- Targeting IκBNS in allergic asthma: Where it resides, matters. [Editorial]
- AAllergy 2017 Jan 18
- The activity NF-κB, a pro-inflammatory transcription factor, and its complex modulation play a central role in in inflammatory airways disease such as allergic airway hyperresponsiveness. In a new st...
The activity NF-κB, a pro-inflammatory transcription factor, and its complex modulation play a central role in in inflammatory airways disease such as allergic airway hyperresponsiveness. In a new study, Yokota and colleagues investigated IκBNS - an atypical inhibitor of NF-kB (IκB). Using elegant bone marrow chimera studies in mice, they found that IκBNS differentially modulated NF-κB activity in hematopoietic and non-hematopoietic cells. They also showed that by binding to the promoter region, this nuclear protein directly induced the MUC5AC gene in airway epithelial cells. This study enhances our understanding of how atypical IκB proteins work in regulating NF-κB activity and allergic airway conditions. It also emphasizes that targeting specific molecular pathways of airway inflammation may result in differential effects depending on the targeted tissue compartment. This is important in the search of novel asthma treatments and supports the fact that global anti-inflammatory approaches alone may not provide sufficient therapy. This article is protected by copyright. All rights reserved.
- New and developing non-adrenoreceptor small molecule drugs for the treatment of asthma. [Journal Article]
- EOExpert Opin Pharmacother 2017 Jan 18
- Introduction Inhaled corticosteroids (ICS) alone or in combination with an inhaled long-acting beta2-agonist (LABA) are the preferred long-term treatment for adults and adolescents with symptomatic a...
Introduction Inhaled corticosteroids (ICS) alone or in combination with an inhaled long-acting beta2-agonist (LABA) are the preferred long-term treatment for adults and adolescents with symptomatic asthma. Additional drugs include leukotriene-receptor antagonists, slow-release theophylline and the long-acting muscarinic antagonist (LAMA) tiotropium (approved in 2015). There is a need for more effective therapies, as many patients continue to have poorly controlled asthma. Areas covered New and developing long-acting non-adrenoreceptor synthetic drugs for the treatment of symptomatic chronic asthma despite treatment with an ICS alone or combined with a LABA. Data was reviewed from studies published up until November 2016. Expert opinion Tiotropium improves lung function and has a modest effect in reducing exacerbations when added to ICS alone or ICS and LABA. The LAMAs umeclidinium and glycopyrronium are under development in fixed dose combination with ICS and LABA. Novel small molecule drugs, such as CRTH2 receptor antagonists, PDE4 inhibitors, protein kinase inhibitors and nonsteroidal glucocorticoid receptor agonists and 'off-label' use of licensed drugs, such as macrolides and statins are under investigation for asthma, although their effectiveness in clinical practice is not established. To better achieve the goal of developing effective novel small molecule drugs for asthma will require greater understanding of mechanisms of disease and the different phenotypes and endotypes of asthma.
- Increased risk of Parkinson disease with diabetes mellitus in a population-based study. [Journal Article]
- MMedicine (Baltimore) 2017; 96(3):e5921
- This nationwide population-based study investigated the risk of Parkinson disease (PD) in relation to diabetes mellitus (DM) through the National Health Insurance Research Database in Taiwan.A retros...
This nationwide population-based study investigated the risk of Parkinson disease (PD) in relation to diabetes mellitus (DM) through the National Health Insurance Research Database in Taiwan.A retrospective study was conducted, consisting of 36,294 patients who were newly diagnosed with DM between January 1, 2000 and December 31, 2006 and 108,882 individuals without DM as healthy controls from insurance claims data from Taiwan's National Health Research Institutes Dataset. The subjects were followed up until December 31, 2011 or until the first manifestation of PD. The hazard ratio (HR) of DM for PD incidence was estimated by Cox proportional hazard regression model.Compared with the non-DM cohort, the incidence density rate of PD was 1.36-fold higher in the DM cohort (1.53 vs 2.08 per 1000 person-years) with an adjusted HR of 1.19 (95% confidence interval = 1.08-1.32) after adjusting for age, sex, comorbidities, and medication use. The adjusted HR of PD for DM with a larger magnitude was observed in females (1.29, 1.12-1.49); individuals age 65 years and older (1.20, 1.06-1.35); those without schizophrenia (1.20, 1.08-1.33), bipolar disorder (1.20, 1.08-1.33), hypertension (1.18, 1.06-1.32), hyperlipidemia (1.21, 1.09-1.34), chronic obstructive pulmonary disease (1.19, 1.06-1.32), coronary artery disease (1.22, 1.09-1.36), stroke (1.23, 1.10-1.37), asthma (1.20, 1.08-1.34), flunarizine use (1.21, 1.08-1.35), zolpidem use (1.16, 1.04-1.30), Charlson comorbidity index score of 0 (1.23, 1.08-1.40), and those using metoclopramide (1.35, 1.14-1.60) and zolpidem (1.46, 1.12-1.90).DM increased the risk of PD during a mean follow-up of 7.3 years. Further mechanistic research on the effect of DM on PD is needed.
- RAGE deficiency predisposes mice to virus-induced paucigranulocytic asthma. [Journal Article]
- EElife 2017 Jan 18; 6
- Asthma is a chronic inflammatory disease. Although many patients with asthma develop type-2 dominated eosinophilic inflammation, a number of individuals develop paucigranulocytic asthma, which occurs...
Asthma is a chronic inflammatory disease. Although many patients with asthma develop type-2 dominated eosinophilic inflammation, a number of individuals develop paucigranulocytic asthma, which occurs in the absence of eosinophilia or neutrophilia. The aetiology of paucigranulocytic asthma is unknown. However, both respiratory syncytial virus (RSV) infection and mutations in the receptor for advanced glycation endproducts (RAGE) are risk factors for asthma development. Here, we show that RAGE deficiency impairs anti-viral immunity during an early-life infection with pneumonia virus of mice (PVM; a murine analogue of RSV). The elevated viral load was associated with the release of high mobility group box-1 (HMGB1) which triggered airway smooth muscle remodelling in early-life. Re-infection with PVM in later-life induced many of the cardinal features of asthma in the absence of eosinophilic or neutrophilic inflammation. Anti-HMGB1 mitigated both early-life viral disease and asthma-like features, highlighting HMGB1 as a possible novel therapeutic target.
- Case 238: Spontaneous Pneumothorax Secondary to Intrapulmonary Necrobiotic Rheumatoid Nodule. [Journal Article]
- RRadiology 2017; 282(2):602-608
- History A 54-year-old white woman with a history of rheumatoid arthritis who was taking glucocorticoids and methotrexate presented to the emergency department in December with worsening shortness of ...
History A 54-year-old white woman with a history of rheumatoid arthritis who was taking glucocorticoids and methotrexate presented to the emergency department in December with worsening shortness of breath and chest heaviness for 1 week. She reported additional symptoms of weakness, headache, and arthralgia primarily involving her bilateral hands, wrist, ankles, and feet. She denied experiencing fevers, syncope or presyncope, focal neurologic deficits, chest pain, nausea, vomiting, unintentional weight loss, or recent trauma. Additional medical history included hypertension, asthma, degenerative disk disease, and migraine, all of which were reportedly controlled with medications. This patient had a smoking history of 80 pack-years, but she had quit smoking 2 months prior to presentation. She denied abuse of alcohol or recreational drugs and reported she was up-to-date on her immunizations, including those for pneumonia and flu. Family history was pertinent for breast cancer in her mother, sister, and maternal aunt. The patient reported normal findings at screening mammography and colonoscopy. A physical examination was remarkable for slightly asymmetric breath sounds, which appeared to be diminished on the right side. This patient had multiple joint deformities, most notably in the bilateral metacarpophalangeal joints. Initial electrocardiography findings and cardiac biomarkers were negative. Her complete blood count and basic metabolic profile were unremarkable. Posteroanterior and lateral chest radiographs were obtained in the emergency department. Subsequently, computed tomography (CT) of the chest was performed.
- Clinical Roles of Lung Volumes Detected by Body Plethysmography and Helium Dilution in Asthmatic Patients: A Correlation and Diagnosis Analysis. [Journal Article]
- SRSci Rep 2017 Jan 18; 7:40870
- Roles of lung volumes in asthma remain controversial. We aimed to evaluate the efficacy of lung volumes in differentiating asthma severity levels. Consecutive outpatients with chronic persistent asth...
Roles of lung volumes in asthma remain controversial. We aimed to evaluate the efficacy of lung volumes in differentiating asthma severity levels. Consecutive outpatients with chronic persistent asthma were enrolled, and body plethysmography (BP) and helium dilution (HD) were performed simultaneously to extract RV%pred, TLC%pred, and RV/TLC. Significant negative correlations were found between FEV1%pred and RV%pred (r = -0.557, P < 0.001), TLC%pred (r = -0.387, P < 0.001), and RV/TLC (r = -0.485, P < 0.001) measured by BP, as well as difference in volumes between these two techniques (ΔRV%pred, ΔTLC%pred and ΔRV/TLC). In mild and moderate asthma, AUC of RV%pred detected by BP and ΔTLC%pred was 0.723 (95%CI 0.571-0.874, P = 0.005) and 0.739 (95%CI 0.607-0.872, P = 0.002) with sensitivity and specificity being 79.41% and 88.24%, and 65.22% and 56.52% at cut-off of 145.40% and 14.23%, respectively. In moderate and severe asthma, AUC of RV%pred detected by BP and ΔTLC%pred was 0.782 (95%CI 0.671-0.893, P < 0.001) and 0.788 (95%CI 0.681-0.894, P < 0.002) with sensitivity and specificity being 77.78% and 97.22%, and 73.53% and 52.94% at cut-off of 179.85% and 20.22%, respectively. In conclusion, lung volumes are reliable complement of FEV1 in identifying asthma severity levels.
- Update on Aspirin-Exacerbated Respiratory Disease. [Review]
- CACurr Allergy Asthma Rep 2017; 17(1):2
- Aspirin-exacerbated respiratory disease (AERD) is an acquired disease characterized by chronic eosinophilic airway inflammation with underlying dysregulation of arachidonic acid metabolism. The purpo...
Aspirin-exacerbated respiratory disease (AERD) is an acquired disease characterized by chronic eosinophilic airway inflammation with underlying dysregulation of arachidonic acid metabolism. The purpose of this paper is to review the latest developments in our understanding of the underlying pathophysiology including the role of eosinophils, mast cells, innate lymphoid cells (ILC2), and platelets. Clinical features such as respiratory reactions induced by alcohol, aggressive nasal polyposis, and anosmia will allow for earlier recognition of these patients in clinical practice. The current state of the art management of AERD will be addressed including the ongoing central role for aspirin desensitization and high-dose aspirin therapy.
- Folic Acid Supplementation for the Prevention of Neural Tube Defects: An Updated Evidence Report and Systematic Review for the US Preventive Services Task Force. [Journal Article]
- JAMAJAMA 2017 Jan 10; 317(2):190-203
- CONCLUSIONS: In studies conducted before the initiation of food fortification in the United States in 1998, folic acid supplementation provided protection against neural tube defects. Newer postfortification studies have not demonstrated a protective association but have the potential for misclassification and recall bias, which can attenuate the measured association of folic acid supplementation with neural tube defects.
- Oxidized CaMKII promotes asthma through the activation of mast cells. [Journal Article]
- JIJCI Insight 2017 Jan 12; 2(1):e90139
- Oxidation of calmodulin-dependent protein kinase II (ox-CaMKII) by ROS has been associated with asthma. However, the contribution of ox-CaMKII to the development of asthma remains to be fully charact...
Oxidation of calmodulin-dependent protein kinase II (ox-CaMKII) by ROS has been associated with asthma. However, the contribution of ox-CaMKII to the development of asthma remains to be fully characterized. Here, we tested the effect of ox-CaMKII on IgE-mediated mast cell activation in an allergen-induced mouse model of asthma using oxidant-resistant CaMKII MMVVδ knockin (MMVVδ) mice. Compared with WT mice, the allergen-challenged MMVVδ mice displayed less airway hyperresponsiveness (AHR) and inflammation. These MMVVδ mice exhibited reduced levels of ROS and diminished recruitment of mast cells to the lungs. OVA-activated bone marrow-derived mast cells (BMMCs) from MMVVδ mice showed a significant inhibition of ROS and ox-CaMKII expression. ROS generation was dependent on intracellular Ca(2+) concentration in BMMCs. Importantly, OVA-activated MMVVδ BMMCs had suppressed degranulation, histamine release, leukotriene C4, and IL-13 expression. Adoptive transfer of WT, but not MMVVδ, BMMCs, reversed the alleviated AHR and inflammation in allergen-challenged MMVVδ mice. The CaMKII inhibitor KN-93 significantly suppressed IgE-mediated mast cell activation and asthma. These studies support a critical but previously unrecognized role of ox-CaMKII in mast cells that promotes asthma and suggest that therapies to reduce ox-CaMKII may be a novel approach for asthma.
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- IgE-Related Chronic Diseases and Anti-IgE-Based Treatments. [Review]
- JIJ Immunol Res 2016; 2016:8163803
- IgE is an immunoglobulin that plays a central role in acute allergic reactions and chronic inflammatory allergic diseases. The development of a drug able to neutralize this antibody represents a brea...
IgE is an immunoglobulin that plays a central role in acute allergic reactions and chronic inflammatory allergic diseases. The development of a drug able to neutralize this antibody represents a breakthrough in the treatment of inflammatory pathologies with a probable allergic basis. This review focuses on IgE-related chronic diseases, such as allergic asthma and chronic urticaria (CU), and on the role of the anti-IgE monoclonal antibody, omalizumab, in their treatment. We also assess the off-label use of omalizumab for other pathologies associated with IgE and report the latest findings concerning this drug and other new related drugs. To date, omalizumab has only been approved for severe allergic asthma and unresponsive chronic urticaria treatments. In allergic asthma, omalizumab has demonstrated its efficacy in reducing the dose of inhaled corticosteroids required by patients, decreasing the number of asthma exacerbations, and limiting the effect on airway remodeling. In CU, omalizumab treatment rapidly improves symptoms and in some cases achieves complete disease remission. In systemic mastocytosis, omalizumab also improves symptoms and its prophylactic use to prevent anaphylactic reactions has also been discussed. In other pathologies such as atopic dermatitis, food allergy, allergic rhinitis, nasal polyposis, and keratoconjunctivitis, omalizumab significantly improves clinical manifestations. Omalizumab acts in two ways: by sequestering free IgE and by accelerating the dissociation of the IgE-Fcε receptor I complex.