Impact of the COVID-19 pandemic on Gastroenterology Divisions in Italy: A national survey.

BACKGROUND: In Italy, the spread of the COVID-19 pandemic has stressed the entire healthcare system and required a huge re-organization of many Divisions, including those of Gastroenterology. AIMS: to assess the impact of COVID-19 pandemic on Gastroenterology Divisions across Italy. METHODS: All members of the Italian Society of Gastroenterology (SIGE) were invited to answer a web-based survey. RESULTS: Data of 121 hospitals from all 20 Italian regions were analyzed. Overall, 10.7% Gastroenterology Divisions have been converted to Covid Units. Outpatients consultations, endoscopic and ultrasound procedures were limited to urgencies and oncology indications in 85.1%, 96.2% and 72.2% of Units, respectively, and 46.7% of them suspended the screening for colorectal cancer. Moreover, 72.2% of the staff received a training for use of personal protective equipment, although 45.5% did not have sufficient devices for adequate replacement. Overall, 132 healthcare workers in 41 Gastroenterology Divisions were found to be infected. CONCLUSION: This is the first study to evaluate, at a country level, the impact of COVID-19 outbreak on Gastroenterology Divisions. Substantial changes of practice and reduction of procedures have been recorded in the entire country. The long-term impact of such modifications is difficult to estimate but potentially very risky for many digestive diseases.

[A review on thyroid autoimmune disorders and HCV chronic infection]. / Rassegna su malattie tiroidee autoimmuni e infezione cronica da HCV.

Frequently, patients with hepatitis C virus (HCV) chronic infection have high levels of serum anti-thyroperoxidase and/or anti-thyroglobulin autoantibodies, ultrasonographical signs of chronic autoimmune thyroiditis, and subclinical hypothyroidism, in female gender, vs healthy controls, or hepatitis B virus infected patients. In patients with "HCV-associated mixed cryoglobulinemia" (MC+HCV), a higher prevalence of autoimmune thyroid disorders was shown not only compared to controls, but also compared to HCV patients without cryoglobulinemia. Patients with MC+HCV or with HCV chronic infection, show an higher prevalence of papillary thyroid cancer than in controls, in particular in patients with autoimmune thyroiditis. Patients with HCV chronic infection, or with MC+HCV, in presence of autoimmune thyroiditis, show higher serum levels of T-helper (Th)1 (C-X-C motif) ligand 10 (CXCL10) chemokine than patients without thyroiditis. Probably, HCV thyroid infection acts by upregulating CXCL10 gene expression and secretion in thyrocytes recruiting Th1 lymphocytes, that secrete interferon-gamma and tumor necrosis factor-alpha. These cytokines might induce a further CXCL10 secretion by thyrocytes, thus perpetuating the immune cascade, that may lead into the appearance of autoimmune thyroid disorders in genetically predisposed subjects. A careful monitoring of thyroid function and nodules are recommanded in HCV patients.

Anti-PR3 and anti-MPO antibodies are not present in sera of patients with pulmonary tuberculosis.

Anti-neutrophil cytoplasmic antibodies (ANCA) are autoantibodies directed to intracellular components of neutrophils and are present in several vasculitic syndromes. Recently, these autoantibodies have been described in other autoimmune disorders as well as in infectious diseases such as tuberculosis (TB). As there are some clinical similarities between TB and granulomatosis with polyangiitis, we searched for ANCA in a group of patients with proven TB. Patients with TB confirmed by chest X-ray and sputum bacilloscopy either before or within 30 days after beginning treatment were included in this study. Anti-MPO and anti-PR3 antibodies were studied using well-standardized ELISA kits (INOVA Diagnostics, Inc.). ANCA were also investigated by indirect immunofluorescence (IIF). Fifty TB patients (26 females, mean age 47.34 ± 17 years) were enrolled in the present study. No patient tested positive for ANCA by IIF, or anti-MPO or anti-PR3 antibodies by ELISA. Although previous studies have shown the presence of ANCA in some infectious diseases, the findings of the present study demonstrated the absence of such antibodies in TB. The discrepancy in the prevalence of ANCA in TB among different studies may be attributed to methodological factors and/or the genetic background of the studied populations.

Tumor necrosis factor-α impairs oligodendroglial differentiation through a mitochondria-dependent process.

Mitochondrial defects, affecting parameters such as mitochondrial number and shape, levels of respiratory chain complex components and markers of oxidative stress, have been associated with the appearance and progression of multiple sclerosis. Nevertheless, mitochondrial physiology has never been monitored during oligodendrocyte progenitor cell (OPC) differentiation, especially in OPCs challenged with proinflammatory cytokines. Here, we show that tumor necrosis factor alpha (TNF-α) inhibits OPC differentiation, accompanied by altered mitochondrial calcium uptake, mitochondrial membrane potential, and respiratory complex I activity as well as increased reactive oxygen species production. Treatment with a mitochondrial uncoupler (FCCP) to mimic mitochondrial impairment also causes cells to accumulate at the progenitor stage. Interestingly, AMP-activated protein kinase (AMPK) levels increase during TNF-α exposure and inhibit OPC differentiation. Overall, our data indicate that TNF-α induces metabolic changes, driven by mitochondrial impairment and AMPK activation, leading to the inhibition of OPC differentiation.

Inflammation and atrial remodeling after a mountain marathon.

Endurance athletes have an increased risk of atrial fibrillation. We performed a longitudinal study on elite runners of the 2010 Jungfrau Marathon, a Swiss mountain marathon, to determine acute effects of long-distance running on the atrial myocardium. Ten healthy male athletes were included and examined 9 to 1 week prior to the race, immediately after, and 1, 5, and 8 days after the race. Mean age was 34.9 ± 4.2 years, and maximum oxygen consumption was 66.8 ± 5.8 mL/kg*min. Mean race time was 243.9 ± 17.7 min. Electrocardiographic-determined signal-averaged P-wave duration (SAPWD) increased significantly after the race and returned to baseline levels during follow-up (128.7 ± 10.9 vs. 137.6 ± 9.8 vs. 131.5 ± 8.6 ms; P < 0.001). Left and right atrial volumes showed no significant differences over time, and there were no correlations of atrial volumes and SAPWD. Prolongation of the SAPWD was accompanied by a transient increase in levels of high-sensitivity C-reactive protein, proinflammatory cytokines, total leucocytes, neutrophil granulocytes, pro atrial natriuretic peptide and high-sensitivity troponin. In conclusion, marathon running was associated with a transient conduction delay in the atria, acute inflammation and increased atrial wall tension. This may reflect exercise-induced atrial myocardial edema and may contribute to atrial remodeling over time, generating a substrate for atrial arrhythmias.

H-Ras-driven tumoral maintenance is sustained through caveolin-1-dependent alterations in calcium signaling.

A growing body of research has highlighted the complex range of tumoral traits acquired during H-Ras-driven transformation and maintenance, which include proliferative signaling, growth suppressor evasion and resistance to cell death. Clear molecular information about these processes is not yet available, but recent evidence has provided solid support for the importance of mitochondria. Here, we show that the induction of oncogenic H-Ras leads to changes in intracellular calcium (Ca(2+)), evaluate the temporal relationship between oncogene expression and mitochondrial physiology, and demonstrate that Ca(2+) homeostasis is altered by caveolin-1, a protein that has a key role in tumor maintenance. Our results indicate that tumor-suppressor caveolin-1 is a core component of the Ca(2+)-dependent apoptotic pathway and participates in the regulation of critical mitochondrial functions during tumor development. The compromised caveolin-1/Ca(2+) axis contributes to failure in both mitochondrial metabolism and apoptosis, thereby sustaining the neoplastic phenotype. These results illustrate a direct link between Ca(2+) regulation and mitochondrial biology in cancer.

Proton pump inhibitor responders who are not confirmed as GERD patients with impedance and pH monitoring: who are they?

BACKGROUND: A short-course of proton pump inhibitors (PPIs) is often used to confirm gastroesophageal reflux disease (GERD). However, some patients with PPI responsive heartburn do not seem to have evidence of GERD on impedance-pH monitoring (MII-pH). The aim of the study was to evaluate patients with reflux symptoms and a negative endoscopy, who well respond to PPIs with MII-pH. METHODS: We enrolled 312 patients with GERD symptoms and negative endoscopy: 144 reported well-controlled symptoms after 8-week PPIs and 155 were non-responders. Symptom relief was evaluated with GERD Impact Scale and visual analog scale score. All patients underwent MII-pH off-therapy. Thirteen patients were excluded from analysis. Patients were grouped as follows: non-erosive reflux disease (NERD; increased acid exposure time, AET); hypersensitive esophagus (HE; normal AET, positive symptom association, SI/SAP); MII-pH-/PPI+ (normal AET, negative SI/SAP) in the responder group; MII-pH-/PPI- in non-responders. KEY RESULTS: MII-pH in PPI responders (symptom relief during PPI therapy > 75%) showed: 79/144 NERD (54.9%); 37/144 HE (25.7%); 28/144 MII-pH-/PPI+ (19.4%). MII-pH-/PPI+ patients reported the same symptom relief when compared with NERD and HE. In non-responder (symptom relief during PPI therapy < 50%) group, 27/155 patients were NERD (17.4%); 53/155 were HE (34.2%); 75/155 were MII-pH-/PPI- (48.4%). NERD diagnosis was significantly higher in responder group (p < 0.01). CONCLUSIONS & INFERENCES: In a substantial subgroup of patients responding to PPI with typical reflux symptoms, the diagnosis of GERD cannot be confirmed with pH-impedance monitoring. Proton pump inhibitor response and presence of typical symptoms are thus not reliable predictors of the diagnosis and antireflux surgery should always be preceded by reflux monitoring.

Management of chronic constipation in general practice.

BACKGROUND: Chronic constipation is often diagnosed and treated by general practitioners (GPs). The aim of the study was to evaluate the management of constipation by a cohort of Italian GPs. METHODS: Over the course of 1 month, 41 GPs recorded tests and therapies suggested to patients complaining of chronic constipation. They were classified according to the Rome III criteria as constipated irritable bowel syndrome (C-IBS), functional constipation (FC), or "self-perceived constipation" (SPC) (not consistent with the Rome criteria). RESULTS: The most frequently prescribed tests for the 229 patients (147 FC, 50 C-IBS, 32 SPC) were routine blood tests (59.3 %), abdominal ultrasounds (37.2 %), thyroid function (36.7 %), fecal occult blood tests (36.7 %), and tumor markers (35 %). Patient sex and age, GP age, and whether the diagnosis was new influenced the GP's request, but FC, C-IBS, or SPC status did not. Dietary suggestions (81.9 %), fiber supplements (59.7 %), reassurance (50.9 %), and laxatives (30.5 %) were the most frequently prescribed treatments. Antispasmodics were more frequently suggested for C-IBS patients; dietary suggestions, fiber, and enemas were more frequently prescribed in SPC patients. Patient and GP age and whether the diagnosis was new influenced the GP's choice of treatment. CONCLUSIONS: The Rome III criteria do not influence diagnostic strategies and only slightly influence therapeutic strategies of GPs. Other factors (age, gender, new or old diagnosis) have more influence on GPs choice of investigations and treatment.

Mixed cryoglobulinemia and thyroid autoimmune disorders.

In patients with hepatitis C virus-associated mixed cryoglobulinemia (MC+HCV) the following thyroid disorders are significantly more frequent than in HCV not infected controls: 1) high levels of serum anti-thyroperoxidase autoantibody (AbTPO), 2) high levels of serum AbTPO and/or anti-thyroglobulin (AbTg) autoantibody; 3) humoral and ultrasonographical signs of thyroid autoimmunity (35%); 4) prevalence of subclinical hypothyroidism (11%). Also, the prevalence of papillary thyroid cancer has been found higher in MC+HCV patients than in controls, in particular in patients with autoimmune thyroiditis. These results suggest a careful monitoring of thyroid function in these patients.

Identification of PTEN at the ER and MAMs and its regulation of Ca(2+) signaling and apoptosis in a protein phosphatase-dependent manner.

The tumor suppressor activity of PTEN (phosphatase and tensin homolog deleted on chromosome 10) is thought to be largely attributable to its lipid phosphatase activity. PTEN dephosphorylates the lipid second messenger phosphatidylinositol 3,4,5-trisphosphate to directly antagonize the phosphoinositide 3-kinase-Akt pathway and prevent the activating phosphorylation of Akt. PTEN has also other proposed mechanisms of action, including a poorly characterized protein phosphatase activity, protein-protein interactions, as well as emerging functions in different compartment of the cells such as nucleus and mitochondria. We show here that a fraction of PTEN protein localizes to the endoplasmic reticulum (ER) and mitochondria-associated membranes (MAMs), signaling domains involved in calcium ((2+)) transfer from the ER to mitochondria and apoptosis induction. We demonstrate that PTEN silencing impairs ER Ca(2+) release, lowers cytosolic and mitochondrial Ca(2+) transients and decreases cellular sensitivity to Ca(2+)-mediated apoptotic stimulation. Specific targeting of PTEN to the ER is sufficient to enhance ER-to-mitochondria Ca(2+) transfer and sensitivity to apoptosis. PTEN localization at the ER is further increased during Ca(2+)-dependent apoptosis induction. Importantly, PTEN interacts with the inositol 1,4,5-trisphosphate receptors (IP3Rs) and this correlates with the reduction in their phosphorylation and increased Ca(2+) release. We propose that ER-localized PTEN regulates Ca(2+) release from the ER in a protein phosphatase-dependent manner that counteracts Akt-mediated reduction in Ca(2+) release via IP3Rs. These findings provide new insights into the mechanisms and the extent of PTEN tumor-suppressive functions, highlighting new potential strategies for therapeutic intervention.

Selective modulation of subtype III IP3R by Akt regulates ER Ca²âº release and apoptosis.

Ca²âº transfer from endoplasmic reticulum (ER) to mitochondria can trigger apoptotic pathways by inducing release of mitochondrial pro-apoptotic factors. Three different types of inositol 1,4,5-trisphosphate receptor (IP3R) serve to discharge Ca²âº from ER, but possess some peculiarities, especially in apoptosis induction. The anti-apoptotic protein Akt can phosphorylate all IP3R isoforms and protect cells from apoptosis, reducing ER Ca²âº release. However, it has not been elucidated which IP3R subtypes mediate these effects. Here, we show that Akt activation in COS7 cells, which lack of IP3R I, strongly suppresses IP3-mediated Ca²âº release and apoptosis. Conversely, in SH-SY 5Y cells, which are type III-deficient, Akt is unable to modulate ER Ca²âº flux, losing its anti-apoptotic activity. In SH-SY 5Y-expressing subtype III, Akt recovers its protective function on cell death, by reduction of Ca²âº release. Moreover, regulating Ca²âº flux to mitochondria, Akt maintains the mitochondrial integrity and delays the trigger of apoptosis, in a type III-dependent mechanism. These results demonstrate a specific activity of Akt on IP3R III, leading to diminished Ca²âº transfer to mitochondria and protection from apoptosis, suggesting an additional level of cell death regulation mediated by Akt.

Randomised clinical trial: twice daily esomeprazole 40 mg vs. pantoprazole 40 mg in Barrett's oesophagus for 1 year.

BACKGROUND: Barrett's oesophagus is regarded as the most important risk factor for development of oesophageal adenocarcinoma. According to current guidelines, treatment should be limited to symptomatic Barrett's oesophagus. AIM: To evaluate the expression of Ki67, cyclooxygenase-2 (COX-2) and apoptosis in Barrett's oesophagus after 12 months of double-dose proton pump inhibitor therapy. The effectiveness of esomeprazole and pantoprazole was also compared. METHODS: Seventy-seven nondysplastic Barrett's oesophagus patients underwent baseline upper endoscopy. Patients were then randomised into two groups: one group was allocated to receive esomeprazole 40 mg b.d. and the other group pantoprazole 40 mg b.d. for 12 months. A follow-up endoscopy was performed at the end of treatment. Sixty-five of 77 patients agreed to undergo oesophageal manometry and 24-h pH-metry. Barrett's oesophagus biopsies, obtained at baseline and after treatment, were analysed using immunohistochemistry to assess Ki67 and COX-2 expression; apoptosis was evaluated using TUNEL. RESULTS: In the esomeprazole group, a significant decrease in Ki67 and COX-2 expression, as well as an increase in apoptosis, were observed (P < 0.05). By contrast, in the pantoprazole group Ki67, COX-2 and apoptosis did not vary significantly from baseline. By 24-h oesophageal pH-monitoring, a normal acid exposure time was recorded in patients treated with esomeprazole, while those allocated to pantoprazole displayed abnormal acid exposure (P < 0.05). CONCLUSIONS: Treatment of Barrett's oesophagus patients with high-dose esomeprazole, but not pantoprazole, promoted a decrease in proliferative markers, concomitantly with a decrease in apoptotic cell death. Moreover, esomeprazole allowed a better oesophageal acid control than pantoprazole.

Diagnostic accuracy of CT colonography in patients with positive faecal occult blood test: results of the Italian project Legatumori 2003-2006.

PURPOSE: In the framework of the 3-year project of the Italian Legatumori (2003-2006), we evaluated the diagnostic accuracy of computed tomography (CT) colonography in detecting colorectal lesions in a screening population with positive faecal occult blood test (FOBT). MATERIALS AND METHODS: Two hundred and thirty asymptomatic subjects (age range 45-80 years) were enrolled in the study. CT colonography was performed with standard patient preparation (no faecal tagging) and a 4-detector-row CT scanner. Image analysis was carried out with primary 2D analysis and the use of 3D endoluminal views to solve difficult cases. Patients were referred for conventional colonoscopy in the following situations: detection of three or more suspected lesions with maximum diameter6 mm; presence of colonic masses (maximum diameter>3 cm). RESULTS: CT colonography detected colonic masses in 12 out of 135 subjects (8%). It generated 93 false positives and 19 false negatives in the identification of diminutive lesions (6 mm. Sensitivity was 83% in smaller lesions and 93% in lesions>6 mm; specificity was 45% and 59%, respectively. CONCLUSIONS: In a screening population with positive FOBT, CT colonography without faecal tagging and no definite size threshold for the reporting of polyps showed very low specificity but high sensitivity in the detection of all colorectal lesions.

CT colonography: Project of High National Interest No. 2005062137 of the Italian Ministry of Education, University and Research (MIUR).

PURPOSE: The aim of this paper is to describe the Web site of the Italian Project on CT Colonography (Research Project of High National Interest, PRIN No. 2005062137) and present the prototype of the online database. MATERIALS AND METHODS: The Web site was created with Microsoft Office Publisher 2003 software, which allows the realisation of multiple Web pages linked through a main menu located on the home page. The Web site contains a database of computed tomography (CT) colonography studies in the Digital Imaging and Communications in Medicine (DICOM) standard, all acquired with multidetector-row CT according to the parameters defined by the European Society of Abdominal and Gastrointestinal Radiology (ESGAR). The cases present different bowel-cleansing and tagging methods, and each case has been anonymised and classified according to the Colonography Reporting and Data System (C-RADS). RESULTS: The Web site is available at http address www.ctcolonography.org and is composed of eight pages. Download times for a 294-Mbyte file were 33 min from a residential ADSL (6 Mbit/s) network, 200 s from a local university network (100 Mbit/s) and 2 h and 50 min from a remote academic site in the USA. The Web site received 256 accesses in the 22 days since it went online. CONCLUSIONS: The Web site is an immediate and up-to-date tool for publicising the activity of the research project and a valuable learning resource for CT colonography.

Effects of smoking on cardiopulmonary baroreceptor activation and peripheral vascular resistance.

PATIENTS AND METHODS: We studied 16 healthy smokers and 16 nonsmokers acting as controls. We subjected smokers and nonsmokers to cardiopulmonary baroreceptor stimulation by studying forearm and common carotid haemodynamic and sympathovagal balance. Smokers repeated the tests after smoking one cigarette. Smokers and controls were subjected to passive elevation of the legs and the trunk in a horizontal position with pressure monitoring and measurement of the calibre and flow in the brachial and common carotid arteries using a colourDoppler ultrasound. We calculated forearm resistance and carotid wall tension. We also studied R-R variability, calculating the ratio between low frequency (LF) and high frequency (HF) R-R interval variability. RESULTS: During stimulation diastolic blood pressure values decreased in controls and in smokers at rest. After smoking one cigarette, smokers showed an increase in systolic and diastolic blood pressure as well as in the heart rate during stimulation. Humeral artery increased the calibre during stimulation in both groups; after cigarette smoking the calibre declined throughout the study phases. Forearm resistance decreased in both groups during stimulation at rest, but increased after cigarette smoking. The LF/HF ratio decreased during stimulation in both groups, and it increased at rest after smoking. Carotid diameter did not change in either group, and wall tension increased in smokers after smoking one cigarette. CONCLUSIONS: Smoking one cigarette increases resistance, impairs baroreflex and increases carotid wall tension in mild smokers. These findings may explain the higher rate of a cardiovascular event in smokers.

The general practitioner's approach to irritable bowel syndrome: from intention to practice.

BACKGROUND: Although general practitioners play a critical role in the management of irritable bowel syndrome because they deal with the most patients, guidelines are developed mainly by specialists. AIMS: To evaluate the clinical features of irritable bowel patients and the general practitioners' approach to irritable bowel syndrome in Italy. SUBJECTS AND METHODS: A questionnaire focusing on the management of this syndrome was completed by 28 general practitioners. Clinical features and diagnostic and treatment measures taken in 229 patients were analysed. RESULTS: Only 35.7% of the general practitioners were familiar with the Rome II criteria. Changes in bowel habits and abdominal pain/discomfort were the most common symptoms. Constipation (74.2%) was more frequent as the main symptom than diarrhoea. Routine blood tests (76.4%) and abdominal ultrasound (42.2%) were requested more frequently than colonoscopy (31.1%). At least one specialist consultation was recommended in 63.3% of patients. Drugs (mainly antispasmodics) were prescribed more frequently for diarrhoea (91.4%) than for constipation (55.7%). CONCLUSIONS: General practitioners are little acquainted with the Rome II criteria. Diagnostic tests and specialist consultations are often recommended; antispasmodics are the most frequently prescribed drug. Guidelines should be developed together by general practitioners and gastroenterologists to effectively manage patients at a lower cost.

Gamma-glutamyltransferase in fine-needle liver biopsies of subjects with chronic hepatitis C.

Serum gamma-glutamyltransferase (GGT) is considered as a sensitive but rather nonspecific marker of hepatobiliary disease, including chronic hepatitis C virus (HCV) infection. Although its increase in HCV infection is associated with poor response to interferon-alpha (IFN-alpha) and poor prognosis, there is little knowledge of the reasons of its increase during disease. Immunohistochemistry and enzyme histochemistry were performed on fine-needle biopsies of subjects with HCV infection. GGT was detected in the lumen of bile ducts and in bile canaliculi. Furthermore, in subjects with elevated serum GGT, immunoreactive and catalytically active GGT was also detected on the sinusoidal surface of hepatocytes and diffuse cytoplasmic positivity appeared in isolated hepatocytes and hepatocellular foci. Antigen unmasking procedures showed the presence of GGT in the cytoplasm of mature and immature bile cells and of inflammatory cells. These results suggest that during chronic HCV infection there is a general enhancement of GGT activity within the liver. As the activity of several inflammatory mediators, such as leukotrienes, nitric oxide, and interleukins is modulated by GGT activity, the present findings suggest a direct relationship between serum GGT, enhanced intrahepatic GGT activity and prognosis and therapeutic outcome of chronic HCV infection.