophils. Furthermore, the autoreactive capacity of CU sera was evaluated and urticaria‐related symptoms were assessed by both UCT and CU‐Q2oL.
Results
Stimulating CU patients’ basophils via FcεRI, we identified three distinct immunologic phenotypes. One subgroup of patients’ basophils reacted to FcεRI stimulation, whereas the others had anti‐FcεRI nonreactive basophils. Among the latter, a subgroup with pronounced basopenia was identified. Of note, this group was characterized by augmented serum‐induced basophil activation, increased levels of autoantibodies against thyroid peroxidase, and also exhibited the strongest disease impact on their quality of life.
Conclusions
Patients with CU can be categorized into three immunologic subgroups based on their basophil reactivity and frequency. These phenotypes are associated with different clinical characteristics, pointing to basophils as important players in CU pathophysiology.
We report results of a search for oscillations involving a light sterile neutrino over distances of 1.04 and 735 km in a ν_{μ}-dominated beam with a peak energy of 3 GeV. The data, from an exposure ...of 10.56×10^{20} protons on target, are analyzed using a phenomenological model with one sterile neutrino. We constrain the mixing parameters θ_{24} and Δm_{41}^{2} and set limits on parameters of the four-dimensional Pontecorvo-Maki-Nakagawa-Sakata matrix, |U_{μ4}|^{2} and |U_{τ4}|^{2}, under the assumption that mixing between ν_{e} and ν_{s} is negligible (|U_{e4}|^{2}=0). No evidence for ν_{μ}→ν_{s} transitions is found and we set a world-leading limit on θ_{24} for values of Δm_{41}^{2}≲1 eV^{2}.
Landscape of two-proton radioactivity Olsen, E; Pfützner, M; Birge, N ...
Physical review letters,
2013-May-31, Letnik:
110, Številka:
22
Journal Article
Recenzirano
Odprti dostop
Ground-state two-proton (2p) radioactivity is a decay mode found in isotopes of elements with even atomic numbers located beyond the two-proton drip line. So far, this exotic process has been ...experimentally observed in a few light- and medium-mass nuclides with Z≤30. In this study, using state-of-the-art nuclear density functional theory, we globally analyze 2p radioactivity and for the first time identify 2p-decay candidates in elements heavier than strontium. We predict a few cases where the competition between 2p emission and α decay may be observed. In nuclei above lead, the α-decay mode is found to be dominating and no measurable candidates for the 2p radioactivity are expected.
The study aim was to evaluate the efficacy and safety of initial combination therapy with saxagliptin + metformin vs. saxagliptin or metformin monotherapy in treatment-naïve patients with type 2 ...diabetes (T2D) and inadequate glycaemic control. In this multicentre, randomized, double-blind, active-controlled phase 3 trial, 1306 treatment-naïve patients with T2D greater-than-or-equal18 to less-than or equal to77 years, glycosylated haemoglobin (HbA1c) greater-than-or-equal8 to less-than or equal to12%, fasting C-peptide concentration greater-than-or-equal1.0 ng/ml, body mass index less-than or equal to40 kg/m² were randomized to receive saxagliptin 5 mg + metformin 500 mg, saxagliptin 10 mg + metformin 500 mg, saxagliptin 10 mg + placebo or metformin 500 mg + placebo for 24 weeks. From weeks 1-5, metformin was uptitrated in 500-mg/day increments to 2000 mg/day maximum in the saxagliptin 5 mg + metformin, saxagliptin 10 mg + metformin and metformin + placebo treatment groups. The main outcome measure was HbA1c change from baseline to week 24. Selected secondary outcomes included change from baseline to week 24 in fasting plasma glucose (FPG), proportion of patients achieving HbA1c <7% and postprandial glucose area under the curve (PPG-AUC). At 24 weeks, saxagliptin 5 mg + metformin and saxagliptin 10 mg + metformin demonstrated statistically significant adjusted mean decreases vs. saxagliptin 10 mg and metformin monotherapies in HbA1c (-2.5 and -2.5% vs. -1.7 and -2.0%, all p < 0.0001 vs. monotherapy) and FPG (-60 and -62 mg/dl vs. -31 and -47 mg/dl, both p < 0.0001 vs. saxagliptin 10 mg; p = 0.0002 saxagliptin 5 mg + metformin vs. metformin; p < 0.0001 saxagliptin 10 mg + metformin vs. metformin). Proportion of patients achieving an HbA1c <7% was 60.3 and 59.7%, respectively, for saxagliptin 5 mg + metformin and saxagliptin 10 mg + metformin (all p < 0.0001 vs. monotherapy). PPG-AUC was significantly reduced -21 080 mg·min/dl (saxagliptin 5 mg + metformin) and -21 336 mg·min/dl (saxagliptin 10 mg + metformin) vs. -16 054 mg·min/dl (saxagliptin 10 mg) and -15 005 mg·min/dl (metformin), all p < 0.0001 vs. monotherapy. Adverse event occurrence was similar across all groups. Hypoglycaemic events were infrequent. Saxagliptin + metformin as initial therapy led to statistically significant improvements compared with either treatment alone across key glycaemic parameters with a tolerability profile similar to the monotherapy components.
Diabet. Med. 29, 1115–1118 (2012)
Aims The aim of this study was to investigate the vascular effects of liraglutide in patients well controlled on metformin monotherapy.
Methods Forty‐four patients ...with Type 2 diabetes were included in the study. Main inclusion criteria were: pretreatment with metformin on a stable dosage, HbA1c < 53 mmol/mol (7.0%), age 30–65 years. Patients were randomized to receive additional liraglutide or to remain on metformin monotherapy. After 6 weeks (1.2 mg) and after 12 weeks (1.8 mg), venous blood was taken for the measurement of several laboratory markers characterizing vascular and endothelial function. In addition, retinal microvascular endothelial function and arterial stiffness were measured.
Results HbA1c levels declined from 45 ± 4 mmol/mol (6.3 ± 0.4%; mean ± sd) to 40 ± 3 mmol/mol (5.8 ± 0.3%) during liraglutide treatment. Asymmetric dimethylarginin was reduced by liraglutide treatment from 0.39 ± 0.08 to 0.35 ± 0.06 μmol/l, E‐selectin from 43.6 ± 15.4 to 40.8 ± 15.1 ng/ml, plasminogen activator inhibitor 1 from 861.6 ± 584.3 to 666.1 ± 499.4 ng/ml and intact proinsulin from 9.0 ± 7.2 to 7.0 ± 4.8 pmol/l at 12 weeks of treatment. The microvascular response to flicker light increased from 7.0 ± 15.1 to 15.4 ± 11.5% after 6 weeks and to 11.1 ± 9.9% after 12 weeks. No change could be observed for high‐sensitivity C‐reactive protein, monocyte chemotactic protein 1, vascular cell adhesion molecule or arterial stiffness parameters.
Conclusions In patients with Type 2 diabetes, well controlled with metformin monotherapy, addition of liraglutide improves several cardiovascular risk markers beyond glycaemic control.
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