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Allergic Sensitization at School Age is a Systemic Low-grade Inflammatory Disorder.

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Allergic Sensitization at School Age is a Systemic Low-grade Inflammatory Disorder.

Allergy. 2016 Dec 19;:

Authors: Chawes BL, Stokholm J, Schoos AM, Rahman N, Brix S, Bisgaard H

Abstract
BACKGROUND: Systemic low-grade inflammation has been demonstrated in a range of the frequent noncommunicable diseases (NCDs) proposing a shared mechanism, but is largely unexplored in relation to allergic sensitization. We therefore aimed to investigate the possible association with childhood allergic sensitization.
METHODS: High sensitivity C-reactive protein (hs-CRP), interleukin-1? (IL-1?), IL-6, tumor necrosis factor-? (TNF-?) and chemokine (C-X-C motif) ligand 8 (CXCL8) were measured in plasma at age 6mo (N=214) and 7yrs (N=277) in children from the Copenhagen Prospective Studies on Asthma in Childhood2000 (COPSAC2000 ) birth cohort. Allergic sensitization against common inhalant and food allergens was determined longitudinally at age ½, 1½, 4 and 6yrs by specific-IgE assessments and skin prick tests. Associations between inflammatory biomarkers and sensitization phenotypes were tested with logistic regression and principle component analyses (PCA).
RESULTS: Adjusted for gender, recent infections and a CRP genetic risk-score, hs-CRP at 7yrs was associated with concurrent elevated specific-IgE against any allergen (adjusted OR (aOR) =1.40; 95% CI, 1.14-1.72; p=0.001), aeroallergens (aOR, 1.43; 1.15-1.77; p=0.001), food allergens (aOR, 1.31; 95% CI, 1.02-1.67; p=0.04), sensitization without any clinical allergy symptoms (aOR=1.40; 1.06-1.85; p=0.02), and with similar findings for skin prick tests. The other inflammatory markers were not univariantly associated with sensitization, but multi-parametric PCA suggested a specific inflammatory response among sensitized children. Inflammatory markers at age 6mo were not associated with subsequent development of sensitization phenotypes.
CONCLUSIONS: Elevated hs-CRP is associated with allergic sensitization in school-aged children suggesting systemic low-grade inflammation as a phenotypic characteristic of this early onset NCD. This article is protected by copyright. All rights reserved.

PMID: 27992959 [PubMed – as supplied by publisher]

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Cysteinyl Leukotrienes Pathway Genes, Atopic Asthma and Drug Response: From Population Isolates to Large Genome-Wide Association Studies.

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Cysteinyl Leukotrienes Pathway Genes, Atopic Asthma and Drug Response: From Population Isolates to Large Genome-Wide Association Studies.

Front Pharmacol. 2016;7:299

Authors: Thompson MD, Capra V, Clunes MT, Rovati GE, Stankova J, Maj MC, Duffy DL

Abstract
Genetic variants associated with asthma pathogenesis and altered response to drug therapy are discussed. Many studies implicate polymorphisms in genes encoding the enzymes responsible for leukotriene synthesis and intracellular signaling through activation of seven transmembrane domain receptors, such as the cysteinyl leukotriene 1 (CYSLTR1) and 2 (CYSLTR2) receptors. The leukotrienes are polyunsaturated lipoxygenated eicosatetraenoic acids that exhibit a wide range of pharmacological and physiological actions. Of the three enzymes involved in the formation of the leukotrienes, arachidonate 5 lipoxygenase 5 (ALOX5), leukotriene C4 synthase (LTC4S), and leukotriene hydrolase (LTA4H) are all polymorphic. These polymorphisms often result in variable production of the CysLTs (LTC4, LTD4, and LTE4) and LTB4. Variable number tandem repeat sequences located in the Sp1-binding motif within the promotor region of the ALOX5 gene are associated with leukotriene burden and bronchoconstriction independent of asthma risk. A 444A > C SNP polymorphism in the LTC4S gene, encoding an enzyme required for the formation of a glutathione adduct at the C-6 position of the arachidonic acid backbone, is associated with severe asthma and altered response to the CYSLTR1 receptor antagonist zafirlukast. Genetic variability in the CysLT pathway may contribute additively or synergistically to altered drug responses. The 601 A > G variant of the CYSLTR2 gene, encoding the Met201Val CYSLTR2 receptor variant, is associated with atopic asthma in the general European population, where it is present at a frequency of ?2.6%. The variant was originally found in the founder population of Tristan da Cunha, a remote island in the South Atlantic, in which the prevalence of atopy is approximately 45% and the prevalence of asthma is 36%. In vitro work showed that the atopy-associated Met201Val variant was inactivating with respect to ligand binding, Ca(2+) flux and inositol phosphate generation. In addition, the CYSLTR1 gene, located at Xq13-21.1, has been associated with atopic asthma. The activating Gly300Ser CYSLTR1 variant is discussed. In addition to genetic loci, risk for asthma may be influenced by environmental factors such as smoking. The contribution of CysLT pathway gene sequence variants to atopic asthma is discussed in the context of other genes and environmental influences known to influence asthma.

PMID: 27990118 [PubMed – in process]

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Single Injection Adductor Canal Block Versus Continuous Adductor Canal Infusion for Total Knee Arthroplasty

Conditions:   Total Knee Arthroplasty;   Pain, Postoperative;   Adductor Canal Block
Interventions:   Procedure: Multimodal Peripheral Nerve Block Injection;   Procedure: Single Shot Adductor Canal Block
Sponsor:   Wake Forest School of Medicine
Not yet recruiting – verified December 2016

View full post on ClinicalTrials.gov: asthma | Studies received in the last 14 days

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[Patient-related independent clinical risk factors for early complications following interventional pulmonology procedures].

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[Patient-related independent clinical risk factors for early complications following interventional pulmonology procedures].

Beijing Da Xue Xue Bao. 2016 Dec 18;48(6):1006-1011

Authors: Huang JJ, Zhang H, Zhang W, Wang X, Gong YH, Wang GF

Abstract
OBJECTIVE: To investigate the early complication rate and identify patient-related independent clinical risk factors for early complications in patients following interventional pulmonology procedures.
METHODS: In the period from December 2014 to December 2015, sufficient data of Peking University First Hospital Respiratory and Critical Care Medicine Department for analysis were identified in 218 subjects. Interventional pulmonology procedures were performed in all the patients. Early complications after the procedures were defined as newly respiratory failure, arrhythmia requiring treatment, severe hemoptysis, pneumothorax, pneumomediastinum, pulmonary edema, tracheoesophageal fistulae, bronchopleural fistulae, acute coronary syndrome, acute cerebrovascular accident, and death. Patient-related clinical risk factors were defined as coronary atherosclerotic heart disease, cerebral infarction, diabetes mellitus, cirrhosis, chronic kidney disease, arrhythmia, asthma, chronic obstructive pulmonary disease, hypertension, and previous interventional pulmonology treatment. The patient-related independent clinical risk factors which had close relations to the occurrence of early complications were analyzed by multivariate statistical analysis with Logistic regression.
RESULTS: There were 56.4% male and 43.6% female subjects in this study. There were 10.6% current smokers, 26.6% former smokers, and 62.8% non-smokers. The overall early complication rate was 8.3%. In all the subjects groups, the patient-related independent clinical risk factors for the early complication rate were coronary atherosclerotic heart disease (B=1.545, P=0.006, OR=4.686, 95% CI 1.568-14.006), chronic obstructive pulmonary disease (B=1.037, P=0.049, OR=2.820, 95% CI 1.675-11.790), and current smoking status (B=1.412, P=0.032, OR=4.139, 95% CI 1.134-15.109); for the newly respiratory failure rates were coronary atherosclerotic heart disease (B=2.207, P=0.004, OR=9.087, 95% CI 2.028-40.714), chronic obstructive pulmonary disease (B=1.646, P=0.048, OR=5.188, 95% CI 1.783-34.375), and lesions involving three central airways (B=1.899, P=0.032, OR=6.680, 95% CI 1.182-37.740). In the malignant group, the patient-related independent clinical risk factor for the early complication rate was current smoking status (B=2.953, P=0.006, OR=19.161, 95% CI 2.360-155.572). In the benign group, the patient-related independent clinical risk factor for the early complication rate was only coronary atherosclerotic heart disease (B=1.976, P=0.022, OR=7.214, 95% CI 1.324-39.298).
CONCLUSION: Closer monitoring of patients with identified clinical risk factors is advisable prior and immediately after interventional pulmonology procedures. In order to avoid or minimize early complications, special attention should be directed toward patients who are current smokers, or patients with lesions involving three central airways, or with coronary atherosclerotic heart disease or chronic obstructive pulmonary disease.

PMID: 27987505 [PubMed – in process]

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Phase 2a, AMP Challenge, Dose Escalation Study to Assess the Dose Response for Topical Efficacy and Systemic Activity in Asthmatic Subjects

Condition:   Asthma
Interventions:   Drug: Fluticasone furoate (FF) Dry Powder Inhaler;   Drug: Fluticasone propionate (FP) Dry Powder Inhaler;   Drug: Budesonide (BUD) Turbuhaler;   Drug: Placebo (ELLIPTA or DISKUS)
Sponsor:   GlaxoSmithKline
Not yet recruiting – verified December 2016

View full post on ClinicalTrials.gov: asthma | Studies received in the last 14 days

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Optimization of substituted imidazobenzodiazepines as novel asthma treatments.

Optimization of substituted imidazobenzodiazepines as novel asthma treatments.

Eur J Med Chem. 2016 Nov 24;126:550-560

Authors: Jahan R, Stephen MR, Forkuo GS, Kodali R, Guthrie ML, Nieman AN, Yuan NY, Zahn NM, Poe MM, Li G, Yu OB, Yocum GT, Emala CW, Stafford DC, Cook JM, Arnold LA

Abstract
We describe the synthesis of analogs of XHE-III-74, a selective ?4?3?2 GABAAR ligand, shown to relax airway smooth muscle ex vivo and reduce airway hyperresponsiveness in a murine asthma model. To improve properties of this compound as an asthma therapeutic, a series of analogs with a deuterated methoxy group in place of methoxy group at C-8 position was evaluated for isotope effects in preclinical assays; including microsomal stability, cytotoxicity, and sensorimotor impairment. The deuterated compounds were equally or more metabolically stable than the corresponding non-deuterated analogs and increased sensorimotor impairment was observed for some deuterated compounds. Thioesters were more cytotoxic in comparison to other carboxylic acid derivatives of this compound series. The most promising compound 16 identified from the in vitro screens also strongly inhibited smooth muscle constriction in ex vivo guinea pig tracheal rings. Smooth muscle relaxation, determined by reduction of airway hyperresponsiveness with a murine ovalbumin sensitized and challenged model, showed that 16 was efficacious at low methacholine concentrations. However, this effect was limited due to suboptimal pharmacokinetics of 16. Based on these findings, further analogs of XHE-III-74 will be investigated to improve in vivo metabolic stability while retaining the efficacy at lung tissues involved in asthma pathology.

PMID: 27915170 [PubMed – as supplied by publisher]

View full post on pubmed: asthma