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Background/Aims:Endoscopic submucosal dissection (ESD) has been proposed for removal of gastrointestinal subepithelial tumors (GI-SETs), but data are still scanty. This study aimed to report a case series from a western country. Patients and Methods:Data of patients with upper GI-SETs suitable for ESD removal observed in 4 centers were retrospectively reviewed. Before endoscopic procedure, the lesion was characterized by endosonographic evaluation, histology, and CT scan. The en blocresection and the R0 resection rates were calculated, as well as incidence of complications, and the 1-year follow-up was reported. Results:Data of 84 patients with esophageal (N= 13), gastric (N= 61), and duodenal (N= 10) GI-SETs were collected. The mean diameter of lesions was 26 mm (range: 12–110 mm). There were 17 gastrointestinal stromal tumors, 12 neuroendocrine tumors, 35 leiomyomas, 18 lipomas, and 2 hamartomas. En blocand R0 resection were achieved in 83 (98.8%) and in 80 (95.2%) patients, respectively. Overall, a complication occurred in 11 (13.1%) patients, including bleeding (N= 7) and perforation (N= 4). Endoscopic approach was successful in all bleedings, but 1 patient who required radiological embolization, and in 2 perforations, while surgery was performed in the other patients. Overall, a surgical approach was eventually needed in 5 (5.9%), including 3 in whom R0 resection failed and 2 with perforation. Conclusions:Our study found that ESD may be an effective and safe alternative to surgical intervention for both benign and localized malignant GI-SETs.

ABSTRACTBackground: Several outstanding pharmacological advances making innovative drugs sophisticateddevices available during the last few years. Nevertheless too many patients still disappointingly fail to meetthe metabolic targets suggested by current guidelines. Incorrect insulin administration techniques may greatly affect metabolic control in T2DM people. The aim of our study was to compare glycemic control associated with a concentrated insulin analog preparation (U-200 lispro) in people with T2DM to the one observed with standard U-100 lispro. The secondary endpoint of our study was patients’ preference and performance ratings of U-200 lispro.Methods: 126 patients with T2DM were enrolled. They were also assessed for limited joint mobility syndrome (LJMS),defined as limitation in at least two anatomical areas of the dominant upper extremity. After a 4-weekstructured insulin injection education period. Half of them were randomized to U-100 lispro, half to U-200 and after 12 weeks they were switched to the other preparation for 12 weeks. At the end a questionnaire was also administered to investigate patient preference.Results: No significant variation in fasting blood glucose, HbA1c, severe or mild hypoglycemic rate and daily fast-acting insulin analog dose was observed with U-100 lispro while U-200 lispro treatment was associated with a significant improvement of all the above mentioned parameters and with around 20% decrease in insulin requirement. Moreover patients’ answers to the questionnaire pointed out a higher preference for U-200 lispro for continuing treatment due to fewer difficulties completing injection.Discussion: The explanation of better metabolic results with the U-200 device might be the lower inner piston inertia and volume and shorter duration of a complete injection.Conclusions: Checking for LJIMS before insulin prescription could be adopted as a standard practiceaimed at choosing the most suitable device for patient's specific characteristics and abilities. The use of U-200 lispro might improve treatment adherence and metabolic control. This would also result intocost reduction by saving about half the amount of pens per year and of time spent to both fill prescriptionand dump the pharmacy.

Clostridium difficiletoxin A is responsible for colonic damage observed in infected patients. Drugs able to restore Clostridium difficiletoxin A-induced toxicity have the potential to improve the recovery of infected patients. Cannabidiol is a non-psychotropic component of Cannabis sativa,which has been demonstrated to protect enterocytes against chemical and/or inflammatory damage and to restore intestinal mucosa integrity. The purpose of this study was to evaluate (a) the anti-apoptotic effect and (b) the mechanisms by which cannabidiol protects mucosal integrity in Caco-2 cells exposed to Clostridium difficiletoxin A. Caco-2 cells were exposed to Clostridium difficiletoxin A (30?ng/ml), with or without cannabidiol (10-7–10-9?M), in the presence of the specific antagonist AM251 (10-7?M). Cytotoxicity assay, transepithelial electrical resistence measurements, immunofluorescence analysis and immunoblot analysis were performed in the different experimental conditions. Clostridium difficiletoxin A significantly decreased Caco-2 cells’ viability and reduced transepithelial electrical resistence values and RhoA guanosine triphosphate (GTP), bax, zonula occludens-1 and occludin protein expression, respectively. All these effects were significantly and concentration-dependently inhibited by cannabidiol, whose effects were completely abolished in the presence of the cannabinoid receptor type 1 (CB1) antagonist, AM251. Cannabidiol improved Clostridium difficiletoxin A-induced damage in Caco-2 cells, by inhibiting the apoptotic process and restoring the intestinal barrier integrity, through the involvement of the CB1 receptor.

Background Clostridium difficiletoxin A is responsible for colonic damage observed in infected patients. Drugs able to restore Clostridium difficiletoxin A-induced toxicity have the potential to improve the recovery of infected patients. Cannabidiol is a non-psychotropic component of Cannabis sativa,which has been demonstrated to protect enterocytes against chemical and/or inflammatory damage and to restore intestinal mucosa integrity.Objective The purpose of this study was to evaluate (a) the anti-apoptotic effect and (b) the mechanisms by which cannabidiol protects mucosal integrity in Caco-2 cells exposed to Clostridium difficiletoxin A.Methods Caco-2 cells were exposed to Clostridium difficiletoxin A (30 ng/ml), with or without cannabidiol (10−7–10−9 M), in the presence of the specific antagonist AM251 (10−7 M). Cytotoxicity assay, transepithelial electrical resistence measurements, immunofluorescence analysis and immunoblot analysis were performed in the different experimental conditions.Results Clostridium difficiletoxin A significantly decreased Caco-2 cells’ viability and reduced transepithelial electrical resistence values and RhoA guanosine triphosphate (GTP), bax, zonula occludens-1 and occludin protein expression, respectively. All these effects were significantly and concentration-dependently inhibited by cannabidiol, whose effects were completely abolished in the presence of the cannabinoid receptor type 1 (CB1) antagonist, AM251.Conclusions Cannabidiol improved Clostridium difficiletoxin A-induced damage in Caco-2 cells, by inhibiting the apoptotic process and restoring the intestinal barrier integrity, through the involvement of the CB1 receptor.

Polymorphisms of genes involved in the regulation of the immune response are risk factors for achalasia, but their contribution to disease pathogenesis is unknown. Nitric oxide is involved both in immune function and inhibitory neurotransmission. The objective of this article is to assess the association and the functional relevance of the CCTTT-inducible nitric oxide synthase (NOS2) gene promoter polymorphism in achalasia. Genomic DNA was isolated from 181 achalasia patients and 220 controls. Genotyping of the (CCTTT)n repeats was performed by PCR and capillary electrophoresis, and data analyzed by considering the frequency of the different alleles. HT29 cells were transfected with iNOS luciferase promoter-reporter plasmids containing different (CCTTT)n. The alleles’ distribution ranged from 7 to 18, with a peak frequency at 12 repeats. Analysis of the allele frequencies revealed that individuals carrying 10 and 13 CCTTT repeats were respectively less and more frequent in achalasia (OR 0.5, 95% CI 0.3–0.5 and OR 1.6, 95% CI 1–2.4, all p?

Background Polymorphisms of genes involved in the regulation of the immune response are risk factors for achalasia, but their contribution to disease pathogenesis is unknown. Nitric oxide is involved both in immune function and inhibitory neurotransmission.Objective The objective of this article is to assess the association and the functional relevance of the CCTTT-inducible nitric oxide synthase (NOS2) gene promoter polymorphism in achalasia.Methods Genomic DNA was isolated from 181 achalasia patients and 220 controls. Genotyping of the (CCTTT)n repeats was performed by PCR and capillary electrophoresis, and data analyzed by considering the frequency of the different alleles. HT29 cells were transfected with iNOS luciferase promoter-reporter plasmids containing different (CCTTT)n.Results The alleles’ distribution ranged from 7 to 18, with a peak frequency at 12 repeats. Analysis of the allele frequencies revealed that individuals carrying 10 and 13 CCTTT repeats were respectively less and more frequent in achalasia (OR 0.5, 95% CI 0.3–0.5 and OR 1.6, 95% CI 1–2.4, all p< 0.05). Long repeats were also significantly associated with an earlier onset of the disease (OR 1.69, 95% CI 1.13–2.53, p= 0.01). Transfection experiments revealed a similar allele-specific iNOS transcriptional activity.Conclusion The functional polymorphism (CCTTT) of NOS2promoter is associated with achalasia, likely by an allele-specific modulation of nitric oxide production.

Tobacco smoke is the single most important modifiable risk factor for coronary diseases and the leading preventable causes of death in the US. While the effect of cigarette smoking on the progression of atherosclerotic diseases is established and well studied, the role of cigarette smoking on cardiac arrhythmia is less clearly defined. In fact the pathophysiological mechanism of cigarette smoking-induced cardiac arrhythmia is very likely a complex one where the pro-fibrotic effect of nicotine on myocardial tissue with consequent increased susceptibility to catecholamine might play a role. Moreover, other constituents of cigarette smoking, such as carbon monoxide and oxidative stress, are likely to contribute to the generation of arrhythmias. Finally, cigarette smoking may induce coronary artery disease and chronic obstructive pulmonary disease, which also might cause arrhythmia independently. The objective of this paper is to summarize the published studies relating to cardiac arrhythmia induced by cigarette smoking, and to identify a pathophysiological mechanism by which cigarette smoking might induce cardiac arrhythmia.

Atrial fibrillation (AF) is associated with a 6 fold increased risk for ischemic stroke. Observational studies suggest that one in four to five strokes is due to AF. Depending on the risk profile of an individual patient, the yearly risk for ischemic stroke is between 2% and 14%. AF is accompanied by an increased propensity for atrial clot formation due to a combination of decreased atrial blood flow, increased activity of the platelet/plasmatic coagulation system and prothrombotic changes at the atrial endocardium. This review summarizes the current guidelines for thromboembolic prevention in patients with AF. In many cases, continuous oral anticoagulation therapy (OAT) with vitamin K antagonists (VitKAs) is indicated if AF is accompanied by more than one additional risk factor for thromboembolic complications. However, therapeutic range of VitKAs (Phenprocoumon, Warfarin, and others), the most commonly used oral anticoagulants, is narrow and their use requires regular anticoagulation monitoring. Possibly due to these limitations, about one third of eligible patients are not treated with VitKAs. Furthermore, in many treated patients OAT is not well controlled. Thus, in clinical practice anticoagulation therapy in AF is suboptimal. Therefore, new and more convenient pharmacologic approaches to prevent thromboembolism with i.e. direct thrombin inhibitors (DTI), synthetic polysaccharides (factor Xa Inhibitors), and others are discussed, and their possible future role in the treatment of AF is evaluated.

Several epidemics of nicotine intoxication have been described among tobacco harvesters; however, little is known about nicotine absorption under typical working conditions. To assess systemic nicotine absorption during a regular working shift, the authors performed an observational field study. Included in the study were 10 healthy, nonsmoking, female tobacco harvesters and a control group of 5 healthy, nonsmoking, female hospital workers. Nicotine and cotinine were measured in sequential samples of blood and urine during a regular workshift. Blood nicotine levels rose from a nadir value of 0.79 ± 0.12 ng/ml to a peak value of 3.45 ± 0.84 ng/ml (p < .05 [Tukey's modified t test]) in the exposed group. In the control group, levels were stable at 0.1 ± 0.1 ng/ml (p < .01). Moreover, the mean blood nicotine level measured 3 mo following the end of exposure in 6 of 10 exposed subjects was 0.24 ± 0.12 ng/ml (p < .01). Corresponding higher values of urine nicotine and urine cotinine were observed in the exposed versus control group (comparative P values were < .01 and < .05, respectively). Overall, tobacco harvesters absorbed approximately 0.8 mg of nicotine daily. Given that nicotine can induce adverse health effects, the authors believe that prevention of nicotine absorption in tobacco harvesters should be sought and that workers should be informed about occupational risks.

Background: Previous studies show that macrophages, lung fibroblasts, and their soluble mediators are responsible for the onset and development of pulmonary fibrosis. This study was conducted to determine whether airway epithelial cells are also directly involved in response to fibrogenic agents and consequently in the pathogenesis of lung fibrosis. To verify the hypothesis, we determined whether silica acts directly on human bronchial epithelial cells by stimulating cytokine and growth factor release and by modifying matrix production. Materials and Methods: An SV40 large T antigen-transformed human airway epithelial cell line, 16HBE14o (16HBE), was used. The expression profile of some proinflammatory interleukins (ILs), such as IL-1α, IL-1βand IL-6 and their modulation by silica, were evaluated by polymerase chain reaction (PCR) analysis. Transforming growth factor beta (TGFβ) and basic fibroblast growth factor (bFGF) mRNA levels were tested by Northern blotting in the presence and in the absence of silica. The silica- and/or bFGF-induced effects on matrix components (total proteins, collagen, and fibronectin) were also evaluated using radio-labeled precursors. Results: The results demonstrated 16HBE internalized silica particles. Silica induced a little IL-6 secretion, without affecting IL-1 and TGFβisoform production and strongly stimulated bFGF mRNA level and bFGF protein secretion. Silica also induced changes in 16HBE production of total proteins, collagen, and fibronectin production. When added in combination with the growth factor, it strengthened bFGF stimulation of matrix component secretion. Conclusions: These results support the hypothesis that the changes in matrix components are due to a direct effect of silica on bronchial epithelial cells. Silica-induced over-secretion of bFGF suggests that autocrine and paracrine differentiation loops for bFGF may also be operative and that these mechanisms may be involved in the pathogenesis of pulmonary fibrosis. In the future, cytokine-directed therapeutic strategies might find a place in clinical practice.

Although chlorine gas is a common irritant exposure, little is known about airway responses to chlorine inhalation among persons with baseline airway hyperreactivity. We wished to determine whether such persons manifest an exaggerated response to chlorine compared with normal subjects. We studied 10 subjects, five with and five without airway hyperresponsiveness (HR) after exposure to 1.0 ppm chlorine and five persons, all with HR, to 0.4 ppm chlorine. After 1.0 ppm inhalation, there was a significant (p<0.05) fall (mean ± SE) in FEV1immediately following exposure among normal (-180±37 mL) and HR subjects (-520±171 mL). The fall was greater among the HR compared with the normal subjects (p=0.04). Specific airway resistance (Sraw) increased to a greater degree among the HR group compared with normal subjects (p=0.04). Among all subjects (n=10), the proportional change in FEV1after 1.0 ppm chlorine correlated with baseline reactivity (Spearman rank correlation r=0.64, p<0.05). At 24-h follow-up, there were no significant chlorine-related pulmonary function deficits. After 0.4 ppm chlorine inhalation, there was no significant pulmonary function effect. These data indicate that persons with hyperreactive airways manifest an exaggerated airway response to chlorine at 1.0 ppm. This suggests that when large numbers of persons are exposed to chlorine, a susceptible subpopulation may acutely respond with a greater decrement in pulmonary function.

Zinc oxide inhalation causes metal fume fever, a flu-like syndrome common among welders. Proinflammatory pulmonary cytokines play a role in mediating this occupational illness. The goal of this investigation was to characterize early pulmonary cytokine responses after experimental human exposure to inhaled purified zinc oxide fume. We quantified bronchoalveolar lavage (BAL) cytokine concentrations in 15 healthy volunteers 3 hr after inhalation of zinc oxide fume. We compared postexposure cytokine responses with postsham exposure responses in the same 15 subjects. We also compared cytokine responses with those of 14 “late follow-up” subjects previously studied by BAL 20 hr after zinc oxide fume exposure. Zinc oxide exposure was a statistically significant, dose-dependent predictor of increases in BAL TNF (mean exposure–sham difference ± SE = 9.5 ± 3.6 pg/mL,P= 0.02), IL-6 (mean exposure–sham difference ± SE = 5.5 ± 1.8 pg/mL,P= 0.009), and IL-8 (mean exposure–sham difference ± SE = 64.1 ± 23.9 pg/mL,P= 0.02). The TNF response was significantly greater at 3 hr follow-up compared with 20 hr follow-up, after adjusting for smoking status, zinc dose, and BAL macrophages (P= 0.004). Our findings provide evidence for a pulmonary inflammatory response 3 hr after inhalation of zinc oxide fume characterized by dose-dependent increases in BAL proinflammatory cytokine concentrations. These data indicate that TNF plays an important initial role in mediating metal fume fever.

Carbon monoxide (CO) poisoning is still common, especially in houses where the sources of CO are numerous and particularly insidious. In 1991, we observed 11 people who were affected by acute CO poisoning; 8 cases of which occurred in the home and 3 in the working environment. Home poisoning often affected more than one person; the cause of the intoxication was always the result of a faulty heating system associated with poor ventilation of rooms. Our experience confirms that CO is an insidious threat more common than is generally believed which can cause incidences of extremely dangerous poison ing, sometimes representing a difficult challenge to medical practitioners. A deeper knowledge and correct prevention of this problem are the primary means of reducing the proportions of this risk.

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