In 1979 our surgical group proposed the Heller-Dor operation (HD) to accomplish new concepts of surgical pathophysiology: to abolish the lower esophageal sphincter with the division of the U-and sling fibers of the lesser gastric curvature, to prevent GER with an effective but not too effective partial fundoplication which protects the myotomy surface. Aim is to report very long-term results of the treatment of esophageal achalasia with the Heller-Dor operation performed with intra operative manometry. In the period 1979-2021 HD was in first instance adopted in 202 patients (97 men; median age 45 years; IQR 31–59) in laparotomy (L-HD) and in 162 (79 men; age 48 years; IQR 35–63) in laparoscopy (V-HD). At intraoperative manometry, the complete abolition of the high-pressure zone was always obtained and the Dor length and pressure were trimmed according to reference values. Follow-up consisted of interview, endoscopy and barium swallow performed every 3 years. The overall outcome was graded from excellent to poor according to the severity of symptoms and esophagitis. Median follow-up was 14.8 years in HD, 7.5 years in V-HD (p<0.001). Esophageal diameter and residual barium column decreased substantially during the first 3 years after the operation, but not successively. In the L-HD group poor results were 22 (10.9%): due to esophagitis in 17 (8.4%) and to recurrent dysphagia in 5 (2.5%). In V-HD, 4 (2.5%) had esophagitis and 2 (1.2%) severe dysphagia. Outcome was satisfactory in 89% of L-HD and in 96% of V-HD (p<0.001). Postoperatively, according to the Kaplan Mayer curve, dysphagia, reflux symptoms and esophagitis occurred within 60-65 months after surgery. Timing of dysphagia relapse and post-myotomy reflux occurrence indicate that after five years, surgical results can be considered definitive. The 96% of satisfactory results we achieved with VL-HD, at a median follow-up time of 8 years, shows the potentiality of this surgical technique. In our experience, the learning process, not the follow-up length or the laparotomy/laparoscopy method is the cause of improved results of the laparoscopy HD.

Literature supporting the adoption of POEM in place of the standard Heller myotomy in the presence of significant chest pain associated with typical symptoms like in case of Achalasia Type III according to the Chicago classification, generally reports on outcome data collected after short follow up periods. We aimed to assess behaviors of chest pain in the long term in a case series of patients submitted to the Heller-Dor operation. Between 1978 and 2021,394 achalasia patients underwent the Heller-Dor operation. Chest pain was evaluated according to its frequency (0: absent; 1: occasional; 2: weekly; 3: daily): 81 preoperatively complained of chest pain (score 2-3) (CP group), 313 did not (score 0-1) (NCP group). Patients were followed up according to a timed protocol based on clinical assessment of dysphagia (D0 absent – D3 each meal), GERD symptoms (RS0 absent-RS3 each meal). Barium swallow and endoscopy (E0: normal, E1: mild esophagitis, E2-3: erosive/ulcerative esophagitis) were performed at each planned control. CP and NCP were compared. CP group had shorter duration of dysphagia (p=0.03), smaller esophageal diameter and lower barium column (p<0.05). At a median follow-up of 10 years for CP and 11 years for NCP (p=0.166), the frequency of dysphagia (p=0.05), GERD symptoms (p=0.3) and esophagitis (p=0.27) was similar in the two groups. Chest pain progressively attenuated in intensity and frequency.; median chest pain score preoperatively was 3, at follow-up it was 0 (p<0.01). Clinical results obtained in CP patients (satisfactory D0–2, RS0–2, and E1 in 95%) were not inferior to those obtained in NCP patients (satisfactory in 93%) (p=0.05). According to our single center case series, in the long term chest pain does not influence negatively HD outcome which is absolutely competitive with that generally reported for POEM and pneumatic dilation. Results presented in this study must be verified: as new randomized prospective studies would require a too long lag time, valid retrospective multi center studies should be performed.

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.

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.

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.

This paper summarizes the presentations submitted for publication of the 12th AIST 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.

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.

Social mining, recommenders and data semantics are moving the focus of enterprise systems towards context-awareness and personalization. However, the design of these software systems needs specific architectures to support intelligent behaviors, still ensuring important non-functional properties, such as flexibility, efficiency and scalability. This paper proposes an architectural pattern that helps designers to easily identify the subsystems that characterize intelligent enterprise systems. By decoupling transactional behavior from batch processing, the pattern avoids the interference of knowledge extraction and reasoning processes with the state and the performance of the transactional subsystem. The pattern has been experimented in e-Commerce by designing an intelligent and scalable virtual mall.

eCommerce is gaining a momentum due to the wide diffusion of Web 2.0 technology. Social mining, recommenders and data semantics are moving the focus of eCommerce applications towards context-awareness and personalization. However, the design of these software systems needs specific architectures to support intelligent behaviors, still ensuring important non-functional properties, such as flexibility, efficiency and scalability. This paper proposes an architectural pattern that helps designers to easily identify the subsystems that characterize intelligent enterprise systems. By decoupling transactional behavior from batch processing, the pattern avoids the interference of knowledge extraction and reasoning processes with the state and the performance of the transactional subsystem, so improving scalability. The pattern has been experimented in eCommerce by designing an intelligent and scalable virtual mall.

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 15–30mg, taken without water or dispersed in water, were found to be comparable with those of lansoprazole 15–30mg 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.

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.

OBJECTIVETo assess the efficacy of Cellfood's therapy in the treatment of fibromyalgia.METHODSThis study was a single-blind, cross-over, randomized placebo-controlled trial. Forty female were selected from 320 cases investigated in the period 2003-2005 of June. To be included in this study, it was required that the diagnosis of fibromyalgia was made by a specialist in according to the ACR classification criteria of 1990. The patient's age was between 35-47 years, the choice of criteria were the absence of improvements with the conventional therapy and the normality of medical check-up. The patients were divided into two different-groups of thirty-one and nine subjects, each-one (group A) treated with Cellfood for six months in according to the Eurodream's scheme, and each-other (group B) treated with placebo for three months and successively with Cellfood for three months. Besides we have estimated the tender points with algometer and the health status of women with the Fibromyalgia Impact Questionnaire (FIQ) at the baseline (T0) and at three (T1) and six month (T2).RESULTThe group A had an appreciable improvement of the parameters at T1 statistically significant compared to the group B, while we observed a stability of they at T2 on the group A and an improvement of the parameters of the group B statistically non significant compared to each-one.CONCLUSIONOur result suggest that the Cellfood's therapy improve fibromyalgia symptoms and health-related quality of life.

UNLABELLED Bisphosphonates (BPs) are pharmacological compounds widely used in the treatment of a variety of bone-related diseases, particularly where the bone-turnover is skewed in favour of osteolysis. The mechanisms by which BPs reduce bone-resorption directly acting on osteoclasts (OCs) are now largely clarified even at molecular level. The researches concerning the BPs effects on osteoblasts (OBs) have instead shown variable results. OBJECTIVES We have investigated the efficacy of neridronate (NER), an amino-BP, as anabolic agent on human OBs. Moreover, we have tried to verify if NER is able to negatively modulate the production of IL-6 on OBs stimulated or not by the pro-inflammatory cytokine IL-1beta. METHODS We have tested if different concentrations of NER (from 10-11 M to 10-3 M), added to primary human OB cultures, could affect the cells number, the endogenous cellular alkaline phosphatase (ALP) activity, the collagen I (COL-I) synthesis, the formation of mineralized nodules and the IL-6 production. Our experimental approach was performed testing a wide range of NER concentrations because, under physiological conditions, OBs seems to be exposed to variable and transient levels of the drug. RESULTS Our results show that NER doesn't negatively affect in vitro the viability, proliferation and cellular activity of human OBs, even after 20 days of exposure to concentrations < or =10-5 M (therapeutic dose). In addition, NER seems to enhance the differentiation of cultured OBs in mature bone-forming cells. A maximum increase of COL-I synthesis (+25% after 4 days; p < 0.05), ALP activity (+50% after 10 days; p < 0.01) and mineralized nodules (+48% after 20 days; p < 0.05) was observed in cultures treated with NER 10-8 M. A maximal reduction of IL-6 secretion (-24% on IL-1beta stimulated cultures and -29% on unstimulated cultures) was observed for NER 10-9 M. CONCLUSIONS These results encourage the use of neridronate in therapy of demineralizing metabolic bone disorders.

This paper analyses the interdependencies existing in wholesale electricity prices in six major European countries. The results of a robust multivariate long-run dynamic analysis reveal the presence of four highly integrated central European markets (France, Germany, the Netherlands and Austria). The trend shared by these four electricity markets appears to be common also to gas prices, but not to oil prices. The existence of a common long-term dynamics among electricity prices and between electricity prices and gas prices can be explained by the similarity of the market design across Europe and by the same marginal generation technology. Since standard unit root and cointegration tests are not robust to the peculiar characteristics of electricity prices time series, we also develop a battery of robust inference procedures that should assure the reliability of our results. Copyright (C) 2009 John Wiley & Sons, Ltd.

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.