The history of Helicobacter pylori: a reflection on the relationship between the medical community and industry.

The paper deals with a viewpoint on the relationship between the drug industry and the medical world taking inspiration from the history of the discovery of Helicobacter pylori as a pathogenic agent in peptic disease.

Large forehead: a novel sign of undiagnosed coeliac disease.

BACKGROUND: The development of cranial proportions is the result of genetic, embriogenetic and environmental factors. Coeliac disease is a genetically inherited disease that is frequently diagnosed in adulthood in individuals, in whom the disease runs unidentified for years and can affect child growth from the moment of dietary gluten introduction up to the moment of gluten withdrawal following diagnosis. Data on the effects of gluten on craniofacial development in coeliac children are not available. AIM: The aim of the present study is to evaluate gluten-related effects on face development in patients with undiagnosed coeliac disease and their clinical relevance. METHODS: The study was a prospective, multivariate analysis. Face photographs of adult patients with coeliac disease and healthy controls were marked at six reference points and distances and the ratios among distances were measured by computer program software. RESULTS: The main finding of the study is that Caucasian Mediterranean adult coeliac individuals tend to have a peculiar aspect of the face characterised by a larger forehead when compared to general population controls. CONCLUSION: The craniofacial morphology of patients with coeliac disease reveals an altered pattern of craniofacial growth. This is the first report of alterations of craniofacial development in coeliac disease. This alteration is a clinical sign that should be included among the extraintestinal manifestation of coeliac disease. It has a frequency comparable to other signs or symptoms such as anaemia and short stature and is a better predictor of coeliac disease than other signs such as recurrent aphthous stomatitis, recurrent abortion and dental enamel hypoplasia. A large forehead is a sign easily evident visually or with very simple measurements; computer analysis is not required for the general practitioner. This sign along with the presence of other clinical signs and symptoms, should alert a physician to test a patient for coeliac disease.

Grown-up coeliac children: the effects of only a few years on a gluten-free diet in childhood.

AIM: To evaluate clinical and psychological status of adults with childhood diagnosis of coeliac disease who were re-exposed to gluten after only a few years and now on a gluten-containing diet, compared with adults with recent diagnosis of coeliac disease, and adults who remained on gluten-free diet after childhood diagnosis. METHODS: A total of 195 adults with a biopsy suggestive of coeliac disease in childhood, who either had adhered to a gluten-free diet for at least 1 year after diagnosis and now are either on gluten-free diet (n = 110) or on gluten-containing diet (n = 85), and adults with newly diagnosed coeliac disease (n = 165) underwent a medical check-up. RESULTS: Body mass index and main laboratory indices were statistically different among groups (lowest in never on gluten-free diet, highest in gluten-free diet). The lowest average levels of bone mineral density were found among never on gluten-free diet patients. Prevalence of autoimmune disorders was increased in never on gluten-free diet when compared with the transient gluten-free diet and gluten-free diet groups. Histology revealed villous subatrophy in all patients of never on gluten-free diet group, in 39 of 110 patients of gluten-free diet and in 84 of 85 of transient gluten-free diet groups. Herpetiform dermatitis was found in three patients of gluten-free diet, three of transient gluten-free diet and three of never on gluten-free diet. Dental enamel defects were found in 15 patients of transient gluten-free diet, 43 of never on gluten-free diet and in zero of the gluten-free diet group. Pregnancy outcome was not significantly different between the two groups, but neonatal weight was lower and breast feeding was shorter in the never on gluten-free diet group. Sexual habits, alcohol intake and cigarette smoking were significantly different in the never on gluten-free diet group when compared with the other two groups. CONCLUSION: Gluten withdrawal in childhood partly protects coeliac adults from clinical and behavioural effects of gluten sensitivity.

Helicobacter pylori impairs iron absorption in infected individuals.

BACKGROUND: Infection with Helicobacter pylori is recognised as a major risk factor for chronic gastritis, peptic ulcer disease and gastric cancer. The association between H. pylori infection and iron deficiency anaemia has been established. Multiple mechanisms have been advocated to explain the relationship between H. pylori and iron status and their association might reduce iron deposit. AIM: Aim of this study was to investigate whether H. pylori infection affects iron absorption. METHODS: The study was designed on a prospective basis. Fifty-five subjects underwent upper gastrointestinal endoscopy and biopsy to investigate the presence of H. pylori and, when this was positive, also search of serum anti-CagA was performed. Tests included an oral iron absorption test with the administration of 1 mg/kg of Fe2+. Iron levels were measured before and 2 h after iron administration (delta iron). H. pylori-positive subjects were administered antibiotic therapy for 1 week and, 2 months later, the oral iron absorption test was repeated and urea-breath test was first performed. RESULTS: H. pylori-positive subjects had lower serum level of ferritin and lower delta iron compared to H. pylori-negative subjects. That difference is significant in anaemic women and is independent of the presence of serum anti-CagA antibodies. After H. pylori eradication iron absorption test was similar to those of non-infected subjects. CONCLUSION: H. pylori infection impairs iron uptake. That mechanism, together with others, may contribute to the depletion of iron in infected patients.

Cigarette smoking and appendectomy are risk factors for extraintestinal manifestations in ulcerative colitis.

OBJECTIVE: Two common factors, cigarette smoking and appendectomy, have been found to play a role in ulcerative colitis (UC). Data on their role in the development of extraintestinal manifestations (EIM) are scarce. METHODS: The relationship between cigarette smoking, appendectomy, and EIM was examined in a prospective study involving 535 (M/F = 319/216) consecutive UC patients followed up for 18 yr. We considered the major EIM: seronegative spondyloarthropathy, pyoderma gangrenosum/erythema nodosum, acute anterior uveitis, and primary sclerosing cholangitis. We excluded patients with a history of EIM or those colectomized before study entry, ex-smokers, and those who started to smoke during the course of UC. RESULTS: In UC patients, seronegative spondyloarthropathy and dermatologic complications were found increased in smokers (p < 0.0001; p = 0.001) or in subjects with appendectomy (p = 0.0003; p = 0.02), while acute anterior uveitis and primary sclerosing cholangitis did not differ. The Kaplan-Meier analysis showed 18-yr rates for EIM of 71% in smokers and 45% in nonsmokers (log-rank test, p = 0.0001), and of 85% in patients with appendectomy and 48% in those without (p = 0.0001). Cox proportional-hazard model showed that cigarette smoking and appendectomy are independent factors promoting EIM. In smokers with appendectomy the adjusted hazard ratio (3.197, 95% CI 1.529-6.684) was higher than in patients with appendectomy alone (2.617, 95% CI 1.542-4.442) or smoking alone (1.947, 95% CI 1.317-2.879). CONCLUSIONS: In UC patients, appendectomy and cigarette smoking are prognostic factors for the development of EIM. The unfavorable effect of cigarette smoking on EIM is additive to that of appendectomy.

Antibiotic treatment of small bowel bacterial overgrowth in patients with Crohn's disease.

BACKGROUND: Small bowel bacterial overgrowth is common in Crohn's disease but its treatment is not clearly defined. Metronidazole and ciprofloxacin are effective antibiotics in active Crohn's disease. AIM: To investigate the efficacy of metronidazole and ciprofloxacin in the treatment of bacterial overgrowth in patients with Crohn's disease. PATIENTS AND METHODS: We performed the lactulose breath test in 145 consecutive patients affected by Crohn's disease. Patients positive to the lactulose breath test underwent a glucose breath test to confirm the overgrowth. These patients were randomized in two treatment groups: metronidazole 250 mg t.d.s. (Group A) and ciprofloxacin 500 mg b.d. (Group B), both orally for 10 days. The glucose breath test was repeated at the end of treatment. The clinical outcome after therapy was also recorded. RESULTS: Bacterial overgrowth was present in 29 patients (20%). Breath test normalization occurred in 13 out of 15 patients treated by metronidazole and in all 14 patients treated by ciprofloxacin (P = ns). In both groups antibiotic treatment induced an improvement of intestinal symptoms: bloating (Group A 85% and Group B 83%), stool softness (44% and 50%), and abdominal pain (50% and 43%). CONCLUSIONS: Small bowel bacterial overgrowth is a frequent condition in Crohn's disease which can be effectively treated by metronidazole or ciprofloxacin.

Glutathione supplementation improves oxidative damage in experimental colitis.

BACKGROUND: The pathogenesis of inflammatory bowel disease is due, in part, to enhanced free-radical production and reduced antioxidant potential in mucosa cells. AIM: We evaluated in a rat model of trinitrobenzensulphonic acid (TNBS) colitis to see whether parenteral administration of glutathione is able to improve mucosal oxidative damage at onset (study A) and during chronic phases of colitis (study B). METHODS: In study A, the rats were injected with a single dose of glutathione (200 mg/kg, i.p.) or saline (0,2 ml, i.p.) 1 h before colitis induction and killed 1 h later. In study B, rats with induced colitis were treated with daily injection of glutathione (50 mg/kg, i.p.) or saline (0,2 ml, i.p.), and killed at 1, 2, 4 and 8 weeks. We evaluated on mucosal samples the macroscopic and histological damage and the oxidative stress assessed by the mucosal levels of lipoperoxides, malonyldialdehyde, glutathione and cysteine. RESULTS: In study A, colitis induction caused a significant increase to the total histological score (p<0.05), lipoperoxide and malonyldialdehyde levels (p<0.001), but did not affect glutathione and cysteine content. Glutathione pre-treatment decreased both total histological score (p<0.05) and lipoperoxide and malonyldialdehyde values (p<0.001). In study B, the extensive macroscopic and histological colonic damage induced by TNBS was accompanied by a reduction of glutathione and cysteine mucosal levels (p<0.01) and increased lipid peroxidation. Glutathione supplementation significantly improved colonic damage (p<0.01), restored glutathione and cysteine levels, and decreased, and even, if not totally, abolished lipid peroxidation (p<0.001). CONCLUSION: This paper further supports the pathogenic role of the imbalance in oxidant/antioxidant content in inducing mucosal colonic damage.

Clinical and neurological abnormalities in adult celiac disease.

We assessed the occurrence of neurological signs and symptoms in adult patients with celiac disease and evaluated the correlation between neurological features and diet. A total of 176 patients and 52 age-matched controls underwent a semistructural interview and a neurologic examination. The effect of gluten-free diet was evaluated by comparing the prevalence of signs and symptoms among patients adhering to a gluten-free diet and patients on an unrestricted diet. The occurrence of headache, dysthymia and signs of peripheral neuropathy was significantly higher in patients with celiac disease than in control subjects. Adherence to a strict gluten-free diet was associated with a significant reduction of headache, dysthymia, cramps and weakness, but did not modify the occurrence of paresthesia or hyporeflexia. Neurological signs and symptoms are associated with celiac disease and can be ameliorated by a gluten-free diet.

Ulcerative colitis, seronegative spondyloarthropathies and allergic diseases: the search for a link.

BACKGROUND: Allergic diseases and seronegative spondyloarthropathies are frequently observed in ulcerative colitis (UC). In this report we have investigated possible relationships between IgE-mediated allergic disease (AD), allergic contact dermatitis (ACD) and seronegative spondyloarthropathy (SpA) in UC patients at different grades and extensions of mucosa inflammation. METHODS: Forty-five UC consecutive outpatients were graded according to clinical, endoscopic and histologic activity scores. SpA was diagnosed according to the European Spondyloarthropathy Study Group criteria. AD was detected by skin prick tests and confirmed by specific provocation tests, while ACD was diagnosed using the European standard series of patch tests. Thirty-seven patients' spouses or partners served as controls. RESULTS: Fourteen patients and 1 control subject showed SpA (P = 0.001). Diagnosis of rhinitis, conjunctivitis or asthma was made in 19 patients and in 5 controls (P = 0.004), while ACD was found in 10 and in 4 (P = 0.17), respectively. In UC, AD coexisted with SpA in 2 cases (P = 0.01), AD with ACD in 1 case (P = 0.03) and ACD with SpA in 5 (P = 0.24). CONCLUSIONS: Notwithstanding the high frequency of AD and SpA found in UC, the concurrence of AD with SpA or ACD is an unusual finding, while SpA and ACD may coexist. These data suggest that, in UC, atopy and seronegative arthritis, as well as atopy and delayed-type allergy, are strongly polarized conditions tending to mutual exclusion. In UC, the presence of AD without SpA or ACD, and of SpA or ACD without AD may indicate subgroups of patients in which T-helper-2 cell or T-helper-1 cell responses predominate.

Selective reduction of intestinal trefoil factor in untreated coeliac disease.

The trefoil factor family (TFF) encompasses small peptides of which intestinal trefoil factor (ITF) is expressed specifically in goblet cells of the small and large intestine. Previous studies have shown that ITF plays an important role in mucosal protection and repair. Coeliac disease represents a model of immune-mediated small intestinal inflammation and damage, with recovery on gluten-free diet. The aim of this study was to investigate the expression of ITF in the distal duodenal mucosa of subjects with coeliac disease, before and after treatment with a gluten-free diet. Expression of ITF and mucin in the distal duodenal biopsies from treated (n = 11) and untreated (n = 9) coeliac subjects and controls (n = 8) was investigated by immunohistochemistry and semiquantitative PCR. In untreated coeliac disease, there was reduction of ITF immunoreactivity in goblet cells but mucin expression was preserved. Mucosal recovery on gluten-free diet was associated with increased ITF immunoreactivity in goblet cells. There was also reduction in the expression of ITF transcripts, relative to MUC2 mRNA, in untreated coeliac duodenal samples, with recovery on gluten-free diet. Our study suggests that there is a selective reduction in the expression of the ITF gene in untreated coeliac disease. Recovery of ITF expression on a gluten-free diet suggests that the mucosal immune system regulates goblet cell differentiation and ITF expression in the human intestinal mucosa.

Abnormal esophageal acid exposure is common in morbidly obese patients and improves after a successful Lap-band system implantation.

BACKGROUND: The relation between gastro-esophageal reflux disease (GERD) and obesity is controversial. The laparoscopic adjustable gastric band (LAGB) procedure is effective for morbid obesity. Its indication in the presence of GERD, however, is still debated. This study aimed to investigate esophageal symptoms, motility patterns, and acid exposure in morbidly obese patients before and after LAGB placement. METHOD: For this study, 43 consecutive obese patients were investigated by a standardized symptoms questionnaire, stationary manometry and 24-h ambulatory pH-metry, and 16 patients with abnormal esophageal acid exposure were reevaluated 18 months after LAGB placement. RESULTS: Symptom scores and abnormal esophageal acid exposure were found to be significantly higher, Lower Esophageal Sphincter (LOS) pressure was significantly lower in obese patients than in control subjects. After LAGB, esophageal acid exposure was significantly reduced in all but two patients, who presented with proximal of gastric pouch dilation. CONCLUSIONS: There is a high prevalence of GERD in the obese population. Uncomplicated LAGB placement reduces the amount of acid in these patients with abnormal esophageal acid exposure.

Increased risk of surgery in undiagnosed celiac disease.

The diagnosis of celiac disease patients may be delayed by misdiagnosis. Our aim was to evaluate in celiac patients the prevalence of surgery before diagnosis. Two hundred forty-four adult celiac patients and 232 controls were retrospectively investigated for surgery before diagnosis of celiac disease. The prevalence of surgery was increased in celiac patients versus controls (P = 0.001). Frequency of appendectomy (P = 0.0001), tonsillectomy (P = 0.009), and hernia repair (P = 0.05) were increased in celiac patients versus controls. Appendectomy was related to anemia (P = 0.006) and abdominal pain (P = 0.005); tonsillectomy was related to diarrhea (P = 0.02) and weight loss (P = 0,04). Appendectomy was elective in 73% of celiac patients and in 46% of controls. Cosmetic surgery was increased in celiac patients versus controls (P = 0.058). In conclusions, surgery before celiac disease diagnosis is increased in celiac patients compared to controls, as a result of doctors' misdiagnosis and/or poor health status, which increases the demand for medical intervention. The frequency of cosmetic surgery in celiac patients may berelated to impaired psychological profile of patients.

Colonoscopic removal of a polypoid arteriovenous malformation.

A 53-year-old male presenting with a 3-month history of intermittent mild rectal bleeding was found, on double contrast barium enema, to have a large polyp on a long stalk in the sigmoid colon. Large bowel endoscopy confirmed the presence of a 2 cm pedunculated polyp which was removed using a diathermic snare, with slight bleeding following the procedure that did not require endoscopic haemostasis. Only after histologic examination was the polyp shown to be a colonic arteriovenous malformation. Endoscopically, arteriovenous malformations generally appear as flat or elevated bright red lesions. A pedunculated polypoid appearance is extremely uncommon. In this case, no gastrointestinal bleeding or polypoid recurrence was observed during the 12 months of clinical and endoscopic follow-up.

Fibromyalgia in patients with irritable bowel syndrome. An association with the severity of the intestinal disorder.

Fibromyalgia (FM) syndrome and irritable bowel syndrome (IBS) are functional disorders in which altered somatic and or visceral perception thresholds have been found. The aim of this study was to evaluate the prevalence of FM in a group of patients with IBS and the possible association of FM with patterns and severity of the intestinal disorder. One hundred thirty consecutive IBS patients were studied. The IBS was divided into four different patterns according to the predominant bowel symptom and into three levels of severity using a functional severity index. All patients underwent rheumatological evaluation for number of positive tender points, number of tender and swollen joints, markers of inflammation, and presence of headache and weakness. Moreover, patients' assessments of diffuse pain, mood and sleep disturbance, anxiety, and fatigue were also measured on a visual analogue scale. The diagnosis of FM was made based on American College of Rheumatology classification criteria. Nonparametric tests were used for statistical analysis. Fibromyalgia was found in 20% of IBS patients. No statistical association was found between the presence of FM and the type of IBS but a significant association was found between the presence of FM and severity of the intestinal disorder. The presence of FM in IBS patients seems to be associated only with the severity of IBS. This result confirms previous studies on the association between the two syndromes.

Factor XIII improves gastric stress lesions in rats.

BACKGROUND/AIMS: Tissue transglutaminase has been reported to be involved in the healing of experimental gastric ulcer; nevertheless, other type(s) of transglutaminase could be involved. The present experiments aimed at examining whether plasma transglutaminase (factor XIIIa) contributes to such healing and at evaluating whether factor XIII supplementation improves gastric mucosal lesions. METHODS: The healing effect of 200 U/kg of factor XIII administered intravenously was examined using a water immersion restraint rat model of stress gastric damage. The rats were sacrified 0, 2, 4, and 12 h after stress. The gastric mucosa was examined macroscopically and microscopically, and the transglutaminase activities were assayed in serum and gastric mucosa. Factor XIIIa and tissue transglutaminase protein levels in the gastric mucosa were analyzed by immunoblot. Immunohistochemistry was used to identify the location of tissue transglutaminase, factor XIIIa, and fibronectin in the gastric mucosa. RESULTS: The transglutaminase activity, reduced by stress in the gastric mucosa, increased up to 12 h after stress, peaking at 4 h, when the ulcer index significantly decreased. The serum transglutaminase level was low at all time points. Exogenous administration of factor XIII allowed a faster reduction of the ulcer index that was coincident with an increased transglutaminase activity in the mucosa. Both tissue transglutaminase and factor XIIIa protein levels were reduced by 6 h of stress and increased after factor XIII administration. Immunohistochemistry showed a colocalization of both factor XIIIa and tissue transglutaminase with fibronectin in the extracellular matrix of the damaged area. CONCLUSIONS: Two forms of transglutaminase are involved in the healing of stress-induced gastric erosions, and factor XIII administration allows faster gastric mucosa healing.

Proximal stomach function in systemic sclerosis: relationship with autonomic nerve function.

Gastrointestinal involvement is frequent in patients with systemic sclerosis (SSc); however, studies on the proximal stomach and its regulation are lacking. It has been hypothesized that the primary event in the pathogenesis of gastrointestinal involvement in SSc is an early neural lesion. This study investigates proximal stomach function and its relation to autonomic nerve function in SSc. Twenty SSc patients classified in to clinical subsets, underwent measurement of proximal stomach function with and without glucagon by electronic barostat and an assessment of autonomic nerve function. SSc patients were not significantly different from 11 controls for gastric compliance (59.5+/-5.0 vs 47.7+/-4.2 ml/mm Hg, P = 0.1). The pressure-volume curves in each participant with and without glucagon were significantly different (P < 0.001). A significant positive association was found between gastric compliance and autonomic nerve function (P < 0.05). The change in gastric compliance during glucagon administration was significant-associated with autonomic function (P < 0.05). The perception cumulative scores did not differ between SSc patients and control subjects (P = 0.2). In conclusion, proximal stomach function is associated with autonomic nerve function in SSc patients. This confirms the frequent association of motility disorders with autonomic dysfunction in SSc.

Serum transglutaminase correlates with endoscopic and histopathologic grading in patients with ulcerative colitis.

Factor XIIIa, a circulating form of transglutaminase, plays a key role in intestinal mucosal repair. We found that transglutaminase levels are decreased in serum of patients with inflammatory bowel diseases and demonstrated in a rat model of chronic colitis that serum transglutaminase is closely related to the severity of intestinal damage. We aimed, therefore, to correlate serum transglutaminase levels with standard endoscopic and histopathologic grading systems in patients affected by ulcerative colitis (UC). In 249 patients with UC, we assayed serum transglutaminase activity by a radioenzymatic method and measured clinical activity index (CAI) according to modified Rachmilewitz's criteria. In a subset of 82 patients undergoing colonoscopy, endoscopic and histologic indices were studied. Biopsy specimens were also taken from 28 patients to measure myeloperoxidase (MPO) as a marker of mucosa inflammation. Serum transglutaminase levels significantly correlated with the CAI scoring (r = -0.63; P < 0.01); likewise serum transglutaminase showed the best correlation with endoscopic (r = -0.71; P < 0.001) and histologic (r = -0.79; P < 0.001) scores. Myeloperoxidase activity was significantly higher in patients with active UC than those in remission (P < 0.01), showing a significant correlation with serum transglutaminase levels (r = -0.68; P < 0.01). Immunohistochemistry showed factor XIIIa localization in the extracellular matrix of damaged mucosa. In conclusion, these results suggest that transglutaminase assay can be useful in managing UC as a serological, noninvasive indicator of intestinal mucosal status.

The prognostic value, in active ulcerative colitis, of an increased intensity of colonic perivisceral fat signal on magnetic resonance imaging with ferumoxil.

OBJECTIVE: In active ulcerative colitis (UC), magnetic resonance imaging (MRI) with ferumoxil, a superparamagnetic oral contrast agent, accurately evaluates, in our experience, the increased wall thickness and frequently shows a stronger perivisceral fat signal intensity (PFSI). The aim of our study was to evaluate the clinical significance of these MRI findings in active UC. METHODS: Twenty-four consecutive patients affected by moderate pancolitis were enrolled. At entry, each patient underwent MRI with ferumoxil to evaluate wall thickness and PFSI. Two groups of patients were individuated: group A (increased PFSI) and group B (normal PFSI). After obtaining remission, the number of relapses and, at each flare-up, the clinical activity index (CAI) were evaluated in all patients in a 2-yr follow-up period. The mean CAI was calculated at the end of the follow-up in each patient. Where there was colectomy, a complete histological examination of the colon was performed. RESULTS: PFSI was increased in 16 patients (group A) and was normal in the remainder (group B). There was a significant difference of wall thickness, number of relapses/yr, and mean CAI between the two groups of patients. No difference was observed with regard the duration of disease. Six patients of group A and no patient of group B underwent colectomy. The histological evaluation showed an increased thickness of the entire colonic wall with significant changes of the perivisceral fat structures. CONCLUSIONS: An increased