1,681 research outputs found
Evaluation of Serious Infection in Pediatric Patients with Low Immunoglobulin Levels Receiving Rituximab for Granulomatosis with Polyangiitis or Microscopic Polyangiitis
Introduction: The aim of this work was to assess the impact of prolonged low immunoglobulin (IgG or IgM) serum concentrations on the potential cumulative serious infection (SI) risk in pediatric patients following rituximab treatment for granulomatosis with polyangiitis or microscopic polyangiitis (GPA/MPA) in PePRS. Methods: Patients aged ≥ 2 to < 18 years received four weekly intravenous rituximab infusions of 375 mg/m2 and concomitant glucocorticoid taper. After 6 months, patients could receive further rituximab and/or other immunosuppressants per investigator discretion. Immunoglobulin levels and SIs were assessed throughout the 4.5-year observation period. Prolonged low IgG or IgM was defined as below the lower limit of normal age-specific reference range for ≥ 4 months. Results: A total of 25 patients were included, of whom 19 (76%) had GPA and six (24%) had MPA; 18 (72%) had newly diagnosed disease and seven (28%) had relapsing disease. All 25 patients completed the rituximab induction regimen; 24 completed ≥ 18 months of follow-up. At month 18, eighteen patients (72%) had prolonged low IgG; 19 (76%), prolonged low IgM; and 15 (60%), both. Seven patients (28%) had nine SIs; one occurred during or after prolonged low IgG only, two during or after prolonged low IgM only, and six during or after concurrent prolonged low IgG and IgM. No patients died or discontinued the study due to SI. All patients had complete and sustained peripheral B-cell depletion for ≥ 6 months. Conclusions: The majority of pediatric patients who received rituximab for GPA/MPA with prolonged low immunoglobulin levels did not experience SIs. In patients with SIs, these events were manageable, and the number of SIs did not increase over time or with multiple rituximab treatments. These observations are consistent with the rituximab safety profile in adults with GPA/MPA. Trial registration: ClinicalTrials.gov identifier, NCT01750697
Mapping genetic determinants of host susceptibility to Pseudomonas aeruginosa lung infection in mice.
Background: P. aeruginosa is one of the top three causes of opportunistic human bacterial infections. The remarkable
variability in the clinical outcomes of this infection is thought to be associated with genetic predisposition. However,
the genes underlying host susceptibility to P. aeruginosa infection are still largely unknown.
Results: As a step towards mapping these genes, we applied a genome wide linkage analysis approach to a mouse
model. A large F2 intercross population, obtained by mating P. aeruginosa-resistant C3H/HeOuJ, and susceptible A/J
mice, was used for quantitative trait locus (QTL) mapping. The F2 progenies were challenged with a P. aeruginosa
clinical strain and monitored for the survival time up to 7 days post-infection, as a disease phenotype associated trait.
Selected phenotypic extremes of the F2 distribution were genotyped with high-density single nucleotide polymorphic
(SNP) markers, and subsequently QTL analysis was performed. A significant locus was mapped on chromosome 6 and
was named P. aeruginosa infection resistance locus 1 (Pairl1). The most promising candidate genes, including Dok1,
Tacr1, Cd207, Clec4f, Gp9, Gata2, Foxp1, are related to pathogen sensing, neutrophils and macrophages recruitment and
inflammatory processes.
Conclusions: We propose a set of genes involved in the pathogenesis of P. aeruginosa infection that may be explored
to complement human studie
Effect of Low Molecular Weight Heparins (LMWHs) on antiphospholipid Antibodies (aPL)-mediated inhibition of endometrial angiogenesis
Antiphospholipid syndrome (APS) is an autoimmune disorder characterized by vascular thrombosis and/or pregnancy morbidity in the presence of circulating antiphospholipid antibodies (aPL). Different pathogenic mechanisms for aPL-mediated pregnancy failure have been proposed. In particular a direct effect of aPL on both maternal and fetal side of the placental tissue has been reported, since their reactivity with \u3b22-glycoprotein I (\u3b22GPI) makes them adhere to trophoblast and human endometrial endothelial cell (HEEC) membranes. \u3b22GPI can be recognized by aPL that, once bound, interfere with both trophoblast functions and with the HEEC differentiation.APS patients can be successfully treated with Low Molecular Weight Heparin (LMWH). Recent reports suggest that LMWH acts through mechanisms alternative to its well known anticoagulant effect, because of its ability to bind \u3b22GPI. In our previous studies, we showed that LMWH is able to reduce the aPL binding to trophoblasts and restore cell invasiveness and differentiation. So far, however, no study has described its effects on endometrial angiogenesis.The aim of our research was to evaluate whether two LMWHs, tinzaparin and enoxaparin, have an effect on the aPL-inhibited endometrial angiogenesis. This prompted us to investigate: (i) in vitro HEEC angiogenesis through a Matrigel assay; (ii) VEGF secretion by ELISA; (iii) matrix metalloproteinase-2 (MMP-2) activity by gelatin zymography; (iv) Nuclear Factor-\u3baB (NF-\u3baB) DNA binding activity by colorimetric assay; (v) STAT-3 activation by a sandwich-ELISA kit. Furthermore, using an in vivo murine model we investigated the LMWHs effects on angiogenesis.We demonstrated that the addition of LMWHs prevents aPL-inhibited HEEC angiogenesis, both in vitro and in vivo, and is able to restore the aPL inhibited NF-\u3baB and/or STAT-3 activity, the VEGF secretion and the MMPs activity.The demonstration of a beneficial role for LMWHs on the aPL-inhibited HEEC angiogenesis might provide additional mechanisms whereby this treatment protects early pregnancy in AP
Sphalerons and the Electroweak Phase Transition in Models with Higher Scalar Representations
In this work we investigate the sphaleron solution in a
gauge theory, which also encompasses the Standard Model, with higher scalar
representation(s) (). We show that the field profiles
describing the sphaleron in higher scalar multiplet, have similar trends like
the doublet case with respect to the radial distance. We compute the sphaleron
energy and find that it scales linearly with the vacuum expectation value of
the scalar field and its slope depends on the representation. We also
investigate the effect of gauge field and find that it is small for the
physical value of the mixing angle, and resembles the case for the
doublet. For higher representations, we show that the criterion for strong
first order phase transition, , is relaxed with respect to
the doublet case, i.e. .Comment: 20 pages, 5 figures & 1 table, published versio
Electroweak Baryogenesis and Dark Matter with an approximate R-symmetry
It is well known that R-symmetric models dramatically alleviate the SUSY
flavor and CP problems. We study particular modifications of existing
R-symmetric models which share the solution to the above problems, and have
interesting consequences for electroweak baryogenesis and the Dark Matter (DM)
content of the universe. In particular, we find that it is naturally possible
to have a strongly first-order electroweak phase transition while
simultaneously relaxing the tension with EDM experiments. The R-symmetry (and
its small breaking) implies that the gauginos (and the neutralino LSP) are
pseudo-Dirac fermions, which is relevant for both baryogenesis and DM. The
singlet superpartner of the U(1)_Y pseudo-Dirac gaugino plays a prominent role
in making the electroweak phase transition strongly first-order. The
pseudo-Dirac nature of the LSP allows it to behave similarly to a Dirac
particle during freeze-out, but like a Majorana particle for annihilation today
and in scattering against nuclei, thus being consistent with current
constraints. Assuming a standard cosmology, it is possible to simultaneously
have a strongly first-order phase transition conducive to baryogenesis and have
the LSP provide the full DM relic abundance, in part of the allowed parameter
space. However, other possibilities for DM also exist, which are discussed. It
is expected that upcoming direct DM searches as well as neutrino signals from
DM annihilation in the Sun will be sensitive to this class of models.
Interesting collider and Gravity-wave signals are also briefly discussed.Comment: 50 pages, 10 figure
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The polygenic nature of telomere length and the anti-ageing properties of lithium
Telomere length is a promising biomarker for age-related disease and a potential anti-ageing drug target. Here, we study the genetic architecture of telomere length and the repositioning potential of lithium as an anti-ageing medication. LD score regression applied to the largest telomere length genome-wide association study to-date, revealed SNP-chip heritability estimates of 7.29%, with polygenic risk scoring capturing 4.4% of the variance in telomere length in an independent cohort (p = 6.17 × 10-5). Gene-enrichment analysis identified 13 genes associated with telomere length, with the most significant being the leucine rich repeat gene, LRRC34 (p = 3.69 × 10-18). In the context of lithium, we confirm that chronic use in a sample of 384 bipolar disorder patients is associated with longer telomeres (p = 0.03). As complementary evidence, we studied three orthologs of telomere length regulators in a Caenorhabditis elegans model of lithium-induced extended longevity and found all transcripts to be affected post-treatment (p  0.05). Consequently, this suggests that lithium may be catalysing the activity of endogenous mechanisms that promote telomere lengthening, whereby its efficacy eventually becomes limited by each individual's inherent telomere maintenance capabilities. Our work indicates a potential use of polygenic risk scoring for the prediction of adult telomere length and consequently lithium's anti-ageing efficacy
Perturbative quantum gravity with the Immirzi parameter
We study perturbative quantum gravity in the first-order tetrad formalism.
The lowest order action corresponds to Einstein-Cartan plus a parity-odd term,
and is known in the literature as the Holst action. The coupling constant of
the parity-odd term can be identified with the Immirzi parameter of loop
quantum gravity. We compute the quantum effective action in the one-loop
expansion. As in the metric second-order formulation, we find that in the case
of pure gravity the theory is on-shell finite, and the running of Newton's
constant and the Immirzi parameter is inessential. In the presence of fermions,
the situation changes in two fundamental aspects. First, non-renormalizable
logarithmic divergences appear, as usual. Second, the Immirzi parameter becomes
a priori observable, and we find that it is renormalized by a four-fermion
interaction generated by radiative corrections. We compute its beta function
and discuss possible implications. The sign of the beta function depends on
whether the Immirzi parameter is larger or smaller than one in absolute value,
and the values plus or minus one are UV fixed-points (we work in Euclidean
signature). Finally, we find that the Holst action is stable with respect to
radiative corrections in the case of minimal coupling, up to higher order
non-renormalizable interactions.Comment: v2 minor amendment
The price of tumor control: an analysis of rare side effects of anti-CTLA-4 therapy in metastatic melanoma from the ipilimumab network
Background: Ipilimumab, a cytotoxic T-lymphocyte antigen-4 (CTLA-4) blocking antibody, has been approved for the treatment of metastatic melanoma and induces adverse events (AE) in up to 64% of patients. Treatment algorithms for the management of common ipilimumab-induced AEs have lead to a reduction of morbidity, e.g. due to bowel perforations. However, the spectrum of less common AEs is expanding as ipilimumab is increasingly applied. Stringent recognition and management of AEs will reduce drug-induced morbidity and costs, and thus, positively impact the cost-benefit ratio of the drug. To facilitate timely identification and adequate management data on rare AEs were analyzed at 19 skin cancer centers.
Methods and Findings: Patient files (n = 752) were screened for rare ipilimumab-associated AEs. A total of 120 AEs, some of which were life-threatening or even fatal, were reported and summarized by organ system describing the most instructive cases in detail. Previously unreported AEs like drug rash with eosinophilia and systemic symptoms (DRESS), granulomatous inflammation of the central nervous system, and aseptic meningitis, were documented. Obstacles included patientĹ› delay in reporting symptoms and the differentiation of steroid-induced from ipilimumab-induced AEs under steroid treatment. Importantly, response rate was high in this patient population with tumor regression in 30.9% and a tumor control rate of 61.8% in stage IV melanoma patients despite the fact that some patients received only two of four recommended ipilimumab infusions. This suggests that ipilimumab-induced antitumor responses can have an early onset and that severe autoimmune reactions may reflect overtreatment.
Conclusion: The wide spectrum of ipilimumab-induced AEs demands doctor and patient awareness to reduce morbidity and treatment costs and true ipilimumab success is dictated by both objective tumor responses and controlling severe side effects
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