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ObjectivesUlcerative colitis (UC) is a chronic inflammatory disorder of unknown aetiology. Gut virome dysbiosis is fundamental in UC progression, although its role in the early phases of the disease is far from fully understood. Therefore, we sought to investigate the role of a virome-associated protein encoded by the Orthohepadnavirusgenus, the hepatitis B virus X protein (HBx), in UC aetiopathogenesis.DesignHBx positivity of UC patient-derived blood and gut mucosa was assessed by RT-PCR and Sanger sequencing and correlated with clinical characteristics by multivariate analysis. Transcriptomics was performed on HBx-overexpressing endoscopic biopsies from healthy donors.C57BL/6 mice underwent intramucosal injections of liposome-conjugated HBx-encoding plasmids or the control, with or without antibiotic treatment. Multidimensional flow cytometry analysis was performed on colonic samples from HBx-treated and control animals. Transepithelial electrical resistance measurement, proliferation assay, chromatin immunoprecipitation assay with sequencing and RNA-sequencing were performed on in vitromodels of the gut barrier. HBx-silencing experiments were performed in vitroand in vivo.ResultsHBx was detected in about 45% of patients with UC and found to induce colonic inflammation in mice, while its silencing reverted the colitis phenotype in vivo. HBx acted as a transcriptional regulator in epithelial cells, provoking barrier leakage and altering both innate and adaptive mucosal immunity ex vivoand in vivo.ConclusionThis study described HBx as a contributor to the UC pathogenesis and provides a new perspective on the virome as a target for tailored treatments.

Fecal calprotectin (FC) is established as a diagnostic marker to differentiate between inflammatory bowel diseases and non‐inflammatory conditions. Furthermore, it may be effective in monitoring response to treatment, and to predict relapse during maintenance therapy. This was a prospective longitudinal study carried out in Italy, France and Spain. The primary objective was to correlate the LIAISON®Calprotectin assay measurements to quiescent ulcerative colitis (UC) or relapse as assessed by clinical data. Patients were assessed every 3 months for 12 months, and at 18 months. The last FC measured prior to relapse was the variable that predicted relapse in a statistically significant manner. With a 62.3 μg/g cut‐off the area under the curve was 0.619, and the sensitivity was 62.9% (95% Confidence Interval [CI] 44.9%–78.5%) and specificity 63.0% (95% CI 53.1%–72.1%). Using machine learning methods, the last FC measurement was shown to have the largest impact in predicting relapse. An algorithm was developed that included other variables available following a clinician's visit, which resulted in an area under the curve of 0.754 for predicting relapse. In the present study FC measured by the LIAISON®Calprotectin assay on the visit before relapse is predictive of relapse in patients with quiescent UC. In a proof of concept, the accuracy of prediction can further be improved including other variables in an algorithm developed by machine learning. The trial is registered at clinicaltrials.govwith reference number NCT05168917.

Ports and airports need to be protected by extensive video security systems; however, these facilities present complex cabling issues which can be incredibly burdensome in terms of higher costs and [...]

Purpose: Usher syndrome (USH) is an autosomal recessive disorder characterized by congenital sensorineural hearing impairment and retinitis pigmentosa. Classification distinguishes three clinical types of which type I (USH1) is the most severe, with vestibular dysfunction as an added feature. To date, 15 genes and 3 loci have been identified with the USH1Ggene being an uncommon cause of USH. We describe an atypical USH1G-related phenotype caused by a novel homozygous missense variation in a patient with profound hearing impairment and relatively mild retinitis pigmentosa, but no vestibular dysfunction.Methods: A 26-year-old female patient with profound congenital sensorineural hearing loss, nyctalopia and retinitis pigmentosa was studied. Audiometric, vestibular and ophthalmologic examination was performed. A panel of 13 genes was tested by next-generation sequencing (NGS).Results: While the hearing loss was confirmed to be profound, the vestibular function resulted normal. Although typical retinitis pigmentosa was present, the age at onset was unusually late for USH1 syndrome. A novel homozygous missense variation (c.1187T>A, p.Leu396Gln) in the USH1Ggene has been identified as causing the disease in our patient.Conclusions: Genetic and phenotypic heterogeneity are very common in both isolated and syndromic retinal dystrophies and sensorineural hearing loss. Our findings widen the spectrum of USH allelic disorders and strength the concept that variants in genes that are classically known as underlying one specific clinical USH subtype might result in unexpected phenotypes.

Polyposis syndromes are encountered in endoscopy practice, and are considered rare entities, accounting for ≤1% of colorectal cancer. Polyposis can occur within inherited syndromes or as “sporadic” cases of unknown etiology. Their proper characterization is relevant for patient management, and should nowadays drive appropriate genetic tests which have a key role in clinical practice for driving surveillance and colorectal cancer prevention, enlarged to relatives. Polyposis classification is based upon polyp number and histology, familial and personal history. This review will explore the polyposis nosology and their genetic determinants in the emerging scenario of Next Generation Sequencing which allow testing multiples genes in parallel. This capability will likely continue to increase the range of polyposis predisposing genes, contributing to define new clinical entities.

Tumour-associated macrophages (TAMs) are a key component of the cancer microenvironment, and influence tumour growth and progressionTAMs can have a dual supportive and inhibitory influence on cancer, depending on the disease stage, the tissue involved, and the host microbiotaTAMs can limit the antitumour activity of conventional chemotherapy and radiotherapy by orchestrating a tumour-promoting repair response to tissue damage, and by providing a protective niche for cancer stem cellsConversely, TAMs contribute to the antitumour activity of selected chemotherapeutic agents, such as doxorubicin (under certain conditions), and of monoclonal antibody therapies via antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis (ADCP)Of note, macrophage depletion has a key role in the antitumour activity of the clinically approved anticancer agent trabectedinTherapeutic strategies targeting macrophages as tumour-promoting factors, and/or aimed at macrophage activation and re-education are undergoing clinical assessment; such strategies have the potential to complement cytoreductive, antiangiogenic, and immune-checkpoint-inhibitor treatments

One of the main challenges for clinicians dealing with Crohns disease (CD) is to distinguish between inflammation and fibrosis, two sequential steps in the evolution of the intestinal disease. While inflammation is amenable to medical treatment, stricturing disease can only benefit from surgery. Magnetic resonance imaging (MRI) is a widely used tool in the diagnosis and assessment of CD. Recent data suggest that this technique might help in discriminating between fibrosis and inflammation and as such potentially guide medical decisions. In this review we will first highlight the main diagnostic techniques for CD. We will then briefly review the main mechanisms of fibrosis in this condition and the use of MRI in CD focusing on findings predictive of fibrosis and fibrotic evolution.

Anorectal involvement in Crohns disease (CD) causes perianal lesions that vary from simple asymptomatic skin tags, to complex disabling fistulas and abscesses. Perianal CD affects approximately one-third of patients; its management is challenging and may require combined medical and surgical treatment, which has proven to offer the best chance of success. An optimal preoperative disease assessment is crucial in order to achieve an optimal outcome and avoid irreversible damage due to incomplete or inaccurate intervention. Imaging modalities are useful in order to confirm diagnosis, to accurately classify the disease, as to plan the most suitable treatment and monitor its results. Endoscopic Ultrasonography (EUS) and pelvic Magnetic Resonance (MRI) represent the best options from this perspective, both in terms of sensitivity and specificity, as well as for their demonstrated role in influencing treatment approach. Transperineal Ultrasonography (TPUS) may be helpful when EUS is contraindicated or not-tolerated. Computed Tomography (CT) and fistulography are generally no longer considered due to their inferior performance and the radiation exposure they involve. All imaging should be done in conjunction with an Evaluation Under Anesthesia (EUA) performed by an expert surgeon, to ensure accurate disease assessment. In this paper we review available data on each imaging modality, comparing performance and focusing on specific pros and cons, in order to assist clinicians in choosing the most appropriate treatment option for each individual patient.

Crohn's disease is a chronic, disabling disease that, over time, can lead to irreversible bowel damage. MRI can be used to diagnose and assess the activity, severity and complications of Crohn's disease; however, the role of MRI in therapeutic monitoring of changes in disease-related intestinal damage is still to be defined. Objective, validated MRI-based scores have been developed to assess the activity of Crohn's disease; these indices are based on the extent and severity of intestinal inflammation, postoperative recurrence and perianal disease. MRI is accurate, safe, reproducible and can allow repeated evaluations of patients without radiation exposure. Evidence that MRI might be valuable in the therapeutic monitoring of patients with Crohn's disease is increasing and, in combination with endoscopy and surgical history, this imaging technique could enable clinicians to assess Crohn's-disease-related intestinal damage. MRI could, therefore, have a crucial role in a future 'damage-driven' treatment paradigm—in which imaging is used to monitor intestinal damage and medication use is targeted to prevent the accumulation of further damage. This damage-driven therapeutic approach could potentially change the course of Crohn's disease.

Ulcerative colitis (UC) is an inflammatory bowel disease (IBD) characterized by chronic inflammation affecting the colonic mucosa, that can extend to the whole large bowel. The severity of mucosal lesions directly reflects the disease activity and severity and may be prognostic for an aggressive behavior of the pathology. Remission, is usually defined as resolution of symptoms. Recently, mucosal healing (MH) has emerged as an important end point of any shortterm medical therapy for IBD. It may predict long-term remission and may impact on the natural history of the disease in Crohns disease (CD), while data in UC patients are still limited. This review of the literature is focused on the recent evidence on the impact of medications on MH in UC and on the impact of MH on the natural course of UC.

Introduction: Three anti TNF-α agents have currently been approved for the treatment of moderate-to-severe or complicated Crohn's disease (CD): infliximab, certolizumab and adalimumab. Infliximab is effective in CD, but for reasons linked to its chimeric structure, response to treatment may be lost overtime and as a result, it can sometimes be unable to provide long term durable treatment of CD. Adalimumab, a fully human anti TNF-α antibody, demonstrates similar treatment efficacy as infliximab and certolizumab, and can easily be self-administered at home. Aim and Methods: A literature search in the Cochrane, MEDLINE, PUBMED, Ovid MEDLINER® and EMBASE databases has been performed on the efficacy, safety and the impact adalimumab has on the quality of life and natural history of CD. Abstracts presented at the DDW, UEGW and ECCO Congresses have also been reviewed as well as references from review articles, meta-analysis studies and published RCTs. Results: Adalimumab induced remission of CD in 64% of patients, and maintained remission in more than 80% of initial responders. Adalimumab did not significantly increase the risk of adverse events compared with conventional medication up to 3 years of follow-up. Adalimumab reduces more than 50% the risk for hospitalisation and surgery due to CD. It is also effective for fistula closure, for the healing of the mucosa, and improving quality of life. Conclusion: Adalimumab is effective in the induction and maintenance of clinical remission in CD and is generally well tolerated. It has been proved to have a positive impact by improving quality of life of patients, and reducing the need for hospitalisation and surgery due to CD. According to the European Crohn's and Colitis Organisation (ECCO), infliximab or adalimumab can be used for the treatment of fistulizing CD.

Importance of the field:The advent of anti-TNF-α monoclonal antibodies has dramatically changed the management of inflammatory bowel diseases (IBD). Unlike Crohn's disease (CD), only one anti-TNF-α agent, infliximab, is currently approved for active moderate-to-severe ulcerative colitis (UC). Adalimumab is a fully human anti-TNF-α antibody that is effective and safe for the treatment of luminal and fistulising CD.Areas covered in this review:This review of the literature summarizes available data on of efficacy and safety profile adalimumab in patients with UC.What the reader will gain:Adalimumab may be effective in inducing and maintaining clinical remission in patients with moderate-to-severe UC. It may also induce mucosal healing and reduce the need for colectomy in patients with severe disease. The safety profile of the drug in UC is consistent with previous experience with this drug in CD.Take home message:Adalimumab may be effective and well tolerated in UC. Its efficacy in maintaining clinical remission needs to be confirmed in a randomized controlled trial.

Inflammatory bowel diseases are chronic diseases that affect the gastrointestinal tract. Mesalamine, corticosteroids, immunosuppressants and biological agents are currently used to treat these diseases. Due to inadequacies of the currently available delivery systems, a large number of patients do not respond to treatment, especially when they are affected by distal colonic disease. Multimatrix (MMX™) technology comprises hydrophilic and lipophilic excipients, enclosed within a gastro-resistant, pH-dependent coating. This new delivery technology has been used to modify some commonly used drugs, including mesalamine and budesonide, as well as heparin, which are now being investigated for their utility in the management of IBD. Aim: The aim of this review is to explore the MMX delivery technology and its efficacy for the treatment of IBD. Results: The results of various studies involving MMX drugs have been published. Mesalamine MMX induces clinical and endoscopic remission in patients with mild to moderate ulcerative colitis (UC) compared with placebo. Positive results have also been observed with MMX budesonide in two phase I studies. In a pilot study involving ten patients with UC, efficacy of heparin-MMX as an IBD therapy was observed. Conclusion: MMX is a promising new delivery system that can improve efficacy of current and new drugs, augmenting targeting to the affected tract, thereby increasing response and remission rates for those drugs in patients with IBD.

Perfluoropolyethers are a well known and widely used family of polymers, suitable as protectives. Their main drawback is the lack of solubility, which is complete only in chlorofluorocarbons. In this work a series of ABA block copolymers FluoPLA, with a relative low molecular weight, were prepared by ROP of L and D,Llactide PLA in the presence of a hydroxyterminated perfluoropolyether as macroinitiator. In fact the use of block copolymers leads to different advantages, i.e. a limited segregation phenomena and higher polymer solubility. The resulting polymers were characterized by NMR, IR, HPLCSEC, DSC, LS and tested as potential protective and surface modifiers for cultural heritage ESEMEDS, solarbox technique, colorimeter analysis.

Inflammatory bowel diseases (IBD) are idiopathic chronic inflammations: the etiology of Crohns disease (CD) and ulcerative colitis (UC) is still largely unknown. Environmental and genetic factors in combination with the microbial flora or specific microorganisms trigger an event, leading to the activation of an intestinal immune response. Immune and non-immune cells create a cross talk via the secretion of soluble mediators and expression of cell adhesion molecules, resulting in further cell activation. Mediators such as cytokines and chemokines play a role in cell recruitment and polarization, intercellular signal amplification or activation and differentiation. Considering these aspects, medical management of inflammatory bowel disease has changed considerably over the past decade. Advances in biotechnology has allowed for the introduction of many biologic therapies, other than anti-TNF therapies. Many of these drugs showed clinical benefit for induction and maintenance therapy, both in UC and CD. Although numerous, at present only monoclonal anti-TNF antibodies are currently available worldwide. Other biological agents have been tested or are under evaluation. This paper systematically reviews the mechanism-of-action, efficacy, short-term and, where available, long-term safety of biological agents that have been approved for the treatment of IBD or are under evaluation which target different molecules other than tumor necrosis factor (TNF-).

Open access endoscopy and screening programs enable detection and removal of an increased number of colon polyps in the early stages of neoplastic transformation. Unfortunately, polyps larger than 3 cm, involving more than one-third of circumference or two haustral folds, or with a flat/depressed morphology are more challenging to remove with standard polypectomy techniques. Endoscopic mucosal resection potentiates the removal, in a minimally invasive way, of certain colonic lesions that would otherwise require surgical or ablative treatment. Because the plane of resection during endoscopic mucosal resection is typically the middle to deep submucosal layer, compared with standard polypectomy, which normally provides resection at a mucosal level, endoscopic mucosal resection offers the advantage of providing en blocresection specimens for histopathologic analysis. Indications to perform endoscopic mucosal resection are adenoma and small, well-differentiated carcinoma, confined to the mucosa or with minimal invasion to submucosa, and without any invasion to lymphatic channels or vessels. The most frequently reported major complications, such as perforation (0-5%) and bleeding (0.5-6%), may be controlled by endoscopic methods and rarely require surgical treatment. Follow-up postendoscopic mucosal resection is essential because of the risk of neoplastic recurrence.

Corticosteroids have represented the mainstay of medical treatment for induction of remission in inflammatory bowel disease. Aim of this paper is to review mechanisms of action, safety and efficacy of beclomethasone dipropionate, a steroid with enhanced topical intestinal activity and low systemic activity, in the treatment of inflammatory bowel disease.

Crohns disease and ulcerative colitis are chronic relapsing inflammatory bowel diseases with extremely great variability in presentation and clinical course. For many decades, corticosteroids and aminosalicylates have been the mainstay of the treatment for both Crohns disease and ulcerative colitis, for the induction and maintenance of remission, respectively. The main limiting factors for the repeated use of corticosteroids or the use as a maintenance treatment are the very high prevalence of systemic side effects, together with the possibility of developing dependency on and/or resistance to the drug, which are reported in more than one third of patients with inflammatory bowel disease. In the last decade, a number of corticosteroids with enhanced topical activity and low systemic activity have been developed. Among them, budesonide and beclomethasone dipropionate are the most used for the treatment of the inflammatory bowel diseases. Indeed, budesonide is the drug of choice for the treatment of ileo(-cecal) active Crohns disease with mild-to-moderate activity, due to controlled ileal release. Budesonide foam and/or enemas are also efficacious in the treatment of left-sided/distal ulcerative colitis. Gastroresistant, extended release tablets characterized by a multimatrix structure (i.e. MMX®-budesonide), have also been developed to allow uniform release along the length of the colon. This paper reviews the mechanism-of-action, safety and efficacy of budesonide in the treatment of inflammatory bowel disease.

The aim of this study was to determine whether mutations in SPINK1/PRSS1genes are associated with benign pancreatic hyperenzymemia (BPH).

To evaluate the adhesion molecule time course in the early phases of acute pancreatitis and to explore the usefulness of these proteins in assessing the severity of the disease. Fifteen consecutive acute pancreatitis patients (10 patients with the mild and 5 with the severe disease) admitted to the hospital within 6 hours after the onset of pain and 15 age- and sex-matched healthy subjects.

The etiology of Crohn's disease and ulcerative colitis, the two major forms of inflammatory bowel disease (IBD), is still largely unknown. However, it is now clear that the abnormalities underlying pathogenesis of intestinal inflammation are not restricted to those mediated by classic immune cells but also involve nonimmune cells. In particular, advances in vascular biology have outlined a central and multifaceted pathogenic role for the microcirculation in the initiation and perpetuation of IBD. The microcirculation and its endothelial lining play a crucial role in mucosal immune homeostasis through tight regulation of the nature and magnitude of leukocyte migration from the intravascular to the interstitial space. Chronically inflamed IBD microvessels display significant alterations in microvascular physiology and function compared with vessels from healthy and uninvolved IBD intestine. The investigation into human IBD has demonstrated how endothelial activation present in chronically inflamed IBD microvessels results in a functional phenotype that also includes leakiness, chemokine and cytokine expression, procoagulant activity, and angiogenesis. This review contemplates the newly uncovered contribution of intestinal microcirculation to pathogenesis and maintenance of chronic intestinal inflammation. In particular, we assess the multiple roles of the microvascular endothelium in innate immunity, leukocyte recruitment, coagulation and perfusion, and immune-driven angiogenesis in IBD.

The etiopathogenesis of Crohns disease (CD) and ulcerative Colitis (UC), the two major forms of inflammatory bowel disease (IBD), is still unknown. Although the exact cause and mechanisms of both IBD have yet to be completely understood, it is widely accepted that both CD and UC result from an inappropriate immune response that occurs in genetically susceptible individuals as the result of a complex interaction among environmental factors, microbial factors, and the intestinal immune system. In the last few years a tremendous advance in knowledge of the mechanisms underling intestinal inflammation in IBD has been achieved, leading to new therapeutic targets and novel drugs. These new therapeutic weapons have been specifically designed to selective shut down intestinal inflammation at different levels. Aim of this review is to summarize the recent advances in IBD pathophysiology and the new therapeutic targets and drugs that are changing the IBD clinical management.

Immune reactivity towards the bacterial intestinal flora plays an important part in the pathogenesis of inflammatory bowel disease. Administration of probiotic bacteria has beneficial effects on infectious and inflammatory diseases, principally in bowel disorders. However, little is known about the administration of soluble bacterial antigens in intestinal inflammation. We investigated the therapeutic effects of colifagina in experimental colitis. To assess this effect, C57BL/6 mice with dextran sulphate sodium-induced colitis were treated with colifagina, or with a placebo, for a period of 10 days. The mice were monitored, and inflammation was assessed by disease activity index (DAI). Analysis of fecal IgA concentration and measurement of IgA and inflammatory chemokine production in organ colonic culture was performed by ELISA. Clinically and histologically, bacterial-lysate-treated mice revealed significantly fewer DAI and a reduction of colonic histological inflammation. Treatment of healthy mice with colifagina significantly increased the fecal concentration of IgA and IgA production in organ culture. Colifagina administration in DSS-treated mice significantly increased the fecal concentration of IgA and IgA production in organ culture. MIP-1, MIP-2 and RANTES concentrations in colonic organ culture were significantly lower in colifagina-treated mice than in the placebo group. The use of colifagina is effective in amelioration of murine colitis.

OBJECTIVE: To assess the prevalence of good clinical response and remission in rheumatoid arthritis (RA) patients with longstanding disease treated with anti-tumor necrosis factor-α (TNF-α) drugs at outpatient clinics. METHODS: Retrospective national study of 14 academic tertiary referral rheumatology medical centers. RA patients with a Disease Activity Score (DAS28) > 3.2 were defined as having active disease and could start TNF- blockers. All patients received one TNF- blocker plus methotrexate (10-20 mg/wk). At the third month the patients were categorized as responders or nonresponders, based on improvement of at least 0.25 of the Health Assessment Questionnaire (HAQ). Those who had improved by at least 0.25 HAQ were analyzed for possible predictors of DAS28 remission at the sixth month. RESULTS: A total of 1257 patients started TNF-α blockers. Of these, 591 (46.7%) reached the sixth month with an improvement of HAQ of 0.25 at the third month. In the cohort of patients reaching HAQ of 0.25, DAS28 remission was seen in 24% of rheumatoid factor (RF)-positive and 36% of RF-negative patients (p = 0.03). Logistic regression analysis for predictors of remission identified age at baseline, HAQ < 1.63, and RF negativity as positive predictors of remission at 6 months along with sex (male). CONCLUSION: We show that only a minority of patients with longstanding RA achieve a good clinical response or remission at the outpatient community level. Predictors of remission identify characteristics commonly observed in subsets with less severe RA.

Crohns disease (CD) is a chronic inflammatory disorder which may involve any part of gastrointestinal tract. Chronic inflammation is primarily due to an immunological imbalance between pro- and anti-inflammatory cytokines, and with a defective apoptosis of lamina propria T cells. Amongst the pro-inflammatory cytokines tumor necrosis factor- (TNF-) seems to play a central role in pathogenesis of CD. Over the last years, increasing knowledge on the pathogenesis of CD together with progresses in bio-technology have led to the development of a number of biological agents targeting specific molecules involved in gut inflammation, most importantly TNF- and its receptors. The aim of this paper is to critically review the rationale and state-of-the art for the use TNF- inhibitors in the treatment of CD.

ObjectiveTo assess the clinical and radiological features of systemic sclerosis (SSc) joint involvement in a prospective cross-sectional study.Design and patientsSeventy-six consecutive patients with SSc divided into clinical and serological subsets were investigated. Clinical and radiological assessments of the hands and feet were carried out. Three radiological patterns of inflammatory, degenerative and fibrotic changes were predefined. The Health Assessment Questionnaire (HAQ) disability index (DI) and individual components of the HAQ-DI were also evaluated.ResultsThe highest impairments on the HAQ-DI (median 0.44; range 0–2.87) were detected in subdimensions such as hygiene, grip and activity components. Clinically articular involvement, arthralgia and finger contractures were seen more frequently than arthritis, and a significantly higher prevalence of finger flexion was found in patients with diffuse cutaneous SSc ( P=0.03) compared with the other SSc subtypes. Radiologically, distal interphalangeal joint space narrowing and flexion deformity indicating periarticular fibrosis were frequently detected. Juxta-articular osteoporosis, joint space narrowing and flexion contractures of the fingers were seen significantly more frequently in the hands. A significantly higher frequency of fibrotic pattern were found in the hands whereas a degenerative pattern was more frequent in the feet ( P<0.05). Finally, significant correlations were detected between flexion contractures and a radiological fibrotic pattern ( P<0.001), and the severity scores of peripheral vascular impairment ( P=0.026) and skin ( P=0.007).ConclusionThis cross-sectional prospective study confirms that an arthropathy is common in SSc patients and shows that it is a major determinant of disability. A classification of radiological alterations into three specific patterns is proposed.

The occurrence of maldigestion and malnutrition was studied in 14 patients who had undergone pancreaticoduodenectomy and occlusion of the Wirsung duct with Neoprene®. Before discharge patients were put on a 70 g/day dietary fat intake. Mean faecal fat excretion was 32·9 g/day without enzyme replacement and fell to 14·2 g/day with pancrelipase supplementation. At discharge all patients were underweight (88 per cent of the usual mean body-weight) and nine patients showed alteration in laboratory nutritional parameters. At the time of discharge a low-fat diet (50 g/day) was prescribed. Six months after surgery, mean faecal fat excretion decreased further to 8·3 g/day (P< 0·01) and all patients but one gained weight, reaching 93 per cent of the usual mean body-weight with normalized nutritional parameters. Our data show that the combination of enzyme replacement therapy and low-fat diet allows good correction of steatorrhoea and a significant improvement in nutritional status.

We studied a new enteric-coated pancreatic extract with very high lipase content in 12 patients with Steatorrhea due to chronic pancreatitis. Fecal fat was measured under standard dietary conditions (100 g lipid/day) with no enzyme supplementation and during treatment with 75,000, 150,000, or 225,000 IU of lipase per day. The median fecal fat output (g/day) was significantly (p < 0.005) lower after each increase in dosage: basal, 20.5 (range, 10.3–92.2); 3 cps/day at meals, 13.3 (6.4–38.2); 6 cps/day, 9.9 (4.8–31.4); 9 cps/day, 7.3 (2.6–17.3). For the five patients with a basal fecal fat output of < 15 g/day, Steatorrhea was totally corrected by 3 cps a day. Of the seven patients with more severe Steatorrhea, the fecal fat output of only two was not normalized with the highest dose of 9 cps/day: for one it was reduced to 13.3 g/day from a basal of 92.2 g/day and for the other to 17.3 g/day from 25.4 g/day. This pilot study demonstrates that the tested pancreatic extract very effectively corrects pancreatic Steatorrhea in a simple low-dose regimen. Good compliance can be expected.

Summary: An impaired pancreatic polypeptide response (PP) after hypoglycemia has been described in type I diabetic patients with overt autonomic neuropathy. Some authors have suggested that PP release might be useful as sensitive indicator of autonomic neuropathy. The meal test is safer and simpler than the insulin infusion test as PP stimulus. The aim of this study was to compare PP response to insulin infusion and protein meal test and to correlate these responses to the presence of measurable neuropathic disturbances. We thus studied 13 IDDM children and adolescents and 6 normal children. In diabetics the PP response to both tests was not different from that of the control subjects, but PP response to insulin infusion was inversely correlated to the duration of illness and was significantly lower in subjects with pathological heart rate response when compared to the control group. PP responses to the two stimuli were not correlated. We suggest that reduced PP response to hypoglycemia is an early sign of autonomic neuropathy as well as impairment of beat-to-beat variation when impaired PP response to meal test is still not evident.

Background:Thoracic duct dilation has been demonstrated in portal hypertension and hepatic cirrhosis by lymphangiography and laparotomy and at autopsy. It is thought to be secondary to increased hepatic lymph flow and has been described in the absence of ascites or esophageal varices. The aim of the present study was to observe thoracic duct morphology by endoscopic ultrasound in various subsets of patients with portal hypertension and hepatic cirrhosis and also to validate existing radiologic/surgical data. Methods:The thoracic duct of 33 patients with cirrhosis and portal hypertension was studied by endoscopic ultrasound. Patients were divided into four groups: 1, patients with ascites and esophageal varices; 2, esophageal varices without ascites; 3, without esophageal varices or ascites; 4, extrahepatic portal hypertension due to pancreatic malignancy. The thoracic duct diameter was also measured in 14 control subjects (group 5). Results:When the thoracic duct diameter for the five groups was compared with analysis of variance, significance was p < 0.0001; by pairwise comparison, group 1 differed from the other four groups (p < 0.05). Thoracic duct dilation (5.61 mm) was seen in group 1 patients, whereas no dilation was present in groups 2 through 4. Additionally, thoracic duct diameter in 33 portal hypertensive and/or cirrhotic patients was significantly different from that in the 14 control subjects (p = 0.003). Conclusion:The thoracic duct can be reliably identified by EUS in patients with hepatic cirrhosis and portal hypertension. Dilation of the duct is seen only in patients with hepatic cirrhosis, ascites, and esophageal varices. No thoracic duct dilation is present in extrahepatic portal hypertension. Contrary to existing radiologic/surgical data, thoracic duct dilation is not seen in all patients with hepatic cirrhosis and portal hypertension signifying advanced disease. A dilated thoracic duct by endoscopic ultrasound should be considered yet another sign of portal hypertension. (Gastrointest Endosc 1998;48:588-92.)

The diagnostic accuracy of the serum CA 19–9 determination was prospectively evaluated in patients selected for the presence of signs or symptoms highly suggestive for pancreatic cancer. Of 110 patients included in the study, 54 had a final diagnosis of pancreatic adenocarcinoma (49 prevalence). CA 19–9 values were higher than 40 U/ml in 45 patients with pancreatic carcinoma and in 18 of the 56 patients with other final diagnosis (sensitivity, 0.83; specificity, 0.68; positive predictive value [PPV], 0.71; negative predictive value [NPV], 0.81). The serum CA 19–9 determination was not capable of shortening the diagnostic workup of patients with strong clinical suspicion of pancreatic cancer since adequate imaging of the pancreas was required to confirm or exclude the diagnosis. However, values above 120 U/ml were strongly suggestive for pancreatic carcinoma in the overall population (PPV, 0.85) and they were diagnostic (PPV, 1.0) in the anicteric portion. Combined with pancreatic imaging, the CA 19–9 was an excellent confirmatory test; a normal value in a patient with negative imaging ruled out pancreatic carcinoma as the cause of symptoms (NPV, 1.0), whereas a pathological result in the presence of positive or equivocal pancreatic radiology was highly suggestive for the presence of the disease (PPV, 0.93).

In order to investigate the intestinal phase of pancreatic polypeptide (PP) release, the hormonal response to food and cerulein was measured in 19 patients with truncal vagotomy and total gastrectomy (10 with simple esophagojejunal anastomosis and 9 with an additional duodenojejunal anastomosis) and in 7 healthy subjects. After gastrectomy, the early peak of the physiologic biphasic PP response to food was lost but the late predominant phase was unchanged so that the overall postprandial release of the hormone was not significantly lowered. Gastrectomized patients with duodenal bypass had postprandial serum levels only slightly lower than those of patients with preserved duodenal transit of food. Serum PP response to cerulein stimulation was significantly lower in vagotomized patients than in healthy subjects. However, in operated patients as well as in controls, cerulein infusion did induce a rapid increase of plasma PP, followed by persistently elevated levels. The PP response to cerulein was abolished by atropine pretreatment. Our findings indicate that the intestinal phase of meal-stimulated PP response is not dependent on the integrity of vagal pancreatic innervation and that the preservation of the duodenal transit of food after total gastrectomy is not crucial for the maintenance of the enteroinsular axis.

Continuous 24-hr intragastric pH-metry was prospectively performed in 801 subjects with different clinical conditions using two pH electrodes placed closely adjacent. The aim was to assess thein situ repeatability of the test and to verify whether the removal of artifacts, interference, and noise usually superimposed onto the fundamental signal recorded by the measuring apparatus improves the clinical usefulness of experimental data. The following debugging/filtering procedure was used: first, pH recordings of each channel were amended separately from artifacts, then they underwent 7 min windowed median interference debugging, and finally Wiener noise filtering was applied. Afterwards, the 24-hr mean pH profile was obtained in each subject by averaging the pH tracings of the two channels every minute (1440 data points/24 hr). The efficiency of this procedure was assessed at each step by evaluating the difference among groups using the O'Brien test, a distribution-free nonparametric method well-suited for evaluating differences among groups allocated onto a two-way layout. The differences among groups calculated from raw pH data of the single channels can be very misleading, in that it is possible to find that they are significant on one channel and not significant on the other channel. Conversely, the significance of the differences among groups increases progressively at each step of the above debugging/filtering procedure applied to raw pH profiles of each channel. Seven minutes was shown to be the most suitable time lag for windowed median removal of interference. The whole procedure increases by 10 up to 108 times the probability of detecting differences among groups, particularly when one rules out pH tracings with a discrepancy time between the two channels which is more than 1 hr over the entire 24-hr period. Our results suggest that removal of artifacts, interference, and noise superimposed onto the endoluminal pH tracings can greatly improve the usefulness of 24-hr intragastric pH-metry in every clinical situation. Moreover, test reliability largely depends on thein situ reproduceability of pH measurements.

Serum CA 19-9 levels were measured in 63 patients with ductal pancreatic adenocarcinoma and in 49 patients with chronic pancreatitis. Concentrations were abnormally high (> 40 U/ml) in 57 (90%) patients with cancer and only in 5 (10%) patients with chronic pancreatitis. All patients with falsely normal serum values had poorly differentiated carcinomas. Median CA 19-9 concentrations were progressively higher in patients with more advanced cancer. Fifteen of 16 (93%) patients with localized cancer has abnormal serum levels but only 5 (31%) of them had values > 120 U/ml, which was the highest score observed in patients with chronic pancreatitis. Pure pancreatic juice was obtained endoscopically from 23 patients with pancreatic cancer and from 20 with chronic pancreatitis. CA 19-9 concentrations in pancreatic juice were significantly higher in patients with cancer than in non-neoplastic patients. All 11 patients with resectable cancer investigated had a ratio of CA 19-9 to secretory protein concentration in pancreatic juice above the range of patients with chronic pancreatitis. We conclude that serum CA 19-9 determination is highly sensitive and specific for the differential diagnosis of pancreatic cancer versus chronic pancreatitis. However, moderately increased values (< 120 U/ml), as seen in patients with localized pancreatic adenocarcinoma, are not conclusive for malignancy. The measurement of CA 19-9 to total protein ratio in pure pancreatic juice is proposed as an adjunctive, accurate diagnostic marker for early stages of pancreatic adenocarcinoma.

Background: This study was aimed to investigate the effect of long-term treatment with high-protease pancreatic extract on the recurrent abdominal pain of patients with chronic pancreatitis. Methods: Twenty-six patients with a firm diagnosis of chronic pancreatitis and a pattern of recurrent pain were recruited and randomly assigned to treatment with pancreatic extract (Pancrex-Duo® capsules, each containing 34,375 USP units of protease in enteric-coated microspheres) or placebo, at a dose of four capsules four times daily, for 4 months. At the end of the first period patients were switched to the other medication for the next 4 months. Four patients did not complete the study because of unbearable recurring pain or inadequate compliance with treatment. The other 22 patients daily recorded the presence, intensity, and duration of pain and the consumption of analgesics, for 8 months. Results: No difference was found when intraindividual records during placebo and extract treatment periods were compared. Conversely, in the second 4 months of follow-up, regardless of the treatment given in the first period, there was a significant reduction in the cumulative pain score (median, 95; range, 0-1005, versus 134; 0-972; p < 0.05), in the number of days (8; 0-132, versus 13; 0-126; p < 0.02) and hours (54; 0-680, versus 80; 0-602; p < 0.05) of pain, and in the analgesic consumption score (0; 0-22, versus 12; 0-44; p = 0.02). Conclusions: Chronic supplementation with pancreatic extract is not beneficial in the management of recurrent pain in patients with chronic pancreatitis.

Gastric mucosal histology and function were evaluated in 57 Italian subjects with dermatitis herpetiformis (DH), by means of multiple endoscopic biopsies, gastrin and pepsinogen I (Pg I) serum levels, and parietal cell antibodies (PCA). One hundred and forty-nine patients with nonulcer dyspepsia served as reference population for the prevalence of atrophic gastritis of the body. Seventeen DH patients (30%) and 23 controls (15.4%) showed atrophic gastritis of the body mucosa (p < 0.05). Nine of the DH patients with atrophic gastritis of the body also had atrophic changes in the antrum. Six patients, all with severe atrophic gastritis, had high gastrin levels and PCA; five of these six also had low Pg I levels. We found an increased prevalence of atrophic gastritis, high gastrin, low Pg I, and PCA with age. The low prevalence of abnormal indirect function tests among patients with atrophic gastritis is due to the younger age of the patients in our series. Thus, atrophic gastritis can be detected early on a histologic basis, but functional impairment occurs later, as the mucosal damage increases in severity.

The complete control of steatorrhea in postsurgical exocrine pancreatic insufficiency is difficult. The aim of this study was to evaluate the effect of the association of ranitidine with pancrelipase on fecal fat excretion in patients who had undergone a pancreatoduodenectomy with suppression of the exocrine pancreatic secretion by Neoprene injection. Ten patients were studied 1 year after surgery. Steatorrhea was measured as an integrated test of 3-day stools, while patients were kept on a diet of 100 g lipid/day, with their usual enzyme supplementation therapy (16,050 USP units of lipaseheal). A basal 24-h gastroenteric pH profile was also obtained. In the following month, patients had ranitidine (150 mg twice a day) in addition to pancrelipase. Then steatorrhea and gastroenteric pH were reassessed. Mean fecal fat was 26.9 (SD 13.7) g/day without ranitidine and 30.5 (SD 13.9) g/day during combined treatment. Body weight and nutritional parameters did not show any significant variation after ranitidine administration. Even in the absence of ranitidine, postprandial gastroenteric pH values were always >4; the H2-receptor antagonist only reduced fasting gastric acidity. In conclusion, the gastroenteric pH and fecal fat determinations showed that ranitidine is not useful in patients with total postsurgical exocrine pancreatic insufficiency.

Increased gastroesophageal acid reflux is frequently found in patients with Barrett's esophagus, and it has been hypothesized that gastric acid hypersecretion could be an important factor aggravating the exposure of esophageal mucosa to acid and then contributing to the development of this disorder. The aim of the present study was to assess whether the circadian pattern of gastric acidity differs between refluxer patients with and without Barrett's esophagus and normal subjects. Continuous 24-hr gastric pH monitoring was performed in 119 healthy volunteers, 20 patients with Barrett's esophagus, 37 patients with moderate and 10 patients with severe reflux esophagitis without Barrett's esophagus. In all these diseases the final diagnosis was ascertained by means of endoscopy plus biopsy. There was no difference in the 24-hr and daytime patterns of gastric pH between healthy subjects and patients with Barrett's esophagus, while nocturnal acidity was significantly lower (P<0.05) in the latter population. Gastric acidity, in contrast, was higher (P<0.05) in controls than in patients with both moderate and severe reflux esophagitis without Barrett's esophagus during the whole 24-hr period. There was no difference between refluxer patients with and without Barrett's esophagus in any of the three time intervals we analyzed. Because normal subjects had lower gastric pH than patients with Barrett's esophagus during the night and than patients with reflux esophagitis during the whole 24-hr period, gastric hyperacidity is not a relevant factor in the development of both metaplastic columnar epithelium and inflammatory changes in the distal esophagus, and other pathophysiological mechanisms are involved in these histological alterations.

Savarino V, Mela GS, Zentilin P, Malesci A, Vigneri S, Sossai P, Di Mario F, Cutela P, Mele MR, Celle G. Circadian acidity pattern in prepyloric ulcers: a comparison with normal subjects and duodenal ulcer patients. Scand J Gastroenterol 1993;28:772-776.We used continuous 24-h pH monitoring to compare the circadian intragastric acidity of 36 patients with prepyloric ulcers (PPU) with that of 101 normal subjects (NS) and that of 206 patients with duodenal ulcer (DU). The ulcer crater was endoscopically ascertained in all cases, and PPU were located within an area up to 2 cm proximal to the pylorus. The pH curve pertaining to DU patients ran below that of NS during most of the circadian period, whereas the pH profile of PPU patients was higher than that of NS, and this was particularly true during the evening and the night. The acidity of PPU patients was significantly lower (p < 0.01) than that of NS during the night only, whereas it was lower (p < 0.05-0.001) than that of DU patients during each time interval analysed (24 h, nighttime, and daytime). Our findings show that the gastric acidity of PPU patients differs greatly from that of DU patients, since it is lower throughout the whole 24-h period, and particularly during the night. Thus these two entities are pathophysiologically different with regard to the acidity pattern and should be considered two distinct subgroups of peptic ulcer disease instead of being incorporated, as usually happens, in the clinical group 'duodenal ulcer disease'.

An enzyme has been partially purified from canine and porcine cerebral cortical extracts that differs from trypsin in that it manifests some degree of hormone specificity since it converts porcine cholecystokinin to smaller immunoreactive forms, i.e., the COOH-terminal dodecapeptide and octapeptide fragments, but fails to convert big gastrin (34 amino acids) to heptadecapeptide gastrin. This enzyme is distinguishable from trypsin not only in substrate specificity, but also in several physiochemical properties. It is not inhibited in the presence of concentrations of lima bean trypsin inhibitor sufficient to inhibit 1 mg of trypsin per ml of incubation mixture. It is inactivated when incubated with substrate at 45°C for 1 hr, whereas trypsin remains fully active when incubated under the same conditions at 55°C. The enzyme elutes in the void volume on Sephadex G-50 and G-75 gel filtration. On sucrose gradient centrifugation, the proteolytic activity associated with trypsin is recovered above albumin but that of the solubilized brain enzyme is recovered below gamma globulin. The enzyme is not detectable in splenic extracts, which do contain nonspecific proteases capable of completely degrading cholecystokinin. Further investigation is required to determine whether the enzyme in the gut that converts cholecystokinin to the bioactive and immunoactive COOH-terminal fragments resembles or is different from the brain converting enzyme.

Background: Barrett's esophagus is mainly regarded as an acquired condition related to increased gastroesophageal reflux. Thus it is conceivable that abolition of acid reflux would lead to its regression. The aim of this study was to assess whether long-term treatment with high-dose omeprazole (60 mg/day) produces a consistent control of gastric acid production and normalizes the esophageal acid exposure, thus reducing the length of Barrett's epithelium. Methods: Fourteen patients (8 men and 6 women, mean age 52 years) with histologic diagnosis of columnar epithelium longer than 3 cm in the distal part of the esophagus were enrolled and began receiving 60 mg of omeprazole in a single daily morning dose. Before therapy and after 6 and 12 months of therapy, all patients had endoscopy with four-quadrant biopsies at 2 cm intervals. A 24-hour esophagogastric pH recording was performed at entry and after 10 days, 6 months, and 12 months of treatment in all patients. Results: The initial length of Barrett's epithelium (4.5 +/- 1.9 cm) was significantly reduced after 6 months (3.1 +/- 1.1; p < 0.01) and 12 months (2.1 +/- 1.6; p < 0.005) of treatment. Values were significantly lower at 12 than at 6 months (p < 0.03). The 24-hour mean gastric pH after 10 days (5.89 +/- 0.58), 6 months (5.71 +/- 0.55), and 12 months (5.54 +/- 0.76) of therapy was always higher (p < 0.001) than the basal level (1.9 +/- 0.49). No significant difference in gastric pH was seen over the treatment period. The 24-hour mean percent of time in which pH in the esophagus was below 4.0 decreased significantly (p < 0.001) from a basal rate of 29.4% to 3.5%, 3.0%, and 4.9% in the various time intervals of therapy. There was a normalization of esophageal acid exposure in all patients but two. Conclusions: It can be concluded that the antisecretory effect of 60 mg/day of omeprazole is consistent and is kept constant throughout the entire 1-year treatment period. The consequent normalization of esophageal acid exposure in almost all patients in our series led to a partial, but significant, regression in the length of Barrett's epithelium. (Gastrointest Endosc 1996;44:700-5)

We compared the diagnostic utility of DU-PAN-2 and CAR-3 with that of CA 19-9 in differentiating pancreatic cancer (23 patients) from chronic pancreatitis (16 patients) and various extra-pancreatic diseases (28 patients) mainly of the upper gastrointestinal and biliary tract. The influence of some pathophysiologic variables on the three markers was also assessed. The sensitivities of the three markers in detecting pancreatic cancer were: CA 19-9, 83%; DU-PAN-2, 56%; and CAR-3, 39%. In patients with chronic pancreatitis and extra-pancreatic diseases, CA 19-9 gave the highest number of false positives. Receiver-operating characteristic curves showed that the ability of CAR-3 to discriminate between pancreatic cancer and other diseases was similar to that of CA 19-9, whereas DU-PAN-2 was a less reliable discriminator. Correlations were found between the behavior of all three markers and that of the cholestasis indices (ALP and GGT). Our findings indicate that DU-PAN-2 and CAR-3 serum determinations do not provide any more information than does CA 19-9 alone. The latter remains the marker of choice in the differential diagnosis of pancreatic cancer, even though it cannot be considered a definitive aid. Serum levels of all three markers increase in the presence of extrahepatic cholestasis, possibly due to interference with the hepatic clearance of glycoproteins and destruction of ductal biliary epithelium.