Person: Drazen, Jeffrey
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Drazen
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Jeffrey
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Drazen, Jeffrey
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Publication A summary of the new GINA strategy: a roadmap to asthma control(European Respiratory Society, 2015) Reddel, Helen K.; Bateman, Eric D.; Becker, Allan; Boulet, Louis-Philippe; Cruz, Alvaro A.; Drazen, Jeffrey; Haahtela, Tari; Hurd, Suzanne S.; Inoue, Hiromasa; de Jongste, Johan C.; Lemanske, Robert F.; Levy, Mark L.; O'Byrne, Paul M.; Paggiaro, Pierluigi; Pedersen, Soren E.; Pizzichini, Emilio; Soto-Quiroz, Manuel; Szefler, Stanley J.; Wong, Gary W.K.; FitzGerald, J. MarkOver the past 20 years, the Global Initiative for Asthma (GINA) has regularly published and annually updated a global strategy for asthma management and prevention that has formed the basis for many national guidelines. However, uptake of existing guidelines is poor. A major revision of the GINA report was published in 2014, and updated in 2015, reflecting an evolving understanding of heterogeneous airways disease, a broader evidence base, increasing interest in targeted treatment, and evidence about effective implementation approaches. During development of the report, the clinical utility of recommendations and strategies for their practical implementation were considered in parallel with the scientific evidence. This article provides a summary of key changes in the GINA report, and their rationale. The changes include a revised asthma definition; tools for assessing symptom control and risk factors for adverse outcomes; expanded indications for inhaled corticosteroid therapy; a framework for targeted treatment based on phenotype, modifiable risk factors, patient preference, and practical issues; optimisation of medication effectiveness by addressing inhaler technique and adherence; revised recommendations about written asthma action plans; diagnosis and initial treatment of the asthma−chronic obstructive pulmonary disease overlap syndrome; diagnosis in wheezing pre-school children; and updated strategies for adaptation and implementation of GINA recommendations.Publication Treatment of Asthma with Drugs Modifying the Leukotriene Pathway(Massachusetts Medical Society, 1999-01-21) Israel, Elliot; Drazen, Jeffrey; O'Byrne, PaulIn 1979 and 1980, the chemical structures of the material previously known as slow-reacting substance of anaphylaxis were elucidated as 5(S)- hydroxy- 6(R)-glutathionyl- 7,9-trans-11,14- cis - eico- satetraenoic acid1 and its cysteinyl-glycyl and cysteinyl congener (also known as leukotrienes C4, D4, and E4, respectively). These molecules were so named because the parent molecule was originally isolated from leukocytes, and its carbon backbone contained three double bonds in series, which constitutes a triene. This structural information provided the key to the oxidative pathway of lipid metabolism known as the 5-lipoxygenase pathway.Publication Unjamming and cell shape in the asthmatic airway epithelium(Nature Publishing Group, 2015) Park, Jin-Ah; Kim, Jae Hun; Bi, Dapeng; Mitchel, Jennifer; Qazvini, Nader Taheri; Tantisira, Kelan; Park, Chan Young; McGill, Maureen; Kim, Sae-Hoon; Gweon, Bomi; Notbohm, Jacob; Steward Jr, Robert; Burger, Stephanie; Randell, Scott H.; Kho, Alvin; Tambe, Dhananjay; Hardin, Corey; Shore, Stephanie; Israel, Elliot; Weitz, David; Tschumperlin, Daniel J.; Henske, Elizabeth; Weiss, Scott; Manning, Mary; Butler, James; Drazen, Jeffrey; Fredberg, JeffreyFrom coffee beans flowing in a chute to cells remodelling in a living tissue, a wide variety of close-packed collective systems— both inert and living—have the potential to jam. The collective can sometimes flow like a fluid or jam and rigidify like a solid. The unjammed-to-jammed transition remains poorly understood, however, and structural properties characterizing these phases remain unknown. Using primary human bronchial epithelial cells, we show that the jamming transition in asthma is linked to cell shape, thus establishing in that system a structural criterion for cell jamming. Surprisingly, the collapse of critical scaling predicts a counter-intuitive relationship between jamming, cell shape and cell–cell adhesive stresses that is borne out by direct experimental observations. Cell shape thus provides a rigorous structural signature for classification and investigation of bronchial epithelial layer jamming in asthma, and potentially in any process in disease or development in which epithelial dynamics play a prominent role.Publication Expired Nitric Oxide after Bronchoprovocation and Repeated Spirometry in Patients with Asthma(American Thoracic Society, 1998-03) Deykin, Aaron; Halpern, Orit; Massaro, Anthony; Drazen, Jeffrey; Israel, ElliotCompared with normal individuals, subjects with asthma have elevated levels of expired nitric oxide (NO). These levels are hypothesized to reflect the degree of airway inflammation. Expired NO levels rise during the late phase of allergen challenge and decrease in asthmatics after steroid treatment. Isocapnic cold air hyperventilation (ISH) is believed to cause airway narrowing through noninflammatory mechanisms. We measured mixed expired NO in 10 individuals with atopic asthma who underwent both ISH challenge and allergen challenge, and compared these measurements with the change in expired NO that occurred after serial spirometry alone. We found that ambient NO levels affected mixed expired NO. Controlling for inspired NO, we found that repeated spirometry alone produced a significant fall in mixed expired NO (p < 0.01) that was maximal after 30 min (36.6 ± 8.5% fall). After allergen and ISH challenges, expired NO was elevated relative to levels after repeated spirometry (p < 0.01 and p = 0.065, respectively). In addition, we found that prechallenge expired NO levels were significantly correlated with the magnitude of the late fall in FEV1 following allergen challenge (r = 0.80, p < 0.01). These data demonstrate that repeated spirometry results in reduced mixed expired NO and suggest that both ISH and allergen-induced bronchoconstriction share pathobiologic mechanisms that produce increases in mixed expired NO.Publication Naturally Occurring Mutations in the Human 5-Lipoxygenase Gene Promoter That Modify Transcription Factor Binding and Reporter Gene Transcription(American Society for Clinical Investigation, 1997-03-01) In, Kwang Ho; Asano, Koichiro; Beier, David R.; Grobholz, James; Finn, Patricia W.; Silverman, Edwin; Silverman, Eric S.; Collins, T; Fischer, Andrew R.; Keith, Tim P.; Serino, Kristina; Kim, S W; De Sanctis, George T.; Yandava, Chandri; Pillari, Anthony; Rubin, Paul; Kemp, James; Israel, Elliot; Busse, William W.; Ledford, Dennis; Murray, John J.; Segal, Allen; Tinkleman, David; Drazen, JeffreyFive lipoxygenase (5-LO) is the first committed enzyme in the metabolic pathway leading to the synthesis of the leukotrienes. We examined genomic DNA isolated from 25 normal subjects and 31 patients with asthma (6 of whom had aspirin-sensitive asthma) for mutations in the known transcription factor binding regions and the protein encoding region of the 5-LO gene. A family of mutations in the G + C-rich transcription factor binding region was identified consisting of the deletion of one, deletion of two, or addition of one zinc finger (Sp1/Egr-1) binding sites in the region 176 to 147 bp upstream from the ATG translation start site where there are normally 5 Sp1 binding motifs in tandem. Reporter gene activity directed by any of the mutant forms of the transcription factor binding region was significantly (P < 0.05) less effective than the activity driven by the wild type transcription factor binding region. Electrophoretic mobility shift assays (EMSAs) demonstrated the capacity of wild type and mutant transcription factor binding regions to bind nuclear extracts from human umbilical vein endothelial cells (HUVECs). These data are consistent with a family of mutations in the 5-LO gene that can modify reporter gene transcription possibly through differences in Sp1 and Egr-1 transactivation.