PubMed Health⌕ Search

Biomedical subjects

Alyn H Morice

Publications and source records attributed to Alyn H Morice.

At least 19 recordsLinked to original sources
PubMed2026

The Genetic Architecture of Chronic Cough: From Sensory Hypersensitivity to Treatable Trait.

Chronic cough is a prevalent global clinical disorder with substantial quality-of-life impairment, and refractory cases remain a major unmet medical need. Cough hypersensitivity syndrome is the core pathological mechanism of chronic cough, and growing genetic evidence has confirmed that inherited susceptibility shapes cough hypersensitivity, clinical heterogeneity and therapeutic responsiveness, redefining chronic cough as a biologically mediated sensory-neural disorder rather than a non-specific secondary symptom of airway diseases. This review summarises genetic evidence for chronic cough from family-based studies, pharmacogenomics and genome-wide association studies (GWAS), revealing distinct genetic architectures of chronic dry cough and sputum production, with enrichment of sensory-neural pathway variants and key genetic loci such as replication factor C subunit 1 (RFC1) functional genomic analyses link genetic variation to vagal afferent excitability, and rare genetic neurological disorders further illuminate the neurogenic basis of cough hypersensitivity. Moreover, genetic insights identify tractable treatable traits and rationalise antitussive drug development, supporting genotype-guided patient stratification. We conclude that integrating genetic architecture into clinical phenotyping and translational research provides a critical framework for precision management of chronic cough, and future progress relies on harmonised deep phenotyping and multi-ancestry genetic studies.

RFC1 gene↗
PubMed2006

Inflammatory mediators modulate thrombin and cathepsin-G signaling in human bronchial fibroblasts by inducing expression of proteinase-activated receptor-4.

Human lung fibroblasts express proteinase-activated receptor-1 (PAR1), PAR2 and PAR3, but not PAR4. Because PAR2 has inflammatory effects on human primary bronchial fibroblasts (HPBF), we asked 1) whether the inflammatory mediators TNF-alpha and LPS could modify HPBF PAR expression and 2) whether modified PAR expression altered HPBF responsiveness to PAR agonists in terms of calcium signaling and cell growth. TNF-alpha and LPS induced PAR4 mRNA expression (RT-PCR) at 6 h and 24 h, respectively. TNF-alpha and LPS also upregulated PAR2 mRNA expression with similar kinetics but had negligible effect on PAR1 and PAR3. Flow cytometry for PAR1, PAR2, and PAR3 also demonstrated selective PAR2 upregulation in response to TNF-alpha and LPS. Intracellular calcium signaling to SLIGKV-NH2 (a selective PAR2-activating peptide; PAR2-AP) and AYPGQV-NH2 (PAR4-AP) revealed that TNF-alpha and LPS induced maximal responses to these PAR agonists at 24 h and 48 h, respectively. Upregulation of PAR2 by TNF-alpha heightened HPBF responses to trypsin, while PAR4 induction enabled cathepsin-G-mediated calcium signaling. Cathepsin-G also disarmed PAR1 and PAR2 in HPBF, while tryptase disarmed PAR2. Induction of PAR4 also enabled thrombin to elicit a calcium signal through both PAR1 and PAR4, as determined by a desensitization assay. In cell growth assays the PAR4 agonists cathepsin-G and AYPGQV-NH2 reduced HPBF cell number only in TNF-alpha-treated HPBF. Moreover, the mitogenic effect of thrombin (a PAR1/PAR4 agonist) but not the PAR1-AP TFLLR-NH2, was ablated in TNF-alpha-treated HPBF. These findings point to an important mechanism, whereby cellular responses to thrombin and cathepsin-G can be modified during an inflammatory response.

Bronchi↗
PubMed2006

Opiate therapy in chronic cough.

RATIONALE: Cough is the most common complaint for which medical attention is sought, and chronic cough can be both physically and mentally debilitating. There is currently no evidence supporting the use of antitussives in chronic treatment-resistant cough. OBJECTIVES: We tested the hypothesis that morphine sulfate in the dose of 5 mg twice daily would bring about a reduction in cough frequency and severity in patients failing to respond to specific measures. METHODS: Patients recruited from the Hull Cough Clinic were enrolled into a randomized double-blind placebo-controlled study using 4 weeks of slow-release morphine sulfate and a corresponding period of matched placebo. An open-labeled extension of the core study allowed dose escalation to 10 mg twice daily. Cough was assessed using the Leicester Cough Questionnaire, daily symptom diary, and citric acid cough challenge. RESULTS: Twenty-seven patients completed the core study. A significant improvement of 3.2 points over baseline was noted on the Leicester Cough Questionnaire (p < 0.01). A rapid and highly significant reduction by 40% in daily cough scores was noted among patients on slow-release morphine sulfate (p < 0.01). Objective testing of the cough reflex using citric acid cough challenge tests did not show any significant changes. Eighteen patients continued into the extension study. Two-thirds of these patients opted to increase the morphine to 10 mg twice daily. At the end of 3 months, there was a similar improvement in cough between the 5- and 10-mg groups. CONCLUSION: Morphine sulfate is an effective antitussive in intractable chronic cough at the doses of 5 to 10 mg twice daily.

Analgesics, Opioid↗
PubMed2006

Comparable long-term safety and efficacy of a novel budesonide/formoterol pressurized metered-dose inhaler versus budesonide/formoterol Turbuhaler in adolescents and adults with asthma.

Budesonide/formoterol in one inhaler is an established therapy for asthma and chronic obstructive pulmonary disease. The long-term safety and efficacy profile of a novel hydrofluoroalkane (HFA) pressurized metered-dose inhaler (pMDI) formulation of budesonide/formoterol was compared with that of budesonide/formoterol in a dry powder inhaler (DPI; Turbuhaler). This multinational, 52-week, randomized, open, parallel-group study included patients aged > or = 12 years with asthma who had a forced expiratory volume in 1s (FEV1)> or = 50% of predicted normal; all patients used inhaled corticosteroids (400-1200 microg/day) and needed additional short-acting beta 2-agonist therapy. Patients were randomized to receive budesonide/formoterol pMDI or DPI 160/4.5 microg, two inhalations twice daily. Safety endpoints included assessment of adverse events and laboratory parameters. Efficacy endpoints included change from baseline in FEV1 and time to first severe asthma exacerbation. Overall, 673 patients (446pMDI, 227DPI) were included. There were no clinically significant differences between treatment groups in the nature, incidence or severity of adverse events or laboratory parameters. The number of patients experiencing adverse events was comparable in the pMDI (332/446 [74%]) and DPI (175/227 [77%]) groups; the most commonly reported adverse event was upper respiratory tract infection. The proportion of patients discontinuing as a result of adverse events was low in both groups (pMDI 12/446 [3%], DPI 2/227 [1%]). Lung function was improved to a similar extent in both groups and there was no detectable difference in time to first severe asthma exacerbation. The novel HFA pMDI formulation of budesonide/formoterol is an equally well tolerated and effective treatment for adults and adolescents with asthma as the budesonide/formoterol DPI.

Adolescent↗
PubMed2006

The automatic recognition and counting of cough.

BACKGROUND: Cough recordings have been undertaken for many years but the analysis of cough frequency and the temporal relation to trigger factors have proven problematic. Because cough is episodic, data collection over many hours is required, along with real-time aural analysis which is equally time-consuming. A method has been developed for the automatic recognition and counting of coughs in sound recordings. METHODS: The Hull Automatic Cough Counter (HACC) is a program developed for the analysis of digital audio recordings. HACC uses digital signal processing (DSP) to calculate characteristic spectral coefficients of sound events, which are then classified into cough and non-cough events by the use of a probabilistic neural network (PNN). Parameters such as the total number of coughs and cough frequency as a function of time can be calculated from the results of the audio processing. Thirty three smoking subjects, 20 male and 13 female aged between 20 and 54 with a chronic troublesome cough were studied in the hour after rising using audio recordings. RESULTS: Using the graphical user interface (GUI), counting the number of coughs identified by HACC in an hour long recording, took an average of 1 minute 35 seconds, a 97.5% reduction in counting time. HACC achieved a sensitivity of 80% and a specificity of 96%. Reproducibility of repeated HACC analysis is 100%. CONCLUSION: An automated system for the analysis of sound files containing coughs and other non-cough events has been developed, with a high robustness and good degree of accuracy towards the number of actual coughs in the audio recording.

Journal Article↗
PubMed2006

Adrenal axis suppression unrelated to the dynamics of dosing with beclomethasone monopropionate.

AIMS: Inhaled corticosteroids (ICS) are the cornerstone of asthma treatment. At high doses they can give rise to systemic side-effects such as hypothalamic-pituitary-adrenal (HPA) axis suppression. This effect may depend on the delivery system, which in turn alters drug deposition and adsorption. We hypothesized that adrenal suppression depends on the rate of steroid absorption rather than the total steroid dose received. METHODS: Eight healthy adult males were recruited for a randomized double-blind placebo controlled trial. Adrenocortical suppression ability was demonstrated by a 30% suppression of early morning cortisol following 1 mg dexamethasone. Subjects then attended in the evening on two occasions receiving 500 microg of intravenous beclomethasone monopropionate (17-BMP) for either 15 min or 2 h. Overnight urinary cortisol : creatinine (C : C) ratio was measured before and after the infusion and an 08.00 h serum cortisol was measured following the infusion. RESULTS: Mean C : C pre and post 15 min infusion was 5.97 and 3.22 (P = 0.005). Mean C : C pre and post 2 h infusion was 6.31 and 4.15 (P = 0.004). Delta C : C and mean 08.00 h cortisol for 15 min and 2 h infusion was 2.74 and 2.16 and 425 nmol l(-1) and 400 nmol l(-1), respectively (P = NS). CONCLUSIONS: The rate of infusion of 17-BMP seemed to have little effect on the degree of adrenal suppression. Individual C : C ratios were reproducible. Differences in absorption of ICS are unlikely to explain observed differences in HPA axis suppression.

Administration, Inhalation↗
PubMed2006

Clinical history in gastroesophageal cough.

Gastroesophageal disease, a common cause of chronic cough, is often poorly recognised. We reviewed the presenting history of 47 chronic cough patients who had been proven to have gastroesophageal disease by oesophageal function testing. Fourty-seven patients (26 female), were enroled. Symptoms which were most common included: cough on phonation, on rising from bed, associated with certain foods or with eating in general. Symptoms known to be associated with laryngopharyngeal reflux, such as throat clearing, dysphonia, globus and dysphagia were also associated. Heartburn or indigestion was present in 63% of those questioned. These data show that symptoms associated with reflux in chronic coughers differ from those commonly perceived to be characteristic of classical heartburn-associated reflux. These data suggest that, contrary to previous reports, a symptom complex which is characteristic of reflux cough can be identified.

Chronic Disease↗
PubMed2006

Proteinase-activated receptor2 agonists upregulate granulocyte colony-stimulating factor, IL-8, and VCAM-1 expression in human bronchial fibroblasts.

Proteinase-activated receptors (PARs) are a novel family of G-protein-coupled receptors. PAR2 has been implicated in inflammatory airways disease. Although fibroblasts are pathologically important in the airways, the proinflammatory role of PAR2 in these cells remains unknown. We assessed PAR expression and functionality in human primary bronchial fibroblasts (HPBFs) before assessing PAR2-mediated HPBF proliferation, cytokine production, and adhesion molecule expression. RT-PCR and flow cytometry demonstrated that HPBFs express hPAR1, hPAR2, and hPAR3, but not hPAR4. Intracellular calcium signaling in HPBFs in response to PAR agonists showed that only hPAR1 and hPAR2 were functional receptors. We used the MTT assay to assess HPBF proliferation. Of the PAR2 agonist proteinases or selective PAR2-activating peptides (PAR2-APs) tested, none stimulated HPBF proliferation, whereas thrombin was a HPBF growth factor. mRNA for IL-8 and granulocyte colony-stimulating factor (G-CSF) was upregulated after addition of SLIGKV-NH2 when assessed by RT-PCR. No significant increase in G-CSF or IL-8 protein was detected. Trypsin stimulated IL-8 and G-CSF release from HPBF in a time- and dose-dependent manner. Leupeptin and soya trypsin inhibitor abrogated trypsin-stimulated cytokine release, indicating a requirement for trypsin's proteolytic activity. Trypsin and SLIGKV-NH2 stimulated an increase in VCAM-1 expression at 12 h after treatment, which declined thereafter. PAR2-driven upregulation of VCAM-1 cell surface expression and the release of IL-8 and G-CSF from bronchial fibroblasts may be important in promoting neutrophilic airways inflammation.

Bronchi↗
PubMed2006

Difficulties in the interpretation of lung function tests in the diagnosis of asthma and chronic obstructive pulmonary disease.

OBJECTIVE: To ascertain differences in the interpretation of spirometry and peak flow measurement between primary care (several practioners and nurses) and specialists in patients with a pre-existing diagnosis of asthma and chronic obstructive pulmonary disease (COPD). DESIGN: A randomized, prospective cohort study of 98 patients with a pre-existing diagnosis of asthma or COPD. Two chest specialists independently interpreted the peak flow and spirometric data and they were also blinded to the primary care results. RESULTS: There was total agreement in interpretation of the data between general practitioners and specialists in only 20 (20.4%). Levels of diagnostic agreement were highest between the two chest specialists (55%) and lowest between the general practice records and the diagnosis assigned by general practitioners (16%). Disagreement between general practitioners and the two chest specialists was consistent (38%) indicating systematic differences in interpretation. CONCLUSIONS: This study raises concerns about differences in the interpretation of spirometry and peak expiratory flow rates in general and hospital practice and the guidelines on which these interpretations are based.

Aged↗
PubMed2005

Evidence based guidelines--a step too far?

The growth of clinical guidelines has helped to improve the standard of patient care with the archetypal document being the British Thoracic Society's guidelines on asthma management. In recent years however the fashion has evolved to style guidelines according to the tenants of 'evidence based medicine'. We examine the evidence behind this fashion and conclude that there is a grave danger of bias and distortion of the data from this approach.

Asthma↗
PubMed2005

Reproducibility and validity of a Yan-style portable citric acid cough challenge.

Although many different methods of measuring cough reflex sensitivity have been published, few are simple enough to use outside of a hospital or laboratory environment. The aim of this study was to develop a simple, quick, and portable cough challenge, assess its reproducibility, and compare its results with those measured by an existing established hospital protocol. Twenty-five volunteers performed cough challenges based on an established hospital dosimeter protocol, and, on a separate occasion, by a protocol inhaling citric acid from DeVilbiss 40 hand-held nebulisers (citric acid concentrations of 10-3000 mM). Reproducibility of the hand-held cough challenge was assessed in 11 volunteers. Cough thresholds were consistently higher by the hand-held method than by the hospital dosimeter method. The geometric mean citric acid concentrations causing two coughs (threshold D2) were 3.14 and 2.77 log mM, respectively (p<0.001). The geometric mean (95% CI) difference between the tests was 0.51 log mM (0.18-0.83) of the average of the two values. Cough D2 thresholds attained by the two techniques did, however, show significant correlation (r=0.95, p<0.0001). The coefficient of repeatability for the hand-held method was 0.40 log mM. Administering citric acid from DeVilbiss 40 hand-held nebulisers offers a rapid, portable, and reproducible cough challenge in healthy volunteers. The results correlate well with an existing Mefar dosimeter challenge, but give two to three times greater cough thresholds.

Anticoagulants↗
PubMed2005

Bronchoprotection with formoterol via dry powder and metered-dose inhalers in patients with asthma.

BACKGROUND: Determination of device comparability for new inhaled medications is essential. OBJECTIVE: To evaluate the methacholine bronchoprotection afforded by formoterol, 12 microg, delivered via Clickhaler and Aerolizer dry powder inhalers and a pressurized metered-dose inhaler (pMDI) in mild-to-moderate asthmatic patients. METHODS: Two separate randomized, double-blind, double-dummy, crossover studies were performed. Peak bronchoprotection (30 minutes) was measured after administration of a single dose in a placebo-controlled study (n = 16). First-dose (8 hours) and trough (12 hours) protection were evaluated after 2 weeks (n = 28). Doubling dilution differences (DDD) in the methacholine provocation concentration that caused a decrease in forced expiratory volume in 1 second of 20% from baseline were compared, with equivalence defined if the 95% confidence interval was within the predefined equivalence limits of +/- 1.5 DDD (peak) and +/- 1.0 DDD (trough). RESULTS: For peak single-dose effects, DDD (95% confidence interval) data showed significant protection vs placebo for all devices but no significant differences among active inhalers. For trough first-dose effects, there was significant protection vs baseline for all devices and equivalence for Clickhaler vs Aerolizer (-0.41; -0.85 to 0.04) and Aerolizer vs pMDI (-0.27; -0.66 to 0.13) but not for Clickhaler vs pMDI (-0.68; -1.12 to -0.23). For trough effects after 2 weeks, there was significant residual protection from baseline and equivalence for Clickhaler vs Aerolizer (-0.32; -0.94 to 0.30), Clickhaler vs pMDI (0.34; -0.96 to 0.27), and Aerolizer vs pMDI (-0.02; -0.57 to 0.52). CONCLUSIONS: Formoterol delivered by 3 different inhalers exhibited a significant degree of peak and trough bronchoprotection after single and repeated dosing, with most comparisons being within predefined equivalence limits.

Administration, Inhalation↗
PubMed2005

Expression and characterization of the intracellular vanilloid receptor (TRPV1) in bronchi from patients with chronic cough.

TRPV1 is a modulator of noxious stimuli known to be important in the cough reflex. We have compared the expression of TRPV1 in normal human airways and those from patients with chronic cough and found that there is up regulation in airways smooth muscle in disease. This increased expression appears to be intracellular and we have therefore examined the role of intracellular rat and human TRPV1 activity was found using intracellular calcium signalling with human intracellular TRPV1 being located in a thapsigargin insensitive compartment. Increase in TRPV1 activity may have a role in the airway hypersensitivity seen in chronic cough.

Animals↗
PubMed2004

Post-nasal drip syndrome--a symptom to be sniffed at?

The syndrome or pseudo-syndrome of post-nasal drip (PNDS) represents a diagnostic label which is unhelpful in the understanding of chronic cough. There is no accepted definition of PNDS and no accepted method of measurement. The symptom of mucus dripping down the back of the throat occurs in normal subjects and is also reported by many patients in ENT clinics who do not have a cough. The lack of any clear pathological or biochemical tests makes the syndrome both a catch-all and a dustbin.

Asthma↗