Chronic constipation in Parkinson's disease: clinical features and molecular insights on the intestinal epithelial barrier.

Background: Chronic constipation (CC) is a severe symptom in Parkinson's disease (PD), with an unclear pathogenesis. Abnormalities of the enteric nervous system (ENS) and/or intestinal epithelial barrier (IEB) may be pathophysiologically relevant in PD patients with CC. We investigated possible molecular changes of the IEB in PD/CCs compared with CCs and controls. Methods: Twelve PD/CCs (2 female, age range 51-80 years), 20 CCs (15 female, age range 27-78 years), and 23 controls (11 female, age range 32-74 years) were enrolled. Ten PD/CCs and 10 CCs were functionally characterized by anorectal manometry (AM) and transit time (TT). Colon biopsies were obtained and assessed for gene and protein expression, and localization of IEB tight junction markers claudin-4 (CLDN4), occludin-1 (OCCL-1), and zonula occludens-1 (ZO-1) by RT-qPCR, immunoblot and immunofluorescence labeling. Results: PD/CCs were clustered in 2 functional categories: patients with delayed TT and altered AM (60%), and a second group showing only modifications in AM pattern (40%). Gene expression of CLDN4, OCCL-1 and ZO-1 was higher in PD/CCs than controls (P<0.05). Conversely, PD/CCs showed a trend to decrease (P>0.05) in CLDN4 and OCCL-1 protein levels than controls, whereas ZO-1 protein was comparable. In PD/CCs compared with controls, decreasing tendency of vasoactive intestinal polypeptide mRNA, protein and immunoreactive fiber density were observed, although the difference was not statistically significant. Conclusion: Transit and anorectal dysfunctions in PD/CCs are associated with difference in ZO-1, OCCL-1 and CLDN4 expression, thus supporting the role of an altered IEB as a contributory mechanism to possible neuronal abnormalities.

Combined Endoscopic Stent-In-Stent Placement by Lumen-Apposing Metal Stents Through Self-Expanding Metal Stents for Simultaneous Malignant Biliary and Duodenal Obstruction.

The palliation of simultaneous biliary and duodenal obstruction in patients with advanced pancreatic cancer is a clinically and technically challenging scenario. Endoscopic procedures are a valid alternative to surgical or percutaneous transhepatic biliary drainage. The availability of self-expanding metal stents (SEMSs) and lumen-apposing metal stents (LAMS) have expanded therapeutic options. We describe a case in which biliary and duodenal obstructions were treated successfully with the combined use of SEMS and LAMS devices. Endoscopic ultrasound-guided biliary drainage with the use of new LAMS and a duodenal SEMS can be a valid option in expert hands as a palliative and minimally invasive treatment for gastric outlet and biliary obstruction.

A new panenteric capsule endoscopy-based strategy in patients with melena and a negative upper gastrointestinal endoscopy: a prospective feasibility study.

OBJECTIVE: patients presenting with melena and nondiagnostic esophagogastroduodenoscopy are usually investigated with colonoscopy and if negative, with small bowel capsule endoscopy. In this pilot study, we tested feasibility and performance of panenteric capsule endoscopy (PCE) in patients presenting with melena and negative esophagogastroduodenoscopy. METHODS: Between January and December 2018, consecutive patients presenting with melena, clinically significant bleeding and negative esophagogastroduodenoscopy were invited to undergo PCE by swallowing PillCam Colon 2 (Medtronic Inc., Dublin, Ireland). PCE results, further diagnostic or therapeutic examinations, rebleeding rates at 30 days and 12 months were recorded. RESULTS: Out of 128 patients with melena, 23 had negative esophagogastroduodenoscopy. Of them, 12 (8 female, mean age 76 years) underwent PCE, which allowed complete small bowel and colonic evaluation in 12 (100%) and 11 (91.7%) patients, respectively. The small bowel and colon cleansing were adequate in 100 and 83.3%, respectively. No PCE-related complications were observed. The PCE diagnostic yield was 83.3%: significant findings were located in the small bowel, colon or both in 5 (41.7%), 4 (33.3%) and 1 (8.3%) patients, respectively. Device-assisted enteroscopy was performed in 6 (50%) patients. Thirty days and 1 year rebleeding rates were 0 and 18.1%, respectively. CONCLUSIONS: In this proof-of-concept study, PCE was feasible and safe in patients with melena and negative esophagogastroduodenoscopy, identifying the bleeding site in 83% of patients. PCE lead to small bowel therapeutic interventions in 50% of patients, thus avoiding unnecessary standard colonoscopy. Further large prospective randomized studies investigating this strategy are warranted.

Right-sided diverticulosis is an independent risk factor for bleeding in patients admitted for diverticular disease.

BACKGROUND: Diverticular bleeding is the main cause of lower gastrointestinal bleeding in both Eastern and Western countries. Several risk factors have been identified, such as comorbidities and concomitant medications. In Eastern population, the prevalence of right-side diverticulosis is higher than in Western one, and some Authors identified bilateral diverticulosis as a risk factor for bleeding. AIMS: To identify risk factors for diverticular bleeding in patients admitted for diverticular disease (DD). METHODS: All patients admitted for DD from January 2017 to December 2018 were retrieved from the hospital Information System. For each patient, age, gender, clinical presentation and concomitant medication were recorded. All patient underwent imaging assessment (computed tomography, ultrasound or MRI) and colonoscopy during hospitalization or within one month. RESULTS: Among 1248 patients discharged with a diagnosis of DD during the study period, 293 (52.2% male, median age 75 years) were finally analyzed; of them, 105 (35.8%) for diverticular bleeding. On multivariate analysis, male gender (OR 4.27), age (OR 1.12), anti-thrombotic medications (OR 2.60) and right-sided DD (OR 5.70) were independently correlated to diverticular bleeding. CONCLUSION: Our study provides evidence that, together with age, male gender and concomitant anti-thrombotic treatment, right-sided DD represents an independent risk factor for bleeding.

Long-term efficacy of vacuum-assisted therapy (Endo-SPONGE®) in large anastomotic leakages following anterior rectal resection.

BACKGROUND: The aim of our study was to test the long-term efficacy of Endo-SPONGE® therapy in a group of patients treated in our center with vacuum-assisted therapy because of anastomotic leakages after colorectal surgery. METHODS: Eleven patients [male: 6; mean age: 71 (range: 44-82) years] who had anastomotic leakage treated with Endo-SPONGE® placement were included in the study. Patient records were examined retrospectively. All patients with documented anastomotic leakage on abdominal computed tomography following an anterior resection of the rectum for rectal cancer underwent sigmoidoscopy to determine the extent of the anastomotic defect and the size of the presacral abscess. RESULTS: Ten of the 11 patients (90.9%) showed closure of the anastomotic leakage after a mean of 16 sponge changes. During follow up [mean: 29 (range: 6-64) months], we observed two cases of anastomotic stricture. Treatment failure was observed in one patient who presented an increased size of dehiscence after 23 sessions of endoscopic treatment, despite an initial good response. CONCLUSIONS: Our study substantially confirms previous conclusions and reaffirms that Endo-SPONGE® treatment for colorectal anastomotic leakages, performed in suitable patients, represents a successful and safe approach. The reduction in wound closure time, mild-to-moderate discomfort and possibly shorter hospitalization suggest that Endo-SPONGE® treatment can be a prominent therapeutic regimen with adequate patient acceptance.

Relationship between indocyanine green retention test, decompensation and survival in patients with Child-Pugh A cirrhosis and portal hypertension.

BACKGROUND & AIMS: Indocyanine green retention test (ICG-r15) is a non-invasive marker of functional hepatic reserve. Among patients with compensated cirrhosis, ICG-r15 correlates to the degree of portal hypertension (PH); however, its prognostic relationship with the occurrence of decompensation events still requires clarification. METHODS: ICG-r15 was prospectively measured in 154 patients with compensated cirrhosis. Patients with hepatocellular carcinoma (HCC), Child-Pugh B-C, MELD>15, bilirubin > 2 mg/dl, INR > 1.5 or portal vein thrombosis were excluded. All patients underwent laboratory tests, upper endoscopy and hepatic venous pressure gradient (HVPG). Decompensation, development of HCC, liver transplant and death were recorded and analysed through competing-risk analysis. RESULTS: The study group was composed of 134 patients who were followed for a median of 39 months. During follow-up, 46 patients (34.3%) developed liver decompensation. Hepatocellular carcinoma occurred in 18 patients and two patients died from non-liver-related causes. The 1-, 2- and 3-year cumulative incidences of decompensation were 9.7%, 28.4% and 33.4% respectively. Patients with ICG-r15 < 10% did not experience any decompensation events during follow-up, while the 3-year cumulative incidence of decompensation of patients with ICG-r15 between 10% and 22.9% was 29.2% and that of patients with ICG-r15 ≥ 23% was 70.0% (P < 0.001). ICG-r15 gave the lowest pseudo-log-likelihood value, in comparison to oesophageal varices present, MELD, low platelet count and HVPG. CONCLUSIONS: ICG-r15 appears to be strictly related to liver decompensation, longitudinally confirming the preliminary findings of its correlation with PH among patients with compensated cirrhosis, and can be used for patient prognostication.

Severe immune thrombocytopenia after peg-interferon-alpha2a, ribavirin and telaprevir treatment completion: A case report and systematic review of literature.

Mild to moderate autoimmune thrombocytopenia (AITP) is a common finding in patients receiving interferon-based antiviral treatment, due to bone marrow suppression. Here we report the case of a patient with chronic genotype 1b hepatitis C virus (HCV) infection treated with pegylated-interferon alpha-2a, ribavirin and telaprevir for 24 wk; the patient developed severe AITP three weeks after treatment withdrawal. We performed a systematic literature search in order to review all published cases of AITP related to HCV antiviral treatment. To our knowledge, this is the second case of AITP observed after antiviral treatment withdrawal. In most published cases AITP occurred during treatment; in fact, among 24 cases of AITP related to interferon-based antiviral treatment, only one occurred after discontinuation. Early diagnosis of AITP is a key factor in order to achieve an early interferon discontinuation; in the era of new direct antiviral agents those patients have to be considered for interferon-free treatment regimens. Prompt prescription of immuno-suppressant treatment (i.e., corticosteroids, immunoglobulin infusion and even rituximab for unresponsive cases) leads to favourable prognosis in most of cases. Physicians using interferon-based treatments should be aware that AITP can occur both during and after treatment, specially in the new era of interferon-free antiviral treatment. Finally, in the case of suspected AITP, presence of anti-platelet antibodies should be checked not only during treatment but also after discontinuation.

Indocyanine green retention test as a noninvasive marker of portal hypertension and esophageal varices in compensated liver cirrhosis.

UNLABELLED: Noninvasive markers would be useful for the assessment of portal hypertension (PH) and esophageal varices (EV) in patients with cirrhosis. The aim of our study was to evaluate the performance of the indocyanine green (ICG) retention test as a noninvasive marker of PH and EV, measured against the gold standards (hepatic venous pressure gradient [HVPG] measurement and upper endoscopy). We prospectively enrolled patients with compensated cirrhosis referral to our unit. All patients underwent laboratory tests, abdominal ultrasound, upper gastrointestinal endoscopy, HVPG measurement, and the ICG 15-minute retention (ICG-r15) test. We evaluated the sensitivity and specificity of the ICG retention test and other noninvasive tools for the diagnosis of PH and EV. Ninety-six consecutive Child-Pugh A patients (67 male and 29 female; 60.3 ± 11.8 years of age) were enrolled. Seventy-four patients had clinically significant portal hypertension (CSPH), of whom 59 had severe portal hypertension (SPH). ICG-r15 and Lok index were independently related to the presence of both CSPH and SPH, whereas ICG-r15 and INR were related to EV. ICG-r15 values (<6.7% and <6.9%, respectively) were able to rule out the presence of CSPH and SPH (LR(-) 0.15 and 0.14); ICG-r15 <10% provided a 97.8% sensitivity (LR(-) 0.042) for the exclusion of EV and a 100% sensitivity (LR(-) 0.0) for large EV. CONCLUSION: The ICG-r15 test is an effective tool for assessment of PH in patients with compensated cirrhosis. Although this would not replace endoscopy, the ICG-r15 appears able to identify patients with advanced liver disease in which endoscopy is mandatory as well as rule out the presence of EV in patients with compensated cirrhosis.

Long-term leukocyte natural α-interferon and ribavirin treatment in hepatitis C virus recurrence after liver transplantation.

AIM: To evaluate the effect of long-term treatment with leukocyte natural α-interferon (ln-α-IFN) plus ribavirin (RBV). METHODS: Forty-six patients with hepatitis C virus (HCV) recurrence received 3 MU three times a week of ln-α-IFN plus RBV for 1 mo; then, patients with good tolerability (n = 30) were switched to daily IFN administration, while the remaining were treated with the same schedule. Patients have been treated for 12 mo after viral clearance while non-responders (NR) entered in the long-term treatment group. Liver biopsies were planned at baseline, 1 year after sustained virological response (SVR) and at 36 mo after start of therapy in NR. MedCalc software package was used for statistical analysis. RESULTS: About 16.7% of genotype 1-4 and 70% of genotype 2-3 patients achieved SVR. Nine patients withdrew therapy because of non-tolerance or non-compliance. A significant improvement in serum biochemistry and histological activity was observed in all SVR patients and long-term treated; 100% of patients with SVR achieved a histological response (fibrosis stabilization or improvement) with a significant reduction in mean staging value (from 2.1 to 1.0; P = 0.0031); histological response was observed in 84% of long-term treated patients compared to 57% of drop-out. Six patients died during the entire study period (follow-up 40.6 ± 7.7 mo); of them, 5 presented with severe HCV recurrence on enrollment. Diabetes (OR = 0.38, 95%CI: 0.08-0.59, P = 0.01), leukopenia (OR = 0.54, 95%CI: 0.03-0.57, P = 0.03) and severe HCV recurrence (OR = 0.51, 95%CI: 0.25-0.69, P = 0.0003) were variables associated to survival. Long-term treatment was well tolerated; no patients developed rejection or autoimmune disease. CONCLUSION: Long-term treatment improves histology in SVR patients and slows disease progression also in NR, leading to a reduction in liver decompensation, graft failure and liver-related death.

High doses of ursodeoxycholic acid up-regulate the expression of placental breast cancer resistance protein in patients affected by intrahepatic cholestasis of pregnancy.

BACKGROUND: Ursodeoxycholic acid (UDCA) administration in intrahepatic cholestasis of pregnancy (ICP) induces bile acids (BA) efflux from the foetal compartment, but the molecular basis of this transplacental transport is only partially defined. AIM: To determine if placental breast cancer resistance protein (BCRP), able to transport BA, is regulated by UDCA in ICP. METHODS: 32 pregnant women with ICP (14 untreated, 34.9±5.17 years; 18 treated with UDCA--25 mg/Kg/day, 32.7±4.62 years,) and 12 healthy controls (33.4±3.32 years) agreed to participate in the study. Placentas were obtained at delivery and processed for membrane extraction. BCRP protein expression was evaluated by immunoblotting techniques and chemiluminescence quantified with a luminograph measuring emitted photons; mRNA expression with real time PCR. Statistical differences between groups were evaluated by ANOVA with Dunn's Multiple Comparison test. RESULTS: BCRP was expressed only on the apical membrane of the syncytiotrophoblast. A significant difference was observed among the three groups both for mRNA (ANOVA, p = 0.0074) and protein (ANOVA, p<0.0001) expression. BCRP expression was similar in controls and in the untreated ICP group. UDCA induced a significant increase in placental BCRP mRNA and protein expression compared to controls (350.7±106.3 vs 100±18.68% of controls, p<0.05 and 397.8±56.02 vs 100±11.44% of controls, p<0.001, respectively) and untreated ICP (90.29±17.59% of controls, p<0.05 and 155.0±13.87%, p<0.01). CONCLUSION: Our results confirm that BCRP is expressed only on the apical membrane of the syncytiotrophoblast and show that ICP treatment with high dose UDCA significantly upregulates placental BCRP expression favouring BA efflux from the foetal compartment.