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Cremona, Italy

Rapizzi E.,University of Florence | Ercolino T.,Endocrinology Unit | Canu L.,University of Florence | Giache V.,University of Florence | And 4 more authors.
Endocrine-Related Cancer | Year: 2012

To date, the consequences of succinate dehydrogenase (SDH) impairment on overall mitochondrial functions are still obscure. In this study, we evaluated SDH activity and expression and mitochondrial homeostasis in 57 tissue samples of pheochromocytoma (PHEO)/paraganglioma (PGL) obtained from patients genotyped for PHEO/PGL susceptibility genes. The resulted SDH activity and content always decreased in SDH-mutated tumors, in one out of two MAX-mutated patients and in four patients resulted wild type (wt) at genetic screening. All these four wt patients were further screened for large deletions in SDH genes, TMEM127 and MAX and resulted wt but two had somatic SDHD mutations. The RT-PCR in the MAX-mutated sample suggests that the decrease in SDH depends on complex instability and not on a reduced SDHB expression. SDH mutations neither alter citrate synthase (CS) activity nor the content of voltage-dependent anion channel (VDAC) while the expression of the mitochondrial complex IV (cytochrome c oxidase (COX)) was found extremely variable in all (mutated and wt) samples suggesting an impairment of mitochondrial cristae in these tumors. In conclusion, tumors from patients with germ line SDH mutations invariably show decreased enzymatic activity and content, but an SDH impairment may also depend on SDH somatic mutations or, seemingly, on MAX mutations. The impaired SDH activity in the two wt tissues suggests mutations in other still unknown susceptibility genes. Finally, the extreme variability in COX expression levels is yet to be explained and this strongly suggests to evaluate other mitochondrial features to better understand the mitochondrial role in the pathogenesis of these tumors. © 2012 Society for Endocrinology Printed in Great Britain. Source

Frazzoni M.,Fisiopatologia Digestiva | Conigliaro R.,Gastroenterologia | Manta R.,Gastroenterologia | Melotti G.,Chirurgia Generale
Alimentary Pharmacology and Therapeutics | Year: 2011

Aliment Pharmacol Ther 2011; 34: 67-75 Summary Background EsophyX is a novel transoral incisionless fundoplication device developed to mimic surgical fundoplication. EsophyX fundoplication improves acid reflux parameters in proton pump inhibitor (PPI)-responsive GERD patients but its efficacy in refractory GERD has been scarcely studied. Aim To assess reflux parameters before and after EsophyX or laparoscopic fundoplication and their relationship with symptoms in refractory GERD. Methods In an open-label study, we enrolled prospectively patients with heartburn/regurgitation persisting despite high-dose PPI therapy. Impedance-pH monitoring was performed on PPI therapy before intervention and off PPI therapy 3 months after intervention. Results Ten patients chose to undergo EsophyX (EndoGastric Solutions, Redmond, WA, USA) fundoplication while ten chose laparoscopic fundoplication, and the baseline characteristics were comparable. Distal and proximal refluxes were significantly reduced post-operatively in the surgical but not in the endoscopic group and the median values were significantly lower in the former than in the latter. The oesophageal acid exposure time was normal in 50% of cases after EsophyX and in 100% of cases after surgery (P = 0.033); the number of distal refluxes was normal in 20% and 90% of cases (P = 0.005) and the number of proximal refluxes was normal in 40% and 100% of cases (P = 0.011), respectively. A positive persisting symptom-reflux association was found post-operatively in 6/10 patients in the EsophyX group and in 0/10 patients in the surgical group (P = 0.011). Conclusions In patients with refractory GERD, EsophyX fundoplication is significantly less effective than laparoscopic fundoplication in improving reflux parameters and accordingly, in inducing symptom remission. © 2011 Blackwell Publishing Ltd. Source

Frazzoni M.,Fisiopatologia Digestiva | Manta R.,Endoscopia digestiva | Mirante V.G.,Endoscopia digestiva | Conigliaro R.,Endoscopia digestiva | And 2 more authors.
Neurogastroenterology and Motility | Year: 2013

Background: Impedance-pH monitoring allows assessment of retrograde and antegrade intra-esophageal movement of fluids and gas. Reflux is followed by volume clearance and chemical clearance, elicited by secondary and swallow-induced peristalsis, respectively. We aimed to assess whether chemical clearance is impaired in gastro-esophageal reflux disease (GERD). Methods: Blinded retrospective review of impedance-pH tracings from patients with erosive reflux disease (ERD) and non-erosive reflux disease (NERD), and from proton pump inhibitor (PPI)-refractory patients before and after laparoscopic fundoplication. The number of refluxes followed within 30 s by swallow-induced peristaltic waves was divided by the number of total refluxes to obtain a parameter representing chemical clearance namely the postreflux swallow-induced peristaltic wave (PSPW) index. Key Results: The PSPW index was significantly lower in 31 ERD (15%) and in 44 NERD (33%) off-PPI patients than in 30 controls (75%), as well as in 18 ERD (16%) and in 48 NERD (31%) on-PPI patients than in 26 on-PPI functional heartburn (FH) cases (67%) (P < 0.05 for all comparisons). In 29 PPI-refractory patients, the median PSPW index was unaltered by otherwise effective antireflux surgery (20% postoperatively, 21% preoperatively). The overall sensitivity, specificity, positive, and negative predictive values of the PSPW index in identifying GERD patients were 97%, 89%, 96%, and 93%. Conclusions & Inferences: Impairment of chemical clearance is a primary pathophysiological mechanism specific to GERD: it is unaffected by medical/surgical therapy, is not found in FH, and is more pronounced in ERD than in NERD. Using the PSPW index could improve the diagnostic efficacy of impedance-pH monitoring. © 2013 Blackwell Publishing Ltd. Source

Frazzoni M.,Fisiopatologia Digestiva | Conigliaro R.,Gastroenterologia | Melotti G.,Chirurgia Generale
Digestive Diseases and Sciences | Year: 2011

Background: Patients with typical reflux symptoms (heartburn/regurgitation) persisting despite proton pump inhibitor (PPI) therapy are not uncommon. Impedance-pH monitoring detects gastroesophageal reflux at all pH levels and may establish if ongoing symptoms on PPI therapy are associated with acid/nonacid reflux. Laparoscopic fundoplication is a therapeutic option in such patients but reflux parameters on PPI therapy and after intervention and their relationship with symptom persistence/remission have been scarcely studied. Aims: The aim of this study was to assess reflux parameters and their relationship with symptoms before and after laparoscopic fundoplication, on and off PPI therapy, respectively, in patients with PPI-unresponsive heartburn/regurgitation and with a positive symptom-reflux association and/or abnormal reflux parameters detected on PPI therapy. Methods: Impedance-pH monitoring was performed on high-dose PPI therapy and 3 months after laparoscopic fundoplication, off PPI therapy, in 40 patients with PPI-unresponsive heartburn/regurgitation. Symptoms were scored by a validated questionnaire. Results: Esophageal acid exposure time as well as the number of total and proximal reflux events and of acid and weakly acidic refluxes decreased significantly after surgery: normal values were found in 100, 77, 95, 92 and 65% of cases, respectively. Weakly alkaline refluxes increased significantly postoperatively but neither before nor after intervention were associated with symptoms. All patients reported total/subtotal remission of heartburn/regurgitation 3 months after surgery. Conclusions: Laparoscopic fundoplication improves acid and weakly acidic reflux parameters when compared with PPI therapy. This improvement justifies the very high post-surgical symptom remission rate that we observed. Prolonged follow-up is warranted but our findings strongly support the surgical option in PPI failures. © 2010 Springer Science+Business Media, LLC. Source

Frazzoni M.,Fisiopatologia Digestiva | Conigliaro R.,Gastroenterologia | Melotti G.,Chirurgia Generale
Alimentary Pharmacology and Therapeutics | Year: 2011

Background In patients with heartburn that persists despite proton pump inhibitor (PPI) therapy, reflux oesophagitis is found rarely, and its pathogenesis has been scarcely studied. Aim To assess reflux parameters by impedance-pH monitoring in PPI-resistant reflux oesophagitis. Methods Impedance-pH monitoring was performed on PPI therapy in patients with symptomatic reflux oesophagitis detected despite standard or high-dose PPI therapy of at least 8-week duration. Results Twenty patients, ten on once daily and ten on twice daily PPI regimens, were studied. The gastric acid exposure time (per cent time pH <4) ranged from 10% to 81% and was >30% in 70% of cases, but the oesophageal acid exposure time (per cent time pH <4) was abnormal in 20% of patients only. The number of acid, weakly acidic and weakly alkaline refluxes was abnormal in 25%, 100% and 15% of patients, respectively. Conclusions Weakly acidic refluxes were above the normal range in all cases, whereas acid reflux parameters and weakly alkaline refluxes were normal in the vast majority of cases. Gastric acid secretion, with consequent intra-gastric pepsins activation, persists despite ongoing PPI therapy and activated pepsins may well be present in weakly acidic refluxes. As activated pepsins maintain their proteolytic activity in a weakly acidic environment, they may be responsible for mucosal damage. We conclude that weakly acidic refluxes have a major role in the pathogenesis of PPI-resistant reflux oesophagitis. Therapeutic interventions in patients with PPI-resistant reflux oesophagitis should be tailored on the basis of impedance-pH-monitoring results. © 2010 Blackwell Publishing Ltd. Source

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