Functional bowel symptoms in quiescent inflammatory bowel diseases: role of epithelial barrier disruption and low-grade inflammation.

OBJECTIVE: To determine the role of colonic barrier defects and low-grade inflammation in irritable bowel syndrome (IBS)-like symptoms in quiescent inflammatory bowel disease (IBD). DESIGN: Caecal biopsies were collected from 51 IBS, 49 quiescent IBD (31 Crohn's disease (CD) and 18 ulcerative colitis (UC)) patients and 27 controls. IBS was assessed using the Rome III criteria and the IBS severity score. Epithelial barrier integrity was evaluated by determining the paracellular permeability of biopsies mounted in Ussing chambers and the mRNA expression of tight junction proteins (ZO-1, α-catenin and occludin). Low-grade inflammation was evaluated by counting cells, including intraepithelial lymphocytes (IELs), eosinophils and mast cells, and by determining the mRNA and protein expression of tumour necrosis factor (TNF)-α in biopsies and culture supernatants. RESULTS: IBS-like symptoms were present in 35.4 and 38% of CD and UC patients, respectively. Paracellular permeability was significantly increased in both quiescent IBD with IBS-like symptoms and IBS compared with quiescent IBD without IBS-like symptoms (p<0.01, respectively) or controls (p<0.01, respectively). Significantly lower expression of ZO-1 and α-catenin was detected in IBS and quiescent IBD with IBS-like symptoms. IELs and TNF-α were significantly increased in quiescent IBD with IBS-like symptoms, but not in IBS. CONCLUSIONS: In quiescent IBD, IBS-like symptoms related to persistent subclinical inflammation associated with increased colonic paracellular permeability. A persistent increase in TNF-α in colonic mucosa may contribute to the epithelial barrier defects associated with abdominal pain in quiescent IBD, but not in IBS. Optimisation of anti-inflammatory therapy may be considered in quiescent IBD with IBS-like symptoms.

Combination of allergic factors can worsen diarrheic irritable bowel syndrome: role of barrier defects and mast cells.

OBJECTIVES: Recent evidence suggests a role for increased colonic permeability and mucosal mast cell (MC) mediators on symptoms related to the irritable bowel syndrome (IBS). Whether allergic factors (AFs) are involved in the pathophysiology of IBS is unclear. We addressed the question of the possible influence of an allergic background on IBS symptoms. METHODS: We assessed paracellular permeability, mucosal MCs counts, and spontaneous release of tryptase of colonic biopsy specimens in 34 IBS patients and 15 healthy subjects. The severity of IBS was assessed through self-reported questionnaires. All individuals were tested for the presence of AF, including self-perception of adverse reaction to food, personal and familial history of atopic disease, elevated total or specific immunoglobulin E against food/inhalant antigens, blood eosinophilia, and skin tests. RESULTS: IBS patients had significant enhanced colonic permeability, higher number of MCs, and spontaneous release of tryptase than healthy subjects. The severity of IBS was significantly correlated with colonic permeability (r=0.48, P=0.004), MCs counts (r=0.36, P=0.03), and tryptase (r=0.48, P=0.01). In 13 IBS patients (38.2%) having at least three AFs, symptoms scores, colonic permeability, MCs counts, and tryptase release by colonic biopsies were significantly higher than in those with less than three AFs. IBS patients with at least three AFs were more prone to diarrhea or alternating symptoms. None AF was found to be predictive of IBS severity. CONCLUSIONS: In IBS patients, the presence of an allergic background correlates with a more severe disease and diarrhea predominance, possibly by enhancing mucosal MC activation and paracellular permeability.

Plasma carnitine is associated with fatigue in chronic hepatitis C but not in the irritable bowel syndrome.

BACKGROUND: Fatigue is an important determinant of altered quality of life in patients affected by chronic hepatitis C or the irritable bowel syndrome (IBS). AIM: In this study, we aimed at determining the contributory role of plasma levels of leptin and carnitine on fatigue in chronic hepatitis C and IBS. METHODS: We enrolled 81 patients with chronic hepatitis C, 42 with IBS and 44 healthy subjects. Fatigue was evaluated using the Fatigue Impact Scale questionnaire. Body composition was assessed through impedance analysis. Plasma carnitine and leptin were measured. RESULTS: Fatigue scores were significantly more elevated in patients with chronic hepatitis C and IBS than in healthy subjects. Patients with chronic hepatitis C but not IBS, had significant lower plasma levels of total and free carnitine adjusted for fat mass compared with healthy subjects. In patients with chronic hepatitis C and not with IBS, fatigue scores were negatively correlated with plasma levels of carnitine. Levels of free carnitine were significantly and independently associated with the severity of fatigue in patients with chronic hepatitis C [OR=2.019, P=0.02, CI 95% (1.01-1.23)]. CONCLUSIONS: In patients with chronic hepatitis C, the severity of fatigue is associated with a low level of carnitine, suggesting that an oral supplementation may be effective to relieve fatigue in chronic hepatitis C. The underlying mechanism of fatigue in IBS does not seem to involve carnitine.

Impact of functional bowel symptoms on quality of life and fatigue in quiescent Crohn disease and irritable bowel syndrome.

BACKGROUND: Patients with irritable bowel syndrome (IBS) and Crohn disease (CD) have impaired quality of life (Qol) associated with fatigue. Whether IBS-like symptoms have a similar impact on Qol and fatigue in quiescent CD than in IBS is currently unknown. Our aims were (i) to evaluate the prevalence of IBS-like symptoms in quiescent CD and (ii) to compare the impact of IBS-like symptoms on Qol and fatigue in both diseases. METHODS: A total of 92 quiescent CD, 40 IBS and 20 healthy subjects similar in age were included prospectively in five French academic centers. IBS symptoms were evaluated through the Rome III criteria. The severity of IBS symptoms, Qol, fatigue, depression and anxiety was measured using questionnaires (Francis Score, Likert scales, Fatigue Impact Scale, short-form Beck and Hospital Anxiety and Depression Scale). KEY RESULTS: Irritable bowel syndrome-like symptoms were found in 42/92 (45.6%) patients with quiescent CD. The presence of IBS-like symptoms was associated with significant more profound alterations of Qol, high scores of fatigue, depression, but similar levels of anxiety. Compared to CD patients with IBS-like symptoms, IBS patients had more severe gastrointestinal symptoms and alterations of Qol, but similar scores of fatigue, depression and anxiety. In quiescent CD patients, fatigue was independently associated with the presence of IBS-like symptoms (OR = 1.018, 95% CI: 1.002-1.034, P = 0.02). CONCLUSIONS & INFERENCES: The prevalence of IBS-like symptoms is elevated in quiescent CD. The presence of IBS-like symptoms in quiescent CD is probably associated with the range of fatigue/depression disorders. The mechanism underlying the occurrence of IBS-like symptoms in quiescent CD needs to be further explored.

Impaired intestinal barrier integrity in the colon of patients with irritable bowel syndrome: involvement of soluble mediators.

BACKGROUND: Growing evidence suggests that patients with irritable bowel syndrome (IBS) have increased intestinal permeability. In addition, mucosal soluble mediators are involved in the pathophysiology of pain in IBS. We aimed to investigate (1) paracellular permeability in colonic biopsies of patients with IBS; and (2) the ability of soluble factors from colonic biopsies to reproduce these alterations in vitro. METHODS: Paracellular permeability in colonic biopsies of healthy subjects and patients with IBS was measured by mounting the biopsies in Ussing chambers. Cleared supernatant (SUP) of the culture from colonic biopsies was collected and applied to Caco-2 cells for 48 h. Paracellular permeability and transepithelial resistance (TER) were evaluated. mRNA expression of the tight junction proteins, zonula occludens (ZO)-1 and occludin, was assessed in colonic biopsies. Abdominal pain was assessed using a validated questionnaire. RESULTS: Permeability of colonic biopsies was significantly higher in patients with IBS compared to healthy subjects. These changes were associated with significantly lower expression of ZO-1 mRNA in biopsies of IBS as compared to healthy subjects. Compared to healthy subjects, SUP of IBS markedly reduced TER and significantly increased permeability in Caco-2 cells. SUP of IBS patients induced a significant decrease of ZO-1 mRNA in Caco-2 as compared to healthy subjects. SUP-induced increased paracellular permeability correlated with the severity of abdominal pain. CONCLUSIONS: Our study shows that colonic soluble mediators are able to reproduce functional (permeability) and molecular (ZO-1 mRNA expression) alterations observed in IBS patients. These findings might pave the way both to identify novel biomarkers as well as new therapeutic targets in IBS.

Mast cells and cellularity of the colonic mucosa correlated with fatigue and depression in irritable bowel syndrome.

BACKGROUND: A subset of patients with irritable bowel syndrome (IBS) have an increased number of mast cells (MCs) in the colonic mucosa. Psychological factors are believed to contribute to the course of IBS. AIMS: To examine associations between fatigue, depression and MCs of the colonic mucosa in IBS. METHODS: Colonic biopsies were taken from 50 Rome II IBS patients, 21 healthy controls and 11 depressed/fatigued patients without IBS. The cellularity of the lamina propria was determined as the number of inflammatory cells per high power field (hpf) through a 400x microscope. The Fatigue Impact Scale (FIS) and the short form Beck Depression Inventory (BDI) evaluated the severity of fatigue and depression. RESULTS: IBS patients had a significant increase in the cellularity of the lamina propria compared with controls or with depressed patients (mean (SD) 94.5 (48-110) vs 68 (58-82) and 78 (87-90) cells per hpf, p = 0.005 and p = 0.05, respectively), in particular of MCs (9.3 (5.6-11.7) vs 4.0 (2.7-6.8) and 4.3 (2.8-7.8) cells per hpf, p = 0.001 and p = 0.005, respectively). Both the FIS and BDI scores were significantly higher in IBS or in depressed patients than in controls (p<0.001). In IBS, the FIS score correlated significantly with the cellularity of the lamina propria (r = 0.51, p<0.0001) and MCs (r = 0.64, p<0.0001). In IBS, the BDI score correlated significantly with MCs (r = 0.29, p = 0.03). CONCLUSIONS: Elevated MCs counts are a key feature of the low-grade inflammatory infiltrate in the caecal mucosa of IBS. Fatigue and depression are associated with mucosal cell counts, in particular MCs, suggesting that psychological factors are associated with the low-grade inflammatory infiltrate in IBS.

Low risk of irritable bowel syndrome after Clostridium difficile infection.

OBJECTIVE: The incidence of postinfectious irritable bowel syndrome (IBS) ranges between 4% and 32% of individuals after bacterial or parasitic infection. This study analyzed IBS symptoms in hospitalized patients three months after a symptomatic Clostridium difficile infection. PATIENTS AND METHODS: All patients with a proven, symptomatic C difficile infection identified in the department of bacteriology over a four-month period were considered for enrolment. Patients were excluded in cases of pre-existing IBS or other organic gastrointestinal diseases. Patients completed both modified Talley and Rome II questionnaires within five days of clinical improvement with metronidazole and at three months postinfection, when stools were cultured and C difficile toxins were examined to exclude ongoing infection. RESULTS: Twenty-three patients were evaluated three months after infection with C difficile. Just after infection, 15 patients were symptom free, whereas eight patients exhibited symptoms suggestive of IBS. Three months after infection, 22 patients remained symptom free, whereas one patient presented with symptoms indicative of IBS. That female patient had a prolonged infection without vomiting. CONCLUSIONS: We have shown that while transient functional bowel disorder occurred in 34.7% of patients (eight of 23 patients) recently infected with C difficile, only 4.3% of patients (one of 23 patients) had symptoms indicative of IBS after three months (ie, postinfectious IBS). Because an age-related reduction in immune responsiveness has been documented, it can be speculated that the low incidence of postinfectious IBS may be explained by the older age of the study population. Therefore, it cannot be excluded that the findings may be different in younger patients.

Influence of body posture on intestinal transit of gas.

BACKGROUND: Patients describe that body posture may affect their abdominal bloating, distension, and flatulence, but whether changes in position have objectively demonstrable effects, either beneficial or deleterious, has not been investigated. AIM: To determine the effect of body posture, upright versus supine, on intestinal transit of gas loads. SUBJECTS: Eight healthy subjects without gastrointestinal symptoms. METHODS: In each subject a gas mixture was continuously infused into the jejunum (12 ml/min) for three hours, and gas evacuation, clearance of a non- absorbable gaseous marker, perception, and abdominal girth were measured. Paired studies were randomly performed in each subject on separate days in the upright and supine positions. RESULTS: In the upright position, intestinal gas retention was much smaller than when supine (13 (52) ml v 146 (75) ml retention at 60 minutes, respectively; p<0.05), and clearance of the gas marker was expedited (72 (10)% clearance v 49 (16)% at 60 minutes, respectively; p<0.05). The gas challenge test was well tolerated both in the upright and supine positions without abdominal distension. CONCLUSION: Body posture has a significant influence on intestinal gas propulsion: transit is faster in the upright position than when supine.

Discrepancies between reported food intolerance and sensitization test findings in irritable bowel syndrome patients.

OBJECTIVE: Irritable bowel syndrome (IBS) is a common gastrointestinal disorder with clinical signs typical of "intestinal" food allergies or intolerance. The aim of this study was to characterize the clinical features of IBS patients suspected of suffering from adverse reactions to food. METHODS: The study involved 128 consecutive IBS patients divided into four groups according to their main symptom on presentation at our outpatient clinic. A detailed medical history was recorded, paying particular attention to any allergies and reported intolerance to food. Each patient was screened for allergies; intestinal permeability tests was performed in randomly selected patients from different groups. Findings were analyzed using the chi2 test. RESULTS: Adverse reactions to one or more foods were reported by 80 patients (62.5%); skin prick tests (SPT) were positive in 67 patients (52.3%) with no significant differences between patients complaining of different symptoms. Patients who reported a food intolerance had more positive SPTs than those who did not (47 of 80 [58.7%] vs 20 of 48 [41.7%]); this difference was not statistically significant, although it suggests a trend (p < 0.0610). There was little consistency between the specific foods reported to cause intolerance and those resulting from the tests (11 of 80 patients, 13.7%). The intestinal permeability test was normal in 29 of 33 patients (87.9%). CONCLUSIONS: More than 50% of IBS patients were found sensitized to some food or inhalant without any typical clinical signs. Patients were unable to identify potentially offending foods. The lack of a correlation between SPT results and reported food allergies needs further investigation to clarify the pathophysiology and improve the diagnosis of intestinal food allergies.

Peripheral neuropathy in styrene-exposed workers.

BACKGROUND: The toxicity of styrene on the peripheral nervous system is still debated. CASES: The paper presents two cases of peripheral sensorimotor neuropathy in styrene-exposed workers. Exposure, evaluated by biological monitoring, ranged between 100 and 150% of the current limits proposed by the American Conference of Governmental Industrial Hygienists (ACGIH). The subjects complained of leg weakness and numbness, cramps, and paresthesia. Electrophysiology revealed a moderate peripheral sensorimotor neuropathy of a demyelinating type. Color-vision testing showed a subclinical deficit. Common inherited and acquired causes of peripheral neuropathy and dyschromatopsia other than styrene were ruled out by personal history, medical examination, laboratory data, and chest X-ray. CONCLUSIONS: The results suggest that long-term occupational exposure to environmental levels of styrene that are equal, or slightly above, the ACGIH limits can induce a clinical form of peripheral neuropathy and a subclinical impairment of color vision. As a consequence, a careful reappraisal of the real preventive meaning of the current ACGIH occupational limit for styrene, at least on an individual basis, is needed.

Inhibition of lymphocytic neuropathy target esterase predicts the development of organophosphate-induced delayed polyneuropathy.

Neuropathy Target Esterase (NTE) is the molecular target in the nervous system for organophosphorus esters (OP) when they cause delayed polyneuropathy. Some NTE activity was recently found also in blood lymphocytes. An unsuccessful suicide attempt with the widely used pesticide chlorpyrifos (0,0-diethyl-0-3,5,6,-trichloro-2-pyridyl phosphorothioate) is reported, where prior inhibition of lymphocytic NTE correlates with the delayed development of polyneuropathy. A 42-year-old man drank approximately 300 mg/kg chlorpyrifos. The subsequent severe cholinergic syndrome lasted for 17 days with varying degrees of severity. Thirty days after intoxication the clinical and electrophysiological examination of the peripheral nervous system was normal but lymphocytic NTE was about 60% inhibited. On day 43 the patient began to complain of paresthesia and leg weakness. Clinical examination, electrophysiology and a nerve biopsy revealed signs of a peripheral polyneuropathy, axonal in type. This case report indicates that measurement of lymphocytic NTE might be used as a clinical test to predict the development of OP-induced delayed polyneuropathy.

[Motor conduction velocities and distal latencies in multiple sclerosis]. / Studio della VCM e delle latenze distali nella sclerosi multipla.

Motor conduction velocities (MCV) and distal latencies (DL) of the ulnar nerve and of the external popliteal sciatic nerve have been recorded in 21 cases of multiple sclerosis. Only in 4 cases (19%) all values were found within normal limits. The maximal MCV of one or both nerves appeared to be slightly reduced in 7 cases (33%) and the minimal MCV was reduced more markedly in 13 cases (62%). The MCV alterations (both minimal and maximal) were more frequent among patients with marked hypertonus. The ulnar nerve was the most frequent site of such alterations. LD were markedly altered in 17 cases (81%), independently from the entity of pyramidal signs.

Effects of folic acid on phenytoin kinetics in healthy subjects.

Phenytoin (DPH) disposition was studied in normal subjects before and after treatment with folic acid for 14 days. Our results suggest that folic acid lowers (DPH) serum levels without significantly modifying its bound fraction and increases the rate of DPH and meta-hydroxydiphenylhydantoin excretion in urine.