Cough is one of the main symptoms of advanced lung disease. However, the efficacy of currently available treatment remains unsatisfactory. Research into the new antitussives requires an objective assessment of cough.The aim of the study was to test the feasibility of a new automatic portable cough analyser and assess the correlation between subjective and objective evaluations of cough in 13 patients with chronic cough. The patients' individual histories, a cough symptom score and a numeric cough scale (1-10) were used as a subjective evaluation of cough and a computerized audio-timed recorder was used to measure the frequency of coughing.The pre-clinical validation has shown that an automated cough analyser is an accurate and reliable tool for the ambulatory assessment of chronic cough. In the clinical part of the experiment for the daytime, subjective cough scoring correlated with the number of all cough incidents recorded by the cough analyser  and the number of cough incidents per hour . However, there was no relation between cough score and the time spent coughing per hour . As assessed for the night-time period, no correlation was found between subjective cough scoring and the number of incidents per hour  or time spent coughing .An automated cough analyser seems to be a feasible tool for the ambulatory monitoring of cough. There is a moderate correlation between subjective and objective assessments of cough during the daytime, whereas the discrepancy in the evaluation of night-time coughing might suggest that subjective analysis is unreliable. Cough is one of the main symptoms of advanced lung disease. However, the efficacy of currently available treatment remains unsatisfactory. Growing knowledge of the pathophysiology of cough has resulted in the implementation of new therapeutic options and research on future potential treatment modalities -3. ReseaIn this study we first tested the feasibility of a new portable automatic cough analyser (CA) which could be applied to 24-hour monitoring in an ambulatory setting Figure . We thenSixteen patients who had been treated at the Department of Pneumonology and Allergology at the Medical University of Gdansk, Poland, were included in the study Table .The inclusion criteria were as follows: chronic cough defined according to the ERS , being oThe exclusion criterion was asthma exacerbation. The study was approved by the Local Research Ethics Committee in Gdansk and patients' individual histories, a cough symptom score and a numeric cough scale (1-10) were used for a subjective evaluation of cough. Portable cough recording was commenced following lung function assessment by spirometry. In the case of ambulatory patients, these were allowed to go home and encouraged to wear the cough-recording device for 24 hours. Moreover, they were asked to self-report their cough during the day and night.The cough analyser (CA) designed for the purpose of the study  was supplied with batteries (2 × AAA 2.4 V) and worn by patients in a special pouch around the thorax Figure . A microThe CA was able to measure acoustic vibrations continuously and the signals being transferred to a recording of sound amplitude. The hardware for the CA allows for a 0.1-second resolution time in registering signals with a cut-off value of 20 dB, whereas the frequency range is 8-1200 Hz.The process of the MES CA validation consisted of three steps.h-m) was assessed according to the following mathematical formula:First - 6 healthy individuals voluntarily produced cough. A comparison of the agreement of manual counting by software using the MES Cough Analyser against counting by the hearing of cough incidents in real time was checked. The counting error  was evaluated for different parameters of automatic analysis, such as time (0.1 s or 1 s) and amplitude of discrimination .Six healthy volunteers coughed in their normal office environments at work  Table . The coua-m was assessed according to the following mathematical formula:ECm - number of incidents counted manually by the software MES Cough AnalyserNa - number of incidents automatically counted by the cough analyserNThe results of the calibration tests showed that the optimal parameters of automatic analysis are time discrimination = 1 second and amplitude discrimination = 10%. This means that the recognition of a signal begins if the amplitude reaches 10% as well as disappearing at the level of 10%.a-m was equal to 2.93% (range 2.27-3.57), thus ECa-m was < 5%.Using these parameters of automatic analysis means that ECThird - automatic counting verified against that achieved via manual counting by the software MES Cough Analyser during prolonged monitoring Table .The thirteen measurements in healthy volunteers lasted a total of 172 hours.The parameters of digital measurement accepted for signal detection were based on the results of the previous step of calibration: discrimination time = 1 second; minimal amplitude of incident = 10%. Thus, the software enabled registration of a 1-second incident as a cough . A 1-second interval was required to discriminate between incidents. The software presented each incident as a percentage of the maximum amplitude achieved by an individual patient. The recognition of a signal began if the amplitude reached 10% and also disappeared at the level of 10%.The results of the validation process enabled the calculation of sensitivity greater than 95% , a specificity greater than 99% , and a median false positive rate = 0.0036 (range 0.0019-0.0054)  during the clinical part, we withdrew signals with an amplitude lower than 50% of the maximum amplitude obtained during cough. We quantified cough in terms of the number of incidents and the time spent coughing in seconds per hour; we analysed day and night periods separately.Patients were asked to self-assess their cough simultaneously with the CA monitoring. The evaluation included the intensity and duration of the symptom based on a Numerical Rating Scale (NRS: 1 = no cough to 10 = worst cough) and a cough scoring system recommended by the ERS ,6.The validation of the CA revealed a sensitivity for discriminating between coughs equal to 95%. Based on clinical experience, we had assumed the sensitivity of the cough score to be 55%. We calculated that to obtain a power of 70% (p = 0.05) for the study we would need a sample size involving 16 patients .The time for monitoring was arbitrarily divided into night (N) and day (D) . The steps for the calculation included: (1) counting the number of cough incidents during D and N separately; and (2) calculating the mean number of incidents per hour for D and N. These mean values were subsequently used for further analysis of correlations between particular features. The same was calculated for time spent coughing. Statistical analysis was conducted using a licensed version of statistical software: STATISTICA PL 5.0 for Windows. The distribution of variables using the Shapiro-Wilk test was abnormal, therefore non-parametric statistical tests were chosen. A Wilcoxon rank test was performed to assess the differences between particular parameters. Spearman correlations were used to examine the relationship between subjective and objective measures of cough.Sixteen patients with chronic cough were included in the CA assessment   who removed it early due to discomfort during the night. Eight other patients decided for themselves to shorten the time of monitoring due to occupational obligations.Among the 16 patients included in the analysis, the median duration time of objective cough monitoring (the entire study period) was 21 hours and 45 minutes (range 15-24 hours) (Table The median time spent coughing for the study group was 16.5 seconds per hour with a wide range between patients (0-52). Time spent coughing was higher during the day than at night. The median time spent coughing during the day was 20 seconds per hour (range 0-78), whereas at night this was 3 seconds per hour . There was a moderate correlation between time spent coughing per hour during D and N .Thirteen patients completed the subjective evaluation form Table . The medFor the daytime, subjective cough scoring correlated moderately with the number of all cough incidents  and the number of cough incidents per hour  (Table In the pre-clinical assessment our new portable automatic cough analyser seemed to be a simple and practical but accurate and reliable method for the objective prolonged monitoring of cough in an ambulatory setting. Our pilot clinical study compared subjective and objective evaluations of cough in patients with chronic cough. The results showed a moderate correlation between cough scoring and the number of cough incidents measured with the CA during the day, whereas there was a lack of correlation between these parameters at night.Until now the relationships between different subjective and objective measures of cough have not been clarified and have been controversial in different trials -11. In cRecently, the need for integrated recording systems for cough assessment has been stressed, particularly in the clinical evaluation of drug efficacy ,5. ThereIt is worth mentioning that a group from Leicester, UK, introduced an automated system for the 24-hour monitoring of cough frequency. Their studies have proved to be significant, with repeatable differences seen in cough frequency between patients with chronic cough and healthy controls ; they haHowever, it is likely that automated cough monitoring is both device and method specific; therefore, the findings of previous studies cannot be extrapolated to new devices.The unsatisfactory effectiveness of currently available antitussives, particularly in patients with advanced lung disease, has provoked increased interest in the development of some novel approaches. One of these is to reach opioid receptors in the trachea-bronchial tract using nebulised opioids  or otherClinical trials on new antitussive drugs would require the thorough objective assessment of the intensity and frequency of cough, which means that introducing portable devices such as a CA might be of clinical relevance.We conclude that appropriate night-time cough evaluation requires both subjective and objective monitoring. The severity of cough defined by a patient may not represent its frequency and duration when measured objectively. The use of ambulatory cough analysers should not be limited to research but might be helpful in clinical practice, particularly when symptomatic treatment is the main or only purpose of the approach.The authors declare that they have no competing interests.MK and IDK were involved in the design of the study protocol, in the patients enrolment and examination, in the analysis and interpretation of data and writing the paper. IDK performed a statistical analysis. LG took a part in the patients enrolment to the study, in a data collection and analysis, and revised the manuscript critically. EJ made substantial contribution to conception and design of the study protocol, analysis and interpretation of data, coordination of the trial and helped to draft the manuscript. All authors read and approved the final manuscript.


This free radical further reacts with oxygen to form the peroxymonosulfate anion radical (−O3SOO•) and sulfate anion radical (SO4• −).Sulfur dioxide, formed during the combustion of fossil fuels, is a major air pollutant near large cities. Its two ionized forms in aqueous solution, sulfite and (bi)sulfite, are widely used as preservatives and antioxidants to prevent food and beverage spoilage. (Bi)sulfite can be oxidized by peroxidases to form the very reactive sulfur trioxide anion radical  to initiate this radical chain reaction, using human serum albumin (HSA) as a model target.We used electron paramagnetic resonance, optical spectroscopy, oxygen uptake, and immuno-spin trapping to study the protein oxidations driven by sulfite-derived radicals.•SO3− was produced, with the concomitant reduction of SOD-Cu(II) to SOD-Cu(I). Further, we demonstrated that sulfite oxidation mediated by Cu,Zn-SOD induced the formation of radical-derived 5,5-dimethyl-1-pyrroline N-oxide (DMPO) spin-trapped HSA radicals.We found that when Cu,Zn-SOD reacted with (bi)sulfite, The present study suggests that protein oxidative damage resulting from (bi)sulfite oxidation promoted by Cu,Zn-SOD could be involved in oxidative damage and tissue injury in (bi)sulfite-exacerbated allergic reactions. At high pH, Cu,Zn-SOD exhibits peroxidase activity, with the initial step of the peroxidase cycle being a reduction of SOD-Cu(II) by H2O2 or its deprotonated form, HO2−, to SOD-Cu(I) (3−) buffer sulfite (HSO3−) and (bi)selenite (HSeO3−), may also stimulate the peroxidase activity of Cu,Zn-SOD in the presence of millimolar H2O2 , a metalloenzyme that catalyzes the dismutation of the superoxide anion into OOD-Cu(I) . At neut) buffer . It has lar H2O2 .2SO3) was a one-electron donor substrate for Cu,Zn-SOD, leading to the generation of reactive sulfur radicals via Equations 2–4. We also applied immuno-spin trapping with 5,5-dimethyl-1-pyrroline N-oxide (DMPO) to investigate oxidation of target proteins  to protein radicals sulfite oxidation and found that, under our experimental conditions, SOD1-Cu(II) is slowly reduced to SOD1-Cu(I) by (bi)sulfite. We used optical spectroscopy, electron spin resonance (ESR), and oxygen uptake experiments to demonstrate that (bi)sulfite  were from Sigma Chemical Co. . We determined the H2O2 concentration from its absorbance at 240 nm (ɛ = 39.4 M −1cm −1). DMPO  from Alexis Biochemicals  was sublimed twice under vacuum at room temperature and stored under an argon atmosphere at −80°C before use. Chelex-100 resin was from Bio-Rad Laboratories .We purchased bovine kidney superoxide dismutase (SOD) from Calzyme Laboratories Inc. . HSA (99.99% purity), diethylenetriaminepentaacetic acid (DTPA), sodium sulfite, thiocyanate, azide, cyanide, and HWe obtained ESR spin-trapping data at room temperature using a Bruker EMX spectrometer with 100 kHz modulation frequency and equipped with an ER 4122 SHQ cavity . We placed samples in a 10-mm flat cell  and initiated recording of the spectra within 1 min of the start of the reaction.We recorded low-temperature ESR data at 77 K after the indicated incubation times. Initially, we mixed SOD with (bi)sulfite at room temperature; after incubation, we transferred the reaction mixtures into 1-mL polyethylene syringes and froze them in liquid nitrogen. We added glycerol (10%) to the samples before freezing to prevent cracking of the frozen texture.For oxygen uptake measurements, we added 500 μL sodium sulfite to a chamber equipped with a Clark electrode and a stirrer. We initiated the reaction (1.8 mL) by SOD, and the oxygen uptake curves were obtained at room temperature with an oxygen monitor .2SO3, and 50 μM Cu,Zn-SOD in the presence or absence of 5 mM DMPO in 100 mM phosphate buffer (Chelex-treated with 25 μM DTPA) at pH 7.4 in a total volume of 30 μL. After 1 hr of incubation at 37°C, we stopped reactions with 5 mM reduced glutathione and then diluted the samples with deionized H2O for electrophoresis and immuno-spin trapping analyses.Typically, we carried out reactions of 600 μM HSA, 500 μM NaWe electrophoresed the reaction mixtures under reducing conditions through duplicate 4–12% BisTris NuPage acylamide gels . We performed Western blotting and ELISA analysis as previously described  with min−1cm−1 in the bovine enzyme), which results from the d-d transitions of the Cu atom  using a 500 μM quartz cuvette. We determined Cu,Zn-SOD concentration from the broad band at 680 nm (ɛ = 300 M Cu atom . We carr|| = 135 G) remained unchanged during the incubation time, indicating that (bi)sulfite does not bind directly to the active site Cu(II) (When we added a 20-fold excess of (bi)sulfite to 1 mM Cu,Zn-SOD, the absorption band at 680 nm characteristic of the active site of SOD1-Cu(II) decreased slowly, then completely disappeared as the wild-type protein was reduced to Cu(I) . We recoe Cu(II) .•SO3− adduct of DMPO, DMPO/•SO3− (aHβ= 16.0 G and aN = 14.7 G) (•SO3− is formed when the protein is treated with 1 mM H2O2 in the presence of 20 mM (bi)sulfite sulfite by H2O2, which is known from the literature (2O2 via the following reaction:To determine whether (bi)sulfite is oxidized by Cu(II) in Cu,Zn-SOD, we also performed room-temperature ESR spin-trapping experiments. When we mixed Cu,Zn-SOD (50 μM) with (bi)sulfite (500 μM) in the presence of the spin trap DMPO (100 mM), it generated an intense ESR signal ( 14.7 G) , 1982b. )sulfite . Accorditerature  to proce2O2 (100 μM) and to confirm that •SO3− is generated because of the enzymatic oxidation of (bi)sulfite, we performed control experiments in the presence and absence of H2O2. Contrary to expectation  or Cu,Zn-SOD resulted in no radical adduct formation (2O2 is not involved (data not shown).To determine the effect of low and nontoxic concentration of Hectation , additio•SO3− by the active Cu(II) site of Cu,Zn-SOD proceeds in a one-electron reduction reaction of Cu(II) by (bi)sulfite, similar to the oxidation of (bi)sulfite by HRP and prostaglandin H synthase  almost completely prevented oxygen uptake (−O3SOO• and SO4• −.The proposed mechanism of enzymatic oxidation of (bi)sulfite to synthase . The resreported . To confntration . Addition uptake , that is•SO3−, we mixed 500 μM Na2SO3 with selected inhibitors and initiated the reactions by 50 μM Cu,Zn-SOD in the presence of 100 mM DMPO sulfite to sulfite-derived radicals is possible.To characterize the importance of Cu redox cycling at the enzyme-active site upon the generation of  mM DMPO . The ESR•SO3−, which will initiate the radical chain reaction with formation of −O3SOO• and SO4• − via Equations 2–4. To characterize the ability of these radicals to oxidize amino acid(s) in target proteins, we incubated HSA with the enzyme and (bi)sulfite in the presence of DMPO and analyzed the reaction products by Western blotting using an anti-DMPO polyclonal antibody sulfite is oxidized by Cu,Zn-SOD to antibody . We chos 120 kDa . We alsoby ELISA . This reHSA-derived nitrone adducts also depended on the (bi)sulfite concentration . Omissio2SO3, and 50 μM Cu,Zn-SOD, Western blotting showed that DMPO-HSA radical-derived nitrone adduct production increased with reaction time, reaching saturation at about 1 hr. ELISA data paralleled those from Western blotting —can attack target proteins   sulfite by Cu,Zn-SOD proceeds via a radical mechanism as demonstrated using optical spectroscopy, oxygen uptake, and ESR experiments. Similar results have been reported for some peroxidases  , 1982b. d SO4• − , which—a plasma)   . Previouor •SO3− . In fact(100 mM) , and a dd SO4• − . The vere SO4• − .(Bi)sulfite is one of the few sulfating agents approved by the Food and Drug Administration as a food preservative and antioxidant to prevent or reduce spoilage . However42−), and it is noteworthy that in cases of sulfite oxidase deficiency, the concentration of sulfite in plasma is abnormal (> 1 mM) (2 [(bi)sulfite] forms oxidation products other than sulfate, such as S-sulfonates sulfite is a deficiency of sulfite oxidase, the molybdenum-containing enzyme that oxidizes sulfite to sulfate (SO(> 1 mM) . The cap(> 1 mM) . Howeverlfonates ; this inlfonates  demonstr− (bi)sulfite as a source for generation of oxidants (−O3SOO• and SO4• −) that are diffusible and radicals themselves to show their capability to oxidize the most abundant plasma protein  to protein radicals sulfite provides an enzymatic pathway to generate the reactive intermediates −O3SOO• and SO4• −, which oxidize HSA residues to protein radicals. We also propose that Cu,Zn-SOD may contribute to oxidative damage and tissue injury in (bi)sulfite (sulfur dioxide)–exacerbated allergic reactions. Our results suggest that SOD-dependent, sulfite-mediated oxidation of albumin residues is likely to occur in vivo, particularly at sites where Cu,Zn-SOD concentration is higher. Further studies are necessary to clarify whether alterations in Cu,Zn-SOD activity affect (bi)sulfite toxicity.In summary, our study showed that Cu,Zn-SOD


Chronic persistent cough can be associated with laryngeal dysfunction that leads to symptoms such as dysphonia, sensory hyperresponsiveness to capsaicin, and motor dysfunction with paradoxical vocal fold movement and variable extrathoracic airflow obstruction (reduced inspiratory airflow). Successful therapy of chronic persistent cough improves symptoms and sensory hyperresponsiveness. The effects of treatment for chronic cough on laryngeal dysfunction are not known.The aim of this study was to investigate effects of therapy for chronic cough and paradoxical vocal fold movement.Adults with chronic cough (n = 24) were assessed before and after treatment for chronic persistent cough by measuring quality of life, extrathoracic airway hyperresponsiveness to hypertonic saline provocation, capsaicin cough reflex hypersensitivity and fibreoptic laryngoscopy to observe paradoxical vocal fold movement. Subjects with chronic cough were classified into those with (n = 14) or without (n = 10) paradoxical vocal fold movement based on direct observation at laryngoscopy.Following treatment there was a significant improvement in cough related quality of life and cough reflex sensitivity in both groups. Subjects with chronic cough and paradoxical vocal fold movement also had additional improvements in extrathoracic airway hyperresponsiveness and paradoxical vocal fold movement. The degree of improvement in cough reflex sensitivity correlated with the improvement in extrathoracic airway hyperresponsiveness.Laryngeal dysfunction is common in chronic persistent cough, where it is manifest as paradoxical vocal fold movement and extrathoracic airway hyperresponsiveness. Successful treatment for chronic persistent cough leads to improvements in these features of laryngeal dysfunction. Chronic persistent cough is responsible for a significant illness burden in the community . LaryngeSubjects with chronic persistent cough (n = 24) were recruited from the Respiratory Ambulatory Care Service at John Hunter Hospital in Newcastle, New South Wales, Australia. Subjects were aged between 18 and 80 years with a persistent cough of more than eight weeks. They were non-smokers or ex-smokers with less than ten pack years, had no other active respiratory or cardiac disease, and were required to have a normal chest radiograph. They were classified into 2 groups based on the presence  or absence  of PVFM observed at fibreoptic laryngoscopy. All subjects provided written informed consent for this study, which was approved by the University of Newcastle's Human Research Ethics Committee and the Hunter New England Human Research Ethics Committee.Subjects attended a total of 5 visits over a period of 18 weeks. At visit 1, clinical history, current respiratory symptoms, medication use, passive smoking history and an in-house rhinitis symptoms score were recorded. A number of questionnaires were also administered and these included a cough specific quality of life questionnaire ) , a gastrAll subjects were non-smokers or ex-smokers with less than 10 pack years and not exposed to current passive smoking and this was confirmed by exhaled carbon monoxide measurement ,15. FracA probability based diagnostic assessment approach was used  with theForced Expired Nitric Oxide (FENO) was measured using an on-line chemiluminescence analyser  according to published European Respiratory Society/American Thoracic Society guidelines . Subject1 fell by more than 15%, 200 μg of salbutamol was administered via a valved holding chamber .Prior to HSC, subjects withheld bronchodilators for their duration of action and antihistamines for 48 hours. Subjects were instructed in the correct performance of inspiratory and expiratory Flow Volume Loops (FVL). The manoeuvre consisted of tidal breathing, deep inspiration to total lung capacity, forced expiration to residual volume followed by deep inspiration to total lung capacity. Hypertonic saline (4.5%) was inhaled for doubling time periods and a inspiratory-expiratory FVL was measured, in duplicate, 60 seconds after each saline dose using a KoKo K323200 Spirometer . Forced expiratory time was held constant at subsequent manoeuvres in order to ensure consistency. If the FEVSolutions of capsaicin  concentrations ranging from 0.98 to 500 μM were prepared daily. Subjects inhaled single breaths  to total lung capacity (TLC)) of capsaicin aerosol from a compressed air-driven nebulizer  controlled by a dosimeter . The inspiratory flow was standardized at 0.5 L/s with an inspiratory flow regulator valve. Cough counting was done for 30 s after exposure to each dose, and the investigation ended when the subject coughed five or more times in response to one dose, or received a dose of the highest concentration.Flexible fibreoptic laryngoscopy  was performed at baseline and immediately after a hypertonic saline challenge ,21. PrioThe gold standard used for the diagnosis of PVFM during the study was a positive laryngoscopy demonstrating paradoxical vocal fold motion at baseline and/or post-HSC while symptomatic.All analyses were performed using statistical and data analysis software STATA . Non parametric quantitative data were compared using the Wilcoxon rank sum test and for parametric data, ttest for matched pair data was used. Significance for 2 group comparison was set at p < 0.05.Twenty-four subjects with a chronic persistent cough participated in the study. The subjects had a median (IQR) cough duration of 24 13–84) months and were predominantly female [Table 3–84 montTen of the 14 subjects with PVFM attended speech language therapy. After treatment, PVFM had resolved in 8 of these 10 subjects (p = 0.039 by McNemar's chi square test). Four of the Cough+PVFM subjects did not attend speech language therapy before returning for their post-treatment visits. PVFM did not resolve in 3 of these 4 subjects but did resolve in 1 subject. Interestingly this subject was the only male in this group of four and had the shortest cough duration (12 months) and youngest age (22 years).In the Cough alone (CC) group, extrathoracic airway responsiveness was not increased and with therapy remained unchanged from baseline Figure . BaselinThis study has identified that paradoxical vocal fold movement and extrathoracic airway hyperresponsiveness are improved by specific treatment for chronic persistent cough, and that this improvement occurs alongside improvements in cough specific quality of life and cough reflex sensitivity. The data provides objective evidence of laryngeal dysfunction in some patients with chronic cough, and shows that it responds to therapy for chronic persistent cough. These results are consistent with Vertigan et al  who founLaryngeal dysfunction is increasingly recognized in chronic persistent cough. Symptoms such as voice hoarseness, dyspnoea, wheeze and cough may all occur as a result of laryngeal dysfunction . Prudon In this study we used an open design with objective measures to assess outcome. Although a nonrandomized design is a limitation, our primary purpose was to determine if the measures of laryngeal dysfunction that occur in chronic persistent cough are responsive to effective therapy. The study achieved these aims by using objective measures and has provided novel data on how PVFM and EAHR improve with therapy of chronic persistent cough. The results extend what is known about how successful therapy works in chronic persistent cough, and provide data that supports the favourable responses reported for symptoms, cough frequency, and measures of cough reflex sensitivity. We now show that laryngeal dysfunction also improves with treatment of chronic persistent cough in those patients with cough and PVFM. Future studies could provide further evidence of efficacy by using a randomized design, and potentially assessing any incremental benefits of speech language treatment.We studied subjects who were representative of those with chronic persistent cough. They were primarily middle-aged females (80%) with a significant cough duration and similar prevalence of the medical conditions that have been associated with persistent cough ,27,28. WThere was a moderately significant  correlation in the Cough+PVFM Group for treatment related changes in extrathoracic airway hyperresponsiveness dose response slope and CRS-C5 Figure . This deIn conclusion, this study identifies that the laryngeal dysfunction that occurs in some patients with chronic persistent cough is responsive to therapy.CC: Chronic Cough; CRS: Cough Reflex Sensitivity; EAHR: Extrathoracic Airway HyperResponsiveness; eCO: exhaled Carbon Monoxide; FENO: Forced Expired Nitric Oxide; FOL: Fibre Optic Laryngoscopy; GORD: GastroOesophageal Reflux Disease; HSC: Hypertonic Saline Challenge; IQR: InterQuartile Range; LCQ: Leicester Cough Questionnaire; LDQ: Laryngeal Dysfunction Questionnaire; PVFM: Paradoxical Vocal Fold MovementThe authors declare that they have no competing interests.NR and PG planned the study. NR recruited the subjects and performed the objective cough and EAHR methods, questionnaires, assisted with fibreoptic laryngoscopy, collected and reviewed data, participated in the design and drafted the manuscript. PG performed patient assessment, physical examinations and fibreoptic laryngoscopy and prescribed medication. AV performed speech pathology treatment and reviewed the manuscript. PG also participated in the manuscript drafting and coordination of the manuscript. All authors read and approved the final manuscript.Nicole M Ryan holds a PhD scholarship from the NHMRC CCRE in Respiratory and Sleep Medicine, Australia.Anne Vertigan holds a post-doctoral fellowship from the NHMRC CCRE in Respiratory and Sleep Medicine, AustraliaProfessor Peter Gibson is an NHMRC Practitioner Fellow.


Nigersaurus taqueti, document for the first time the cranial anatomy of a rebbachisaurid sauropod. Its extreme adaptations for herbivory at ground-level challenge current hypotheses regarding feeding function and feeding strategy among diplodocoids, the larger clade of sauropods that includes Nigersaurus. We used high resolution computed tomography, stereolithography, and standard molding and casting techniques to reassemble the extremely fragile skull. Computed tomography also allowed us to render the first endocast for a sauropod preserving portions of the olfactory bulbs, cerebrum and inner ear, the latter permitting us to establish habitual head posture. To elucidate evidence of tooth wear and tooth replacement rate, we used photographic-casting techniques and crown thin sections, respectively. To reconstruct its 9-meter postcranial skeleton, we combined and size-adjusted multiple partial skeletons. Finally, we used maximum parsimony algorithms on character data to obtain the best estimate of phylogenetic relationships among diplodocoid sauropods. Nigersaurus taqueti shows extreme adaptations for a dinosaurian herbivore including a skull of extremely light construction, tooth batteries located at the distal end of the jaws, tooth replacement as fast as one per month, an expanded muzzle that faces directly toward the ground, and hollow presacral vertebral centra with more air sac space than bone by volume. A cranial endocast provides the first reasonably complete view of a sauropod brain including its small olfactory bulbs and cerebrum. Skeletal and dental evidence suggests that Nigersaurus was a ground-level herbivore that gathered and sliced relatively soft vegetation, the culmination of a low-browsing feeding strategy first established among diplodocoids during the Jurassic.Fossils of the Early Cretaceous dinosaur,  Rebbachisaurus, came to light in Upper Cretaceous rocks in Morocco Some 50 years ago the first bones of an unusual sauropod, dubbed Nigersaurus taqueti  scans of the bones of a single adult individual to recompose the extremely lightweight skull . The del2 . These dNigersaurus have never been reported in any other sauropodomorph dinosaur including closure of the supratemporal opening, five additional fenestrae on the lateral aspect of the skull, and teeth packed into terminal dental batteries that extend laterally beyond the side of the skull Several cranial features of Nigersaurus, however, that fenestra is closed and the line of action to the lower jaw blocked by a sharp bend in the quadrate. As the quadrate shows no sign of a synovial surface or trochlea to bend this line of action (as occurs in some turtles), the origin of the adductor musculature must have migrated onto the quadrate , likewise, appear to have been relatively weak. The elongate basipterygoid processes that buttress the palate against the pull of pterygoideus musculature taper distally to rods no more than 2 mm in diameter.DiplodocusNigersaurus  on the lingual  surface of the upper teeth, which is similar to that in advanced titanosaurs . Light mDicraeosaurusDiplodocusA second high-angle wear facet (ca. 40° from the long axis of the crown) forms on the labial  surface of the upper teeth. This facet is D-shaped, rather than circular, owing to its intersection with the lingual  facet . The labNigersaurus as compared to an average hadrosaurid  composed of only 13 vertebrae, and an adult body length of only approximately 9 m  and modest body length of 10 meters or less characterizes nearly all rebbachisaurids Pneumatic invasion of the centra of the presacral vertebrae has reduced the vertebral body to a hollow shell divided by a thin median septum , left, mNigersaurus forces a consideration of the biomechanical limits of skull and axial design for a large-bodied, land-based herbivore and impacts our understanding of several aspects of sauropod paleobiology and evolution. No other herbivorous tetrapod has evolved a skull of comparable size with as little bone that is able to withstand sustained impact from tooth-to-tooth shearing. The shearing action of its jaws, furthermore, ground down crowns at a faster rate than ever recorded among dinosaurian herbivores and accomplished this dental degradation in the most challenging location from a biomechanical perspective—at the distal end of its jaws, as far as possible from the jaw joint and adductor musculature  when Nigersaurus lived. Previous reference to “head down” feeding by “ventriflexion” Here we distinguish Nigersaurus in particular suggests increasing adaptation to ground-level browsing. Broadening of the muzzle Nigersaurus and the squared muzzles in other diplodocoids would enhance gathering and cropping near a relatively flat surface.Squaring of the muzzle in diplodocoids in general and Nigersaurus  aspect of the dentition in ersaurus  are alsoNigersaurus, in particular, the snout could not have been directed anteriorly to strip leaves or generate an external wear facet without disarticulation of the skull from the neck. Estimating ‘feeding envelopes’ based on cervical vertebrae is revealing The spectrum of previous explanations for tooth form and wear in diplodocoids include molluscivory or piscivory Nigersaurus, this interpretation is open to question. Although the dentition in Diplodocus and some diplodocoids is less compact and more prognathous than Nigersaurus, there are several fundamental similarities, including the distal position of most of the tooth row in a squared jaws, slender crown shape, and increased rate of tooth replacement (judging from the number of crowns in the replacement series). Like Diplodocus and Dicraeosaurus, Nigersaurus has a high-angle labial  wear facet, the product of abrasion against plant or other materials  facet in Nigersaurus and possibly other diplodocoids, thus, as evidence of tooth-to-plant abrasion that occurred as vegetation was gathered near the ground prior to orthal shearing.Finally, jaw movement in dicraeosaurids and diplodocids has long been interpreted as propalinal (fore-aft), either with aterials . Nigersay crowns  that proDiplodocus and Nigersaurus and constraints on forward rotation of the skull seem to favor browsing near the ground, which would have lowered and diversified the ‘browsing profile’ of faunas with several sauropods In sum, although the paradigm for feeding among diplodocoids has shifted from high browsing Nigersaurus and other diplodocoids is speculative due to the paucity of evidence from stomach or fecal contents, the true composition of local flora, and the poor correlation between tooth form/wear and plant type. Nevertheless, the weak bite force and fine scale of scratches on the wear facets in Nigersaurus favor soft understory vegetation, possibly immature ferns or horsetails Nigersaurus and the iguanodontian LurdusaurusThe identity of specific plant groups as food resources for Nigersaurus and other diplodocoids due to their height, resistant structure, absence of a suitable local habitat, and late appearance in the fossil record, respectively. Aquatic vegetation is difficult to imagine as a primary resource in the varied habitats that have yielded diplodocoid remains. Cross-bedded sandstones, rather than sediments indicative of still water, comprise nearly all of the Elrhaz Formation, where the bones of Nigersaurus are found  abrasion facet on its teeth may have been generated during ground-level browsing. The low-angle, planar facet on in the inside of the maxillary crowns indicates that Nigersaurus many cranial and dental features including a squared end to the lower jaw and a labial abrasion facet, they may have shared aspects of their feeding strategies. It seems plausible, at the very least, that other diplodocoids had orthal, rather than a propalinal (fore-aft), jaw movement.Because other diplodocoids share with Nigersaurus are conditions that characterize many diplodocoids and now represent an alternative basal condition for the clade. Nigersaurus is the culmination of a low-browsing feeding strategy among diplodocoids that originated in the mid Jurassic and may have had an ecologically significant impact on surface vegetation on several land areas during the Cretaceous.Modest body length, a proportionately short neck, and downward deflection of the muzzle in Figure S1Nigersaurus taqueti (MNN GAD517) discovered during the 2000 Expedition to Niger. Expedition member G. Lyon is seated inside the curve of the proximal caudal vertebrae of a skeleton planed flat by wind-blown sand at a site in Gadoufaoua, Ténéré Desert, Niger (photo by M. Hettwer).Partial skeleton of (0.34 MB TIF)Click here for additional data file.Figure S2Nigersaurus taqueti were found.Location of outcrops of the Elrhaz Formation where fossils of (0.13 MB TIF)Click here for additional data file.Figure S3Nigersaurus taqueti built from prototyped skull bones (tooth batteries and reconstructed teeth in red) with unknown bones in green modeling clay (photo by T. Keillor).Assembled semi-translucent skull model of (3.47 MB TIF)Click here for additional data file.Figure S4Nigersaurus taqueti (MNN GAD512) derived from surface renderings of µCT scan data. (A)-left lateral view. (B)-left anteroventrolateral view. -ventral view. -dorsal view. -anterior view. -posterior view. Color scheme: cyan blue, cranial endocast; pink, endosseous labyrinth; yellow, nerve canals ; red, arterial canals; dark blue, smaller venous canals. Abbreviations: car, cerebral carotid artery canal; cer, cerebral hemisphere; cvcm, caudal middle cerebral vein; de, dural expansion; fl, flocculus ( = cerebellar auricle); lab, endosseous labyrinth; ob, olfactory bulb; ocv, orbitocerebral vein; opt?, possible optic tectum ( = lobe); pfo, pituitary  fossa; II, optic nerve canal; III, oculomotor nerve canal; IV, trochlear nerve canal; V, trigeminal nerve canal; VI, abducens nerve canal; VII, facial nerve canal; VIII, canal for vestibular branch of vestibulocochlear nerve; IX-XI, shared canal for glossopharyngeal, vagus, and accessory nerves and accompanying vessels; XII, hypoglossal canal.Cranial endocast, endosseous labyrinth, and some endocranial vascular structures in (7.88 MB TIF)Click here for additional data file.Figure S5Nigersaurus taqueti (MNN GAD512), (D-E) the diplodocid Diplodocus longus (CM 11161), and (F-G) the basal neosauropod Camarasaurus lentus (CM 11338). -left lateral view. -dorsal view. (C)-posterior view. Abbreviations: c, cochlea; csc, caudal  semicircular canal; fc, fenestra cochlea ( = round window); fv, fenestra vestibuli ; lsc, lateral  semicircular canal; rsc, rostral  semicircular canal; ve, vestibule of inner ear.Endosseous labyrinths of the left inner ear of  the rebbachisaurid (2.41 MB TIF)Click here for additional data file.Figure S6Nigersaurus taqueti. Colors highlight the partitions used for digital assessment of endocast volumes.Partitioned endocast with transparent osseous labyrinth from (1.27 MB TIF)Click here for additional data file.Text S1Geologic setting.(0.07 MB PDF)Click here for additional data file.Text S2The prototype skull.(0.08 MB PDF)Click here for additional data file.Text S3Endocast and labyrinth.(0.15 MB PDF)Click here for additional data file.Text S4Microwear and incremental lines of von Ebner.(0.13 MB PDF)Click here for additional data file.Text S5Phylogenetic analysis.(0.16 MB PDF)Click here for additional data file.


Outpatient surgery accounts for a significant percentage of anaesthetics delivered in the United States and may be appropriate in infants for certain procedures. The most concerning adverse event after general anaesthesia in an infant is postoperative apnea.There is little specific evidence of the risk of apnea in full term infants. There are facilities that feel comfortable performing outpatient surgeries if the infant is born at greater than 37 wk postconceptual age. However, other ambulatory centers prefer to wait untill the infant is 2-4 wk of age to ensure decreased physiologic jaundice, decreased pulmonary vascular resistance and to give time for the ductus arteriosus to close. As far as sudden infant death syndrome(SIDS) there is no evidence anaesthesia increases the risk−1). In the nonanemicchild with a gestational age of 32 wk and a postconceptual age of 56 wk, the probability of apnea was <1%. With a gestational age of 35 wk, a postconceptual age of 54 wk was the cutoff for apnea to be present in <1% of patients.In the premature infant, apnea is more likely to occur as well as other airway complications such as atelectasis, aspiration pneumonia, stridor, and coughing with desaturation in infants undergoing inguinal herniorrhaphy−1 or placebo, the caffeine group had no postoperative bradycardia, prolonged apnea, periodic breathing or postoperative oxygen saturation <90%, whereas 81% of the patients in the control group had prolonged apnea at 4-6 h postoperativelyCaffeine has been shown to decrease the risk of apnea in preterm infants undergoing general anaesthesia. In 32 preterm infants  who received caffeine 10 mg.kgSpinal anaesthesia alone has been shown to have a lower incidence of postoperative apnea and bradycardia in former premature infants when compared to spinal plus sedation or general anaesthesia9Patients <60wk postconceptual age for hernia repair had shorter times to extubation with no postoperative apnea after thiopental or halothane induction with desflurane maintenance than either halothane or sevoflurane for the entire anaestheticThe cutoff for outpatient surgery in infants born before 37 wk may be 50-52 wk postconceptual age as long as there is no anemia, prior apnea or coexisting disease. However, looking at the evidence based literature to decrease the risk of apneas to <1% patients should be greater than 54 wk postconceptual age without anemia, ongoing apnea or other significant medical problems. Postoperative monitoring ranges from 12-24h, including oxygen saturation, heart rate and impedance pneumography and whether the infants are apnea-free before discharge.Caffeine or spinal anaesthesia may decrease the risk of apnea, but patients should not be discharged if they are not eligible for anaesthesia on an outpatient basis. Full-term infants are acceptable for outpatient procedures provided that they are otherwise healthy and the procedure is not likely to result in significant physiologic changes or postoperative pain requiring opioid medication and the anaesthetic is uneventful. Even in term infants some facilities will not allow outpatient surgery untill they are of 44-46 wk post conceptual age or require longer observation if younger, e.g., 4 h.


Hepatitis E, Central African Republic To the Editor: Outbreaks of hepatitis E virus (HEV) have been documented in many geographic regions and nonindustrialized countries  and Médecins sans Frontières (MSF) teams working in the Begoua Commune Health Center, north of CAR’s capital Bangui, reported an increased number of patients from the Yembi I neighborhood who were showing signs of jaundice and extreme fatigue.Patients suspected of having hepatitis E were defined as those with clinical jaundice (yellow discoloration of the sclera) and symptoms of malaise, anorexia, abdominal pain, arthralgia, and fever. Confirmed cases were those in which patients’ serum samples were positive for HEV immunoglobulin (Ig) M or IgG.Initially, 16 pairs of serum and stool samples were collected from jaundiced patients. Fecal samples were stored at –20°C and sent to the National Reference Center of Enterically Transmitted Hepatitis, Hospital Val de Grâce  for HEV marker testing; serum samples were tested at the Bangui Pasteur Institute for yellow fewer (YF) IgM by MAC-ELISA.,The HEV epidemic was confirmed by the detection of HEV markers: HEV IgG , HEV IgM (Abbott Laboratories), amplification of RNA  had relatives with suspected HEV, and 163 (73.5%) had drunk untreated water from their own wells.These epidemiologic findings suggest the water-borne nature of this outbreak. Environmental testing of water from 2 wells (before chlorination was implemented) showed the water to be unsafe to drink  (The outbreak was not surprising because a 1995 survey in Bangui showed anti-HEV antibodies in 24% of patients tested (,>30% in pregnant women (The observed CFR was similar to that in other reported HEV outbreaks, in which CFR varied from 1% to 4% (We recommended application of preventive measures, including water disinfection, safe disposal of excreta, community health education, and the strengthening of case management and disease surveillance. For the CAR, free access to a safe water supply and drugs was the only way to achieve these goals.The number of HEV cases in the Yembi I neighborhood declined after the crisis team implemented hygienic and chlorination measures in the district, although the number of cases remained constant in other neighborhoods of the commune . DefinitOur results agree with international data on HEV outbreaks in other nonindustrialized countries. However, studies to improve our understanding of this epidemic and to identify the main risk factors involved would be beneficial.


Complex and unusual root canal morphology is an often occurring phenomenon. Understanding the unusual root canal morphology contributes to success in endodontic treatment. One such variant root canal morphology is the ‘S’ shaped or bayonet shaped root canal. This case report discusses endodontic treatment of a maxillary second premolar with an ‘S’ shaped root canal. Variations in root canal system occur so often that it is considered a normally occurring phenomenon. Endodontic therapy will be successful only when a thorough disinfection of the entire root canal system is achieved. Understanding these unusual root canal morphology will contribute to success in endodontics.According to Vertucci,–3 maxillThis report discusses the endodontic management of an ‘S’ shaped root canal.A 34-year-old female patient was referred to the Department of Conservative Dentistry and Endodontics, for the management of a right maxillary second premolar. On clinical examination, tooth 15 had a large carious lesion on the disto-proximal aspect. The patient gave a history of severe pain for the past three days. Radiographic examination of the tooth revealed radiolucency in the disto-proximal aspect, very close to the pulp space. The roots were doubly curved (Bayonet or ‘S’ shaped). From the clinical and radiographic findings, a diagnosis of irreversible pulpitis was made in relation to 15. Hence, endodontic treatment was initiated in 15.The right upper maxillary premolar was anaesthetized with 2% lignocaine and access was opened with a No: 2 round bur, under rubber dam isolation . The comFor determining the patency of the root canals, No:10 SS K-files were used . The bucUnlike the buccal root, the palatal root was negotiable only up to the middle third of the root canal. There was resistance to the movement of the patency file. The palatal root canal was enlarged with protaper rotary instruments (Sx) in a crown down motion, right up to the straight portion of the canal. Once this was done, the patency file slid in easily, to the full length. The working length was established using an apex locator  and confirmed using a radiograph . The roord of the canal (at the expense of the tooth structure) to reduce the angle of curvature. Once this is done, it is easy to negotiate the remainder of the root canal.The ‘S’ shaped canal has two curves, with the apical curve being very difficult to negotiate. The chances of strip perforation are very high in these root canals.  Guttman suggesteIn this case, both the canals were not S-shaped. The buccal canal had only a mild distal curvature; hence this canal was prepared in a crown-down technique using protaper rotary instrument.As the palatal canal was doubly curved, a double flare technique was used to enlarge this canal. The access cavity was flared in the coronal-third, in order to reduce the angle of curvature to the first curve. Reducing the angle of curvature by flaring the access (at the expense of the tooth structure) will make the approach to the second curve much easier. PreflariUnderstanding the complex root canal morphology and choosing a canal preparation technique more suited for such morphology, will contribute to successful endodontic treatment.


Cough is a common and distressing symptom in lung cancer patients. The clinical management of cough in lung cancer patients is suboptimal with limited high quality research evidence available. The aim of the present paper is to present a clinical guideline developed in the UK through scrutiny of the literature and expert opinion, in order to aid decision making in clinicians and highlight good practice.Two systematic reviews, one focusing on the management of cough in respiratory illness and one Cochrane review specifically on cancer, were conducted. Also, data from reviews, phase II trials and case studies were synthesized. A panel of experts in the field was also convened in an expert consensus meeting to make sense of the data and make clinical propositions.A pyramid of cough management was developed, starting with the treatment of reversible causes of cough/specific pathology. Initial cough management should focus on peripherally acting and intermittent treatment; more resistant symptoms require the addition of (or replacement by) centrally acting and continuous treatment. The pyramid for the symptomatic management starts from the simpler and most practical regimens  to weak opioids to morphine and methadone before considering less well-researched and experimental approaches.The clinical guidelines presented aim to provide a sensible clinical approach to the management of cough in lung cancer. High quality research in this field is urgently required to provide more evidence-based recommendations. Cough is a common symptom in about 23-37% of general cancer patients and 47-86% of lung cancer patients . The firWith currently available information, clinicians have difficulty in making appropriate treatment choices, often treating patients on a trial-and-error basis. This has been highlighted through discussions with many clinicians. Our own work with lung cancer patient interviews over time  has showhttp://www.ceco.org.uk) is a collaborative of five UK universities and their clinical partners, funded in 2005 by the National Cancer Research Institute to develop critical mass, capacity and high quality research in supportive and palliative care. Besides its research objectives, the Collaborative also has a remit to have the maximum positive impact on policy and practice. The APM  is a professional society aiming to provide a national and regional network for palliative medicine doctors with a strong focus on developing and implementing educational material, and has strong links with the European Association for Palliative Care.The Task Group was led by the Cancer Experiences Research Collaborative (CECo) with invited experts from the Association for Palliative Medicine (APM). CECo  field. The group met twice, once to agree on the methodology to be used and review the available evidence and once to make sense of this data and develop recommendations.A literature review preceded the meetings over the previous year, with two systematic reviews being undertaken, one with a focus on cough and respiratory illnesses (other than cancer)  and a seAn assessment of the appropriateness, usability and clarity of the guidelines was carried out by international experts N = 15), including 9 consultants in palliative medicine, 4 in medical oncology and 2 specialist palliative care nurses (independent prescribers). This was done through clinicians reading the report and recommendations, and completing a feedback form. A number of items structured in a Likert-type format of 1 = strongly disagree to 5 = strongly agree were included. The areas explored were: the rationale and need for the guidelines ; the need for the development of the guidelines (= 4.8); completeness of literature search (= 4.3); the description of evidence (= 4.6); the methods used to summarise and interpret the evidence (= 4.1); interpretation of the evidence presented (= 4); clarity of the recommendations (= 3.7); agreement with the recommendations made (= 4.1), and feeling comfortable having these guidelines applied in their hospital (= 4). The likelihood of using these guidelines in the reviewers' own practice was explored with a single-item scale ranging from 1 = 'not at all likely to use' to 10 = 'very likely to use', achieving a score of 8.1. After the feedback, the guidelines were modified primarily in relation to the dosages in some drugs, and the clarity and levels of drugs proposed in the cough pyramid  and Aδ fibres (mechanoreceptors) in the airways, carried by the vagus nerve. In disease states, excessive coughing can occur by excessive noxious stimulation of these afferent fibres and/or as a result of sensitization of neurons involved in the cough reflex. In patients with lung cancer, for example, tumour tissue in the central airways may cause mechanoreceptor stimulation directly or indirectly via obstruction and sputum accumulation. The inflammatory mediators associated with infection distal to such an obstruction or mediators released by tumour tissue may further induce coughing by sensitizing peripheral nerves.Patients with lung cancer can experience cough as a result of non-cancer related underlying pathology or cancer itself. The cancer-related causes of cough can include a direct effect of the tumour mass (ie. obstruction), pleural or pericardial effusion, atelectasis, infections, oesophagorespiratory fistulas, lympangitic carcinomatosis, superior vena cava syndrome and treatment-induced cough as a result of radiotherapy or more rarely chemotherapy .Positive and negative trials from our systematic review of cough management in respiratory and non-respiratory diseases are summarized in Table Research into cancer-related cough was even more disappointing, and our Cochrane systematic review  identifiWe also assessed other trials that were not included in the above reviews, phase II trials and experimental case studies. A randomized double blind crossover trial of 16 patients with chronic stable cough was included, receiving Dextromethorphan or Codeine 20 mg) . Results mg . ResThere are, however, some issues with some propositions in the literature, particularly in relation to the effects of opioids. For example Homsi et al  mentioneA thorough history is fundamental to identify the cause of cough and should be taken for each patient with lung cancer in order to identify the causes of cough. This assessment should include the type of cough (productive/non-productive), trigger factors, whether cough is nocturnal or day-time cough, its effects on quality of life or any specific concerns patients may have (e.g. fear of choking during a cough). This assessment should include a careful medication review. Use of a cough scale should be useful in identifying not only the frequency of cough but also its severity and distress. A visual analogue scale is recommended, until validated scales specific for cancer patients are available, which also could be used to assess the effectiveness and responsiveness of initiated interventions. Many of the lung cancer patients have comorbidities with other respiratory diseases (e.g. chronic obstructive pulmonary disease-COPD) and cough may be the result of the underlying respiratory pathology rather than the cancer. The timing of the start of cough is important; any change in cough since the diagnosis with cancer or any new cough is likely to be related with the cancer whereas more chronic cough may be related to underlying respiratory comorbidity. Iatrogenic causes of cough should also be considered, such as radiotherapy and certain medication . Lung cancer patients may not need new investigations, as they may already have x-rays or CT scans that can provide adequate information regarding the cancer-related causes of cough. It may, however, be necessary to carry out such investigations if the causes of cancer-related cough are not apparent from a detailed history.The therapeutic overall goal should first be to treat reversible causes or specific pathology. If the patient has an identified underlying pathology potentially causing cough, he/she should be treated as per available guidelines (ie. BTS guidelines). In cough due to airway diseases such as COPD or asthma, treatments directed at the underlying condition should be used. This could be achieved with the use of inhaled bronchodilators and corticosteroids; for example, salbutamol has little effect in non-asthmatic cough but may be useful when bronchoconstriction is present. The same principle applies to anticholinergics and theophylline. Anticholinergics (e.g. Hyoscine) may be particularly important in the end of life, where the aim is to suppress secretions and subsequent cough. Oral corticosteroids (e.g. Prednisolone 30 mg once daily for 14 days) may also provide rapid relief of cough due to airway inflammation either as a direct result of tumour involvement or associated asthmatic/eosinophilic inflammation. With cough thought to be originating from gastro-oesophageal reflux, PPIs and H2-receptor antagonists may be tried. However, increasing evidence suggests that non-acid reflux pH 4-7) may be associated with chronic coughing in some individuals. Metoclopramide and Domperidone are frequently used to promote GI motility and they should be considered in selected patients where non-acid reflux is suspected. The BTS guidelines . Rap. Rap30]]Symptomatic treatment should start with demulcents such as Glycerol-based ones  and Initial cough management should focus on peripherally acting and intermittent treatment (i.e demulcents); more resistant symptoms require the addition of (or replacement by) centrally acting and continuous treatment. It is noted, however, that peripheral mechanisms may be different in cancer-ulcerated mucosa in localized cancer may result in more or less sensitivity to peripheral agents such as lidocaine or steroids. Furthermore, many patients with advanced cancer will be already receiving strong opioids for pain management which may mean that centrally acting approaches are maximized and less well established treatments should be explored. Behavioural interventions, such as speech pathology training  and vocaA combination of cancer-specific treatments and symptomatic control approaches is likely to be necessary in all patients. The specific balance of these treatments should be determined by the individual patient's needs and a logical stepwise approach to seeking reversible causes and introducing treatments.With the exception of chemoradiotherapy and some treatments for respiratory diseases, the recommendations in the cough management pyramid of Figure Cough is a symptom that has received little attention in cancer supportive care research and it is frequently undertreated in practice as there is a dearth of good quality evidence on which clinicians can base their treatment decisions. These guidelines provide an attempt to rationalize the available evidence and offer a sensible and practical way of managing cough in lung cancer patients. There is an urgent need for more high quality research in the management of cough. Also, as traditional antitussives and other cough suppressants have variable effectiveness and significant side effects, more novel cough treatments need to be developed in the future based on improved understanding of pathophysiological causes of cough in patients with cancer.The authors declare that they have no competing interests.Conception of study, set up of Task Group and coordination: AM.Literature review: AM, JAS, MIB.Task Group participation: All authors.Development of guidelines/recommendations: All authors.Drafting paper: AM.All authors read and approved the final manuscript.


Chronic cough has negative effects on quality of life. However, the changes in health-related quality of life and clinical implications remain unclear in Chinese patients with chronic cough.A standard Chinese version of Leicester cough questionnaire (LCQ) was developed by an established translation procedure and its repeatability was assessed in a preliminary study involving 20 untreated patients with stable chronic cough. The quality of life was measured with the Short form-36 health survey and compared between 110 patients with chronic cough and 90 healthy volunteers. The changes in health-related quality of life were evaluated in the patients with chronic cough with the LCQ just before the specific treatment was initiated and a week after the cough had resolved completely. Cough threshold with inhaled capsaicin, expressed as the lowest concentration of capsaicin required for the induction of ≥5 coughs, was also measured.P < 0.0001). There was a significant correlation between the total score of the LCQ and physical  or mental  component summary of the Short form-36 health survey but not between the LCQ and capsaicin cough threshold.The repeatability of the Chinese version of the LCQ was validated at a four day interval with the intraclass correlation coefficients of 0.89-0.94 for total and domain score (n = 20). The scores of the Short form-36 health survey were significantly lower in patients with chronic cough than those in healthy volunteers. In general, there was no significant difference in overall quality of life between different causes of chronic cough or genders although embarrassment, frustration and sleep disturbance were more common in female patients, as indicated by the LCQ. However, the successful treatment of cough obviously increased the total scores of the LCQ from 14.2 ± 2.7 to 19.5 ± 1.9 (t = 13.7, The quality of life is significantly impaired in Chinese patients with chronic cough. The Chinese version of the LCQ is a valid measure of cough related quality of life and is repeatable and responsive. Chronic cough is a common symptom that involves 20%-38% of the patients seeking medical advice in the respiratory clinic ,2, and aCough symptom score, generic instruments such as the Short form-36 health survey (SF-36), Sickness impact profile and the other respiratory health questionnaires were common tools for the evaluation of HRQOL in chronic cough in early years . Cough sIt has been demonstrated that chronic cough has negative effects on HRQOL of patients in many aspects including physical, psychological and social domains, among which the adverse impact on the psychosocial domain is the most notable and possibly related to gender . Success1) > 80% of predicted and a ratio with forced vital capacity (FEV1/FVC) >70%. Current smokers and ex-smokers of < 2 years were excluded.110 patients with chronic cough referred consecutively to the Department of Respiratory Medicine in Tongji hospital were selected for the study. They were eligible for inclusion in case of the presence of an isolated persistent cough of > 8 weeks, the absence of adventitious lung sounds on physical examination, normal findings on plain chest radiography, a forced expiratory volume in 1 s  of the Chinese version of LCQ over time. The reliability was assessed by administering the LCQ to 20 untreated patients with stable chronic cough at baseline and four day later when the patients did not feel that their cough had changed.cough sensitivity was measured according to the method described by Fujimura  with minThe etiologies of chronic cough were identified and treated by our established protocol . Just bes except for duration of cough and cough threshold C5 which were presented as median (range). Comparisons of variables between the patients with chronic cough and healthy volunteers were made using unpaired t-tests while the difference of gender distribution was examined using X2 analysis. Changes in HRQOL before and after treatment were analyzed by paired t tests. Comparisons between the different etiologies of chronic cough were performed with one way analysis of variance followed by q-test. The repeatability of Chinese version of LCQ was analyzed by calculating intraclass correlation coefficients of LCQ total and domain scores between the two evaluations. The relationships between log transformed cough threshold C5 (Log C5) and LCQ or SF-36 score were calculated using Spearman rank order correlation coefficient. SPSS 10.0 software  was used for statistical calculations. A P-value < 0.05 was considered significant.The data was expressed as P = 0.000) for total score, 0.89  for the physical domain score, 0.93  for the psychological domain score and 0.92  for the social domain score respectively.The intraclass correlation coefficient of LCQ repeatability was 0.94  or MCS  of SF-36 respectively. The median of cough threshold C5 was 3.9 μmol/L . No significant correlation was found between Log C5 and LCQ , PCS  or MCS  of SF-36.There was a weak but significant correlation between the total score of LCQ and PCS (r = 0.39, The quality of life is an important outcome parameter in the study of chronic cough. To investigate HRQOL of Chinese patients with chronic cough, we compared the scores of items in SF-36 between patients with chronic cough and healthy volunteers. The reasons for selection of SF-36 were that SF-36 is one of the most common instruments in general health survey, its reliability and validity have been established with extensive application . MoreoveThe results showed that the quality of life in patients with chronic cough deteriorated significantly when compared with healthy volunteers. The scores of patients with chronic cough were lower in 7 testing multi-item scales of SF-36 except for physical pain than those of healthy volunteers. Among the affected domains, the decrease in the scores of RE, GH and RP related to emotional problems was more obvious. These observations were in accordance with previous reports on HRQOL in patients with chronic cough -8,19.There was comparable HRQOL among the patients in spite of causes of chronic cough, which confirmed the findings of French and Canonica who had observed that HRQOL in the chronic coughers was unrelated to the causes of cough ,20. The Gender is one possible factor determining the quality of life of patients with chronic cough. Most studies have demonstrated that women accounted for the majority of patients with chronic cough seeking medical care, with the ratio of 1:1.2-3.6 between males and females ,25. It sAnother possibility is that the quality of life in the patients with chronic cough visiting hospital was affected in a similar level regardless of gender. Women with chronic cough were more likely to see a doctor than men because of embarrassment and the other psychosocial issues provoked by cough-related urinary incontinence . HoweverWhen cough resolved with successful treatment specific for the cause, the quality of life in the patients could be significantly improved as judged by total score and domain scores in LCQ, which is in accordance with the previous study . TherefoBirring and Kalpaklioglu have found that there was a negative correlation between LCQ and the other tools such as cough symptom score and visual analogue scale respectively ,27. ReceThere was no obvious correlation between LCQ and capsaicin cough threshold, which was similar to the results reported by Birring  and ChanIn conclusion, HRQOL is adversely affected by chronic cough but improves when cough resolves. In general, the changes in HRQOL are not related to the causes of cough and gender differences although some negative emotions are more obvious in female Chinese patients. The Chinese version of LCQ is useful tool for evaluation of the health status in Chinese patients with chronic cough.The authors declare that they have no competing interests.WM was in charge of collection of cases and writing the manuscript, LY was in charge of collection, process, and statistical analysis of data and took part in review of the manuscript, YW, XL and HL took part in the collection of cases and review of the manuscript, ZQ was in charge of design and coordination of the program, review and correction of the manuscript. All authors read and approved the final manuscript.LCQ in Chinese. The Chinese version of Leicester Cough Questionnaire provided is the translation of the original one.Click here for file


Many tussive agents are components of foods, but little is known about the relationship between cough reflex and oral chemesthesis sensitivities. We investigated the relationships between cough reflex and oral chemesthesis in individuals using two transient receptor potential vanilloid 1 (TRPV1) agonists with different potencies: capsaicin and capsiate.Twenty-eight healthy never-smokers were allocated to evaluate cough and oral chemesthesis of capsinoids. Cough reflex sensitivities are estimated by the lowest concentrations generating five coughs by each TRPV1 agonist inhalation. Oral chemesthesis sensitivities are estimated by the lowest concentrations which generate a hot sensation when filter paper loaded with each TRPV1 agonist is placed on the tongue.There were strong correlations between capsaicin- and capsiate-induced cough reflex sensitivities, and between capsaicin- and capsiate-induced oral chemesthesis sensitivities. However, there were no significant correlations between cough reflex and oral chemesthesis sensitivities induced by both capsaicin and capsiate. The cough reflex sensitivities are significantly greater in females than in males whereas there were no gender differences in oral chemesthesis.The results showed that the sensitivities of sensory afferents were different between cough reflex and oral chemesthesis, suggesting that TRPV1 sensitivities differ between organs within healthy individuals. Capsiate could be a tussigen for the cough challenge test. Although many tussive agents, such as capsaicin, citric acid, and acetic acid, are components of foods, it is unknown whether these chemical stimuli equally stimulate sensory nerves in bronchial airways and the oral cavity. The inhalation of tussive agents as a cough challenge test is a useful method to quantify cough in a clinical setting and to assess the antitussive effects of specific therapies in a laboratory setting . The inhThe physiological effects of capsaicin on cough may be modulated by oral sensory stimuli. Activation of capsaicin-sensitive afferents in the tongue and palate evoke local release of neuropeptides such as substance P and calcitonin gene-related peptides, which are contained in the nerve terminal of the sensory neurons ,4. The nMoreover, in the brain, the gustatory fibers and the sensory fibers that initiate cough may interact with each other because of the close anatomical relationship . In ordeCapsium fruits are used worldwide in foods for their pungency. The pungency felt when eating Capsium fruits is mainly attributed to the activation of oral TRPV1 [Capsaicin acts mainly on the afferent neurons of the non-myelinated C-fibers by the opening of a non-selective cation channel of capsaicin receptor, transient receptor potential vanilloid 1 (TRPV1) . Capsiatal TRPV1 .TRPV1 receptors found on sensory airway nerves are important in the cough reflex . IsolateCapsaicin-induced cough may not solely be mediated through the nerves expressing TRPV1 receptors. Capsaicin inhalation elicits cough through the activation of rapidly adapting receptors (PAR) ,18. The In order to investigate the possible relationship between the perception of sensations mediated by TRPV1, whether directly or indirectly, in different organs, e.g. lung and tongue within individuals, we compared cough reflex and oral chemesthesis sensitivities using two TRPV1 agonists with differential potencies, capsaicin and capsiate. In addition, we evaluated the possibility of the use of capsiate as a cough challenge test.Twenty-eight healthy never-smokers  were allocated to evaluate cough and oral chemesthesis of capsinoids. All were originally recruited via public postings in and around the Tohoku University School of Medicine campus. The mean age was 36.4 ± 2.3 (SE) years. The study was approved by the Institutional Review Boards of Tohoku University School of Medicine. Subjects were without history of pulmonary disease, recent (within 4 weeks) suggestive symptoms, respiratory tract infection and seasonal allergies. Subjects did not take any regular medication.Subjects underwent the sensitivity tests on four successive days at 10:00 am. Each of the four days was assigned to the capsaicin cough sensitivity test, the capsaicin oral chemethesis test, the capsiate cough sensitivity test, or the capsiate oral chemesthesis test. The order of the four tests was randomly decided using a computer program. The day before the start of the test and during the four days, subjects were prohibited from taking any capsinoids in meals or beverages. In order to ensure subjects avoid consumption of capsinoids during meals, various foods and dishes that contain them were explained to the subjects.Cough reflex sensitivities to capsaicin and capsiate were measured on different days using the modification of the method by Fujimura and colleagues . 30.5 mgCapsiate was extracted from CH-19 sweet . Compared with capsaicin, capsiate has an ester bond instead of the amide bond between the vanillyl moiety and fatty acid chain . Increasing concentrations were inhaled until five or more coughs were elicited. The nebulizer output was 0.21 ml/min. The cough reflex sensitivities to capsaicin and capsiate were defined as the lowest concentration of capsaicin or capsiate that elicited five or more coughs (C5). In our preliminary experiments, it was confirmed that the Tween 80 and/or caprylic acid dilutions at any concentration used in saline without capsinoids did not induce cough for 15 s inhalation.Chemesthesis to capsaicin and capsiate was measured with a modification of the semi-quantitative clinical gustometry using a filter-paper disc, which is routinely used for the evaluation of dysgeusia in a clinical setting . Again, In our preliminary experiments, it was confirmed that the Tween 80 and/or caprylic acid dilutions at any comparable concentrations in distilled water without capsinoids did not induce oral chenesthesis, and it was certified that there was no tachyphylaxis of responses to capsinoids with 24-hour intervals for both cough reflex sensitivities oral chemesthesis.Results are expressexd as mean ± SE. Comparisons between each threshold concentration in differential stimuli were performed by a paired t-test. Comparisons between the sensitivities in males and females were performed by the Mann-Whitney test. The correlations between each threshold concentration in differential stimuli were estimated by Pearson's correlation coefficient. A value of p < 0.05 was considered statistically significant.5 value) was significantly greater in capsiate (2.55 ± 0.09 log μM) than in capsaicin (1.20 ± 0.09 log μM) (p < 0.0001). The mean threshold concentration to induce oral chemesthesis by capsiate (2.22 ± 0.10 log μM) was significantly greater than that by capsaicin (1.55 ± 0.11 log μM) (p < 0.0001). The mean threshold concentration for capsaicin application was significantly greater in cough reflex sensitivity than that in oral chemesthesis (p < 0.03).Both cough reflex sensitivities and oral chemesthesis tests were performed without any unpleasant feelings or side effects after the tests for all subjects. The mean threshold concentration to induce cough .As shown in Figure However, there was no significant correlation between cough reflex and pungent taste sensitivities induced by capsaicin . Similarly, there was no significant correlation between cough reflex and pungent taste sensitivities induced by capsiate . These results suggest that the same TRPV1 stimulation induce differential strength of sensation according to the organs within individuals.Table In this study, no significant relationship between cough reflex sensitivity and oral chemesthesis to capsinoids within individuals was found. The cough reflex to TRPV1 stimulations are less sensitive in males than in females whereas there was no significant gender difference in the oral chemesthesis to capsinoids. Here we showed that the usefulness of capsinoids with respect to both their action as a tussigen and the capability to evoke oral chemesthesis.A strong correlation between the threshold concentrations between capsaicin- and capsiate-induced cough was found. Similarly, the threshold concentrations between capsaicin- and capsiate-induced oral chemesthesis significantly correlated. In both sensations, capsiate required a much higher concentration than capsaicin. The intragastric administration of capsiate increases adrenalin secretion and oxygen consumption in mice ,22. In aIndividual variations in cough reflex sensitivities were shown in the cough challenge test even in healthy subjects. The variation exists regardless of methods of cough challenge and tussive stimulants. Cough reflex is reportedly less sensitive in men than women ,9. AlthoThe explanation for an increase in cough reflex sensitivity in healthy females is unknown. One hypothesis is an endocrine influence on the cough reflex. Recently, prolactin was reported to enhance TRPV1 response in the presence of estrogen in rat sensory neurons . HoweverBoth the peripheral and central explanations for why oral chemesthesis are not correlated to cough reflex sensitivity are postulated. The lack of relationship between oral chemesthesis and cough reflex sensitivity within individuals may suggest a differential expression of TRPV1 according to the organs within individuals. In patients with chronic cough, increased expression of TRPV1 in airway nerves was reported . InflammMore importantly, the differential sensitivities to capsinoids between cough reflex and oral chemesthesis could be reflected in the differential contribution of indirect activation of afferent neurons. In cough response, capsaicin is known to activate not only C-fibers that have TRPV1 but also rapidly adapting airway mechanoreceptors (PAR) that do not have TRPV1 ,18. PAR Besides the peripheral factors, central factors may be involved in the differential sensitivities of TRPV1 stimulation between cough reflex and oral chemesthesis within individuals. In contrast to oral chemesthesis, which was finally integrated by cortical processing, cough reflex is essentially a brainstem reflex. Therefore, there is a possibility that the gain of a cortical neural process is involved in the differences in oral chemesthesis, but not in cough reflex. Evidence of gustatory brainstem taste nuclei and cortical connections, which potentially modulate these processes, provide a plausible neural basis for a central gain mechanism ,36. ReceThe lack of relationship between oral chemesthesis and cough reflex sensitivity within individuals might suggest the low possibility of a modulatory effect of capsinoids which were deposited in the oral cavity during the cough challenge test. Although the concentration to induce oral chemesthesis to capsinoids is relatively smaller than that of cough reflex, oral chemesthesis did not trigger cough responses in the present healthy subjects. The lack of gender difference in oral chemesthesis also supports the no modulation hypothesis.In the present study, we found that the capsiate does not induce the sustained irritant airway feeling that is frequently observed in the case of the capsaicin cough challenge test. This might be attributed to the lipohilicity and instability of capsiate. Although this biophysical feature of capsiate is a disadvantage for the preparation procedure, this could be a benefit for the subject to avoid uncomfortable feelings after the cough challenge test .In conclusion, the results showed that the sensitivities of sensory afferents were different between cough reflex and oral chemesthesis, suggesting that TRPV1 sensitivities differ among organs within healthy individuals. The results also suggest that capsiate could be a useful tussigen for the cough challenge test.The author(s) declare that they have no competing interests.MY, SE and TE participated the design of the study, collected and analyzed data, and drafted the manuscript. SF, SY, AM and MY participated in the design of the study and collected the data. HA participated in design of the study and helped to draft the manuscript. All the authors read and approved the final manuscript.


The microcapsules were discrete, large, almost spherical and free flowing with encapsulation efficiency in the range of 75% to 89%, drug loading 75% to 86% and size 440 μm to 500 μm. Rifampicin release from these microcapsules was slow and extended over longer periods of time depending on the polymer coat. Drug release was diffusion controlled and followed first order kinetics. The formulation MC1 with a coating ratio of 1:1  was found to be suitable for oral controlled release.Rifampicin biodegradable microcapsules were prepared by feasible emulsification-ionic gelation method for a novel controlled release product. Sodium alginate and Carbopol 974P were used as coating polymers in different ratios 1:1, 1:2, 1:3 and 1:4 to obtain elegant microcapsules. The formulations were characterized for encapsulation efficiency, drug loading, sieve analysis, scanning electron microscopy and  Controlled release dosage forms are becoming increasingly important, either to achieve the desired level of therapeutic activity required for a new drug entity or to extend life cycle of an existing drug through improved performance or patient compliance. Microsphere technology is one of the established techniques for controlled delivery used to deliver several different types of drugs, such as steroids, peptide4Rifampicin, a semi synthetic hydrazine derivative of rifampicin B was chosen for the study because it is one of the established first-line drugs used to treat tuberculosis and its biological half-life varies from 1.5 to 5 h.Carbopol 974P is a synthetic high molecular weight cross-linked polymer of acrylic acid. It is a safe and nontoxic. It is an excellent thickening, emulsifying, suspending and gelling agent. Because2+, giving both strength and flexibility. Such a cross-linking process stiffens and roughens the polymer and reduces the swelling in solvents. The soluble sodium alginate was cross-linked with calcium chloride, resulting in the formation of the insoluble calcium alginate. This strong thermo stable gel has properties that largely depend on the characteristics of the polymer and the preparation method[Alginates are a family of polysaccharides composed of α-L-glucoronic acid (G) and β-D-mannuronic acid (M) residues, arranged in homopolymeric blocks of each type  and in heteropolymeric blocks of each composition. Alginates form strong gels with divalent cations like Caon method–9.Rifampicin was obtained as gift sample from On Top Pharmaceuticals . Carbopol 974P was obtained from Astra Zeneca Labs. . Sodium alginate was procured from Rolex Laboratories . Tween-80, ascorbic acid LR and calcium chloride were purchased from S. D. Fine Chemicals . Toluene and petroleum ether were purchased from Nice Chemicals , while castor oil was procured from Standard Labs. . All other reagents used were of analytical grade.Microcapsules containing rifampicin were prepared employing carbopol 974P in combination with sodium alginate as coat materials. No methods are reported for micro encapsulation by these polymers. The ionic gelation process11, whichSize of the rifampicin microcapsules was determined by sieve analysis. The microcapsules were separated in to different size fractions by sieving using standard sieves. The particle size distributions of the microcapsules were determined to know the mean particle size of microcapsules. All readings are average of three trials ±SD.The shape and surface morphology of the rifampicin microcapsules were investigated using a Hitachi-S5-20, scanning electron microscope at room temperature using the required magnification. The sample was deposited on alluminium stubs and coated with gold in HUS-5GB vacuum evaporator, to render it electrically conductive. Encapsulation efficiency was calculated using the formula, Encapsulation efficiency= ×100.Rifampicin content in the microcapsules was estimated by using UV spectrophotometer method. A quantity of microcapsules equivalent to 100 mg were powdered and transferred into a 100 ml volumetric flask, sufficient amount of methanol was added to produce 100 ml, shaken for 20 min and filtered. Two milliliters of the filtrate was diluted to 100 ml with phosphate buffer (pH 7.4) containing ascorbic acid (200 μg/ml) and the drug content was analyzed at 475 nm. Three dDissolution studies were carried out using USP XXIV rotating basket method. The stirring rate was 75 rpm. 900 ml of pH 7.4 phosphate buffer having ascorbic acid (200 μg/ml) was used as dissolution medium and maintained at 37±1°. Samples of 5 ml each were withdrawn at regular time intervals, filtered, diluted suitably, analyzed using double beam UV spectrophotometer at 475 nm and an equal volume of fresh medium was immediately added to maintain the dissolution volume. Dissolution studies were carried out up to 12 h. The drug release experiments were conducted in triplicate.t/Mα = Ktn, where Mt/Mα is the fractional solvent absorbed or drug release at time ‘t’; K denotes a constant incorporating the properties of the macromolecular polymeric system and the drug and ‘n’ is a kinetic constant which depends on time and is used to characterize the transport mechanism. While n= 0.45 for case I or Fickian diffusion which is characterized by a square root time dependence in both the amount diffused and the penetrating diffusion front position; n= 0.89 for case II transport, which is completely governed by the rate of polymer relaxation, exhibits a linear time dependence in both the amount diffused and the penetrating swelling front position; n= 0.45<n<0.89 for anomalous behavior or non-Fickian diffusion and polymer relaxation are comparable[The results obtained were fitted according to the following exponential equation, Momparable.IR studies (not shown) indicated that the qualitative composition of the drug formulation and verified the identity of each of the components. No drug interaction or complexation occurred during the manufacturing process.et al, have prepared carbopol microspheres by using modified U-shaped beaker, a two blade paddle stirrer and maintaining a temperature of 60° for a period of 24 h to promote the evaporation of water[Kockisch  of water15. Micro of water17. HenceRifampicin release from the microcapsules was studied in phosphate buffer pH 7.4 containing ascorbic acid (200 μ/ml) in dissolution test apparatus USP XXIV using rotating basket. Rifampicin release from the microcapsules was slow and spread over a period of 12 h and depended on coating ratio  and size of the microcapsules. As the proportion of carbopol 974P was increased, rifampicin release rate was decreased from 91.2, 81.7, and 80.5 to 69.5% respectively.t/Mα) versus Log t . If the polymer does not hydrate quickly the surface barrier or gel is not formed immediately, it results in a large portion of drug to be released during the initial phase of release profile (MC1) . Sodium Spherical microcapsules with a coat consisting of alginate and carbopol could be prepared by emulsification-ionic gelation process. Microencapsulation efficiency was found to be in the range 76-90%. Rifampicin release from the polymer coated microcapsules was slow and extended over longer periods of time and depended on core: coat ratio and size of microcapsules. Drug release from the polymer coated microcapsules was by fickian diffusion and followed first order kinetics. Thus carbopol 974P and sodium alginate coated rifampicin microcapsules were found suitable for oral controlled release products.


A 58-year-old nonsmoker female was referred for evaluation of chronic cough of 13 months duration. After an initial work-up, the patient was diagnosed to have chronic cough due to eosinophilic bronchitis. The diagnostic work-up for eosinophilic bronchitis and bronchial biopsy is discussed. Eosinophilic bronchitis is differentiated from asthma. In addition, the patient developed dyspnea, flushing, and wheezing after the administration of adenosine during a cardiac stress test in spite of a negative methacholine challenge. This indirect stimulus of airway hyperresponsiveness suggests the possible involvement of mast cells in eosinophilic bronchitis. Eosinophilic bronchitis is an uncommon cause of chronic cough in the general practice; however, this entity has been found to be present in 10–20% of patients referred for an investigation by a specialist  and has A 58-year-old post menopausal nonsmoker Caucasian female was evaluated for chronic cough of 13 months duration. The patient has a past medical history significant for hyperlipidemia, and obstructive sleep apnea. The cough was described as a dry cough and was severe enough to cause her to gag and vomit. She reported frequent nighttime awakenings due to cough. Initial work-up at another facility was reported as normal pulmonary function tests, negative methacholine challenge test, normal chest radiogram, normal chest and sinus CT scans, and a normal inspection of vocal cords, trachea, and bronchi by flexible bronchoscopy. A bronchial biopsy was performed during the bronchoscopy and results are reviewed below. She was prescribed an empiric one-week trial of prednisone which resulted in near resolution of her cough. The patient was then started on inhaled fluticasone and tiotropium without a clear diagnosis given. As a consequence, she was uncertain about the use of the inhalers and was noncompliant. The cough came back prompting another evaluation. The cough was not associated with rhinorrhea, sneezing, wheezing, dyspnea, postnasal drip, heartburn, chest pain, fever, sputum production, hemoptysis, weight loss, or night sweats. She denied ever having had exposure to immigrants or any travel outside her home state. No history of ACE inhibitors intake was noted. The patient worked with Christmas trees helping to shear, bale, and make wreaths. She has a dog at home but no other pets. She has no prior history of allergies or allergy testing. The patient did not have a history of childhood asthma, sinusitis, GERD, hayfever or tuberculosis, and no history of indoor hot tub. In addition, the patient complained of bilateral sharp chest discomfort for about 10 months, associated with the cough episodes, nonradiating and not associated with exercise, nausea, or diaphoresis.9/L , and differential evidenced 60% Neutrophils, 1% eosinophils, 35% lymphocytes, and 4% monocytes. Electrolytes including sodium, potassium, chloride, calcium, magnesium, and phosphorus were within normal limits. Serum creatinine and BUN were 0.8 mg/dL , and 12 mg/dL  respectively. Serology for Bordetella pertussis and Respiratory Syncytial virus (RSV) were negative. Her oral exhaled nitric oxide was elevated to 158 parts/billion . The biopsy of the left main bronchus was reviewed and revealed peribronchiolar chronic inflammation with eosinophils and thickened basement membrane . Chest CT showed no infiltrates or pleural effusions, and no abnormal hilar or mediastinal lymphadenopathy. CT scan of the sinuses showed normal mucosal thickening and no air-fluid levels. A 24-hour esophageal pH probe of proton pump inhibitor excluded gastroesophageal reflux disease. CBC showed hemoglobin of 13.6 g/dL , the WBC was 9.2 × 10membrane . Sputum The diagnosis of eosinophilic bronchitis is usually made in patients with chronic cough and airway eosinophilia in the absence of dyspnea, wheezing, airflow limitation, and lack of airway hyperresponsiveness measured by the methacholine challenge test. When facing a patient with chronic cough, it is always very important to exclude other common causes of chronic cough such as gastroesophageal reflux disease, asthma, or upper airway cough syndrome. Asthma, cough variant asthma, and EB share many features including chronic cough and airway eosinophilia . However, the hyperresponsiveness provocative test with methacholine is positive with asthma or cough variant asthma; whereas it is negative with EB and helps to differentiate these entities .Erlich described the eosinophil more than 100 years ago and its presence in the sputum was initially recognized as an important marker in asthma . EosinopThe histological changes described in the biopsy of EB are seen also in asthma and cough variant asthma, and a similar Th2 cytokine driven airway inflammation has been proposed in both entities , 9; howeThe presence of elevated oral exhaled nitric oxide (eNO) has been correlated with predominantly eosinophilic airway inflammation and can be seen in both asthma and EB , 5. TreaOur patient developed symptoms and signs suggestive of airway hyperresponsiveness after the administration of intravenous adenosine for the cardiac stress test that was ordered to evaluate her atypical chest pain. Adenosine type 2 receptors are found in the mast cells and when stimulated can potentiate the histamine release from these cells and therefore precipitate bronchoconstriction . InteresEosinophilic bronchitis is a common cause of chronic cough in referral centers. It shares similarities with asthma such as increased eosinophils in the airways, increased IL-4 and IL-5, and improvement of symptoms with inhaled corticosteroids; however, eosinophilic bronchitis differs from asthma because it presents with normal pulmonary function and normal airway responsiveness. We described the first case of airway hyperresponsiveness after systemic administration of adenosine in a patient with eosinophilic bronchitis presenting as chronic cough.