Cervical spinal cord hemisection impacts sigh and the respiratory reset in male rats.

Cervical spinal cord injury impacts ventilatory and non-ventilatory functions of the diaphragm muscle (DIAm) and contributes to clinical morbidity and mortality in the afflicted population. Periodically, integrated brainstem neural circuit activity drives the DIAm to generate a markedly augmented effort or sigh-which plays an important role in preventing atelectasis and thus maintaining lung function. Across species, the general pattern of DIAm efforts during a normal sigh is variable in amplitude and the extent of post-sigh "apnea" (i.e., the post-sigh inter-breath interval). This post-sigh inter-breath interval acts as a respiratory reset, following the interruption of regular respiratory rhythm by sigh. We examined the impact of upper cervical (C2 ) spinal cord hemisection (C2 SH) on the transdiaphragmatic pressure (Pdi ) generated during sighs and the post-sigh respiratory reset in rats. Sighs were identified in Pdi traces by their characteristic biphasic pattern. We found that C2 SH results in a reduction of Pdi during both eupnea and sighs, and a decrease in the immediate post-sigh breath interval. These results are consistent with partial removal of descending excitatory synaptic inputs to phrenic motor neurons that results from C2 SH. Following cervical spinal cord injury, a reduction in the amplitude of Pdi during sighs may compromise the maintenance of normal lung function.

Enhanced Diaphragm Muscle Function upon Satellite Cell Transplantation in Dystrophic Mice.

The diaphragm muscle is essential for breathing, and its dysfunctions can be fatal. Many disorders affect the diaphragm, including muscular dystrophies. Despite the clinical relevance of targeting the diaphragm, there have been few studies evaluating diaphragm function following a given experimental treatment, with most of these involving anti-inflammatory drugs or gene therapy. Cell-based therapeutic approaches have shown success promoting muscle regeneration in several mouse models of muscular dystrophy, but these have focused mainly on limb muscles. Here we show that transplantation of as few as 5000 satellite cells directly into the diaphragm results in consistent and robust myofiber engraftment in dystrophin- and fukutin-related protein-mutant dystrophic mice. Transplanted cells also seed the stem cell reservoir, as shown by the presence of donor-derived satellite cells. Force measurements showed enhanced diaphragm strength in engrafted muscles. These findings demonstrate the feasibility of cell transplantation to target the diseased diaphragm and improve its contractility.

Postnatal survival of phrenic motor neurons is promoted by BDNF/TrkB.FL signaling.

The number of motor neurons (MNs) declines precipitously during the final trimester before birth. Thereafter, the number of MNs remains relatively stable, with their connections to skeletal muscle dependent on neurotrophins, including brain-derived neurotrophic factor (BDNF) signaling through its high affinity full length tropomyosin related kinase receptor subtype B (TrkB.FL) receptor. As a genetic knockout of BDNF leads to extensive MN loss and postnatal death within 1-2 days after birth; we tested the hypothesis that postnatal inhibition of BDNF/TrkB.FL signaling is important for postnatal PhMN survival. In the present study, we used a 1NMPP1-sensitive TrkBF616A mutant mouse to evaluate the effects of inhibition of TrkB kinase activity on phrenic MNs (PhMNs) numbers and diaphragm muscle (DIAm) fiber cross-sectional area (CSA). Pups were exposed to 1NMPP1 or vehicle (DMSO) from birth to 21 days old (weaning) via the mother's ingestion in the drinking water. Following weaning, the right phrenic nerve was exposed in the neck and the proximal end dipped in a rhodamine solution to retrogradely label PhMNs. After 24 h, the cervical spinal cord and DIAm were excised. Labeled PhMNs were imaged using confocal microscopy, while DIAm strips were frozen at ~1.5x resting length, cryosectioned and stained with H&E to assess CSA. We observed an ~34% reduction in PhMN numbers and increased primary dendrite numbers in 1NMPP1 treated TrkBF616A mice. The distribution of PhMN size (somal surface area) DIAm fiber cross-sectional areas did not differ. We conclude that survival of PhMNs during early postnatal development is sensitive to BDNF/TrkB.FL signaling.

Profile of cough triggers and their relationship with capsaicin cough sensitivity in chronic cough.

BACKGROUND: Cough hypersensitivity is an important part of the neurophysiology of cough, which presents with increased cough response to a lower level of stimuli or triggers. Classification of stimuli might bring about additional insight into the underlying mechanisms and management. OBJECTIVES: This study investigated the profile of cough triggers in chronic cough patients and their relationship with capsaicin cough sensitivity. DESIGN: This was a cross-sectional observational study. METHODS: We enrolled patients with different causes of chronic cough from 2006 to 2021. Cough triggers were defined as cough response to chemical triggers, mechanical triggers, meal triggers, or thermal trigger. Cough sensitivity to capsaicin was evaluated by the capsaicin challenge test, which was expressed as the lowest concentration of capsaicin inducing 5 or more coughing (C5). RESULTS: Among 1211 patients with chronic cough, 1107 (91.4%) patients reported at least one cough trigger. Chemical triggers (66.9%) were the most common cough triggers, followed by thermal exposure (50.6%), mechanical triggers (48.2%), and meal triggers (21.2%). There was no difference in the proportion of chemical triggers among different etiologies. Patients with refractory chronic cough reported the highest prevalence of cough triggers (97.1%). A higher number of meal triggers (34.9%) was associated with gastroesophageal reflux-related cough, and meal triggers and mechanical triggers were more common in refractory chronic cough. Among 254 patients who completed capsaicin challenge test, both the number of total triggers and the number of chemical triggers had a significant but mild correlation with capsaicin cough sensitivity. CONCLUSION: Cough hypersensitivity as reflected by a variety of cough triggers is a common feature in chronic cough patients, but different etiologies present specific profiles of cough triggers, which could not be evaluated comprehensively by capsaicin cough sensitivity.

Profiles of Cough and Associated Risk Factors in Nonhospitalized Individuals With SARS-CoV-2 Omicron Variant Infection: Cross-Sectional Online Survey in China.

BACKGROUND: Cough is a common symptom during and after COVID-19 infection; however, few studies have described the cough profiles of COVID-19. OBJECTIVE: The aim of this study was to investigate the prevalence, severity, and associated risk factors of severe and persistent cough in individuals with COVID-19 during the latest wave of the Omicron variant in China. METHODS: In this nationwide cross-sectional study, we collected information of the characteristics of cough from individuals with infection of the SARS-CoV-2 Omicron variant using an online questionnaire sent between December 31, 2022, and January 11, 2023. RESULTS: There were 11,718 (n=7978, 68.1% female) nonhospitalized responders, with a median age of 37 (IQR 30-47) years who responded at a median of 16 (IQR 12-20) days from infection onset to the time of the survey. Cough was the most common symptom, occurring in 91.7% of participants, followed by fever, fatigue, and nasal congestion (68.8%-87.4%). The median cough visual analog scale (VAS) score was 70 (IQR 50-80) mm. Being female (odds ratio [OR] 1.31, 95% CI 1.20-1.43), having a COVID-19 vaccination history (OR 1.71, 95% CI 1.37-2.12), current smoking (OR 0.48, 95% CI 0.41-0.58), chronic cough (OR 2.04, 95% CI 1.69-2.45), coronary heart disease (OR 1.71, 95% CI 1.17-2.52), asthma (OR 1.22, 95% CI 1.02-1.46), and gastroesophageal reflux disease (GERD) (OR 1.21, 95% CI 1.01-1.45) were independent factors for severe cough (VAS>70, 37.4%). Among all respondents, 35.0% indicated having a productive cough, which was associated with risk factors of being female (OR 1.44, 95% CI 1.31-1.57), having asthma (OR 1.84, 95% CI 1.52-2.22), chronic cough (OR 1.44, 95% CI 1.19-1.74), and GERD (OR 1.22, 95% CI 1.01-1.47). Persistent cough (>3 weeks) occurred in 13.0% of individuals, which was associated with the risk factors of having diabetes (OR 2.24, 95% CI 1.30-3.85), asthma (OR 1.70, 95% CI 1.11-2.62), and chronic cough (OR 1.97, 95% CI 1.32-2.94). CONCLUSIONS: Cough is the most common symptom in nonhospitalized individuals with Omicron SARS-CoV-2 variant infection. Being female, having asthma, chronic cough, GERD, coronary heart disease, diabetes, and a COVID-19 vaccination history emerged as independent factors associated with severe cough, productive cough, and persistent cough.

Sputum Transcriptomics Reveals FCN1+ Macrophage Activation in Mild Eosinophilic Asthma Compared to Non-Asthmatic Eosinophilic Bronchitis.

PURPOSE: Eosinophilic asthma (EA) and non-asthmatic eosinophilic bronchitis (EB) share similar eosinophilic airway inflammation. Unlike EA, EB did not present airway hyperresponsiveness or airflow obstruction. We aimed to compare the mechanism underlying the different manifestations between EA and EB via sputum transcriptomics analysis. METHODS: Induced-sputum cells from newly physician-diagnosed EA, EB patients, and healthy controls (HCs) were collected for RNA sequencing. RESULTS: Bulk RNA sequencing was performed using sputum cells from patients with EA (n = 18), EB (n = 15) and HCs (n = 28). Principal component analysis revealed similar gene expression patterns in EA and EB. The most differentially expressed genes in EB compared with HC were also shared by EA, including IL4, IL5 IL13, CLC, CPA3, and DNASE1L3. However, gene set enrichment analysis showed that the signatures regulating macrophage activation were enriched in EA compared to EB. Sputum cells were profiled using single-cell RNA sequencing. FABP4+ macrophages, SPP1+ macrophages, FCN1+ macrophages, dendritic cells, T cells, B cells, mast cells, and epithelial cells were identified based on gene expression profiling. Analysis of cell-cell communication revealed that interactions between FCN1+ macrophages and other cells were higher in EA than in EB. A wealth of transforming growth factor beta (TGF-ß) and vascular endothelial growth factor (VEGF) interactions between FCN1+ macrophages and other cells have been shown in EA. The gene expression levels of EREG, TGFBI, and VEGFA in FCN1+ macrophages of EA were significantly higher than those of EB. Furthermore, signatures associated with the response to TGF-ß, cellular response to VEGF stimulus and developmental cell growth were enriched in FCN1+ macrophages of EA compared to those of EB. CONCLUSIONS: FCN1+ macrophage activation associated with airway remodeling processes was upregulated in EA compared to that in EB, which may contribute to airway hyperresponsiveness and airflow obstruction.

Identification of cough-variant asthma phenotypes based on clinical and pathophysiologic data.

BACKGROUND: Cough-variant asthma (CVA) may respond differently to antiasthmatic treatment. There are limited data on the heterogeneity of CVA. OBJECTIVE: We aimed to classify patients with CVA using cluster analysis based on clinicophysiologic parameters and to unveil the underlying molecular pathways of these phenotypes with transcriptomic data of sputum cells. METHODS: We applied k-mean clustering to 342 newly physician-diagnosed patients with CVA from a prospective multicenter observational cohort using 10 prespecified baseline clinical and pathophysiologic variables. The clusters were compared according to clinical features, treatment response, and sputum transcriptomic data. RESULTS: Three stable CVA clusters were identified. Cluster 1 (n = 176) was characterized by female predominance, late onset, normal lung function, and a low proportion of complete resolution of cough (60.8%) after antiasthmatic treatment. Patients in cluster 2 (n = 105) presented with young, nocturnal cough, atopy, high type 2 inflammation, and a high proportion of complete resolution of cough (73.3%) with a highly upregulated coexpression gene network that related to type 2 immunity. Patients in cluster 3 (n = 61) had high body mass index, long disease duration, family history of asthma, low lung function, and low proportion of complete resolution of cough (54.1%). TH17 immunity and type 2 immunity coexpression gene networks were both upregulated in clusters 1 and 3. CONCLUSION: Three clusters of CVA were identified with different clinical, pathophysiologic, and transcriptomic features and responses to antiasthmatics treatment, which may improve our understanding of pathogenesis and help clinicians develop individualized cough treatment in asthma.

Predictive value of clinical features for anti-reflux therapy response in suspected gastroesophageal reflux-induced chronic cough.

Background: Not all gastroesophageal reflux-induced cough (GERC) patients respond to anti-reflux treatment. It is not certain whether reflux-related symptoms or other clinical characteristics could indicate a successful response to anti-reflux treatment. In this study, we aimed to investigate the relationship between clinical features and anti-reflux response. Methods: We retrospectively analyzed the clinical characteristics of suspected GERC who had reflux-related symptoms or reflux evidence based on abnormal 24-hour esophageal pH value monitoring, or who had no evidence of other common causes of chronic cough in our chronic cough database with a standard case report form. All patients experienced anti-reflux treatment with proton pump inhibitors (PPIs) plus prokinetic agents for at least 2 weeks and were divided into responders and non-responders based on the treatment response. Results: Among 241 patients with suspected GERC, 146 (60.6%) showed a successful response. There was no significant difference in regard to the proportion of reflux-related symptoms, and results of 24-hour esophageal pH value monitoring between responders and non-responders. Compared with non-responders, responders had higher proportions of nasal itching (21.2% vs. 8.4%; P=0.014), tickle in the throat (51.4% vs. 35.8%; P=0.025) and lower proportion of pharyngeal foreign body sensation (32.9% vs. 54.7%; P=0.001). Multivariate analysis showed that nasal itching [hazard ratio (HR): 1.593, 95% confidence interval (CI): 1.025-2.476, P=0.039], tickle in the throat (HR: 1.605, 95% CI: 1.152-2.238, P=0.005), pharyngeal foreign body sensation (HR: 0.499, 95% CI: 0.346-0.720, P<0.001) and sensitivity to at least one cough trigger (HR: 0.480, 95% CI: 0.237-0.973, P=0.042) were associated with the therapeutic response. Conclusions: Over half of suspected GERC patients benefited from anti-reflux therapy. A few clinical features rather than reflux-related symptoms might indicate a response to anti-reflux treatment. Further study is needed for the predictive value.

Electrophysiological effects of BDNF and TrkB signaling at type-identified diaphragm neuromuscular junctions.

Previous studies show that synaptic quantal release decreases during repetitive stimulation, i.e., synaptic depression. Neurotrophin brain-derived neurotrophic factor (BDNF) enhances neuromuscular transmission via activation of tropomyosin-related kinase receptor B (TrkB). We hypothesized that BDNF mitigates synaptic depression at the neuromuscular junction and that the effect is more pronounced at type IIx and/or IIb fibers compared to type I or IIa fibers given the more rapid reduction in docked synaptic vesicles with repetitive stimulation. Rat phrenic nerve-diaphragm muscle preparations were used to determine the effect of BDNF on synaptic quantal release during repetitive stimulation at 50 Hz. An ∼40% decline in quantal release was observed during each 330-ms duration train of nerve stimulation (intratrain synaptic depression), and this intratrain decline was observed across repetitive trains (20 trains at 1/s repeated every 5 min for 30 min for 6 sets). BDNF treatment significantly enhanced quantal release at all fiber types (P < 0.001). BDNF treatment did not change release probability within a stimulation set but enhanced synaptic vesicle replenishment between sets. In agreement, synaptic vesicle cycling (measured using FM4-64 fluorescence uptake) was increased following BDNF [or neurotrophin-4 (NT-4)] treatment (∼40%; P < 0.05). Conversely, inhibiting BDNF/TrkB signaling with the tyrosine kinase inhibitor K252a and TrkB-IgG (which quenches endogenous BDNF or NT-4) decreased FM4-64 uptake (∼34% across fiber types; P < 0.05). The effects of BDNF were generally similar across all fiber types. We conclude that BDNF/TrkB signaling acutely enhances presynaptic quantal release and thereby may serve to mitigate synaptic depression and maintain neuromuscular transmission during repetitive activation.NEW & NOTEWORTHY Neurotrophin brain-derived neurotrophic factor (BDNF) enhances neuromuscular transmission via activation of tropomyosin-related kinase receptor B (TrkB). Rat phrenic nerve-diaphragm muscle preparations were used to determine the rapid effect of BDNF on synaptic quantal release during repetitive stimulation. BDNF treatment significantly enhanced quantal release at all fiber types. BDNF increased synaptic vesicle cycling (measured using FM4-64 fluorescence uptake); conversely, inhibiting BDNF/TrkB signaling decreased FM4-64 uptake.

Novel regenerative drug, SPG302 promotes functional recovery of diaphragm muscle activity after cervical spinal cord injury.

Spinal cord hemisection at C2 (C2 SH), sparing the dorsal column is widely used to investigate the effects of reduced phrenic motor neuron (PhMN) activation on diaphragm muscle (DIAm) function, with reduced DIAm activity on the injured side during eupnoea. Following C2 SH, recovery of DIAm EMG activity may occur spontaneously over subsequent days/weeks. Various strategies have been effective at improving the incidence and magnitude of DIAm recovery during eupnoea, but little is known about the effects of C2 SH on transdiaphragmatic pressure (Pdi ) during other ventilatory and non-ventilatory behaviours. We employ SPG302, a novel type of pegylated benzothiazole derivative, to assess whether enhancing synaptogenesis (i.e., enhancing spared local connections) will improve the incidence and the magnitude of recovery of DIAm EMG activity and Pdi function 14 days post-C2 SH. In anaesthetised Sprague-Dawley rats, DIAm EMG and Pdi were assessed during eupnoea, hypoxia/hypercapnia and airway occlusion prior to surgery (C2 SH or sham), immediately post-surgery and at 14 days post-surgery. In C2 SH rats, 14 days of DMSO (vehicle) or SPG302 treatments (i.p. injection) occurred. At the terminal experiment, maximum Pdi was evoked by bilateral phrenic nerve stimulation. We show that significant EMG and Pdi deficits are apparent in C2 SH compared with sham rats immediately after surgery. In C2 SH rats treated with SPG302, recovery of eupneic, hypoxia/hypercapnia and occlusion DIAm EMG was enhanced compared with vehicle rats after 14 days. Treatment with SPG302 also ameliorated Pdi deficits following C2 SH. In summary, SPG302 is an exciting new therapy to explore for use in spinal cord injuries. KEY POINTS: Despite advances in our understanding of the effects of cervical hemisection (C2 SH) on diaphragm muscle (DIAm) EMG activity, very little is understood about the impact of C2 SH on the gamut of ventilatory and non-ventilatory transdiaphragmatic pressures (Pdi ). Recovery of DIAm activity following C2 SH is improved using a variety of approaches, but very few pharmaceuticals have been shown to be effective. One way of improving DIAm recovery is to enhance the amount of latent local spared connections onto phrenic motor neurons. A novel pegylated benzothiazole derivative enhances synaptogenesis in a variety of neurodegenerative conditions. Here, using a novel therapeutic SPG302, we show that 14 days of treatment with SPG302 ameliorated DIAm EMG and Pdi deficits compared with vehicle controls. Our results show that SPG302 is a compound with very promising potential for use in improving functional outcomes post-spinal cord injury.

Clinical characteristics of protracted bacterial bronchitis in adults.

There are few data regarding adult protracted bacterial bronchitis (PBB). This study aimed to delineate the clinical features of PBB and evaluate their potential diagnostic value in adults. We recruited 55 adult patients with PBB and selected randomly 220 patients with non-PBB as control. A diagnosis of PBB was considered if patients had a cough lasting ≥3 weeks, no abnormalities of chest computed tomography, positive bacterial culture in sputum and/or response well to oral moxifloxacin for 1-4 weeks. The clinical manifestations and laboratory investigations were compared between PBB patients and non-PBB patients. Of the 55 patients with PBB, approximately three-fifths (34, 61.8%) were females with a median age of 46.0 years, which were similar to that of patients with non-PBB. We observed a shorter cough duration in PBB than non-PBB (median 3.0 versus 24.0 months, p < 0.001). Compared to non-PBB patients, PBB patients had higher incidences of productive cough, yellow phlegm and a sensation of mucus in the throat (SMIT) (all p < 0.001). Sputum neutrophils and lymphocytes were markedly elevated in PBB patients than non-PBB patients (both p = 0.004). Bacterial pathogens were detected in eight (28.6%) of 28 cases with PBB. The multivariate analyses showed yellow phlegm, productive cough, SMIT, increased sputum lymphocytes (≥2.3%) and cough duration ≤8.5 months with moderate sensitivity (50.9-81.8%) and moderate-high specificity (60.5-94.4%) for determining PBB. In summary, adults with PBB are characterized by productive cough, yellow phlegm, SMIT and neutrophilic airway inflammation. These cough features and increased sputum lymphocytes may be useful to indicate PBB.

Clinical characteristics in adult patients with somatic cough syndrome.

OBJECTIVE: The data in regard of the clinical characteristics and diagnosis of somatic cough syndrome in adults were limited. The aim of this study was to fill that gap. METHODS: This was a retrospective analysis of patients with somatic cough syndrome. We described clinical characteristics of adult patients with somatic cough syndrome. RESULTS: Twenty-three somatic cough syndrome patients were identified in 543 adult patients with chronic cough. Psychiatric disorder of these patients was identified as anxiety (n = 8), obsessive-compulsive (n = 7), somatoform (n = 6), depression (n = 3), and cognitive bias (n = 1). Twelve patients showed abnormal results of investigations related with common causes of chronic cough, including gastroesophageal reflux, sputum eosinophilia, bronchial hyper-responsiveness, or signs of sinusitis but did not respond to the treatments directed to those conditions. All these patients were ever misdiagnosed as other causes of chronic cough. Compared to 520 non-somatic cough syndrome patients, patients with somatic cough syndrome were younger (32 (29.0-43.0) vs 42.0 (32.0-55.0) years, p = 0.013), longer disease duration (48.0 (19.5-102.0) vs 24.0 (9.0-72.0) months, p = 0.037), more common in dry cough (100% vs 57.6%, p < 0.001), and lower proportion of nocturnal cough (13.0% vs 40.2%, p = 0.009). Common cold (60.9%) was the most common initial trigger of cough and itchy throat (60.9%) was the most common accompanying symptom in patients with somatic cough syndrome. Notably, there were similar distribution in cough triggers and accompanying symptoms between two groups. CONCLUSION: In spite of much higher proportion of dry cough and smaller proportion of nocturnal cough, adult patients with somatic cough syndrome show similar clinical characteristics with other chronic cough patients, in regard of cough triggers, accompanying symptoms as well as abnormal results of investigations, which should be an important reason for misdiagnosis of somatic cough syndrome. Psychiatric disorder should be addressed in clinical management of chronic cough.

Prevalence and risk factors for postinfectious cough in discharged patients with coronavirus disease 2019 (COVID-19).

Background: Cough is one of the most common symptoms of coronavirus disease 2019 (COVID-19). However, the prevalence of persistent cough in recovered patients with COVID-19 during a longer follow-up remained unknown. This study aims to investigate the prevalence, and risk factors for postinfectious cough in COVID-19 patients after discharge. Methods: We conducted a follow-up study for 129 discharged patients with laboratory-confirmed COVID-19 in two large hospitals located in Hubei Province, China from January 2020 to December 2020. Baseline demographics, comorbidities and smoking history were extracted from the medical record. Current symptoms and severity were recorded by a uniform questionnaire. Spirometry, diffuse function and chest computed tomography (CT) were performed on part of patients who were able to return to the outpatient department at follow-up. Results: The median (interquartile range) follow-up time was 8.1 (7.9-8.5) months after discharge. The mean (standard deviation) age was 51.5 (14.9) years and 57 (44.2%) were male. A total of 27 (20.9%) patients had postinfectious cough (>3 weeks), 6 patients (4.7%) had persistent cough by the end of follow-up, including 3 patients with previous chronic respiratory diseases or current smoking. Other symptoms included dyspnea (6, 4.7%), sputum (4, 3.1%), fatigue (4, 3.1%), and anorexia (4, 3.1%) by the end of follow-up. Thirty-six of 41 (87.8%) patients showed impaired lung function or diffuse function, and 39 of 50 (78.0%) patients showed abnormal CT imaging. Patients with postinfectious cough demonstrated more severe and more frequent cough during hospitalization (P<0.001), and more chronic respiratory diseases (P=0.01). In multivariate logistic regression analysis, digestive symptoms during hospitalization [odds ratio (OR) 2.95, 95% confidence interval (CI): 1.10-7.92] and current smoking (OR 6.95, 95% CI: 1.46-33.14) were significantly associated with postinfectious cough of COVID-19. Conclusions: A small part of patients developed postinfectious cough after recovery from COVID-19, few patients developed chronic cough in spite of a higher proportion of impaired lung function and abnormal lung CT image. Current smoking and digestive symptoms during hospitalization were risk factors for postinfectious cough in COVID-19.

Diaphragm muscle function in a mouse model of early-onset spasticity.

Spasticity is a common symptom in many developmental motor disorders, including spastic cerebral palsy (sCP). In sCP, respiratory dysfunction is a major contributor to morbidity and mortality, yet it is unknown how spasticity influences respiratory physiology or diaphragm muscle (DIAm) function. To investigate the influence of spasticity on DIAm function, we assessed in vivo transdiaphragmatic pressure (Pdi - measured using intraesophageal and intragastric pressure catheters under conditions of eupnea, hypoxia/hypercapnia and occlusion) including maximum Pdi (Pdimax via bilateral phrenic nerve stimulation), ex vivo DIAm-specific force and fatigue (using muscle strips stimulated with platinum plate electrodes), and type-specific characteristics of DIAm fiber cross sections (using immunoreactivity against myosin heavy chain slow and 2A) in spa and wildtype mice. Spa mice show reduced Pdimax, reduced DIAm specific force, and altered fatigability and atrophy of type IIx/IIb fibers. These findings suggest marked DIAm dysfunction may underlie the respiratory phenotype of sCP.NEW & NOTEWORTHY Developmental motor control dysfunctions, including spastic cerebral palsy (sCP) often have respiratory components. Spa mutant mice exhibit a spastic phenotype closely resembling sCP symptoms. Using the spa mouse model of spastic cerebral palsy (sCP), we quantified transdiaphragmatic pressure deficits, diaphragm muscle weakness, and fiber type-specific atrophy, improving our understanding of respiratory dysfunctions in sCP.

Cervical spinal hemisection alters phrenic motor neuron glutamatergic mRNA receptor expression.

Upper cervical spinal cord injuries (SCI) disrupt descending inputs to phrenic motor neurons (PhMNs), impairing respiratory function. Unilateral spinal hemisection at C2 (C2SH) results in loss of ipsilateral rhythmic diaphragm muscle (DIAm) EMG activity associated with lower force behaviors accomplished by recruitment of smaller PhMNs in rats. Activity during higher force, non-ventilatory behaviors that recruit larger PhMNs is minimally impaired following C2SH. We previously showed neuroplasticity in glutamatergic receptor expression in PhMN post-C2SH with changes in NMDA receptor expression reflecting functional recovery over time. We hypothesize that C2SH-induced changes in glutamatergic receptor (AMPA and NMDA) mRNA expression in PhMNs vary with motor neuron size, with more pronounced changes in smaller PhMNs. Retrogradely-labelled PhMNs were classified in tertiles according to somal surface area and mRNA expression was measured using single-cell, multiplex fluorescence in situ hybridization. Ipsilateral to C2SH, a pronounced reduction in NMDA mRNA expression in PhMNs was evident at 3 days post-injury with similar impact on PhMNs in the lower size tertile (~68% reduction) and upper tertile (~60%); by 21 days, there was near complete restoration of NMDA receptor mRNA expression across all PhMNs. There were no changes in NMDA mRNA expression contralateral to C2SH. There were no changes in AMPA mRNA expression at PhMNs on either side of the spinal cord or at any time-point post-C2SH. In summary, following C2SH there is ipsilateral reduction in PhMN NMDA mRNA expression at 3 days that is not limited to smaller PhMN recruited in the generation of lower force ventilatory behaviors. The recovery of NMDA mRNA expression by 21 days post-C2SH is consistent with evidence of spontaneous recovery of ipsilateral DIAm activity at this timepoint. These findings suggest a possible role for NMDA receptor mediated glutamatergic signaling in mechanisms supporting postsynaptic neuroplasticity at the PhMN pool and recovery of DIAm activity after cervical SCI.

Acute intrathecal BDNF enhances functional recovery after cervical spinal cord injury in rats.

Unilateral C2 hemisection (C2SH) disrupts descending inspiratory-related drive to phrenic motor neurons and thus, silences rhythmic diaphragm muscle (DIAm) activity. There is gradual recovery of rhythmic DIAm EMG activity over time post-C2SH, consistent with neuroplasticity, which is enhanced by chronic (2 wk) intrathecal BDNF treatment. In the present study, we hypothesized that acute (30 min) intrathecal BDNF treatment also enhances recovery of DIAm EMG activity after C2SH. Rats were implanted with bilateral DIAm EMG electrodes to verify the absence of ipsilateral eupneic DIAm EMG activity at the time of C2SH and at 3 days post-C2SH. In those animals displaying no recovery of DIAm EMG activity after 28 days (n = 7), BDNF was administered intrathecally (450 mcg) at C4. DIAm EMG activity was measured continuously both before and for 30 min after BDNF treatment, during eupnea, hypoxia-hypercapnia, and spontaneous sighs. Acute BDNF treatment restored eupneic DIAm EMG activity in all treated animals to an amplitude that was 78% ± 9% of pre-C2SH root mean square (RMS) (P < 0.001). In addition, acute BDNF treatment increased DIAm RMS EMG amplitude during hypoxia-hypercapnia (P = 0.023) but had no effect on RMS EMG amplitude during sighs. These results support an acute modulatory role of BDNF signaling on excitatory synaptic transmission at phrenic motor neurons after cervical spinal cord injury.NEW & NOTEWORTHY Brain-derived neurotrophic factor (BDNF) plays an important role in promoting neuroplasticity following unilateral C2 spinal hemisection (C2SH). BDNF was administered intrathecally in rats displaying lack of ipsilateral inspiratory-related diaphragm (DIAm) EMG activity after C2SH. Acute BDNF treatment (30 min) restored eupneic DIAm EMG activity in all treated animals to 78% ± 9% of pre-C2SH level. In addition, acute BDNF treatment increased DIAm EMG amplitude during hypoxia-hypercapnia but had no effect on EMG amplitude during sighs.

The spectrum, clinical features and diagnosis of chronic cough due to rare causes.

BACKGROUND: Chronic cough has many diverse causes, including common and uncommon causes. There are few comprehensive reports on rare causes of chronic cough. The purpose of this study is to determine the etiological distribution, clinical features, and diagnostic value of special examinations in patients with rare causes of chronic cough. METHODS: A retrospective analysis of patients with chronic cough who underwent medical history taking, full examination, and etiological treatment over a 13-year period was conducted. Causes of chronic cough with a prevalence of less than 3% were defined as rare causes. RESULTS: A total of 1,554 patients were enrolled, and 39 causes of chronic cough were identified. Among them, 1,055 cases were due to common causes, whereas 235 cases were due to rare causes; the causes involved 7 bodily systems. The top five rare causes were protracted bacterial bronchitis, somatic cough syndrome, diffuse panbronchiolitis, obstructive sleep apnea syndrome (OSAS), and interstitial lung disease, accounting for 67.2% of all rare causes. Among 235 patients with rare causes, causes in 90 (38.3%) patients were detected by chest high-resolution computed tomography (HRCT), in 44 (18.7%) patients by bronchoscopy/nasopharyngoscopy, and in 21 (8.9%) patients by pulmonary spirometry and diffusing capacity testing. CONCLUSIONS: Among the 31 rare causes of chronic cough in this cohort, the top five were protracted bacterial bronchitis, somatic cough syndrome, diffuse panbronchiolitis, OSAS, and interstitial lung disease. Special examinations, such as chest HRCT and bronchoscopy, should be considered after excluding common causes of chronic cough.

Clinical and Inflammatory Characteristics of the Chinese APAC Cough Variant Asthma Cohort.

BACKGROUND: The AtyPical Asthma in China (APAC) cohort is a multi-center prospective, observational cohort set-up to investigate the clinical, pathophysiological features, prognosis, and mechanisms of cough variant asthma (CVA). OBJECTIVES: To present the characteristics of newly physician-diagnosed adults with CVA (n = 328) compared to mild-moderate classic asthma (CA, n = 206). METHODS AND MAIN RESULTS: CVA subjects showed a higher proportion of female (67.1 vs. 55.3%, P = 0.0084), abnormal laryngopharyngeal sensations (71 vs. 51%, p < 0.0001) than CA, but presented with near normal spirometry and higher methacholine PD20-FEV1 values [4.2 (1, 8.6) vs. 0.8 (0.4, 4.7), P < 0.0001]. Lower fractional exhaled nitric oxide (FENO) levels [38.5 (19.8, 72.5) vs. 53. (28.5, 92.2), P = 0.0019], blood eosinophil counts [0.2 (0.1, 0.4) vs. 0.3 (0.2, 0.5), P = 0.0014], and sputum eosinophils [2.3 (0.3, 8.0) vs. 12.2 (2, 34.5), p < 0.0001] were found in CVA. Despite lower total serum IgE levels in CVA, there was similar proportion of atopy in both groups. The prevalence of cough in CA was 86.4%, while CVA reported more severe cough on Visual Analog Scale, Cough Evaluation Test, and Leicester Cough Questionnaire, similar anxiety and depression scores but better asthma control scores as reflected by Asthma Control Test compared to CA. No correlation was found between cough assessment outcomes and sputum eosinophil count, blood eosinophil count, FENO, spirometry variables, or PD20-FEV1. CONCLUSION: Cough variant asthma is distinctive from classic asthma in regard to clinical features, lung function, and airway inflammation. Quality of life is badly impaired as well in spite of better asthma control scores.

The Predicative Clinical Features Associated with Chronic Cough That Has a Single Underlying Cause.

BACKGROUND: Few studies have investigated the usefulness of the clinical characteristics of cough in the diagnosis of chronic cough. OBJECTIVE: To evaluate the diagnostic value of clinical characteristics and concomitant symptoms of chronic cough in predicting its cause. METHODS: We recruited adult patients with chronic cough as a primary presenting symptom and identified those with a single underlying cause. Clinical features of cough were recorded with a custom-designed questionnaire and the relationships between clinical features and cause of cough were analyzed. RESULTS: A total of 1162 patients with a single underlying cause were enrolled. Nocturnal cough alone was a predictor of cough variant asthma (odds ratio [OR], 2.037; 95% CI, 1.003-4.139) with high specificity (97.6%) and low sensitivity (8.1%). Heartburn (OR, 2.671; 95% CI, 1.544-4.620), belching (OR, 2.536; 95% CI, 1.620-3.971), and acid regurgitation (OR, 2.043; 95% CI, 1.299-3.212) indicated gastroesophageal reflux-related cough with high specificity (85.5%-94.9%) and low sensitivity (22.8%-40.7%). Cough after meals had a high specificity (91.2%) and a low sensitivity (24.8%) for gastroesophageal reflux-related cough. Postnasal dripping (OR, 2.317; 95% CI, 1.425-3.767) and history of sinusitis (OR, 4.137; 95% CI, 2.483-6.892) were indicators for upper airway cough syndrome with high specificity (80.8% and 90.2%, respectively). Rhinitis/sinusitis-related symptoms showed moderate sensitivity (72.9%); however, they showed mild specificity (46.1%) for upper airway cough syndrome. CONCLUSIONS: Cough timing, several concomitant symptoms associated with gastroesophageal reflux or rhinitis/sinusitis, and medical history are useful to indicate common causes of chronic cough.