Training Groups

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Editorial Board

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Racial differences in Atopic Dermatitis

Atopic dermatitis (AD), the most common chronic inflammatory skin disease,1 usually starts in early infancy, and can develop into a life-long therapeutic challenge, especially in its moderate-to-severe form.2 The etiology of this complex disease remains only partly understood, but it is most likely based on a complex interplay of genetic predisposition, skin barrier dysfunction, and environmental factors.3 AD is now understood to be an immune mediated disease with contributions of multiple inflammatory pathways, and particularly Type 2-associated inflammation.

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"Drug Allergy in children and adults: is it the double X chromosome?"

It is well established that autoimmune diseases, atopic conditions and asthma affect adult females more frequently than adult males. This discrepancy typically develops after childhood and affects females differently depending on their life cycle. As children, males have higher total and allergen specific IgE levels than females and are more likely to suffer from atopic disease and asthma than girls. However, as adults, this prevalence reverses and females are more likely to develop atopic conditions such as food allergies, atopic dermatitis, urticaria, angioedema and asthma.

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Implementation of the NIAID Peanut Allergy Guidelines: Outcomes and Experience

The publication of the Learning Early About Peanut Allergy (LEAP) study in 2015 represented a paradigm shift in the field of food allergy with the finding of an 81% reduction in the incidence of peanut allergy when early introduction of peanut was compared to strict avoidance in high risk infants.1 In 2017, the National Institute of Allergy and Infectious Disease (NIAID) provided official recommendations for early peanut introduction with the publication of the Addendum Guidelines to the 2010 Guidelines for Diagnosis and Management of Food Allergy in the United States.

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AllergyWatch - Feb-19

From Allergy Watch Vol 20, July-Aug 2018

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The Glycerin Associated Pain (GAP) Study

Fifty percent glycerin is often used in allergen immunotherapy (AIT) extracts to preserve extract potency.1 However, glycerin is also an irritant and it is recommended to dilute glycerin to reduce pain and inflammation associated with immunotherapy.2, 3 The 2011 allergen immunotherapy practice parameter warns that "higher glycerin concentrations are associated with injection pain, which correlates with the total amount of glycerin injected."4 To date, two studies evaluating the role of glycerin during allergen immunotherapy differed regarding their methods and conclusions.

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Immediate-hypersensitivity reactions to proton pump inhibitors – experience in a medical department

Proton pump inhibitors (PPIs) are prescribed worldwide for the treatment of acid-peptic diseases1,2,3. They antagonize the enzyme H+/K+ ATPase in gastric cells, inhibiting acid secretion and raising gastric pH3,4. Side effects related to PPIs are reported in only 1-3% of treated patients1,5. Omeprazole, esomeprazole and pantoprazole have a similar chemical structure, differing from rabeprazole and lansoprazole1,5.

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Asthma in the Melting Pot

America is becoming more diverse, with minority groups increasing at higher rates than whites. The health implications are vast, impacting all medical conditions. However, as asthma remains a persistent public health problem where the disease burden is higher in minorities and low income populations – the need to find solutions is crucial 1. These disparities or differences have been documented and defined to a significant degree in the literature, but what is lacking are solutions to tackle these differences.

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Inpatient Beta-lactam test-dose Protocol promotes Antimicrobial Stewardship in Patients with History of Penicillin Allergy

Penicillin allergy is the most commonly reported drug allergy in hospitalized patients, resulting in increased second-line antibiotic use, nosocomial infections, and healthcare utilization. Given that the vast majority of patients are not truly allergic, a safe strategy that empowers the admitting physician is needed.

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A CASE OF NON-IMMUNOLOGIC ANAPHYLAXIS TO N-ACETYLCYSTEINE IN A PATIENT WHO OVERDOSED ON ACETAMINOPHEN

Management of acetaminophen toxicity typically involves administering N-acetylcysteine (NAC) in order to prevent hepatic injury. While NAC is considered the gold standard of therapy, it is also associated with risk of non-immunologic anaphylaxis. This case illustrates a less commonly recognized reaction to NAC and provides an opportunity to review management of acetaminophen toxicity in patients who demonstrate such a reaction.

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Oral & Maxillofacial surgery is ready for patient-centred eHealth interventions − the outcomes of a scoping review

Within the field of oral and maxillofacial (OMF) surgery, eHealth is expected to be a tool to improve quality of care. The aim of this study is to map the research of patient-centred eHealth interventions within OMF surgery by means of a scoping review.After a systematic literature search, relevant studies on patient-centred eHealth interventions for OMF-surgery patients were selected. The interventions were mapped based on their key components, target population and outcome measures. To gain insight in the research phase of evaluation, the framework of the Medical Research Council (MRC) was used.

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Deep cheek fat flap: new technique to augment the soft tissues of the mandibular alveolus

Deep cheek fat is found in distinct compartments, which are separated by septae1 and, together with other compartments of facial fat, are currently "hot" topics in the rejuvenation of the face. They serve as a map for facial ageing, and are considered to be the best positioning system for injecting fillers.2 Apart from the buccal fat pad, however, this extraoral fat has not, to the best of my knowledge, been used in implant dentistry.

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Fc{gamma}RIIb on B Cells and Myeloid Cells Modulates B Cell Activation and Autoantibody Responses via Different but Synergistic Pathways in Lupus-Prone Yaa Mice [AUTOIMMUNITY]

C57BL/6 (B6).FcRIIb^–/–.Yaa mice spontaneously develop lethal lupus nephritis. To define the cell type–specific role of FcRIIb in Yaa-associated lupus, we established B cell– (CD19^Cre.Yaa), myeloid cell– (C/EBPα^Cre.Yaa), and dendritic cell– (DC) (CD11c^Cre.Yaa) specific FcRIIb-deficient B6.Yaa mouse strains. CD19^Cre.Yaa mice developed milder lupus than B6.FcRIIb^–/–.Yaa mice, indicating that FcRIIb deficiency on B cells is not sufficient for the development of severe disease. Surprisingly, C/EBPα^Cre.Yaa mice also showed autoantibody production and mild lupus similar to that in CD19^Cre.Yaa mice, whereas CD11c^Cre.Yaa mice stayed disease free. These observations indicate that FcRIIb deficiency in B cells and myeloid cells, but not DCs, contributes to the severe disease in B6.FcRIIb^–/–.Yaa mice. Flow cytometric analysis showed that the frequency of peripheral Gr-1^– but not Gr-1⁺ monocyte was increased in B6.FcRIIb^–/–.Yaa and C/EBPα^Cre.Yaa but not CD19^Cre.Yaa mice, suggesting a link between FcRIIb deficiency on myeloid cells and the high frequency of Gr-1^– monocytes. RNA sequencing revealed that compared with Gr-1⁺ monocytes, Gr-1^– monocytes expressed higher levels of the B cell–stimulating cytokines BSF-3, IL-10, and IL-1β, the DC markers CD11c, CD83, and Adamdec1, and the antiapoptotic factors Bcl2 and Bcl6. In conclusion, in Yaa-associated lupus nephritis, FcRIIb on B cells and myeloid cells modulates B cell activation via different but synergistic pathways. Gr-1^– monocytes are the most likely candidate myeloid cells involved.

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TAOK3 Regulates Canonical TCR Signaling by Preventing Early SHP-1-Mediated Inactivation of LCK [MOLECULAR AND STRUCTURAL IMMUNOLOGY]

Activation of LCK is required for canonical TCR signaling leading to T cell responses. LCK activation also initiates a negative feedback loop mediated by the phosphatase SHP-1 that turns off TCR signaling. In this article, we report that the thousand-and-one amino acid kinase 3 (TAOK3) is a key regulator of this feedback. TAOK3 is a serine/threonine kinase expressed in many different cell types including T cells. TAOK3-deficient human T cells had impaired LCK-dependent TCR signaling resulting in a defect in IL-2 response to canonical TCR signaling but not to bacterial superantigens, which use an LCK-independent pathway. This impairment was associated with enhanced interaction of LCK with SHP-1 after TCR engagement and rapid termination of TCR signals, a defect corrected by TAOK3 reconstitution. Thus, TAOK3 is a positive regulator of TCR signaling by preventing premature SHP-1–mediated inactivation of LCK. This mechanism may also regulate signaling by other Src family kinase-dependent receptors.

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Aeroallergens Exacerbate Histoplasma capsulatum Infection [INFECTIOUS DISEASE AND HOST RESPONSE]

Allergens such as house dust mites (HDM) and papain induce strong Th2 responses, including elevated IL-4, IL-5, and IL-13 and marked eosinophilia in the airways. Histoplasma capsulatum is a dimorphic fungal pathogen that induces a strong Th1 response marked by IFN- and TNF-α production, leading to rapid clearance in nonimmunocompromised hosts. Th1 responses are generally dominant and overwhelm the Th2 response when stimuli for both are present, although there are instances when Th2 stimuli downregulate a Th1 response. We determined if the Th2 response to allergens prevents the host from mounting a Th1 response to H. capsulatum in vivo. C57BL/6 mice exposed to HDM or papain and infected with H. capsulatum exhibited a dominant Th2 response early, characterized by enhanced eosinophilia and elevated Th2 cytokines in lungs. These mice manifested exacerbated fungal burdens, suggesting that animals skewed toward a Th2 response by an allergen are less able to clear the H. capsulatum infection despite an intact Th1 response. In contrast, secondary infection is not exacerbated by allergen exposure, indicating that the memory response may suppress the Th2 response to HDM and quickly clear the infection. In conclusion, an in vivo skewing toward Th2 by allergens exacerbates fungal infection, even though there is a concurrent and unimpaired Th1 response to H. capsulatum.

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In This Issue [IN THIS ISSUE]

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Loss of Canonical Notch Signaling Affects Multiple Steps in NK Cell Development in Mice [IMMUNE REGULATION]

Within the hematopoietic system, the Notch pathway is critical for promoting thymic T cell development and suppressing the B and myeloid lineage fates; however, its impact on NK lymphopoiesis is less understood. To study the role of Notch during NK cell development in vivo, we investigated different NK cell compartments and function in Rbp-Jk^fl/flVav-Cre^tg/+ mice, in which Rbp-Jk, the major transcriptional effector of canonical Notch signaling, was specifically deleted in all hematopoietic cells. Peripheral conventional cytotoxic NK cells in Rbp-Jk–deleted mice were significantly reduced and had an activated phenotype. Furthermore, the pool of early NK cell progenitors in the bone marrow was decreased, whereas immature NK cells were increased, leading to a block in NK cell maturation. These changes were cell intrinsic as the hematopoietic chimeras generated after transplantation of Rbp-Jk–deficient bone marrow cells had the same NK cell phenotype as the Rbp-Jk–deleted donor mice, whereas the wild-type competitors did not. The expression of several crucial NK cell regulatory pathways was significantly altered after Rbp-Jk deletion. Together, these results demonstrate the involvement of canonical Notch signaling in regulation of multiple stages of NK cell development.

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Opening the Black Box of Immunosuppression [PILLARS OF IMMUNOLOGY]

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Circulating Plasma Extracellular Vesicles from Septic Mice Induce Inflammation via MicroRNA- and TLR7-Dependent Mechanisms [INNATE IMMUNITY AND INFLAMMATION]

We have previously reported that a group of host cellular microRNAs (miRNAs; miR-34a-5p, miR-122-5p, miR-145-5p, miR-146a-5p, miR-210-3p) are released into the blood during sepsis, some of which are capable of inducing complement activation, cytokine production, and leukocyte migration. Extracellular vesicles (EVs) have been proposed as vehicles for extracellular miRNA-mediated intercellular communication. However, the biological function of plasma EVs and the associated miRNAs in sepsis are largely unknown. In this study, we tested the hypothesis that plasma EVs in sepsis are proinflammatory and EV-associated miRNAs are responsible for EV-induced cytokine production. Compared with those of sham mice, the plasma EVs from septic mice were slightly smaller (157 ± 2 versus 191 ± 6 nm, p < 0.0001), but more abundant [(1.6 ± 0.14) x 10¹⁰ versus (0.93 ± 0.14) x 10¹⁰/ml plasma, p < 0.003]. miRNA array revealed that among 65 miRNAs, 8 miRNAs exhibited >1.5-fold increase in septic EVs compared with sham EVs, including miR-126-3p, miR-122-5p, miR-146a-5p, miR-145-5p, miR-26a-5p, miR-150-5p, miR-222-3p, and miR-181a-5p. Septic but not sham EVs were proinflammatory, promoting IL-6, TNF-α, IL-1β, and MIP-2 production. The effects of EVs were resistant to polymyxin B (an endotoxin inhibitor) but significantly inhibited by anti-miR inhibitors against miR-34a, miR-122, and miR-146a. Moreover, the septic EV-induced cytokine production was attenuated in TLR7^–/– or MyD88^–/– cells but remained the same in TLR3^–/– or Trif^–/– cells. In vivo, mice i.p. injected with septic EVs had marked peritoneal neutrophil migration, which was significantly attenuated in MyD88^–/– mice. Taken together, these data demonstrate that plasma EVs of septic animals play an important role in inflammation, and EV-associated miRNAs likely mediate the cytokine production via TLR7-MyD88 signaling.

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Pillars Article: Cyclosporin A Specifically Inhibits Function of Nuclear Proteins Involved in T Cell Activation. Science. 1989. 246: 1617-1620 [PILLARS OF IMMUNOLOGY]

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Correction: Nasopharyngeal Exposure to Streptococcus pneumoniae Induces Extended Age-Dependent Protection against Pulmonary Infection Mediated by Antibodies and CD138+ Cells [CORRECTIONS]

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IL-17 in Renal Immunity and Autoimmunity [BRIEF REVIEWS]

The kidney is an organ particularly susceptible to damage caused by infections and autoimmune conditions. Renal inflammation confers protection against microbial infections. However, if unchecked, unresolved inflammation may lead to kidney damage. Although proinflammatory cytokine IL-17 is required for immunity against extracellular pathogens, dysregulated IL-17 response is also linked to autoimmunity. In this review, we will discuss the current knowledge of IL-17 activity in the kidney in context to renal immunity and autoimmunity and raise the intriguing question to what extent neutralization of IL-17 is beneficial or harmful to renal inflammation.

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Unique Composition of Intronless and Intron-Containing Type I IFNs in the Tibetan Frog Nanorana parkeri Provides New Evidence To Support Independent Retroposition Hypothesis for Type I IFN Genes in Amphibians [IMMUNOGENETICS]

In vertebrates, intron-containing and intronless type I IFN genes have recently been reported in amphibian model species Xenopus tropicalis and X. laevis. However, whether intronless type I IFNs in amphibians are the ancestral genes of type I IFNs in amniotes or just represent the independent divergence in amphibians is unknown or even uninvestigated. In this study, both intron-containing and intronless type I IFN genes, as well as their receptor genes, were identified in the Tibetan frog Nanorana parkeri. The evidence obtained from homology, synteny, phylogeny, and divergence time showed that intronless type I IFN genes in N. parkeri and in Xenopus might have arisen from two independent retroposition events occurred in these two lineages, and the retrotransposition causing the generation of intronless type I IFN genes in amniotes is another independent event beyond the two in amphibians. It can then be proposed that intronless type I IFNs in N. parkeri and Xenopus may not be the ancestral genes of intronless type I IFNs in amniotes but may just represent two independent bifurcations in the amphibian lineage. Furthermore, both intronless and intron-containing type I IFNs in N. parkeri showed strong ability in inducing the expression of IFN-stimulated genes and the strong antiviral activity against frog virus 3. The present study thus provides the evolutionary evidence to support the independent retroposition hypothesis for the occurrence of intronless type I IFN genes in amphibians and contributes to a functional understanding of type I IFNs in this group of vertebrates.

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Cutting Edge: Human Vagus Produces Specialized Proresolving Mediators of Inflammation with Electrical Stimulation Reducing Proinflammatory Eicosanoids [CUTTING EDGE]

Inflammatory resolution is a process that, when uncontrolled, impacts many organs and diseases. As an active, self-limited inflammatory process, resolution involves biosynthesis of specialized proresolving mediators (SPM) (e.g., lipoxins, resolvins [Rv], protectins, and maresins). Because vagal stimulation impacts inflammation, we examined human and mouse vagus ex vivo to determine if they produce lipid mediators. Using targeted lipid mediator metabololipidomics, we identified lipoxins, Rv, and protectins produced by both human and mouse vagus as well as PGs and leukotrienes. Human vagus produced SPM (e.g., RvE1, NPD1/PD1, MaR1, RvD5, and LXA₄) on stimulation that differed from mouse (RvD3, RvD6, and RvE3), demonstrating species-selective SPM. Electrical vagus stimulation increased SPM in both human and mouse vagus as did incubations with Escherichia coli. Electrical vagus stimulation increased SPM and decreased PGs and leukotrienes. These results provide direct evidence for vagus SPM and eicosanoids. Moreover, they suggest that this vagus SPM circuit contributes to a new proresolving vagal reflex.

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ABIN2 Function Is Required To Suppress DSS-Induced Colitis by a Tpl2-Independent Mechanism [INNATE IMMUNITY AND INFLAMMATION]

The A20-binding inhibitor of NF-B 2 (ABIN2) interacts with Met1-linked ubiquitin chains and is an integral component of the tumor progression locus 2 (Tpl2) kinase complex. We generated a knock-in mouse expressing the ubiquitin-binding–defective mutant ABIN2[D310N]. The expression of Tpl2 and its activation by TLR agonists in macrophages or by IL-1β in fibroblasts from these mice was unimpaired, indicating that the interaction of ABIN2 with ubiquitin oligomers is not required for the stability or activation of Tpl2. The ABIN2[D310N] mice displayed intestinal inflammation and hypersensitivity to dextran sodium sulfate–induced colitis, an effect that was mediated by radiation-resistant cells rather than by hematopioetic cells. The IL-1β–dependent induction of cyclooxygenase 2 (COX2) and the secretion of PGE₂ was reduced in mouse embryonic fibroblasts and intestinal myofibroblasts (IMFs) from ABIN2[D310N] mice. These observations are similar to those reported for the Tpl2 knockout (KO) mice (Roulis et al. 2014. Proc. Natl. Acad. Sci. USA 111: E4658–E4667), but the IL-1β–dependent production of COX2 and PGE₂ in mouse embryonic fibroblasts or IMFs was unaffected by pharmacological inhibition of Tpl2 in wild-type mice. The expression of ABIN2 is decreased drastically in Tpl2 KO mice. These and other lines of evidence suggest that the hypersensitivity of Tpl2 KO mice to dextran sodium sulfate–induced colitis is not caused by the loss of Tpl2 catalytic activity but by the loss of ABIN2, which impairs COX2 and PGE₂ production in IMFs by a Tpl2 kinase–independent pathway.

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Divergent TCR-Initiated Calcium Signals Govern Recruitment versus Activation of Human Alloreactive Effector Memory T Cells by Endothelial Cells [ANTIGEN RECOGNITION AND RESPONSES]

Early human allograft rejection can be initiated when circulating human host versus graft Ag-specific CD8 and CD4 effector memory T cells directly recognize MHC class I and II, respectively, expressed on the luminal surface by endothelium lining graft blood vessels. TCR engagement triggers both graft entry (TCR-driven transendothelial migration or TEM) and production of proinflammatory cytokines. Both TCR-driven TEM and cytokine expression are known to depend on T cell enzymes, myosin L chain kinase, and calcineurin, respectively, that are activated by cytoplasmic calcium and calmodulin, but whether the sources of calcium that control these enzymes are the same or different is unknown. Using superantigen or anti-CD3 Ab presented by cultured human dermal microvascular cells to freshly isolated peripheral blood human effector memory T cells under conditions of flow (models of alloantigen recognition in a vascularized graft), we tested the effects of pharmacological inhibitors of TCR-activated calcium signaling pathways on TCR-driven TEM and cytokine expression. We report that extracellular calcium entry via CRAC channels is the dominant contributor to cytokine expression, but paradoxically these same inhibitors potentiate TEM. Instead, calcium entry via TRPV1, L-Type Ca_v, and pannexin-1/P2X receptors appear to control TCR-driven TEM. These data reveal new therapeutic targets for immunosuppression.

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Consequences of Hypoxia for the Pulmonary Alveolar Epithelial Cell Innate Immune Response [INNATE IMMUNITY AND INFLAMMATION]

Pulmonary innate immune responses involve a highly regulated multicellular network to defend the enormous surface area of the lung. Disruption of these responses renders the host susceptible to pneumonia. Alveolar epithelial cells (AEC) are a critical source of innate immune molecules such as GM-CSF, which determine the functional maturation of alveolar macrophages. In many pulmonary diseases, heterogeneous ventilation leads to regional hypoxia in the lung. The effect of hypoxia on AEC innate immune function is unknown. We now report that exposure of primary murine AEC to hypoxia (1% oxygen) for 24 h results in significant suppression of key innate immune molecules, including GM-CSF, CCL2, and IL-6. This exposure did not cause toxicity but did induce stabilization of hypoxia-inducible factor 1α protein (HIF-1α) and shift to glycolytic metabolism. Focusing on GM-CSF, we found that hypoxia greatly decreased the rate of GM-CSF transcription. Hypoxia both decreased NF-B signaling in AEC and induced chromosomal changes, resulting in decreased accessibility in the GM-CSF proximal promoter of target sequences for NF-B binding. In mice exposed to hypoxia in vivo (12% oxygen for 2 d), lung GM-CSF protein expression was reduced. In vivo phagocytosis of fluorescent beads by alveolar macrophages was also suppressed, but this effect was reversed by treatment with GM-CSF. These studies suggest that in critically ill patients, local hypoxia may contribute to the susceptibility of poorly ventilated lung units to infection through complementary effects on several pathways, reducing AEC expression of GM-CSF and other key innate immune molecules.

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Calcium-Sensing Receptor Autoantibodies in Patients with Autoimmune Polyendocrine Syndrome Type 1: Epitopes, Specificity, Functional Affinity, IgG Subclass, and Effects on Receptor Activity [AUTOIMMUNITY]

A major manifestation of autoimmune polyendocrine syndrome type 1 (APS1) is hypoparathyroidism, which is suggested to result from aberrant immune responses against the parathyroid glands. The calcium-sensing receptor (CaSR), which plays a pivotal role in maintaining calcium homeostasis by sensing blood calcium levels and regulating release of parathyroid hormone (PTH), is an autoantibody target in APS1. In this study, the aim was to characterize the binding sites, specificity, functional affinity, IgG subclass, and functional effects of CaSR autoantibodies using phage-display technology, ELISA, and bioassays. The results indicated that CaSR autoantibody binding sites were at aa 41–69, 114–126, 171–195, and 260–340 in the extracellular domain of the receptor. Autoantibodies against CaSR epitopes 41–69, 171–195, and 260–340 were exclusively of the IgG1 subclass. Autoantibody responses against CaSR epitope 114–126 were predominantly of the IgG1 with a minority of the IgG3 subclass. Only autoantibodies recognizing CaSR epitopes 114–126 and 171–195 affected receptor activity; inositol-phosphate accumulation was increased significantly in HEK293-CaSR cells, and PTH secretion from PTH-C1 cells was reduced significantly when either were incubated with purified Ab and Ca²⁺ compared with Ca²⁺ alone. In conclusion, although the majority of APS1 patients do not have CaSR-stimulating autoantibodies, the hypoparathyroid state in a small minority of patients is the result of functional suppression of the parathyroid glands.

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Type 2 Innate Lymphoid Cells Impede IL-33-Mediated Tumor Suppression [TUMOR IMMUNOLOGY]

Although a number of studies have recently explored the contribution of the adaptive immunity in IL-33–mediated antitumor effects, innate immune involvement has been poorly characterized. Utilizing Rag1^–/– mice (lacking T and B lymphocytes), we show in this study that either systemic administration of recombinant IL-33 or ectopic expression of IL-33 in melanoma cells is sufficient to inhibit tumor growth independent of adaptive antitumor immunity. We have demonstrated that IL-33–mediated antitumor effects depend on expansion and activation of NK cells. Interestingly, IL-33 also promoted the expansion of active type 2 innate lymphoid cells (ILC2s) via its receptor, ST2, which in turn inhibited NK activation and cytotoxicity. This IL-33–induced ILC2 activity coincided with greater expression of the immunosuppressive ectoenzyme CD73. Removal of CD73 from ILC2s in culture with NK cells resulted in markedly increased activation levels in NK cells, offering a potential mechanism by which ILC2s might suppress NK cell–mediated tumor killing. Thus, our data reveal an important contribution of IL-33–induced ILC2 to tumor growth by weakening NK cell activation and tumor killing, regardless of adaptive immunity.

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Sublytic C5b-9 Induces IL-23 and IL-36a Production by Glomerular Mesangial Cells via PCAF-Mediated KLF4 Acetylation in Rat Thy-1 Nephritis [AUTOIMMUNITY]

Sublytic C5b-9 formation on glomerular mesangial cells in rat Thy-1 nephritis (Thy-1N), a model of human mesangioproliferative glomerulonephritis, is accompanied by the production of proinflammatory cytokines, but the relationship between sublytic C5b-9 and cytokine synthesis and the underlying mechanism remains unclear. To explore the problems mentioned above, in this study, we first examined the levels of proinflammatory ILs (e.g., IL-23 and IL-36a) as well as transcription factor (KLF4) and coactivator (PCAF) in the renal tissues of Thy-1N rats and in the glomerular mesangial cell line (HBZY-1) stimulated by sublytic C5b-9. Then, we further determined the role of KLF4 and PCAF in sublytic C5b-9–induced IL-23 and IL-36a production as well as the related mechanism. Our results showed that the levels of KLF4, PCAF, IL-23, and IL-36a were obviously elevated. Mechanistic investigation revealed that sublytic C5b-9 stimulation could increase IL-23 and IL-36a synthesis through KLF4 and PCAF upregulation, and KLF4 and PCAF could form a complex, binding to the IL-23 or IL-36a promoter in a KLF4-dependent manner, causing gene transcription. Importantly, KLF4 acetylation by PCAF contributed to sublytic C5b-9–induced IL-23 and IL-36a transcription. Besides, the KLF4 binding regions on IL-23 or IL-36a promoters and the KLF4 lysine site acetylated by PCAF were identified. Furthermore, silencing renal KLF4 or PCAF gene could significantly inhibit IL-23 or IL-36a secretion and tissue damage of Thy-1N rats. Collectively, these findings implicate that the KLF4/PCAF interaction and KLF4 acetylation by PCAF play a pivotal role in the sublytic C5b-9–mediated IL-23 and IL-36a production of Thy-1N rats.

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Kimishige Ishizaka, M.D., Ph.D. (AAI 58), December 3, 1925 to July 6, 2018 [IN MEMORIAM]

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Thymic Epithelial Cell Support of Thymopoiesis Does Not Require Klotho [IMMUNE SYSTEM DEVELOPMENT]

Age-related thymic involution is characterized by a decrease in thymic epithelial cell (TEC) number and function parallel to a disruption in their spatial organization, resulting in defective thymocyte development and proliferation as well as peripheral T cell dysfunction. Deficiency of Klotho, an antiaging gene and modifier of fibroblast growth factor signaling, causes premature aging. To investigate the role of Klotho in accelerated age-dependent thymic involution, we conducted a comprehensive analysis of thymopoiesis and peripheral T cell homeostasis using Klotho-deficient (Kl/Kl) mice. At 8 wk of age, Kl/Kl mice displayed a severe reduction in the number of thymocytes (10–100-fold reduction), especially CD4 and CD8 double-positive cells, and a reduction of both cortical and medullary TECs. To address a cell-autonomous role for Klotho in TEC biology, we implanted neonatal thymi from Klotho-deficient and -sufficient mice into athymic hosts. Kl/Kl thymus grafts supported thymopoiesis equivalently to Klotho-sufficient thymus transplants, indicating that Klotho is not intrinsically essential for TEC support of thymopoiesis. Moreover, lethally irradiated hosts given Kl/Kl or wild-type bone marrow had normal thymocyte development and comparably reconstituted T cells, indicating that Klotho is not inherently essential for peripheral T cell reconstitution. Because Kl/Kl mice have higher levels of serum phosphorus, calcium, and vitamin D, we evaluated thymus function in Kl/Kl mice fed with a vitamin D–deprived diet. We observed that a vitamin D–deprived diet abrogated thymic involution and T cell lymphopenia in 8-wk-old Kl/Kl mice. Taken together, our data suggest that Klotho deficiency causes thymic involution via systemic effects that include high active vitamin D levels.

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Associations of hemodynamics, morphology, and patient characteristics with aneurysm rupture stratified by aneurysm location

Abstract

Purpose

The mechanisms of cerebral aneurysm rupture are not fully understood. We analyzed the associations of hemodynamics, morphology, and patient age and gender with aneurysm rupture stratifying by location.

Methods

Using image-based models, 20 hemodynamic and 17 morphological parameters were compared in 1931 ruptured and unruptured aneurysms with univariate logistic regression. Rupture rates were compared between males and females as well as younger and older patients and bifurcation versus sidewall aneurysms for different aneurysm locations. Subsequently, associations between hemodynamics and morphology and patient as well as aneurysm characteristics were analyzed for aneurysms at five locations.

Results

Compared to unruptured aneurysms, ruptured aneurysms were characterized by a more irregular shape and were exposed to a more adverse hemodynamic environment described by faster flow, higher wall shear stress, more oscillatory shear, and more unstable and complex flows. These associations with rupture status were consistent for different aneurysm locations. Rupture rates were significantly higher in males at the internal carotid artery (ICA) bifurcation, ophthalmic ICA, and the middle cerebral artery (MCA) bifurcation. At the anterior communicating artery (ACOM) and MCA bifurcation, they were significantly higher for younger patients. Bifurcation aneurysms had significantly larger rupture rates at the MCA and posterior communicating artery (PCOM). In these groups with higher rupture rates, aneurysms were characterized by adverse hemodynamics and more complex shapes.

Conclusion

Hemodynamic and morphological differences between ruptured and unruptured aneurysms are consistent across locations. Adverse morphology and hemodynamics are related to rupture as well as younger age, male gender, and bifurcation aneurysms.

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A COMMON THERAPY FOR ALLERGIC REACTION YET A RARELY SUSPECTED CAUSE OF HYPERSENSITIVITY

While corticosteroid allergy is uncommon, reactions have been described. Increasing reports suggest the frequency of steroid reactions may be increasing, though the exact incidence is unknown.

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TOXIC EPIDERMAL NECROLYSIS COMPLICATED BY CHRONIC INFLAMMATORY KERATITIS/CONJUNCTIVITIS AND INFLAMMATORY PERIPHERAL NEURITIS

We present a patient who developed chronic keratitis and conjunctivitis, inflammatory neuropathy of the hands, and onychomadesis as complications of her toxic epidermal necrolysis (TEN). Neuropathy was treated with glucocorticoids, methotrexate, and high dose IVIG; however the keratitis and conjunctivitis were resistant and required adalimumab. To the best of our knowledge, there are no other reports of inflammatory neuropathy as a sequelae of Stevens Johnson Syndrome (SJS)/TEN, nor management of chronic ocular inflammation with adalimumab.

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SEMINAL FLUID SENSITIVITY: ABSTINENCE IS NOT THE ANSWER

Seminal fluid sensitivity with localized late phase symptoms and successful intravaginal desensitization is described.

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A CASE OF VERY EARLY ONSET INFLAMMATORY BOWEL DISEASE, CHRONIC LUNG DISEASE, AND RECURRENT INFECTIONS

Very early onset inflammatory bowel disease (VEOIBD) may correlate with multiple immunodeficiencies, including severe combined immunodeficiency (SCID), common variable immunodeficiency (CVID), chronic granulomatous disease (CGD), Wiskott-Aldrich syndrome (WAS), and IL-10 signaling defects. It may be difficult to differentiate between intestinal inflammation and immune dysfunction leading to systemic symptoms and elevated inflammatory markers. This patient, a 5-year-old male with very early onset Crohn's disease, chronic lung disease, 1p36 duplication, failure to thrive, eczema, and systemic infections including Candidemia, Klebsiella bacteremia, histoplasmosis, recurring pneumonia, multiple upper respiratory and sinus infections, and recurring IBD flares, presented due to concern for underlying primary immunodeficiency.

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NOT ALL LIP SWELLING IS ANGIOEDEMA

Cheilitis granulomatosa (CG) is a rare form of recurrent or persistent swelling of one or both lips and one form of orofacial granulomatosis. It is important for allergists to consider the need for mucosal biopsy in patients initially referred for angioedema, especially if the lip swelling has been persistent.

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THREE CASES OF DELAYED-ONSET REPETITIVE EMESIS AFTER AVOCADO INGESTION

Food Protein-Induced Enterocolitis (FPIES) is a non-IgE mediated gastrointestinal food hypersensitivity typically presenting in infancy with vomiting and diarrhea, but can progress to shock. Rarely reported as an FPIES trigger, avocado is listed as among low-risk complementary foods to introduce for infants in the first international consensus guidelines for FPIES. Here we report 3 cases of FPIES to avocado.

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EDUCATIONAL OUTCOMES OF AN ANAPHYLAXIS SIMULATION ACTIVITY AMONG MEDICAL STUDENTS AND RESIDENTS¶

Failure to recognize anaphylaxis or delayed epinephrine auto-injector (EAI) administration may result in poor patient outcomes.  Clinical simulation is an educational method used for environment-controlled, team-based learning.

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GENETIC TESTING IDENTIFIES CAUSE OF ENTEROPATHY AND GROWTH FAILURE IN A 10 YEAR OLD MALE

Enteropathies with features of celiac disease or inflammatory bowel disease (IBD) should spark consideration of an immunodeficiency when presenting at an early age.

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HIGHER STARTING DOSE PROTOCOLS IN CORONARY ARTERY DISEASE PATIENTS WITH ASPIRIN HYPERSENSITIVITY

Aspirin is a cornerstone of atherosclerosis therapy, but 1.5% of coronary artery disease (CAD) patients report aspirin allergy. Past protocols of challenge and/or desensitization for aspirin allergy excluded acute coronary syndrome (ACS) patients and/or started at low doses. Recent studies propose higher starting doses with fewer steps. The safety and efficacy of these newer protocols are not established, especially in the acute setting where the ability to tolerate aspirin is time-sensitive.

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NEWBORN T-CELL RECOMBINATION EXCISION CIRCLE SCREENING REVEALS NON-ARCHETYPAL DIGEORGE PATIENT

DiGeorge Syndrome (DGS) is a spectrum of disorders with variable manifestations including congenital heart malformations, immunodeficiency, facial dysmorphism, hypocalcemia, and developmental delay, leading to diagnosis at a wide age range.1 Patients without classic cardiac malformations frequently remain undiagnosed longer, diagnosed only after developing recurrent infections, learning difficulties, or mental health problems. 2

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SOCIO-DEMOGRAPHIC DIFFERENCES IN PATIENTS HOSPITALIZED FOR ANAPHYLAXIS IN THE UNITED STATES

Anaphylactic shock is a life-threatening emergency that can lead to significant morbidity and mortality. Data from European studies have shown significant disparities in healthcare utilization for anaphylaxis, however there are limited studies describing the association between socioeconomic status and patient characteristics for hospitalizations related to anaphylaxis in the United States.

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URTICARIA, NAUSEA, AND VOMITING, IS THIS THE GALT ENZYME DEFICIENCY?

Galactosemia is a rare genetic disorder not frequently encountered in clinical practice. GALT enzyme deficiency is in the spectrum of non IgE mediated food intolerance. However, when encountered with symptoms consistent anaphylaxis, the possibility of an IgE mediated reaction should not be excluded.

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DIRECT ORAL AMOXICILLIN CHALLENGE WITHOUT PRELIMINARY SKIN TESTING IN PATIENTS WITH REPORTED PENICILLIN ALLERGY

10% of hospitalized patients report penicillin allergy; studies indicate that ∼98% are not truly allergic. Unconfirmed penicillin allergy labels pose public health risks, and evaluation is recommended to improve antibiotic stewardship. While the most widely accepted protocol is penicillin skin testing (PST) followed by oral amoxicillin challenge, time constraints and resources may preclude this. Recent literature supports the safety and efficacy of direct oral amoxicillin challenge in low-risk individuals.

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IMPROVING EMERGENCY CARE FOR ANAPHYLAXIS: IMPACT OF A CLINICAL PATHWAY IN A PEDIATRIC EMERGENCY DEPARTMENT

Emergency Department (ED) management of anaphylaxis has not kept pace with advances in knowledge. Epinephrine use and utilization of guideline-based practice recommendations remains sub-optimal, particularly in children. We implemented a clinical pathway in our pediatric ED in August 2017 to improve care.

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SECONDARY IMMUNODEFICIENCY DUE TO GAMING DISORDER

Gaming disorder is a new ICD-11 diagnosis wherein obsessive video-gaming results in an interference of daily activities, which can lead to downstream health effects such as cachexia and malnutrition. We report a patient whose gaming disorder led to severe malnutrition and secondary immunodeficiency.

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PREDICTIVE DECLINE IN PEANUT SKIN TEST AND RAST AMONG PEANUT-ALLERGIC CHILDREN UNDERGOING HIGH-DOSE ORAL IMMUNOTHERAPY

Peanut immunotherapy remains a limited form of treatment for peanut allergic children. Limitations primarily stem from small study sizes, significant adverse events, unclear long-term immunological outcomes and the inability to reach tolerance. In our cohort of peanut anaphylaxis patients undergoing tolerance induction oral immunotherapy, we sought to determine the rate of decline in peanut skin prick testing (SPT) and RAST results following one year of high-dose, weekly peanut immunotherapy.

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DIFFERENTIAL DIAGNOSIS IN PEDIATRIC SEVERE ASTHMA

Despite drug treatment, a small percentage of patients with asthma cannot reach control. Therefore, it is important to have differential diagnosis in mind.

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PERCEPTION AND PRACTICE OF SUBLINGUAL IMMUNOTHERAPY AMONG PRACTICING ALLERGISTS IN THE US: 2018 FOLLOW-UP SURVEY.

Limited information regarding current trends of sublingual immunotherapy (SLIT) use in the United States and perception of SLIT relative to 2007 and 2013 is available, especially in light of recent FDA-approved SLIT options.

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RESOLUTION OF MILK-PROTEIN ALLERGY AFTER HEMATOPOIETIC STEM CELL TRANSPLANT IN A PATIENT WITH IPEX SYNDROME

Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is due to a FOXP3 gene mutation leading to regulatory T cell dysfunction and multi-organ autoimmunity. Patients present in infancy with protracted diarrhea, dermatitis, insulin-dependent diabetes mellitus, and thyroiditis. Some patients may have severe food allergies. We present a patient with IPEX syndrome whose milk protein allergy resolved after receiving a stem cell transplant for his primary immunodeficiency.

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COMPARATIVE STUDY OF βS-LACTAM DE-LABELING ON THE FREQUENCY OF PERI-OPERATIVE VANCOMYCIN USE

Vancomycin is the antibiotic of choice in β-lactam allergic adults undergoing surgical antibiotic prophylaxis. Because it is a suboptimal option, in 2015 a pre-operative drug allergy screening program began at the Montreal General Hospital (MGH). It de-labeled 94 % of patients evaluated, reducing vancomycin use to 3 %. To validate the program effectiveness a prospective study comparing the Royal Victoria Hospital (RVH), which lacked de-labeling was undertaken.The aim of the study was to determine the effect of a de-labeling program on vancomycin use.

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European Society of Neuroradiology (ESNR)

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Syzygium cumini extract induced reactive oxygen species mediated apoptosis in human oral squamous carcinoma cells

Abstract

Background

Syzygium cumini (L.) Skeels (jambolan) is commonly used in Indian traditional medicine to treat a variety of diseases such as obesity, diabetes etc. The cytotoxic potential of Syzygium cumini (SC) against oral cancer cell line is remains elusive. Therefore, in this study, we evaluated the cytotoxic effect of S. cumini in human oral squamous cell carcinoma (OSCC) cell line (SCC‐25 cells).

Material and Methods

OSCC cells are treated with different concentrations (10, 20 and 40 μg/mL) of S. cumuni for 24 h and cytotoxicity was analyzed by MTT assay. The intracellular reactive oxygen species (ROS) was measured using the indicator dye, 2',7'‐dichlorofluorescin diacetate staining. Apoptosis‐related morphological changes were evaluated by dual acridine orange/ethidium bromide (AO/EB) fluorescent staining and phosphatidylserine externalization was measured by annexin V assays. The protein and gene expression of cadherin‐1 was evaluated by western blotting and PCR analysis.

Results

SC treatments caused cytotoxicity of OSCC cell line and induced intracellular ROS accumulation. This treatment also caused apoptosis related morphological changes and externalization of phosphatidylserine in OSCC cells. Further, SC treatments increased protein and gene expression of cadherin‐1.

Conclusion

S. cumini extract inhibits the proliferation of OSCC cells and induces apoptosis through ROS accumulation and therefore, it could be used for the prevention of OSCC.

This article is protected by copyright. All rights reserved.

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Effect of glycerol on reconstructed human oral mucosa

The majority of severely ill patients experience dry mouth. For institutionalized patients, this condition is commonly treated using glycerol as a lubricant. However, because of its possibly desiccating effect, some countries do not advocate the use of glycerol. This study aimed to investigate dose‐dependent effects of glycerol on homeostasis and tissue integrity of in vitro‐reconstructed normal human buccal mucosa (RNHBM). Primary keratinocytes and fibroblasts were isolated and expanded from biopsies of mucosa from eight healthy volunteers. Ninety‐six samples of RNHBM were prepared and exposed for 24 h to 17%, 42.5%, or 85% glycerol, or to distilled H₂O (control). Sections were stained with haematoxylin and eosin (H&E) to evaluate epithelial thickness or used for immunohistochemistry to measure expression of Ki67 (proliferation), cleaved caspase‐3 (apoptosis), and E‐cadherin (tissue‐integrity). Positive cells and cell layers, as detected by immunohistochemistry, were counted. Epithelial thickness, proliferation, and apoptosis were significantly increased by exposure to 42.5% and 85% glycerol. No significant differences in apoptosis or proliferation were found between controls and RNHBM exposed to 17% glycerol. E‐cadherin expression was not significantly affected by exposure to any of the concentrations of glycerol tested. This study shows that glycerol affects tissue homeostasis, but not tissue integrity, of RNHBM at glycerol concentrations above 42.5%.

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Schneiderian Membrane Perforation via Transcrestal Sinus Floor Elevation: A Randomized Ex Vivo Study with Endoscopic Validation

Abstract

Objective

To endoscopically determine the incidence of Schneiderian membrane perforation during transcrestal maxillary sinus floor elevation (SFE), in relation to the bone preparation technique, amount of bone graft, membrane elevation height and different surgical steps.

Materials and methods

Seven cadaver heads corresponding to 12 maxillary sinuses were used to perform 3 SFE via transcrestal approach per sinus (36 elevations). Each sinus was randomly assigned to either the Sinus Crestal Approach (SCA) drill kit technique (experimental group) or the conventional osteotome technique (control group). During all phases of the surgery, the integrity of the sinus membrane was monitored through endoscopic examination.

Results

A significant difference was found in the incidence of perforation (P = 0.007) and vertical elevation height (P < 0.001) between the study groups, favoring the experimental group. A safety elevation threshold of 5 mm without bone graft and implant placement was estimated. A significant correlation was observed between residual ridge height and incidence of perforation (P < 0.001) (OR = 0.51).

Conclusion

The SCA drill kit may demonstrate superior osteotomy preparation and membrane elevation capabilities to the osteotome technique, and significantly when 6 mm SFE is indicated. Residual ridge height and vertical elevation height are risk determinants factors.

This article is protected by copyright. All rights reserved.

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Inhibition of arachidonate 15‐lipoxygenase reduces the epithelial–mesenchymal transition in eosinophilic chronic rhinosinusitis with nasal polyps

Background

The epithelial–mesenchymal transition (EMT) is a distinguishing characteristic of chronic rhinosinusitis with nasal polyps (CRSwNP). The underlying mechanism remains largely unknown. Arachidonate 15‐lipoxygenase (ALOX15), an enzyme involved in arachidonic acid metabolism, has been reported to cause airway epithelial injury and thus may further promote the EMT. The aim of this study was to evaluate the role of ALOX15 during the EMT process in CRSwNP.

Methods

A total of 54 samples were obtained, including 10 from healthy control, 16 from non‐eosinophilic CRSwNP, and 28 from eosinophilic CRSwNP. Hematoxylin and eosin staining was performed to determine the basement membrane (BM) thickness. The concentration of molecules mediating remodeling was assayed by Luminex. The messenger RNA (mRNA) and protein levels of target genes were measured by quantitative real‐time polymerase chain reaction (PCR) and Western blotting.

Results

EMT was enhanced in eosinophilic CRSwNP compared with the healthy controls and non‐eosinophilic CRSwNP infiltrated with lymphocytes and/or plasma cells. The expression pattern of molecules related to remodeling, including matrix metalloproteinases (MMPs), tissue inhibitor of metalloproteinases (TIMPs), and transforming growth factor β (TGF‐β) family members, differed between the subtypes of CRSwNP. The mRNA level of ALOX15 was correlated with the BM thickness and MMP‐1 and TGF‐β3 expression. The inhibition of ALOX15 by PD146176 could induce claudin‐1, claudin‐4, claudin‐7, zonula occludens (ZO)‐1, ZO‐2, E‐Cadherin, TIMP‐1, and TIMP‐3 expressions and reduce the levels of MMP‐1 and N‐Cadherin in epithelial cells acquired from eosinophilic CRSwNP patients.

Conclusion

The specific inhibition of ALOX15 could attenuate the EMT, which may provide an alternative method for the treatment of CRSwNP.

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In‐office balloon sinus dilation versus medical therapy for recurrent acute rhinosinusitis: a randomized, placebo‐controlled study

Background

A limited number of studies have demonstrated symptomatic improvement for recurrent acute rhinosinusitis (RARS) patients after endoscopic sinus surgery. In this randomized, controlled study we evaluated 24‐week outcomes for balloon sinus dilation (BSD) performed in‐office (IO) with medical management (MM) as compared with MM only for RARS patients.

Methods

Adults diagnosed with RARS were randomized to groups with BSD plus MM (n = 29) or MM alone (n = 30). Patients who received MM alone also received a sham BSD‐IO procedure to blind them to group assignment. Patients were followed to 48 weeks posttreatment. The primary outcome was the difference between arms in change in Chronic Sinusitis Survey (CSS) score from baseline to 24 weeks. Secondary endpoints included comparisons of Rhinosinusitis Disability Index (RSDI) score, medication usage, medical care visits, and sinus infections.

Results

Change in patient‐reported quality of life (QOL), as measured by the CSS total score from baseline to 24 weeks, was significantly greater in the BSD plus MM group compared with the MM‐only group (37.3 ± 24.4 [n = 26] vs 21.8 ± 29.0 [n = 27]; p = 0.0424).

Conclusion

BSD plus MM proved superior to MM alone in enhancing QOL for RARS patients. BSD plus MM should be considered as a viable treatment option for properly diagnosed RARS patients.

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Quality of recovery in patients undergoing endoscopic sinus surgery after general anesthesia: total intravenous anesthesia vs desflurane anesthesia

Background

For sinus surgery, some centers favor total intravenous anesthesia (TIVA) over inhalation anesthesia. However, whether TIVA affects the patient's perceived quality of recovery remains unclear. This study used the Quality of Recovery–40 questionnaire (QoR‐40) to compare patient recovery between surgical patients who received TIVA and those who received desflurane (DES) anesthesia.

Methods

Eighty patients (20 to 65 years old) undergoing endoscopic sinus surgery were prospectively enrolled and randomized to either the TIVA (propofol and remifentanil infusion) or DES (desflurane inhalation and remifentanil infusion) group. The QoR‐40 was administered before surgery, at 6 hours after surgery, and on postoperative day 1 (POD1). Incidence of nausea and vomiting, remifentanil consumption, blood loss, and pain treatment were recorded. The influence of lesion extent (indexed as Lund‐Mackay [LM] score) on recovery quality was also assessed.

Results

Forty patients were randomized into the TIVA group, and 40 patients were randomized into the DES group. The QoR‐40 score at 6 hours after surgery was significantly higher in the TIVA group compared with the DES group (188.2 vs 182.6, respectively; p = 0.049), indicating a better quality of recovery in the TIVA group. TIVA resulted in less blood loss (p < 0.0001). A high LM score (≥12) was associated with lower QoR‐40 scores at 6 hours after surgery (180.2 vs 187.2, p = 0.028) and on POD1 (181.5 vs 190.3, p = 0.003).

Conclusion

This study shows that the quality of recovery for endoscopic sinus surgery patients was better with TIVA than with desflurane anesthesia. A high LM score was related to poorer recovery quality.

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In this Issue: Graphical Abstracts

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Issue Information ‐ TOC

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Corrigendum

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Issue Information ‐ Cover and Editorial Board

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Comparison of regulatory B cells in asthma and allergic rhinitis

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