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      An advanced recording and analysis system for the differentiation of guinea pig cough responses to citric acid and prostaglandin E 2 in real time

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          Abstract

          Cough number and/or sound have been used to assess cough sensitivity/intensity and to discriminate cough patterns in clinical settings. However, to date, only manual counting of cough number in an offline manner is applied in animal cough studies, which diminishes the efficiency of cough identification and hinders the diagnostic discrimination of cough patterns, especially in animals with pulmonary diseases. This study aims to validate a novel recording/analysis system by which cough numbers are automatically counted and cough patterns are comprehensively differentiated in real time. The experiment was carried out in conscious guinea pigs exposed to aerosolized citric acid (CA, 150 mM) and prostaglandin E 2 (PGE 2, 0.43 mM). Animal body posture (video), respiratory flow, and cough acoustics (audio) were simultaneously monitored and recorded. Cough number was counted automatically, and cough sound parameters including waveform, duration, power spectral density, spectrogram, and intensity, were analyzed in real time. Our results showed that CA- and PGE 2-evoked coughs had the same cough numbers but completely different patterns [individual coughs vs. bout(s) of coughs]. Compared to CA-evoked coughs, PGE 2-evoked coughs possess a longer latency, higher cough rate (coughs/min), shorter cough sound duration, lower cough sound intensity, and distinct cough waveforms and spectrograms. A few mucus- and wheeze-like coughs were noted in response to CA but not to PGE 2. In conclusion, our recording/analysis system is capable of automatically counting the cough number and successfully differentiating the cough pattern by using valuable cough sound indexes in real time. Our system enhances the objectivity, accuracy, and efficiency of cough identification and count, improves the intensity evaluation, and offers ability for pattern discrimination compared to traditional types of cough identification. Importantly, this approach is beneficial for assessing the efficacy of putative antitussive drugs in animals without or with pulmonary diseases, particularly in cases without significant change in cough number.

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          Most cited references64

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          TRPA1 agonists evoke coughing in guinea pig and human volunteers.

          Cough is the most frequent reason for consultation with a family doctor, or with a general or respiratory physician. Treatment options are limited and one meta-analysis concluded that over-the-counter remedies are ineffective. There is also increasing concern about their use in children. Environmental irritants such as air pollution and cigarette smoke are thought to evoke cough by stimulating airway sensory nerves; however, how this occurs is not fully understood. We hypothesized that the TRPA1 (transient receptor potential cation channel, subfamily A, member 1) receptor may have a role as a novel target for tussive agents given that many potential irritants have been shown to activate this channel. We investigated the effect of TRPA1 ligands on vagal sensory nerve activity in vitro and in guinea pig and human tussive challenge models. We demonstrated that TRPA1 agonists such as acrolein activate cloned human TRPA1 channels in HEK293 cells and also vagal sensory nerves in murine, guinea pig, and human tissues. A role for TRPA1 was confirmed, using specific inhibitors and tissue from Trpa1(-/-) gene-deleted animals. Finally, TRPA1 ligands evoked reproducible tussive responses in both a guinea pig model and normal volunteers. This study identifies the TRPA1 receptor as a promiscuous receptor, activated by a wide range of stimuli, making it a perfect target for triggering cough and as such one of the most promising targets currently identified for the development of antitussive drugs.
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            The Leicester Cough Monitor: preliminary validation of an automated cough detection system in chronic cough.

            Chronic cough is a common condition that presents to both primary and secondary care. Assessment and management are hampered by the absence of well-validated outcome measures. The present study comprises the validation of the Leicester Cough Monitor (LCM), an automated sound-based ambulatory cough monitor. Cough frequency was measured with the LCM and compared with coughs and other sounds counted manually over 2 h of a 6-h recording by two observers in nine patients with chronic cough in order to determine the sensitivity and specificity of the LCM. Automated cough frequency was also compared with manual counts from one observer in 15 patients with chronic cough and eight healthy subjects. All subjects underwent 6-h recordings. A subgroup consisting of six control and five patients with stable chronic cough underwent repeat automated measurements > or = 3 months apart. A further 50 patients with chronic cough underwent 24-h automated cough monitoring. The LCM had a sensitivity and specificity of 91 and 99%, respectively, for detecting cough and a false-positive rate of 2.5 events x h(-1). Mean+/-SEM automated cough counts x patient x h(-1) was 48+/-9 in patients with chronic cough and 2+/-1 in the control group (mean difference 46 counts x patient x h(-1); 95% confidence interval (CI) 20-71). The automated cough counts were repeatable (intra-subject SD 11.4 coughs x patient x h(-1); intra-class correlation coefficient 0.9). The cough frequency in patients undergoing 24-h automated monitoring was 19 coughs x patient x h(-1); daytime (08:00-22:00 h) cough frequency was significantly greater than overnight cough frequency (25 versus 10 coughs x patient x h(-1); mean difference 15 coughs x patient x h(-1), 95% CI 8-22). The Leicester Cough Monitor is a valid and reliable tool that can be used to assess 24-h cough frequency in patients with cough. It should be a useful tool to assess patients with cough in clinical trials and longitudinal studies.
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              Chronic cough as the sole presenting manifestation of bronchial asthma.

              Six patients with chronic cough, without history of dyspnea or wheezing, had normal base-line spirometry but hyper-reactive airways, as demonstrated with methacholine. Maintenance therapy with bronchodilators promptly eliminated the cough in all patients. Three to 12 months later therapy was discontinued for three days, cough returned, and detailed pulmonary-function studies were carried out. Again, base-line values were normal, but after methacholine one-second forced expiratory volume decreased an average of 40 per cent in the patients as compared to 30 per cent in normal controls (P less than 0.001). The point of identical flow was increased by methacholine to 43.5 per cent of vital capacity in the patients, as compared to 6 per cent in normal controls (P less than 0.001), and the alveolar plateau was 4.8 deltaN2 per liter, as compared to 1.4 in normal controls (P less than 0.01). Specific airway conductance was lowered in patients and controls, but the post-methacholine value was significantly lower in the patients. On the basis of their persistently hyper-reactive airways, inducible diffuse airway bronchoconstriction and excellent response to bronchodilator therapy, these patients appear to have a variant form of asthma in which the only presenting symptom is cough.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: ResourcesRole: SoftwareRole: SupervisionRole: ValidationRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: Data curationRole: Formal analysisRole: Investigation
                Role: Data curationRole: Formal analysisRole: InvestigationRole: Writing – review & editing
                Role: ConceptualizationRole: Funding acquisitionRole: Project administrationRole: SupervisionRole: ValidationRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                22 May 2019
                2019
                : 14
                : 5
                : e0217366
                Affiliations
                [001]Pathophysiology Program, Lovelace Respiratory Research Institute, Albuquerque, NM, United States of America
                National Yang-Ming University, TAIWAN
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Author information
                http://orcid.org/0000-0002-4579-046X
                Article
                PONE-D-19-08304
                10.1371/journal.pone.0217366
                6530870
                31116792
                c3da2941-d68c-4fc5-97a0-37abd007f810
                © 2019 Zhuang et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 5 April 2019
                : 10 May 2019
                Page count
                Figures: 7, Tables: 1, Pages: 19
                Funding
                This study is internally funded by Lovelace Respiratory Research Institute.
                Categories
                Research Article
                Biology and Life Sciences
                Physiology
                Physiological Processes
                Coughing
                Medicine and Health Sciences
                Physiology
                Physiological Processes
                Coughing
                Medicine and Health Sciences
                Diagnostic Medicine
                Signs and Symptoms
                Coughing
                Medicine and Health Sciences
                Pathology and Laboratory Medicine
                Signs and Symptoms
                Coughing
                Research and Analysis Methods
                Animal Studies
                Experimental Organism Systems
                Animal Models
                Guinea Pigs
                Biology and Life Sciences
                Organisms
                Eukaryota
                Animals
                Vertebrates
                Amniotes
                Mammals
                Rodents
                Guinea Pigs
                Biology and Life Sciences
                Physiology
                Physiological Processes
                Sneezing
                Medicine and Health Sciences
                Physiology
                Physiological Processes
                Sneezing
                Medicine and Health Sciences
                Diagnostic Medicine
                Signs and Symptoms
                Sneezing
                Medicine and Health Sciences
                Pathology and Laboratory Medicine
                Signs and Symptoms
                Sneezing
                Physical Sciences
                Physics
                Acoustics
                Bioacoustics
                Biology and Life Sciences
                Bioacoustics
                Biology and Life Sciences
                Physiology
                Physiological Processes
                Respiration
                Inhalation
                Medicine and Health Sciences
                Physiology
                Physiological Processes
                Respiration
                Inhalation
                Physical Sciences
                Materials Science
                Materials
                Mixtures
                Aerosols
                Physical Sciences
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                Acoustics
                Acoustic Signals
                Biology and Life Sciences
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                Medicine and Health Sciences
                Anatomy
                Body Fluids
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                Biology and Life Sciences
                Physiology
                Body Fluids
                Mucus
                Medicine and Health Sciences
                Physiology
                Body Fluids
                Mucus
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