Ablation of prion protein in wild type human amyloid precursor protein (APP) transgenic mice does not alter the proteolysis of APP, levels of amyloid-β or pathologic phenotype

The cellular prion protein (PrPC) has been proposed to play an important role in the pathogenesis of Alzheimer's disease. In cellular models PrPC inhibited the action of the β-secretase BACE1 on wild type amyloid precursor protein resulting in a reduction in amyloid-β (Aβ) peptides. Here we have assessed the effect of genetic ablation of PrPC in transgenic mice expressing human wild type amyloid precursor protein (line I5). Deletion of PrPC had no effect on the α- and β-secretase proteolysis of the amyloid precursor protein (APP) nor on the amount of Aβ38, Aβ40 or Aβ42 in the brains of the mice. In addition, ablation of PrPC did not alter Aβ deposition or histopathology phenotype in this transgenic model. Thus using this transgenic model we could not provide evidence to support the hypothesis that PrPC regulates Aβ production

Treosulfan, Fludarabine Conditioning for HSCT in Children with Primary Immunodeficiency: UK Experience

We previously published results of 70 children who received treosulfan with cyclophosphamide (30) or fludarabine (40) before haematopoietic stem cell transplantation (HSCT) for Primary Immunodeficiency (PID). Toxicity was lower and T cell chimerism better in those receiving fludarabine, but numbers were relatively small and follow-up short. We now report outcome of 160 children who received homogeneous conditioning with treosulfan, fludarabine mostly with alemtuzumab (n=124). Median age at transplant was 1.36 years (0.09-18.25). Donors were: matched unrelated, 73; 1-3 antigen mismatched unrelated, 54; matched sibling, 12; other matched family, 17; haploidentical, 4. Stem cell source was: peripheral blood stem cells (PBSCs), 70; Bone marrow, 49; Cord Blood, 41. Median follow up was 4.3 years (0.8-9.4). Overall survival was 83%. There was no veno- occlusive disease. Seventy-four (46%) had acute GVHD, but only 14(9%) greater than grade II. Four patients were successfully retransplanted for graft loss or poor immune reconstitution. One further patient who rejected the graft, died. There was no association between T cell chimerism > 95% and stem cell source, but a significant association with myeloid chimerism > 95% and use of PBSC without an increased risk of significant GVHD compared to other sources. All 11 patients with severe combined immunodeficiency diagnosed at birth are alive with up to 8.7 years follow up. Long-term studies are required to determine late gonadotoxic effects and pharmacokinetic studies are needed to identify whether specific targeting is advantageous. The combination of treosulfan, fludarabine and alemtuzumab gives excellent results in HSCT for PID

Mechanisms of NK Cell-Macrophage Bacillus anthracis Crosstalk: A Balance between Stimulation by Spores and Differential Disruption by Toxins

NK cells are important immune effectors for preventing microbial invasion and dissemination, through natural cytotoxicity and cytokine secretion. Bacillus anthracis spores can efficiently drive IFN-γ production by NK cells. The present study provides insights into the mechanisms of cytokine and cellular signaling that underlie the process of NK-cell activation by B. anthracis and the bacterial strategies to subvert and evade this response. Infection with non-toxigenic encapsulated B. anthracis induced recruitment of NK cells and macrophages into the mouse draining lymph node. Production of edema (ET) or lethal (LT) toxin during infection impaired this cellular recruitment. NK cell depletion led to accelerated systemic bacterial dissemination. IFN-γ production by NK cells in response to B. anthracis spores was: i) contact-dependent through RAE-1-NKG2D interaction with macrophages; ii) IL-12, IL-18, and IL-15-dependent, where IL-12 played a key role and regulated both NK cell and macrophage activation; and iii) required IL-18 for only an initial short time window. B. anthracis toxins subverted both NK cell essential functions. ET and LT disrupted IFN-γ production through different mechanisms. LT acted both on macrophages and NK cells, whereas ET mainly affected macrophages and did not alter NK cell capacity of IFN-γ secretion. In contrast, ET and LT inhibited the natural cytotoxicity function of NK cells, both in vitro and in vivo. The subverting action of ET thus led to dissociation in NK cell function and blocked natural cytotoxicity without affecting IFN-γ secretion. The high efficiency of this process stresses the impact that this toxin may exert in anthrax pathogenesis, and highlights a potential usefulness for controlling excessive cytotoxic responses in immunopathological diseases. Our findings therefore exemplify the delicate balance between bacterial stimulation and evasion strategies. This highlights the potential implication of the crosstalk between host innate defences and B. anthracis in initial anthrax control mechanisms

International Consensus Statement on Rhinology and Allergy: Rhinosinusitis

Background: The 5 years since the publication of the first International Consensus Statement on Allergy and Rhinology: Rhinosinusitis (ICAR‐RS) has witnessed foundational progress in our understanding and treatment of rhinologic disease. These advances are reflected within the more than 40 new topics covered within the ICAR‐RS‐2021 as well as updates to the original 140 topics. This executive summary consolidates the evidence‐based findings of the document. Methods: ICAR‐RS presents over 180 topics in the forms of evidence‐based reviews with recommendations (EBRRs), evidence‐based reviews, and literature reviews. The highest grade structured recommendations of the EBRR sections are summarized in this executive summary. Results: ICAR‐RS‐2021 covers 22 topics regarding the medical management of RS, which are grade A/B and are presented in the executive summary. Additionally, 4 topics regarding the surgical management of RS are grade A/B and are presented in the executive summary. Finally, a comprehensive evidence‐based management algorithm is provided. Conclusion: This ICAR‐RS‐2021 executive summary provides a compilation of the evidence‐based recommendations for medical and surgical treatment of the most common forms of RS

A Cost-Effective Semi-Ab Initio Approach to Model Relaxation in Rare-Earth Single-Molecule Magnets

We discuss a cost-effective approach to understand magnetic relaxation in the new generation of rare-earth single-molecule magnets. It combines ab initio calculations of the crystal field parameters, of the magneto-elastic coupling with local modes, and of the phonon density of states with fitting of only three microscopic parameters. Although much less demanding than a fully ab initio approach, the method gives important physical insights into the origin of the observed relaxation. By applying it to high-anisotropy compounds with very different relaxation, we demonstrate the power of the approach and pinpoint ingredients for improving the performance of single-molecule magnets