Chronic cough in adults: recommendations from an Italian intersociety consensus.

BACKGROUND: Chronic cough (CC) is a burdensome health problem in adult and older people, with a major impact on quality of life. Its management is often troublesome, and many guidelines have been released. Notwithstanding, a proportion of cases still do not reach a definite diagnosis and resolutive treatment. A coordinated approach between different specialists would be highly recommended, but its implementation in clinical practice suffers from the lack of shared protocols and poor awareness of the problem. The present consensus document has been implemented to address these issues. AIMS: To develop evidence-based recommendations for the management of adults with CC. METHODS: A 12-member expert task force of general practitioners, geriatricians, pneumologists, allergologists, otorhynolaringologists and gastroenterologists was established to develop evidence-based recommendations for the diagnostic and therapeutic approach to subjects with CC. A modified Delphi approach was used to achieve consensus, and the US Preventive Services Task Force system was used to rate the strength of recommendations and the quality of evidence. RESULTS: A total of 56 recommendations were proposed, covering 28 topics and concerning definitions and epidemiology, pathogenesis and etiology, diagnostic and therapeutic approach along with the consideration of specific care settings. CONCLUSION: These recommendations should ease the management of subjects with CC by coordinating the expertise of different specialists. By providing a convenient list of topics of interest, they might assist in identifying unmet needs and research priorities.

Barrier Effect of a New Topical Agent on Damaged Esophageal Mucosa: Experimental Study on an ex vivo Swine Model.

PURPOSE: AL2106 is a new medical device based on a mixture of chondroitin sulphate in a xyloglucan and glycerol solution made to maximize its bioadhesive capability to the esophageal mucosa. The aim of the present study was twofold to evaluate the AL2106 protective effect on the esophageal mucosa when exposed to an acidic solution mimicking gastric reflux and to assess the resilience of this effect to saline washing. MATERIALS AND METHODS: A porcine ex vivo model was used and the effects of the new medical device were compared to a sodium alginate suspension (SAS) already present on the market which was assumed as reference. Mucosal damage was induced in 19 porcine esophagi by perfusion with an acidic solution added with pepsin, and Evans blue dye (EBD) tissue uptake was used as an indicator of mucosal permeability. The EBD penetration, expressed as EBD µg/g of dry tissue, was assessed in specimens of untreated damaged mucosa and in specimens treated with AL2106 or SAS. The same evaluation was carried out after washing with normal saline. RESULTS: Both topical agents tested significantly reduced the EBD uptake by more than 60% (AL2106 8.4±4.5, SAS 3.6±2.7 vs control 23.2±13.1, p<0.01). The saline washing did not cause any significant reduction in the protective effect of AL2106 (8.6±5.9), while it significantly reduced that of SAS (5.9±4.3, p<0.05). CONCLUSION: The new AL2106 medical device showed a good barrier effect against a reflux-like damaging solution and preserved this effect after the mucosal washing test, thus suggesting its possible relevance for the treatment of gastroesophageal reflux disease.

A novel ex vivo porcine model of acid-induced esophageal damage for preliminary functional evaluations of anti-gastroesophageal reflux disease medical devices.

AIM: The aim of the study was to set up a porcine ex vivo model of acid-induced damage and to evaluate its performance by means of multichannel intraluminal impedance and pH (MII-pH) live recording, histology, and Evans blue (EB) permeability assay. MATERIALS AND METHODS: Thirteen esophagi, collected at a slaughterhouse, were ablated of their sphincters, pinned upright on a support, and placed in a thermostatic hood at 37°C with two infusion tubes and an MII-pH probe inserted in the top end. Three esophagi (histology controls) were only left in the hood for 3.5 h before sampling, while the remaining organs underwent the experimental protocol including saline infusion and recovery recording, and acid solution infusion and recovery recording. RESULTS: MII-pH analysis highlighted a significantly stronger decrease during acid infusion when compared to saline, but a better post-infusion recovery for saline solution. At the end of the protocol, MII was still statistically lower than baseline. The acid-damaged esophagi significantly absorbed more EB dye, and histology revealed strong mucosal exfoliation. CONCLUSION: The proposed model of esophageal acid damage seems to be repeatable, reliable, and achievable using organs collected at the slaughterhouse. MII recording proved to have good sensitivity in detecting mucosal alterations also in ex vivo trials.

Effectiveness of antireflux surgery for the cure of chronic cough associated with gastroesophageal reflux disease.

BACKGROUND: The effectiveness of surgical therapy for chronic cough secondary to gastroesophageal reflux disease remains controversial. The purpose of this study was to assess the efficacy of surgery and to identify the preoperative clinical profile that could predict the positive effects of treatment on chronic cough. STUDY DESIGN: Of 299 patients who underwent antireflux surgery between 1995 and 2010, 67 patients were affected by chronic cough and typical symptoms. In addition, 83 patients with typical symptoms were selected to form the control group, according to the parameters of age, sex, and the period of surgical activity. Preoperatively, all patients underwent a workup, including symptom assessment, barium swallow, upper gastrointestinal endoscopy, esophageal manometry, and 24-h pH recording or intraluminal impedance/pH monitoring in the absence of esophagitis. Patients with chronic cough also were administered a high-resolution computed tomography scan of the chest, a methacholine challenge test, and spirometry. Surgery was performed on patients positive for gastroesophageal reflux disease and negative for pulmonary diseases. The patients were followed up for a median of 84 months after surgery. RESULTS: No significant differences in preoperative reflux symptoms or esophagitis were found between the two groups. After surgery, chronic cough was absent in 57 (85 %) patients. Of the ten patients who still reported chronic cough, reflux symptoms relapsed in five, two of whom developed esophagitis. In the other five patients, typical symptoms were absent, and their chronic cough had improved but had not disappeared. CONCLUSIONS: Surgery is effective for the treatment of chronic cough secondary to gastroesophageal reflux disease, particularly if associated with severe and long-standing typical symptoms.

Barrier effect of Esoxx(®) on esophageal mucosal damage: experimental study on ex-vivo swine model.

The aim of the present study was to assess the potential barrier effect of Esoxx(®), a new nonprescription medication under development for the relief of gastroesophageal reflux symptoms. Esoxx is based on a mixture of hyaluronic acid and chondroitin sulfate in a bioadhesive suspension of Lutrol(®) F 127 polymer (poloxamer 407) which facilitates the product adhesion on the esophageal mucosa. The mucosal damage was induced by 15 to 90 minutes of perfusion with an acidic solution (HCl, pH 1.47) with or without pepsin (2000 U/mL, acidified to pH 2; Sigma-Aldrich). Mucosal esophageal specimens were histologically evaluated and Evans blue dye solution was used to assess the permeability of the swine mucosa after the chemical injury. The results show that: (1) esophageal mucosal damage is related to the perfusion time and to the presence of pepsin, (2) mucosal damage is associated with an increased permeability, documented by an evident Evans blue staining, (3) perfusion with Esoxx is able to reduce the permeability of the injured mucosa, even after saline washing of the swine esophagus. These preliminary results support further clinical studies of Esoxx in the topical treatment of gastroesophageal reflux symptoms.

LRRK2 p.G2019S mutation is not common among Alzheimer's disease patients in Brazil.

Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene have emerged as a potential common cause for both sporadic and familial Parkinson's Disease (PD) in different populations. The pleomorphic features exhibited by LRRK2 mutation carriers and the central role of Lrrk2 protein in the proper functioning of central nervous system suggest that mutations in this protein might be involved in multiple cellular processes leading to other neurodegenerative disorders than PD. The location of LRRK2 gene on chromosome 12, close to a linkage peak for familial late-onset Alzheimer's Disease (AD), highlights that LRRK2 mutations might be involved in AD pathogenesis. We screened the most common LRRK2 mutation (p.G2019S) in a series of 180 consecutive patients clinically diagnosed with Alzheimer Disease (AD). We identified the p.G2019S in one AD patient with no PD signs, indicating that this mutation is not a common etiological factor for AD in our population (0.5%), corroborating recent data found in Norwegian, North American, Chinese and Italian populations. Nevertheless, these observations together with new information about the Lrrk2 critical multifunctionality do not rule out the possible influence of other variants within LRRK2 in AD, so that other screenings focusing in the whole extension of the LRRK2 using larger sized confirmed AD sample are urgently needed.

Focus on acute diarrhoeal disease.

Diarrhoea is an alteration of normal bowel movement characterized by an increase in the water content, volume, or frequency of stools. Diarrhoea needs to be classified according to the trends over time (acute or chronic) and to the characteristics of the stools (watery, fatty, inflammatory). Secretory diarrhoeas, mostly acute and of viral aetiology in more than 70% of cases, are by far the most important subtype of diarrhoeas in terms of frequency, incidence and mortality (over 2.5 million deaths/year in developing countries). Natural and synthetic opiates such as morphine, codeine, and loperamide which react with endogenous opiates (enkephalins, beta-endorphins, dynorphins) mainly act on intestinal motility and slow down transit. An antidiarrhoeal drug developed in recent years, racecadotril, acts as an enkephalinase inhibitor. Clinical studies have shown that it is just as effective as loperamide in resolving acute diarrhoea but with greater reduction in pain and abdominal distension. Some studies have explored the prevalence of diarrhoea in old age. An epidemiological study carried out in Italy by 133 General Practitioners on 5515 elderly outpatients reported a prevalence of diarrhoea, defined according to the Rome criteria, of 9.1%. Infectious diseases (19%) and drug use (16%) were the most common causes of diarrhoea in old age. Regardless of the cause, the treatment of elderly patients with diarrhoea must include rehydration and nutritional support. Every year, more than 50 million tourists travel from industrialized countries to places where hygiene levels are poor. At least 75% of those travelling for short periods mention health problems, and in particular traveller's diarrhoea.

Body weight, lifestyle, dietary habits and gastroesophageal reflux disease.

While lifestyle modifications are currently used as first-line treatment for subjects with gastroesophageal reflux disease (GERD), the pathogenetic role of lifestyle factors and consequently, the efficacy of lifestyle measures is controversial. Our aim was to systematically review the pathogenetic link between overweight/obesity, dietary habits, physical activity and GERD, and the beneficial effect of specific recommended changes, by means of the available literature from the 1999 to the present. Obesity, in particular, abdominal obesity, plays a key role in determining GERD symptoms and complications through mechanical and metabolic effects. Controlled weight loss (by diet or surgery) is effective in improving GERD symptoms. No definitive data exist regarding the role of diet and, in particular, of specific foods or drinks, in influencing GERD clinical manifestations. Moderate physical activity seems to be beneficial for GERD, while vigorous activity may be dangerous in predisposed individuals. In conclusion, being obese/overweight and GERD-specific symptoms and endoscopic features are related, and weight loss significantly improves GERD clinical-endoscopic manifestations. The role of dietary behavior, mainly in terms of specific dietary components, remains controversial. Mild routine physical activity in association with diet modifications, i.e. a diet rich in fiber and low in fat, is advisable in preventing reflux symptoms.

Co-occurrence of sporadic parkinsonism and late-onset Alzheimer's disease in a Brazilian male with the LRRK2 p.G2019S mutation.

Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene represent the most common known genetic cause of inherited and idiopathic Parkinson's disease (PD) in different populations. The predicted multifunctionality of LRRK2 product and the pleomorphic pathology associated with LRRK2 mutations place this gene as a potential candidate for other neurodegenerative disorders, mainly Alzheimer's disease (AD). We report a Brazilian male expressing both late-onset AD and slowly progressive parkinsonism signs, and who presented the most frequent LRRK2 mutation (p.G2019S). Although the co-occurrence of PD and AD would be expected occasionally, the shared mechanisms between the two complex disorders are still unclear and are discussed herein. In light of recent findings about the wide role of LRRK2 under normal and pathological conditions, it is tempting to speculate that LRRK2 mutations might play an upstream influence on the etiology of not just PD but also several alpha-synuclein and tau pathologies, including AD.

Proton pump inhibitor treatment of patients with gastroesophageal reflux-related chronic cough: a comparison between two different daily doses of lansoprazole.

AIM: To compare two different daily doses of lansoprazole given for 12 weeks and to assess the role of gastrointestinal (GI) investigations as criteria for selecting patients. METHODS: Out of 45 patients referred for unexplained chronic persistent cough, 36 had at least one of the GI investigations (endoscopy, 24-h esophageal pH-metry and a 4-week trial of proton pump inhibitor (PPI) therapy) positive and were randomly assigned to receive either 30 mg lansoprazole o.d. or 30 mg lansoprazole b.i.d. for 12 weeks. Symptoms were evaluated at baseline (visit 1) after the PPI test (visit 2) and after the 12-week lansoprazole treatment period (visit 3). RESULTS: Thirty-five patients completed the study protocol. Twenty-one patients (60.0%) reported complete relief from their cough with no difference between the two treatment groups (58.8% and 61.1% had no cough in 30 mg lansoprazole and 60 mg lansoprazole groups, respectively). More than 80% of the patients who had complete relief from their cough at the end of the treatment showed a positive response to the PPI test. CONCLUSION: Twelve weeks of lansoprazole treatment even at a standard daily dose, is effective in patients with chronic persistent cough. A positive response to an initial PPI test seems to be the best criterion for selecting patients who respond to therapy.

Lansoprazole oro-dispersible tablet : pharmacokinetics and therapeutic use in acid-related disorders.

Lansoprazole is an H+, K+-adenosine triphosphatase proton pump inhibitor (PPI) used for management of acid-related disorders. Lansoprazole has been reformulated as an oro-dispersible tablet (LODT) that quickly dissolves in the mouth without water. In healthy adults the safety and bioavailability of LODT 15-30 mg, taken without water or dispersed in water, were found to be comparable with those of lansoprazole 15-30 mg capsules. Moreover, the bioavailability of LODT administered without water has been found to be similar to that of water-dispersed LODT given via a nasogastric tube. In a clinical study, the vast majority of patients found the mouth feel of LODT acceptable and almost all found it easy to take. A comparison of LODT with esomeprazole in a small group of patients with non-erosive reflux disease showed similar decreases in symptoms from baseline and no significant difference between groups. In conclusion, LODT is effective, bioequivalent to the capsule formulation and acceptable to patients. LODT offers an alternative dose administration method to all patients requiring a PPI, especially those who have difficulty swallowing, and may increase patient convenience and compliance.

Artificial neural networks are able to recognize gastro-oesophageal reflux disease patients solely on the basis of clinical data.

BACKGROUND: Artificial neural networks (ANN) are modelling mechanisms that are highly flexible and adaptive to solve the non-linearity inherent in the relationship between symptoms and underlying pathology. OBJECTIVES: To assess the efficacy of ANN in achieving a diagnosis of gastro-oesophageal reflux disease (GORD) using oesophagoscopy or pH-metry as a diagnostic gold standard and discriminant analysis as a statistical comparator technique in a group of patients with typical GORD symptoms and with or without GORD objective findings (e.g. a positive oesophagoscopy or a pathological oesophageal pH-metry). METHODS: The sample of 159 cases (88 men, 71 women) presenting with typical symptoms of GORD, were subdivided on the basis of endoscopy and pH-metry results into two groups: GORD patients with or without oesophagitis, group 1 (N=103), and pH and endoscopy-negative patients in whom both examinations were negative, group 2 (N=56). A total of 101 different independent variables were collected: demographic information, medical history, generic health state and lifestyle, intensity and frequency of typical and atypical symptoms based on the Italian version of the Gastroesophageal Reflux Questionnaire (Mayo Clinic). The diagnosis was used as a dependent variable. Different ANN models were assessed. RESULTS: Specific evolutionary algorithms selected 45 independent variables, concerning clinical and demographic features, as predictors of the diagnosis. The highest predictive performance was achieved by a 'back propagation' ANN, which was consistently 100% accurate in identifying the correct diagnosis compared with 78% obtained by traditional discriminant analysis. CONCLUSION: On the basis of this preliminary work, the use of ANN seems to be a promising approach for predicting diagnosis without the need for invasive diagnostic methods in patients suffering from GORD symptoms.

Ultrasonographic study of Achilles tendon and plantar fascia in chondrocalcinosis.

OBJECTIVE: To investigate by high frequency grey-scale ultrasonography (US) and power Doppler sonography (PDS) the modality and frequency of involvement of the Achilles tendon and plantar fascia in chondrocalcinosis (CC), and to correlate these findings with clinical complaints and radiographic evidence. METHODS: The heels of 57 consecutive patients with CC were evaluated by US, PDS, and radiography. One control group of 50 consecutive patients with osteoarthritis (OA) without signs of CC was studied in the same way. A second control group of 50 healthy subjects underwent only US/PDS examination. All subjects also underwent clinical assessment. RESULTS: US revealed Achilles tendon calcifications in 57.9% of those with CC, but none in the control groups. Plantar fascia calcifications were observed in 15.8% of CC and in 2% of OA cases, but not in healthy controls. US showed no significant difference in postero-inferior and inferior calcaneal enthesophytosis between subjects with CC (59.6% and 61.4%, respectively) and those with OA (46% and 44%, respectively). Such alterations were also present, in lower percentages, in the healthy controls. Posterior and inferior calcaneal erosions were absent in all groups. Achilles enthesopathy was found in 22.8% of patients with CC (14.9% of heels, with vascular signals in 11.4% of heels on PDS). Deep retrocalcaneal bursitis was found in 10.5% of patients with CC (7% of heels, with vascular signals in 5.2% of heels on PDS). Plantar fasciitis was found in 40.3% of patients with CC (36% of heels, with vascular signals in 2.6% of heels on PDS) and in 14% of OA patients, but not in healthy controls. No significant correlation was found between talalgia or sex of patients and presence of calcifications. A significant correlation was observed between talalgia and Achilles enthesopathy (r = 0.78, p < 0.0001), deep retrocalcaneal bursitis (r = 0.7, p < 0.0001), and plantar fasciitis (r = 0.31, p < 0.001). A significant correlation between talalgia and vascular signals on PDS was observed in Achilles enthesopathy (r = 0.91, p < 0.0001) and deep retrocalcaneal bursitis (r = 0.65, p < 0.0001). The presence of vascular signals on PDS was significantly associated with the presence of tendinous and bursal grey-scale US alterations. Achilles tendon calcifications were 39% sensitive, 100% specific, and 77% accurate for the presence of CC, whereas plantar fascia calcifications were 15% sensitive, 98% specific, and 54% accurate. Excellent agreement was found between US and radiography in detecting Achilles tendon calcifications (k = 0.86), plantar fascia calcifications (k = 0.77), postero-inferior enthesophytosis (k = 0.90), and inferior enthesophytosis (k = 0.83). CONCLUSION: Calcaneal tendon calcifications are frequent and asymptomatic findings in patients with CC, and they have a high specificity for this disease. US shows high agreement with radiography in depicting calcifications and enthesophytosis. Inflammatory changes of the calcaneal soft tissues are frequently observed by US and PDS in patients with chondrocalcinosis.

Long-term effects of neridronate on human osteoblastic cell cultures.

UNLABELLED: Bisphosphonates (BPs) are widely used in the treatment of a variety of bone-related diseases, particularly where the bone turnover is skewed in favor of osteolysis. The mechanisms by which BPs reduce bone resorption directly acting on osteoclasts are now largely clarified even at molecular level. Researches concerning the BP's effects on osteoblast have instead shown variable results. Many in vitro studies have reported positive effects on osteoblasts proliferation and mineralization for several BPs; however, the observed effects differ, depending on the variety of different model system that has been used. OBJECTIVES: We have investigated if neridronate, an aminobisphosphonate suitable for pulsatory parenteral administration, could have an effect on human osteoblastic proliferation and differentiation in vitro. METHODS: We have investigated whether prolonged addition of neridronate (from 10(-3) to 10(-11) M) to different human osteoblasts cultures, obtained from 14 different bone specimens, could affect the cells number, the endogenous cellular alkaline phosphatase (ALKP) activity, and the formation of mineralized nodules. RESULTS: Our results show that neridronate does not negatively affect in vitro the viability, proliferation, and cellular activity of normal human osteoblasts even after a long period addition of the drug (20 days) at concentrations equal or lower than 10(-5) mol/l (therapeutic dose). In addition, neridronate seems to enhance the differentiation of cultured osteoblasts in mature bone-forming cells. A maximum increase of alkaline phosphatase activity (+50% after 10 days; P < 0.01) and mineralized nodules (+48% after 20 days; P < 0.05) was observed in cultures treated with neridronate 10(-8) M. CONCLUSIONS: These results encourage the use of neridronate in long-term therapy of demineralizing metabolic bone disorders.

Effects of high dose methylprednisolone pulse therapy on bone mass and biochemical markers of bone metabolism in patients with active rheumatoid arthritis: a 12-month randomized prospective controlled study.

OBJECTIVE: To study the effects of one year of high dose 6-methylprednisolone pulse therapy (MPPT) on bone mass, seric bone alkaline phosphatase (sBAP), and urinary deoxypyridinoline (uDpyr) in patients with active rheumatoid arthritis (RA), and to compare results with those of patients with active RA treated with oral methylprednisolone (OMP). METHODS: Thirty-one women with active RA were given 1000 mg of MP IV for 3 alternate days, with a mean interval of administration of 76 days (+/- 8.3 SD) for one year (MPPT group). Bone mineral density (BMD) (total body, lumbar spine, and femur neck), plasma levels of sBAP, and urinary concentrations of uDpyr were assessed at the beginning of the treatment and every 3 months until the end of the study. Moreover, erythrocyte sedimentation rate (ESR), Thompson joint score, and early morning stiffness were assessed at study entry and every month. The control group, 31 women with active RA treated with oral MP, was followed in the same way (OMP group). RESULTS: In the MPPT group there was no significant reduction of BMD at any site compared to significant reductions in lumbar BMD at 6 and 12 months and total body BMD and femur neck BMD at 12 months in the OMP group. Also in the OMP group, a significant reduction in the mean sBAP was observed. The mean uDpyr levels were not significantly reduced in either group. CONCLUSION: Our results show that MPPT, compared to continuous therapy with oral corticosteroids, preserves bone mass without modifying the biochemical markers of bone metabolism.

[The gastroesophageal reflux disease (GERD) and the general practitioner]. / La malattia da reflusso gastroesofageo ed il medico di medicina generale. Progetto ICEBERG: Indagine clinico-epidemiologica sulla base emersa del reflusso gastroesofageo.

UNLABELLED: In Italy few data are available on which patients, coming from a self-medication experience, turn to their general practitioners (GPs) due to gastro-oesophageal reflux symptoms. Aim of this study was to describe the clinical characteristics of these patients. METHODS: Observational trial involving a large number of GPs; the GPs were expected to enroll > or = 3 consecutive adult patients with typical reflux symptoms. During the visit, a computerized network was used to collect electronic data on demographics, reflux and associated symptoms, concomitant diseases and therapies, investigations for GERD. RESULTS: On 1345 patients enrolled in all (sex: 52% M; median age class: 48-52 yrs) a high prevalence of non-smokers (68%) was observed, regular use of coffee/tea or alcohol was seen in 52% and 23% of patients, respectively. At study entry, the typical reflux symptoms prevalence was 36%, 9% and 38% for heartburn, regurgitation, heartburn plus regurgitation. The 71% of patients had a previous history of reflux symptoms (duration > 3 yrs for 39% of them). No differences found in the typical reflux symptoms frequency and severity between naive and relapsed patients. An average number of 3 associated symptoms was reported. The main associated disease reported was irritable bowel syndrome (27%). CONCLUSIONS: The ICEBERG study provides a picture of the main features of GERD at primary care level, on the basis of a large amount of Italian patients' data.

Lansoprazole fast disintegrating tablet: a new formulation for an established proton pump inhibitor.

Lansoprazole is a proton pump inhibitor (PPI) which is an effective and well-tolerated treatment option in the management of acid-related disorders. Lansoprazole fast disintegrating tablet (LFDT)--a new, patient-friendly and more convenient formulation of lansoprazole which can be taken with or without water--is the first PPI to be made available as an orally disintegrating tablet. It represents an innovative drug delivery system, comprising enteric-coated microgranules of lansoprazole compressed with an inactive, rapidly dispersing matrix to form a tablet. When the tablet is placed on the tongue and sucked gently it disintegrates rapidly in the mouth, releasing the enteric-coated microgranules which are swallowed with the patient's saliva without water. Alternatively, the tablet can be swallowed with a drink of water. Studies have shown that the bioavailability of LFDT is comparable to lansoprazole capsules, at both 15 and 30 mg doses; the indications and recommended dosages for LFDT are therefore identical to lansoprazole capsules. The new formulation may be of particular benefit to those with active life-styles who do not always have water available, patients who have difficulty in swallowing, and elderly patients.