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Background: Chronic cough is a major health problem worldwide and patients are best managed in specialised tertiary centres. Little information is available on the characteristics of chronic cough patients in several European countries, including Italy. Aims: We report on the demographic, anthropometric and clinical features of a large Italian population of adult chronic cough outpatients (about 1200), who were referred to a specialised clinic in Florence, Italy, from 2008 to 2018. Methods: Demographic, environmental, lifestyle and clinical information was collected at enrolment by means of a custom-designed electronic questionnaire that only allowed for uniform responses. A subjective measure of cough-related discomfort (cough score) was also obtained using a modified Borg Scale. A multivariable logistic regression model was defined to identify the patients’ characteristics associated with the cough score. Results: The characteristics of the examined population (n= 1204 outpatients) were strikingly similar to those described elsewhere. Female patients outnumbered the males [n= 847 females, (70.0%)]; both females and males displayed the same average cough score. The median age of outpatients was 61 (quartile 1 = 48; quartile 3 = 70) years; age and cough duration were unrelated to the cough score. Nasal obstruction, coughing during consultation, coughing during meals, throat clearing and the presence of respiratory abnormalities were correlated with the degree of discomfort caused by coughing. Discussion: The features of chronic cough patients are similar worldwide. The process of cough reflex hypersensitisation may soothe sex-related perceptual differences, leading to similar levels of discomfort. Conclusions: There seem to be clinical indicators that help in assessing the level of cough-related discomfort.

This paper summarizes the presentations submitted for publication of the 12thAIST National Congress (Associazione Italiana Studio Tosse/Italian Association for Cough Study) entitled “The thousand facets of cough. A clinical and therapeutic update”, which occurred last February 2nd-3rd, 2018 in Bologna (Italy). It summarizes the contributions from leading experts of the sector, who, as in the previous editions, also this year have analyzed a problem too often underestimated which still has many dark sides as regards both the diagnosis and the therapy of cough. The Scientific Committee has chosen topics that had less space in previous editions and these are topical subjects representing a concrete opportunity for learning and comparison of opinions, as well as indispensable elements for the correct management of the symptoms. Hereby we report the abstracts of the works submitted for publication in this Meeting report. The main topics have covered Cough relationship with nerve vagus, ATP, air pollution, GERD, imaging, COPD, pediatric and therapy. Of particular interest it is the preliminary data on cough hydration ratio that shows a highly significant correlation between dehydration and cough.

Cough is produced by the same neuronal pool implicated in respiratory rhythm generation, and antitussive drugs acting at the central level, such as opioids, may depress ventilation. Levodropropizine is classified as a nonopioid peripherally acting antitussive drug that acts at the level of airway sensory nerves. However, the lack of a central action by levodropropizine remains to be fully established. We set out to compare the effects of levodropropizine and the opioid antitussive agent dihydrocodeine on the respiratory responses to a conventional CO2rebreathing test in patients with chronic cough of any origin.

Acute cough is one of the most frequent symptoms prompting a visit to a health care provider, usually following a viral upper respiratory tract infection (URTI). The disproportionate use of antibiotics in children with URTIs, recently highlighted in the medical literature, could lead to associated side effects, without any beneficial effect. Although an early, albeit inappropriate, antibiotic prescription increases parental satisfaction, URTIs are predominantly viral infections and are generally self-limiting. Therefore the aim of this study was to analyze the effectiveness of antibiotics compared to symptomatic drugs (central and peripheral antitussives) on URTI-related cough in a pediatric population. This is a prospective observational study of 330 children who required pediatric consultation for acute cough. Severity, frequency and type of cough were assessed at baseline and after 6 days of treatment (antitussives n= 123, antibiotics n= 89 or combination of them n= 38) or no treatment (n= 80). The outcome of cough management after 6 days was analyzed in terms of resolution, improvement, no change or worsening of symptoms. Study assessments were performed using a standardized questionnaire administered to parents. Between children treated with antitussives or antibiotics, there was a statistically significant difference in the resolution of cough. Moreover, if considering peripheral antitussives, the resolution of cough was significantly higher with antitussives than with antibiotics (p< 0.01). There was no difference in cough resolution between children treated with antitussives and those receiving a combination of antibiotics and antitussives, either central and peripheral antitussives. Antibiotics are generally not useful nor appropriate in treating acute cough due to the common cold. Furthermore, inappropriate antibiotic use introduces the possibility of adverse side effects as well as promotion of antibiotic resistance. The findings of the present study suggest that antitussives, especially peripherally acting agents, represent an effective treatment option for acute pediatric cough caused by URTIs.

Fashion is a complex social and cultural phenomenon with strong economic implications. Historical analysis reveals that the mechanisms of creating and spreading fashion have not remained constant, but have varied according to social structures, forms of producing and distributing apparel and social media, while the level of influence of fashion on society has increased in line with economic development. This special issue of Investigaciones de Historia Económica-Economic History Researchis dedicated to fashion as an economic phenomenon in the contemporary period. The four articles which make it up show the plurality of the subject areas, sources and methodological approaches in the current research on this topic.

Patients with deflation cough (DC), the cough-like expulsive effort(s) evoked by maximal lung emptying during a slow vital capacity maneuver, also present symptoms of gastroesophageal reflux. DC can be inhibited by prior intake of antacids. We wished to assess DC prevalence and association between DC and chemical characteristics of refluxate in patients with gastroesophageal reflux symptoms.

Cough is one of the most common symptoms for which patients seek medical attention from primary care physicians and lung specialists. About 40% of the population at any one time report cough. Cough is associated with significantly impaired health-related quality of life. Levodropropizine is an effective and very well tolerated peripheral antitussive drug. We want to compare it to central cough suppressants efficacy (opioids and non-opioids) that may be associated with side effects limiting their use. After a comprehensive literature search, a meta-analysis of 7 clinical studies of levodropropizine vs. control, including a total of 1,178 patients, was performed with the aim to evaluate the overall comparative efficacy of levodropropizine in the pediatric and adult population. Three electronic databases and reference list were used to search for studies that assessed the efficacy of levodropropizine for treating cough in children and adults using as standardized efficacy parameters the cough frequency and severity, and number of night awakenings as outcome parameters. The meta-analysis of all standardized efficacy parameters showed a highly statistically significant difference in the overall antitussive efficacy in favor of levodropropizine vs. control treatments (p = 0.0015). The heterogeneity test for the efficacy outcome was not statistically significant (p = 0.0534). Seven studies met out inclusion criteria. A meta-analysis of the eligible ones showed a statistically significant difference in the overall anti-tussive effect of levodropropizine versus control (p = 0.0015). This analysis indicates that levodropropizine is an effective antitussive drug in children and adults, with statistically significant better overall efficacy outcomes vs. central antitussive drugs (codeine, cloperastine, dextromethorphan) in terms of reducing cough intensity and frequency, and nocturnal awakenings. This result further reinforces the favorable benefit/risk profile of levodropropizine in the management of cough. The efficacy of levodropropizine in the treatment of cough in children and adults is higher than that of the common centrally-acting anti-tussive.

In 2008, the first transplantation of a tissue-engineered trachea in a human being was done to replace an end-staged left main bronchus with malacia in a 30-year-old woman. We report 5 year follow-up results.

Aim: Spacer devices are inhalation aids of varying dimension and complexity, specifically designed to overcome problems with the use of pressurised metered dose inhalers (pMDIs). The aim of this review is to examine the current understanding about these inhalation devices and discuss their advantages and disadvantages. Methods: The pertinent literature concerning the characteristics and effects of spacers on delivery and lung deposition of inhaled medications, as well as their clinical efficacy in patients with reversible airway obstruction, is examined. Results: Spacers minimise problems of poor inhalation technique with pMDI, reduce oropharyngeal deposition and increase lung deposition. Spacers improve the clinical effect of inhaled medications, especially in patients unable to use a pMDI properly. Compared to both pMDIs and dry-powder inhalers, spacers may increase the response to β-adrenergic bronchodilators, even in patients with correct inhalation technique. A pMDI plus spacer has proven to be viable lower cost alternative to the use of a nebuliser for delivering large bronchodilator doses in patients with severe acute asthma or chronic obstructive pulmonary disease. The use of large-volume spacers is recommended for delivering high doses of inhaled corticosteroids, and may permit a lower maintenance dose to be used. Conclusion: pMDIs may be routinely fitted with a spacer, especially in situations where correct pMDI use is unlikely.

We investigated the effects of static and rhythmic handgrip on the time course of recovery of airway resistance measured with the interrupter technique (Rint) following bronchoconstriction induced by methacholine (MCh) inhalation in 17 asthmatic patients. On three separate occasions, a 100 ± 5% increase in baseline Rint was induced by MCh inhalation. Subsequently, patients either rested [control trials (CTs)] or performed 3-min bouts of static or rhythmic handgrip. Respiratory and cardiovascular variables were continuously monitored. Rint changes were assessed at 1-min intervals for 30 min after rest and both types of handgrip. Plasma catecholamine concentrations were also determined at scheduled intervals. Bronchoconstriction increased ventilation (P< 0.01) but did not affect cardiovascular variables and plasma catecholamine concentrations. Handgrip provoked an increase in cardiovascular variables (P< 0.01) and plasma norepinephrine concentrations (P< 0.05) but caused no additional changes in ventilation. Rint only partially recovered within 30 min after CTs, whereas it consistently decreased 1 min after both handgrip paradigms and remained lower than after CTs (Palways <0.01) for the whole 30-min observation period. Sympathetic activation and withdrawal of cholinergic input to the airway smooth muscle reflexly induced by activation of skeletal muscle and carotid sinus receptors may be the primary events accounting for the bronchodilator response induced by handgrip. Mediators co-released in response to sympathetic activation may also have contributed.

In this paper, some physico-chemical properties of a novel class of α–ω hydrofluoropolyethers (HFPEs) having terminal hydrogen atoms are presented and compared with those of similar perfluorinated structures. The effect of –CF2H end groups has been studied for the lower members of this family and its group contributions, determined for some physico-chemical properties, have been calculated and can be used to predict properties of new structures.

We investigated the behavior of medullary respiratory neurons in cats under pentobarbitone anesthesia, vagotomized, paralysed, and artificially ventilated to elucidate neural mechanisms underlying apnea and poststimulatory respiratory depression induced by superior laryngeal nerve (SLN) stimulation. Inspiratory neurons were completely inhibited during SLN stimulation and poststimulatory apnea. During recovery of inspiratory activity, augmenting inspiratory neurons were depressed, decrementing inspiratory neurons were excited, and late inspiratory neurons displayed unchanged bursts closely locked to the end of the inspiratory phase. Augmenting expiratory neurons were either silenced or displayed different levels of tonic activity during SLN stimulation; some of them were clearly activated. These expiratory neurons displayed activity during poststimulatory apnea, before the onset of the first recovery phrenic burst. Postinspiratory or decrementing expiratory neurons were activated during SLN stimulation; their discharge continued with a decreasing trend during poststimulatory apnea. The results support the three-phase theory of rhythm generation and the view that SLN stimulation provokes a postinspiratory apnea that could represent the inhibitory component of respiratory reflexes of laryngeal origin, such as swallowing. In addition, because a subpopulation of augmenting expiratory neurons displays activation during SLN stimulation, the hypothesis can be advanced that not only postinspiratory, or decrementing expiratory neurons, but also augmenting expiratory neurons may be involved in the genesis of apnea and poststimulatory phenomena. Finally, the increase in the activity of decrementing inspiratory neurons after the end of SLN stimulation may contribute to the generation of poststimulatory respiratory depression by providing an inhibitory input to bulbospinal augmenting inspiratory neurons.

Bronchoconstriction and hypoxemia have been reported to occur during airway challenges, but the correlation between changes in forced expiratory volume in 1 s (FEV1) and transcutaneous oxygen partial pressure (tcPo2) during methacholine provocation tests has not yet been established (to our knowledge). In 15 symptom-free atopic asthmatic patients and 5 normal subjects, variations in tcPo2and FEV1were simultaneously measured during inhalation of doubling methacholine concentrations; the drug concentrations causing a 20 percent decrease in control FEV1and tcPo2(PC20FEV1and PC20tcPo2, respectively) were subsequently calculated. In patients, geometric mean PC20FEV1and PC20tcPo2were 1.31 (range, 0.16 to 5.19) and 1.26 (range, 0.29 to 5.82) mg/ml, respectively. In addition, in six patients, methacholine-induced fall in tcPo2was accompanied by similar changes in arterial Po2. Methacholine inhalation caused no change in tcPo2or FEV1in normal subjects. The independent effects of deep breath tests and bronchoconstriction on PC20tcPo2were studied in five patients challenged on two separate occasions, with and without FEV1assessment; in these patients, PC20tcPo2were similar on both the study days. The results indicate that, in asthmatic patients, methacholine-induced bronchoconstriction causes parallel decreases in FEV1and tcPo2. The tcPo2monitoring may serve as a tool in the assessment of airway hyperreactivity when active patient's cooperation is scarce.

A high yield method for the preparation of (+)-cis-pinononic acid starting from the inexpensive (+)-α-pinene has been developed. The capture of the cyclobutyl radical from decarboxylation of (+)-cis-pinononic acid has been investigated. Moreover the radical decarboxylation of (+)-cis-pinonic acid to the corresponding nor-alkane was studied.

We aimed to ascertain whether monitoring changes in transcutaneous (tc) oxygen partial pressure (PO2) may be used to determine the slope of the dose-response curves to inhaled methacholine. In 10 adult asthmatic patients, FEV1 and tcPO2 were simultaneously measured during inhalation of doubling methacholine concentrations. In each patient, the slopes of the methacholine dose-response curves for FEV1 and tcPO2 were similar and strongly correlated (r = 0.72; p < 0.05). The results indicate that tcPO2 monitoring represents a useful, reliable tool for analysis of the slope of dose-response curves to inhaled methacholine in asthmatic patients. It can also be used to investigate the pathophysiological implications of bronchial hyperreactivity.

CD38, a type II transmembrane glycoprotein predominantly expressed in blood cells, is a bifunctional ectoenzyme directly involved in the metabolism of cADP-ribose (cADPR). This is a potent Ca2+ mobilizer in several types of cells. The relationship between the ectocellular site of cADPR production and its intracellular calcium-related functions is poorly understood. Cultured rat cerebellar granule cells showed both enzymic activities of CD38, ADP-ribosyl cyclase and cADPR hydrolase, at a ratio of 16 to 1 respectively, and were immunostained by the anti-(human CD38) monoclonal antibody IB4. In these cells externally added cADPR and β-NAD+ (the precursor of cADPR), but not α-NAD+ or ADP-ribose, enhanced the peak of the depolarization-induced rise in intracellular Ca2+ concentration. This effect was inhibited by 1 µM ryanodine, suggesting a potentiation of calcium-induced calcium release by cADPR. CD38 ectoenzyme activities, ADP-ribosyl cyclase and cADPR hydrolase, were also demonstrated in vivo by microdialysis of adult rat cerebellum, where IB4 bound to granule neurons selectively. Trace amounts (11.5±3.8 nM) of NAD+ were detected by microdialysis sampling and sensitive assays in the basal interstitial fluid of the cerebellum. These results provide a link between ectocellular cADPR turnover and intracellular calcium mobilization in cerebellum.

1Nitric oxide (NO) synthase activity was studied in slices of human temporal cortex samples obtained in neurosurgery by measuring the conversion of L‐[3H]‐arginine to L‐[3H]‐citrulline.2Elevation of extracellular K+to 20, 35 or 60 mMconcentration‐dependently augmented L‐[3H]‐citrulline production. The response to 35 mMKCl was abolished by NG‐nitro‐L‐arginine (100 μM) demonstrating NO synthase specific conversion of L‐arginine to L‐citrulline. Increasing extracellular MgCl2concentration up to 10 mMalso prevented the K+(35 mM)‐induced NO synthase activation, suggesting the absolute requirement of external calcium ions for enzyme activity.3However, the effect of high K+(35 mM) on citrulline synthesis was insensitive to the antagonists of ionotropic and metabotropic glutamate receptors dizocilpine (MK‐801), 6‐nitro‐7‐sulphamoylbenzo(f)quinoxaline‐2–3‐dione (NBQX) or L‐2‐amino‐3‐phosphonopropionic acid (L‐AP3) as well as to the nicotinic receptor antagonist, mecamylamine.4The 35 mMK+response was insensitive to ω‐conotoxin GVIA (1 μM) and nifedipine (100 μM), but could be prevented in part by ω‐agatoxin IVA (0.1 and 1 μM). The inhibition caused by 0.1 μMω‐agatoxin IVA (∼30%) was enhanced by adding ω‐conotoxin GVIA (1 μM) or nifedipine (100 μM). Further inhibition (up to above 70%) could be observed when the three Ca2+channel blockers were added together. Similarly, synthetic FTX 3.3 arginine polyamine (sFTX) prevented (50% at 100 μM) the K+‐evoked NO synthase activation. This effect of sFTX was further enhanced (up to 70%) by adding 1 μMω‐conotoxin GVIA plus 100 μMnifedipine. No further inhibition could be observed upon addition of MK‐801 or/and NBQX.5It was concluded that elevation of extracellular [K+] causes NO synthase activation by external Ca+entering cells mainly through channels of the P/Q‐type. Other Ca2+channels (L‐ and N‐type) appear to contribute when P/Q‐channels are blocked.

Dendrosomes prepared from substantia nigra are able to take up and release [3H]dopamine in a Ca2+-dependent manner. The Vmax values of [3H]dopamine uptake in substantia nigra dendrosomes was about 5 times lower than that in caudate putamen synaptosomes. The pattern of the K+-dependency of the [3H]dopamine release in substantia nigra dendrosomes was significantly different from that found in caudate putamen synaptosomes. The release of [3H]dopamine evoked by 15 mmol/l KCl from superfused dendrosomes was increased in a concentration-dependent manner by acetylcholine. The maximal potentiation produced by acetylcholine was about 40%. The potentiation of [3H]dopamine release by 10 µmol/l acetylcholine was insensitive to mecamylamine but antagonized by atropine and by pirenzepine. The effects of acetylcholine on the release of [3H]acetylcholine from substantia nigra nerve endings was also studied. Exogenous acetylcholine added to the superfusion medium decreased in a concentration-dependent manner the release of acetylcholine. This effect was not antagonized by mecamylamine or pirenzepine but fully antagonized by atropine. The data suggest the existence, in the substantia nigra of the rat, of two distinct muscarinic receptor subtypes regulating respectively dopamine release from dopamine dendrites and acetylcholine release from cholinergic nerve terminals.

Inhaled therapy has a central place in the management of obstructive lung diseases, but a large number of patients are unable to use their inhalers correctly with a consequent reduction in therapeutic benefit. Correct use of inhalers is, therefore, crucial for efficient therapy, and acceptance of the device can improve patients' compliance. The choice of the most appropriate inhaler for a given patient is often not straightforward. The ease-of-use and performance characteristics of the inhaler will markedly influence patients' acceptance of the device, as well the patients' attitudes to their illness and chronic medication use in general. Choosing the most appropriate inhaler for a specific patient and regular assessment of ability to correctly use their inhaler will promote better adherence to therapy with improved disease outcome. Further, patients' preference for a particular inhaler should be taken into consideration. In patients with obstructive airway diseases, inhaler choice is as critical as the choice of medication itself.

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