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"Williams, Mark E"
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Agreement between self-reported asthma symptoms and exhaled nitric oxide levels: impact on inhaled corticosteroid prescribing in general practice. An observational study
Background
The National Review of Asthma Deaths UK highlighted that 46% of deaths could be avoided and recommended that all sufferers receive a structured asthma annual review which assess asthma control. In primary care this is commonly achieved using symptom-based questionnaires such as the Asthma Control Test (ACT). A newer method of assessing asthma control is Fractional Exhaled Nitric Oxide (FeNO) testing, which is currently recommended for the diagnosis of asthma, but not for monitoring of asthma control. The study aim was to assess the correlation between self-reported symptoms as measured by the ACT and FeNO testing and the subsequent impact of FeNO testing on prescribing of asthma medication.
Methods
A retrospective review of 65 patients who had received both ACT and FeNO testing as part of their asthma annual review. A spearman correlation was used to estimate the correlation between ACT scores and FENO levels. A χ
2
test was used to compare prompting frequency of the measures and Kendalls τ statistic was made to estimate their concordance and influence on subsequent ICS medication prescription.
Results
The mean age of the participants was 41 years (4–93 years). There was no statistically significant correlation between ACT and FeNO (ρ = 0.195, p = 0.120). The median FeNO was 26 ppb (range 8–279 ppb), and the ACT score 20 (range 5 to 25 points). Furthermore, FeNO more frequently prompts a change in medication than ACT, 66% versus 42% (p = 0.005). A low concordance between the measures was found (Kendall’s τ statistic − 0.321).
Conclusion
FeNO should be considered for monitoring of control in asthma. To balance the cost of implementing this technology into primary care a risk stratified approach could be applied to testing.
Journal Article
A Dynamic Mass Redistribution Assay for the Human Sweet Taste Receptor Uncovers G-Protein Dependent Biased Ligands
The sweet taste receptor is rather unique, recognizing a diverse repertoire of natural or synthetic ligands, with a surprisingly large structural diversity, and with potencies stretching over more than six orders of magnitude. Yet, it is not clear if different cell-based assays can faithfully report the relative potencies and efficacies of these molecules. Indeed, up to now, sweet taste receptor agonists have been almost exclusively characterized using cell-based assays developed with overexpressed and promiscuous G proteins. This non-physiological coupling has allowed the quantification of receptor activity via phospholipase C activation and calcium mobilization measurements in heterologous cells on a FLIPR system, for example. Here, we developed a novel assay for the human sweet taste receptor where endogenous G proteins and signaling pathways are recruited by the activated receptor. The effects of several sweet taste receptor agonists and other types of modulators were recorded by measuring changes in dynamic mass redistribution (DMR) using an Epic ® reader. Potency and efficacy values obtained in the DMR assay were compared to those results obtained with the classical FLIPR assay. Results demonstrate that for some ligands, the two assay systems provide similar information. However, a clear bias for the FLIPR assay was observed for one third of the agonists evaluated, suggesting that the use of non-physiological coupling may influence the potency and efficacy of sweet taste receptor ligands. Replacing the promiscuous G protein with a chimeric G protein containing the C-terminal tail 25 residues of the physiologically relevant G protein subunit Gα gustducin reduced or abrogated bias.
Journal Article
Automated plethysmographic measurement of the ankle-brachial index: a comparison with the doppler ultrasound method
The ankle-brachial index is widely regarded as a pivotal tool for the diagnosis and quantification of peripheral arterial disease. It is, however, plagued by issues relating to its time consuming nature and the skills required to undertake its measurement using the gold standard Doppler ultrasound method. Automated ankle-brachial index measurement devices aim to address such issues; this study aimed to compare the performance of such a device with the Doppler method. Three hundred and eighty participants, with risk factors for cardiovascular disease (mean age: 64, 57% male), underwent ankle-brachial index measurement firstly with a plethysmographic device followed by the Doppler method. The mean difference between the two methods was 0.016±0.1, 95% limits of agreement:±0.2. Sensitivity for detection of peripheral arterial disease, as defined by Doppler ankle-brachial index⩽0.9, was 70%, specificity 96%, accuracy 94%. A receiver operating curve revealed an area under the curve of.96, with a 1.04 plethysmographic ankle-brachial index cutoff for optimal sensitivity (98%) and specificity (75%). Automated measurements were significantly faster than Doppler measurements (7 min 55 s vs. 17 min 45 s, respectively, P <0.01). Although is it unclear if the plethysmographic device has sufficient diagnostic accuracy to be used as a stand alone test for the diagnosis of peripheral arterial disease, it is concluded that it can be used as a fast and amenable method of identifying people who require further arterial assessment; the higher cutoff point of 1.04 should be used for this purpose.
Journal Article
Voltage-gated sodium channels in taste bud cells
Background
Taste bud cells transmit information regarding the contents of food from taste receptors embedded in apical microvilli to gustatory nerve fibers innervating basolateral membranes. In particular, taste cells depolarize, activate voltage-gated sodium channels, and fire action potentials in response to tastants. Initial cell depolarization is attributable to sodium influx through TRPM5 in sweet, bitter, and umami cells and an undetermined cation influx through an ion channel in sour cells expressing PKD2L1, a candidate sour taste receptor. The molecular identity of the voltage-gated sodium channels that sense depolarizing signals and subsequently initiate action potentials coding taste information to gustatory nerve fibers is unknown.
Results
We describe the molecular and histological expression profiles of cation channels involved in electrical signal transmission from apical to basolateral membrane domains. TRPM5 was positioned immediately beneath tight junctions to receive calcium signals originating from sweet, bitter, and umami receptor activation, while PKD2L1 was positioned at the taste pore. Using mouse taste bud and lingual epithelial cells collected by laser capture microdissection, SCN2A, SCN3A, and SCN9A voltage-gated sodium channel transcripts were expressed in taste tissue. SCN2A, SCN3A, and SCN9A were expressed beneath tight junctions in subsets of taste cells. SCN3A and SCN9A were expressed in TRPM5 cells, while SCN2A was expressed in TRPM5 and PKD2L1 cells. HCN4, a gene previously implicated in sour taste, was expressed in PKD2L1 cells and localized to cell processes beneath the taste pore.
Conclusion
SCN2A, SCN3A and SCN9A voltage-gated sodium channels are positioned to sense initial depolarizing signals stemming from taste receptor activation and initiate taste cell action potentials. SCN2A, SCN3A and SCN9A gene products likely account for the tetrodotoxin-sensitive sodium currents in taste receptor cells.
Journal Article
Randomized Trial of an Inhibitor of Formation of Advanced Glycation End Products in Diabetic Nephropathy
Background/Aims: Pimagedine inhibits the formation of advanced glycation end products and slows the progression of diabetic complications in experimental models. This study was undertaken to determine if pimagedine ameliorates nephropathy in type 1 (insulin-dependent) diabetes mellitus. Methods: This was a randomized, double-masked, placebo-controlled study performed in 690 patients with type 1 diabetes mellitus, nephropathy, and retinopathy. The patients received twice daily dosing with placebo, pimagedine 150 mg, or pimagedine 300 mg for 2–4 years. The primary end point was the time to doubling of serum creatinine; the secondary end points included evaluations of proteinuria, kidney function, and retinopathy. Results: Serum creatinine doubled in 26% (61/236) of the placebo-treated patients and in 20% (91/454) of those who received pimagedine (p = 0.099). The estimated glomerular filtration rate decreased more slowly in the pimagedine-treated patients with a 36-month decrease from baseline of 6.26 ml/min/1.73 m 2 as compared with 9.80 ml/min/1.73 m 2 in the placebo-treated patients (p = 0.05), and pimagedine reduced the 24-hour total urinary proteinuria. (The mean reduction from baseline at month 36 was 732 mg/24 h at the low dose and 329 mg/24 h at the high dose as compared with 35 mg/24 h in the placebo group; p ≤ 0.001.) Fewer pimagedine-treated patients with baseline and end point evaluations (31/324; 10%) as compared with those receiving placebo (16%; 28/179) experienced a three-step or greater progression of the retinopathy (Early Treatment of Diabetic Retinopathy Study) score (p = 0.030). Three patients receiving high-dose pimagedine but none receiving low-dose treatment developed glomerulonephritis. Conclusions: While this study did not demonstrate a statistically significant beneficial effect of pimagedine on the progression of overt nephropathy resulting from type 1 diabetes, it is noteworthy in providing the first clinical proof of the concept that inhibiting advanced glycation end product formation can result in a clinically important attenuation of the serious complications of type 1 diabetes mellitus.
Journal Article
Clinician perception of a novel cardiovascular lifestyle prescription form in the primary and secondary care setting in Wales, UK
Issues addressed: To establish the views of clinicians on the feasibility and effectiveness of using a novel lifestyle prescription form (LRx) which requires co-signing by clinician and patient and is uniquely based on the design of the standard drug prescription form, in the primary and secondary health care settings.
Methods: Thirty-six participants were issued with a \"prescription\" pad, of 20 LRx scripts, for 1 month and requested to issue an LRx prescription to patients they deemed suitable during their consultation, recording their reason for use of the LRx. Each clinician was then asked to complete a comprehensive feedback questionnaire.
Results: Feedback of the LRx was overwhelmingly positive. The script was viewed as a more effective way to convey and support cardiovascular lifestyle advice, than usual care. Forty per cent (196 of 480) of the LRx scripts that were provided to primary and secondary care clinicians during the study period were issued. In most consultations, the LRx script was issued to reaffirm dietary advice. Nurses and health care assistants were more likely than doctors to use the LRx in response to a request for lifestyle advice from a patient.
Conclusions: The LRx may be a useful addition to the clinician's communication toolkit to stimulate lifestyle behaviour changes in their patients. The main barrier to use in the study was lack of consultation time.
Journal Article
Diabetic Nephropathy: The Proteinuria Hypothesis
Background/Aims: Proteinuria, nearly a universal finding in progressive kidney disease, has been the subject of frequent recent analyses in the renal literature. Proteinuria is a hallmark of diabetic nephropathy: microalbuminuria is the principal early predictor for progression of diabetic glomerulopathy, and proteinuria may be viewed as a measure of the severity and promoter of progression of nephropathy. Methods: This article critically reviews for the first time the full scope of diabetic proteinuria – complex molecular mechanisms, natural history, and analysis of treatment trials – in order to address the validity of ‘the proteinuria hypothesis’, i.e., that diabetic proteinuria is a modifiable determinant of renal progression. This hypothesis is analyzed in detail, including recent studies on the primary therapy of diabetic nephropathy, renin-angiotensin blockade. Results: As fully developed, this hypothesis consists of three postulates: that higher amounts of proteinuria predict progressive loss of function, that proteinuria reduction correlates with slowing progression, and that proteinuria is a surrogate endpoint for clinical trials. The latter postulate has not before been adequately linked to growing information about the first two postulates as they apply to diabetic kidney disease. Conclusion: While diabetic nephropathy is a disease model for the potential use of proteinuria as a surrogate marker for renal progression, this shift in perspective will require prospective data from additional clinical trials, particularly of non-renin-angiotensin blocking drugs, to be complete.
Journal Article
Home management of lower limb lymphoedema with an intermittent pneumatic compression device: a feasibility study
Background
Lymphoedema is a chronic condition that causes swelling in the body tissues. Presently, there is no cure for lymphoedema; instead, current treatment is aimed at lifelong management to help control symptoms. Intermittent pneumatic compression (IPC) therapy can be considered as an adjunct to standard lymphoedema care; however, research regarding the efficacy of this treatment modality is limited.
Methods
Twenty participants were recruited from an outpatient lymphoedema clinic (South Wales, UK) to a feasibility randomised control trial designed to evaluate the efficacy of an IPC device (LymphAssist, Huntleigh Healthcare) in reducing lower limb volume. The primary objective was to assess feasibility in terms of (1) study feasibility, including recruitment, retention and assessment of outcome measures, and (2) intervention feasibility, including intervention fidelity and acceptability to participants. Participants were randomly assigned to a control group (
n
= 10) or intervention group (
n
= 10). The control group received their standard lymphoedema care only for a 6-month period, whereas the intervention group received their standard lymphoedema care plus an IPC device to use for 6 months. A bilateral lower limb assessment and quality of life survey were undertaken at baseline and 3- and 6-month time points.
Results
The study recruited to target within the planned time frame with a retention rate of 80%. Issues relating to potential recruitment bias and study attrition were identified and possible solutions explored. In addition, supplementary primary outcome measures that are important to the study population were identified and will be incorporated into the design of future studies.
Conclusion
This feasibility study identified that a larger randomised controlled trial investigating the efficacy of home use IPC devices is feasible with modifications to the study protocol.
Trial registration
This trial is registered with clinicaltrials.gov (
NCT03825263
).
Journal Article
Classification of Tidal Breathing Airflow Profiles Using Statistical Hierarchal Cluster Analysis in Idiopathic Pulmonary Fibrosis
In idiopathic pulmonary fibrosis (IPF) breathing pattern changes with disease progress. This study aims to determine if unsupervised hierarchal cluster analysis (HCA) can be used to define airflow profile differences in people with and without IPF. This was tested using 31 patients with IPF and 17 matched healthy controls, all of whom had their lung function assessed using spirometry and carbon monoxide CO transfer. A resting tidal breathing (RTB) trace of two minutes duration was collected at the same time. A Euclidian distance technique was used to perform HCA on the airflow data. Four distinct clusters were found, with the majority (18 of 21, 86%) of the severest IPF participants (Stage 2 and 3) being in two clusters. The participants in these clusters exhibited a distinct minute ventilation (p < 0.05), compared to the other two clusters. The respiratory drive was greatest in Cluster 1, which contained many of the IPF participants. Unstructured HCA was successful in recognising different airflow profiles, clustering according to differences in flow rather than time. HCA showed that there is an overlap in tidal airflow profiles between healthy RTB and those with IPF. The further application of HCA in recognising other respiratory disease is discussed.
Journal Article