Defining and Assessing the Reproducibility of Crohn's Disease Endoscopic Lesions: A Delphi-like Method from the GETAID.

BACKGROUND AND AIMS: Defining and assessing the reproducibility of Crohn's disease [CD] endoscopic lesions is essential in assessing endoscopic healing. METHODS: Twelve endoscopic CD experts from the GETAID defined aphthoid erosions [AE], superficial ulcerations [SU], deep ulcerations [DU], stenosis, and fistulas according to a Delphi-like method. Thirty different GETAID physicians declared if they found acceptable each definition. Intra- and inter-observer agreements were investigated using 100 videos with one tagged specific lesion [AE, SU, DU, or sham lesion] read by 15 independent endoscopists at baseline and 1 month later in a randomised order. Video quality was determined by an external reader. According to kappa estimate [κ ±standard error], intra or inter-observer agreement was qualified as 'moderate' [0.4-0.6], 'substantial' [0.6-0.8], or 'almost perfect' [0.8-1.0]. RESULTS: Among 30 different experts, 83% to 97% found acceptable the definitions retrieved from the Delphi-like method. Intra-observer κ was 0.717 [±0.019] for SU, 0.681 [±0.027] for AE, 0.856 [±0.014] for DU, showing 'substantial' agreement. It was 0.801 [±0.016] for any ulceration [DU or SU]. There was a high variability across readers from 'moderate' to 'almost perfect' agreement. Inter-observer κ was 0.548 [±0.042] for SU, 0.554 [±0.028] for AE 0.694 [±0.041] for DU, and 0.705 [±0.042] for any ulceration. Inter-observer agreement increased when reading the 53 high-quality videos: 0.787 [±0.064] [p = 0.001], 0.607 [±0.043] [p = 0.001], and 0.782 [±0.064][p = 0.001] for DU, AE, and any ulceration, respectively. CONCLUSIONS: Despite variable intra-agreement level across readers, the GETAID definitions for CD endoscopic lesions provided 'substantial' inter-observer agreements, especially in case of high-quality videos.

Chemistry of free radicals produced by oxidation of endogenous α-aminoketones. A study of 5-aminolevulinic acid and α-aminoacetone by fast kinetics spectroscopy.

BACKGROUND: Excess 5-aminolevulinic acid (ALA) and α-aminoacetone (AA) are implicated in ketosis, porphyrinpathies and diabetes. Pathologic manifestations involve O2⁻, H2O2, OH, enoyl radicals (ALA and AA) and their oxidation end products. METHODS: To characterize enoyl radicals resulting from reaction of OH radicals with ALA and AA, micromolar OH concentrations were produced by pulse radiolysis of ALA and AA in aqueous solutions. RESULTS: ALA and AA react with OH at k=1.5 × 109 M⁻¹s⁻¹. At pH7.4, the ALA absorbance spectrum has a maximum at 330 nm (ε=750 M⁻¹cm⁻¹). This band appears as a shoulder at pH8.3 where two ALA species are present: (NH3)⁺-CH2-CO-CH2-CH2-COO⁻ and NH2-CH2-CO-CH2-CH2-COO⁻ (pKa=8.3). At pH8.3, ALA reacts with oxygen (k=1.4 × 108 M⁻¹s⁻¹) but not with O2⁻. At pH8.3, AA oxidation produces two AA species characterized by an absorbance spectrum with maxima at 330 and 450 nm. ALA and AA are repaired by antioxidants (quercetin (QH), catechin, trolox, ascorbate) which are semi-oxidized (k>10(8)M⁻¹s⁻¹). QH bound to HSA or to apoferritin and ferritin repairs ALA and AA. In O2-saturated apoferritin solutions, Q, O2⁻, AA and reaction product(s) react with QH. CONCLUSIONS: The optical absorption properties and the time evolution of ALA and AA were established for the first time. These radicals and their reaction products may be neutralized by antioxidants free in solution or bound to proteins. GENERAL SIGNIFICANCE: Adjuvant antioxidant administration may be of interest in pathologies related to excess ALA or AA production.

Gastrointestinal mucosal abnormalities using videocapsule endoscopy in systemic sclerosis.

BACKGROUND: To date, there are no large studies on videocapsule endoscopy in systemic sclerosis (SSc). Consequently, the prevalence and features of gastrointestinal mucosal abnormalities in SSc have not been determined. AIMS: To determine both prevalence and characteristics of gastrointestinal mucosal abnormalities in unselected patients with SSc, using videocapsule endoscopy. To predict which SSc patients are at risk of developing potentially bleeding gastrointestinal vascular mucosal abnormalities. METHODS: Videocapsule endoscopy was performed on 50 patients with SSc. RESULTS: Prevalence of gastrointestinal mucosal abnormalities was 52%. Potentially bleeding vascular mucosal lesions were predominant, including: watermelon stomach (34.6%), gastric and/or small intestinal telangiectasia (26.9%) and gastric and/or small intestinal angiodysplasia (38.5%). SSc patients with gastrointestinal vascular mucosal lesions more often exhibited: limited cutaneous SSc (P = 0.06), digital ulcers (P = 0.05), higher score of nailfold videocapillaroscopy (P = 0.0009), anaemia (P = 0.02), lower levels of ferritin (P < 0.0001) and anti-centromere antibody. CONCLUSIONS: Our study identifies a high frequency of gastrointestinal mucosal abnormalities in SSc, with a marked predominance of vascular mucosal damage. Furthermore, our study shows a strong correlation between gastrointestinal vascular mucosal lesions and presence of severe extra-digestive vasculopathy (digital ulcers and higher nailfold videocapillaroscopy scores). This latter supports the theory that SSc-related diffuse vasculopathy is responsible for both cutaneous and digestive vascular lesions. Therefore, we suggest that nailfold videocapillaroscopy may be a helpful test for managing SSc patients. In fact, nailfold videocapillaroscopy score should be calculated routinely, as it may result in identification of SSc patients at higher risk of developing potentially bleeding gastrointestinal vascular mucosal lesions.

Innate mucosal-associated invariant T (MAIT) cells are activated in inflammatory bowel diseases.

Inflammatory bowel diseases are characterized by a deregulated immune response targeting the gut bacterial flora. Mucosal-associated invariant T (MAIT) cells are major histocompatibility complex (MHC) class Ib-restricted innate-like lymphocytes with anti-bacterial functions. They display an effector/memory phenotype and are found in large numbers in the blood, mucosae and liver. They have also been implicated in inflammatory diseases such as multiple sclerosis. Therefore, we aimed to analyse the possible involvement of MAIT cells in Crohn's disease (CD) and ulcerative colitis (UC). To this end, a phenotypical and functional analysis of MAIT cells isolated from the blood of healthy subjects, CD and UC patients was undertaken. MAIT cells were also quantified in ileal biopsies of CD patients. The frequency of blood MAIT cells was specifically reduced in IBD patients compared with healthy donors, whereas it was dramatically greater in the inflamed versus healthy tissue. MAIT cells were activated as they expressed significantly more the Ki67 antigen, and this was accompanied by phenotypical changes such as increased expression of natural killer (NK)G2D and B and T lymphocyte attenuator (BTLA). Finally, in-vitro-activated MAIT cells from CD and UC patients secreted significantly more interleukin (IL)-17, together with a decreased interferon (IFN)-γ in CD but an increased IL-22 in UC. These data show that MAIT cells are activated in IBD, which results in an increased recruitment towards the inflamed tissues, an altered phenotype and a switch in the pattern of cytokine secretion. This is the first demonstration that MAIT cells are immune players in IBD, whose precise functions in this context need to be addressed.

On the repair of oxidative damage to apoferritin: a model study with the flavonoids quercetin and rutin in aerated and deaerated solutions.

Ferritin (Ft) impairment through (•)O2(-), H2O2, and (•)OH production occurs in the cases of ketoses, diabetes mellitus, acute intermittent porphyria and tyrosinemia. In addition to (•)Trp and TyrO(•) radical production, ferrous iron liberation and Ft synthesis stimulation, site-specific oxidation reactions are induced leading to toxic iron accumulation in organs with high Ft content, for example, liver and brain. To elucidate the potential pathways to Ft recovery, repair of oxidative damage to horse spleen apoferritin (apoFt) and Ft by quercetin (QH) or rutin (RH) was studied in the presence and absence of oxygen. (•)Trp and TyrO(•) radicals were produced in pulse radiolysis through apoFt oxidation by (•)Br2(-) radicals. QH and RH bind to apoFt on eight sites with binding constants of ˜80,000 and ˜32,000 M(-1), respectively. In deaerated solutions, a repair of apoFt radicals is observed involving both bound and free flavonoids. This repair occurs by a fast intra- and a slow inter-molecular electron transfer from bound and free flavonoids, respectively. With QH, the rate constants are 10(4) s(-1) and 3.5 × 10(7) M(-1) s(-1) for the intra- and intermolecular repair reactions, respectively. Oxygen does not interfere with repair of apoFt or Ft by bound QH but inhibits 90% of Ft repair by RH. These results taken together indicate that flavonoid antioxidants may help alleviate Ft impairment in diseases involving an oxidative stress.

The changing pattern of Crohn's disease incidence in northern France: a continuing increase in the 10- to 19-year-old age bracket (1988-2007).

BACKGROUND: Crohn's disease incidence rates have stabilised in industrialised countries since the 1980s. Conversely, a continuing increase in childhood-onset Crohn's disease incidence has been reported. AIM: To confirm trends in inflammatory bowel disease (IBD) incidence in northern France over an extended time period (1988-2007) with a focus on childhood-onset Crohn's disease. METHODS: The IBD patients recorded in the EPIMAD registry between 1988 and 2007 were included. Standardised incidence rates were calculated for Crohn's disease and ulcerative colitis in the entire population, and separately according to age. Evolution of phenotypes at diagnosis was also studied. RESULTS: A total of 12 084 incident IBD cases (7428 Crohn's disease and 4656 ulcerative colitis) were recorded. Crohn's disease incidence rates increased from 5.2 cases/100 000 persons in 1988-1990 to 6.7 in 2006-2007 (+29%), stabilising after a peak at 7.1 in 1997-1999. Crohn's disease incidence rates in the 10-19-year age category increased by 71%, from 6.5 (1988-1990) to 11.1 (2006-2007). The frequency of initial ileo-colonic localisation increased from 52.9% in 1988-1990 to 68.6% in 2006-2007 (P<0.0001). Ulcerative colitis incidence rates decreased during the same period. CONCLUSIONS: From 1988 to 2007, Crohn's disease incidence increased by 29% in northern France and by 71% in the 10-19-year-old age group. Consequently, studies on Crohn's disease risk factors should focus on the population under 20 years of age.

Successive treatment with cyclosporine and infliximab in steroid-refractory ulcerative colitis.

OBJECTIVES: Rescue therapy with either cyclosporine (CYS) or infliximab (IFX) is an effective option in patients with intravenous steroid-refractory attacks of ulcerative colitis (UC). In patients who fail, colectomy is usually recommended, but a second-line rescue therapy with IFX or CYS is an alternative. The aims of this study were to investigate the efficacy and tolerance of IFX and CYS as a second-line rescue therapy in steroid-refractory UC or indeterminate colitis (IC) unsuccessfully treated with CYS or IFX. METHODS: This was a retrospective survey of patients seen during the period 2000-2008 in the GETAID centers. Inclusion criteria included a delay of <1 month between CYS withdrawal (when used first) and IFX, or a delay of <2 months between IFX (when used first) and CYS, and a follow-up of at least 3 months after inclusion. Time-to-colectomy, clinical response, and occurrence of serious adverse events were analyzed. RESULTS: A total of 86 patients (median age 34 years; 49 males; 71 UC and 15 IC) were successively treated with CYS and IFX. The median (± s.e.) follow-up time was 22.6 (7.0) months. During the study period, 49 patients failed to respond to the second-line rescue therapy and underwent a colectomy. The probability of colectomy-free survival (± s.e.) was 61.3 ± 5.3% at 3 months and 41.3 ± 5.6 % at 12 months. A case of fatal pulmonary embolism occurred at 1 day after surgery in a 45-year-old man. Also, nine infectious complications were observed during the second-line rescue therapy. CONCLUSIONS: In patients with intravenous steroid-refractory UC and who fail to respond to CYS or IFX, a second-line rescue therapy may be effective in carefully selected patients, avoiding colectomy within 2 months in two-thirds of them. The risk/benefit ratio should still be considered individually.

A fulminant colitis index greater or equal to 8 is not predictive of colectomy risk in infliximab-treated moderate-to-severe ulcerative colitis attacks.

INTRODUCTION: In severe attacks of ulcerative colitis (UC) treated with intravenous corticosteroids, a fulminant colitis index (FCI) greater or equal to 8 has been associated with a greater likelihood of colectomy (72 vs 16% with an FCI<8). This retrospective study aimed to assess the accuracy of such an association in infliximab-treated patients with moderate-to-severe bouts of UC. PATIENTS AND METHODS: The study was based on the medical files of 43 patients who had received at least one infusion of infliximab to treat moderate-to-severe UC (partial Mayo Clinic score). Remission and clinical response were also assessed using the partial Mayo score. The accuracy of an FCI greater or equal to 8 to predict the likelihood of colectomy was assessed by calculating the sensitivity, specificity, positive and negative predictive values, Yule's Q coefficient, Youden's index and statistical significance (Chi(2) test). RESULTS: After treatment with infliximab, 10 patients were in remission (23.3%), 21 (48.8%) had a clinical response, four (9.3%) had treatment failure (without, however, requiring colectomy) and eight (18.6%) had a colectomy. Calculation of the above-mentioned indicators revealed that an FCI greater or equal to 8 was not an indicator of the risk of colectomy in this patient population, and found that only an FCI greater or equal to 16 was statistically significant. However, low values for sensitivity, positive predictive value and Youden's index preclude the clinical application of this latter result. CONCLUSION: In patients treated with infliximab for moderate-to-severe UC attacks, the FCI is not a predictor of colectomy. In such patients, the factors predictive of a response to treatment or likelihood of colectomy, currently acknowledged with corticosteroid treatment, need to be further assessed for infliximab treatment.

[Embolization of recurrent bleeding jejunal varices]. / Embolisation de varices jéjunales hémorragiques récidivantes.

We report a case of recurrent digestive haemorrhage due to bleeding ectopic jejunal varices complicating portal hypertension in a 51-year-old cirrhotic patient, treated 1 year ago by transjugular intrahepatic porto-systemic shunt (TIPS) for the same problem. Successful embolisation with coils, of ectopic varices, was performed using original transjugular and trans-TIPS route, without complication, and no recurrence during a follow-up of 24 months.

Surgical conservative treatment of recurrent bleeding duodenal ulcer.

BACKGROUND/AIMS: Endoscopic hemostasis and proton pump inhibitors (PPI) have decreased the incidence of rebleeding and reduced the need for surgery for bleeding duodenal ulcer (BDU). The gold standard surgical treatment of BDU remains vagotomy-antrectomy. Currently, no recommendation is made on the best procedure when emergency surgery is necessary. The aim of this study was to assess the results of a systematic conservative treatment (CT): under-running bleeding gastroduodenal artery (GDA) and ulcer suture through a duodenotomy with (CT+L group) or without (CT group) GDA double ligation along with continuous intravenous PPI. METHODOLOGY: From 1995 to 2006, 22 consecutive patients (11 per group) underwent emergency surgery for BDU. Mean age was 63 +/- 18 years, ASA score 2.64 +/- 0.7. Ten patients (45%) presented collapse. Mean transfusion number was 11 +/- 9, number of therapeutic endoscopies 1.7 +/- 1, and Rockall score 6 +/- 2. RESULTS: Overall, 2 patients (9%) had rebleeding and 5 patients (22%) died. No death was reported secondary to rebleeding. In the CT+L group, 9 patients (82%) had intravenous PPI, no patient had rebleeding and 2 patients died (22%). CONCLUSIONS: Surgical CT of BDU with continuous PPI is effective, with a low rate of rebleeding. The standard use of vagotomy-antrectomy is questionable.

Assessment of asymptomatic liver fibrosis in alcoholic patients using fibroscan: prospective comparison with seven non-invasive laboratory tests.

BACKGROUND: Systematic screening for liver fibrosis in heavy-drinking patients is a challenge. Aims To assess Fibroscan for non-invasive diagnosis of asymptomatic liver fibrosis in alcohol abuse patients, to determine diagnostic liver stiffness cut-off values and to compare performance of Fibroscan with seven non-invasive laboratory tests. METHODS: One hundred and three alcoholic patients were studied. Liver fibrosis was staged by METAVIR system. Fibroscan, Fibrotest, Fibrometer, Hepascore, APRI, PGA, PGAA and hyaluronic acid tests were performed. Liver stiffness cut-offs were determined using receiver-operating characteristic (ROC) curves. RESULTS: Liver stiffness was correlated with fibrosis (r = 0.72, P < 0.014), with median at 5.7, 6.3, 8.4, 15 and 47.3 kPa for F0 (n = 8), F1 (n = 18), F2 (n = 24), F3 (n = 20) and F4 (n = 33) stage fibrosis respectively. For Fibroscan, areas under ROC curves (AUROCs) were 0.84 (95% CI: 0.73-0.95) (F > or = 1), 0.91 (0.85-0.98) (F > or = 2), 0.90 (0.82-0.97) (F > or = 3) and 0.92 (0.87-0.98) (F = 4), yielding diagnostic stiffness cut-offs of 5.9 (F > or = 1), 7.8 (F > or = 2), 11 (F > or = 3) and 19.5 (F4) kPa. Sensitivity, specificity, PPV and NPV were 80%, 90.5%, 93% and 70% for F > or = 2, and 85.7%, 84.2%, 68.6% and 87.9% for F = 4. Performance of Fibroscan was higher than seven laboratory tests, for which AUROCs ranged from 0.66 to 0.77 (F > or = 1), from 0.54 to 0.82 (F > or = 2), from 0.43 to 0.88 (F > or = 3) and from 0.56 to 0.89 (F = 4), with significant difference only vs. APRI (P < 0.001) and Hepascore (P = 0.04). Combining Fibroscan with each tests did not improve performance. CONCLUSIONS: Fibroscan is effective to assess liver fibrosis in alcoholic patients. Instant screening of liver fibrosis in heavy drinkers is feasible without liver biopsy.

Colorectal carcinoma with potentially resectable metastases: factors associated with the failure of curative schedule.

BACKGROUND: The management of patients with colorectal cancer (CRC) and synchronous liver metastases (SLM) depends on the primitive tumor, resectability of the metastatic disseminations and the patient's comorbid condition(s). Considering all patients with potentially resectable primary CRC and SLM, curative resection (R0) will be possible in some patients, although in others surgery will never be performed. The purpose of our study was to identify factors of failure of the curative schedule in these patients. METHODS: We reviewed the data of patients with CRC and SLM between January 2002 and March 2007. Two groups were defined: group R0 when complete metastatic and primary tumor resection was finally achieved after one and more surgical stages and group R2 when curative resection was not possible at the end of the schedule. Clinical, pathologic and outcome data were retrospectively analyzed as well as preoperative management of SLM (chemotherapy, radiofrequency, portal vein embolization). RESULTS: Forty-five patients were included. Curative resection (group R0) was performed in 31 patients (69%) with 48% undergoing major hepatic resection. Mortality of hepatic resection was 0% although it was 9% for primitive tumor. Portal vein embolization was performed preoperatively in eight patients and radiofrequency ablation in 13. Median follow-up was 21 months. Overall survival was 86% at one year and 39% at three years. Survival in group 1 was 97 and 57% at one and three years respectively. Disease-free survival was 87 and 40% at one and three years. Tumor recurrence was noted in 61% of resected patients. At multivariate analysis, number of hepatic metastases superior than three and complicated initial presentation of primitive tumor were found to be significant and predictors of failure of hepatic resection. CONCLUSION: Aggressive management with curative resection of SLM may enable long-term survival. More than three SLM and complicated initial presentation of primitive tumor are factors predictive of failure of the curative schedule.

Ineffectiveness of Lactobacillus johnsonii LA1 for prophylaxis of postoperative recurrence in Crohn's disease: a randomised, double blind, placebo controlled GETAID trial.

BACKGROUND AND AIMS: Early endoscopic recurrence is frequent after intestinal resection for Crohn's disease. Bacteria are involved, and probiotics may modulate immune responses to the intestinal flora. Here we tested the probiotic strain Lactobacillus johnsonii LA1 in this setting. PATIENTS AND METHODS: This was a randomised, double blind, placebo controlled study. Patients were eligible if they had undergone surgical resection of <1 m, removing all macroscopic lesions within the past 21 days. Patients were randomised to receive two packets per day of lyophilised LA1 (2 x 10(9) cfu) or placebo for six months; no other treatment was allowed. The primary endpoint was endoscopic recurrence at six months, with grade >1 in Rutgeerts' classification or an adapted classification for colonic lesions. Endoscopic score was the maximal grade of ileal and colonic lesions. Analyses were performed primarily on an intent to treat basis. RESULTS: Ninety eight patients were enrolled (48 in the LA1 group). At six months, endoscopic recurrence was observed in 30/47 patients (64%) in the placebo group and in 21/43 (49%) in the LA1 group (p = 0.15). Per protocol analysis confirmed this result. Endoscopic score distribution did not differ significantly between the LA1 and placebo groups. There were four clinical recurrences in the LA1 group and three in the placebo group. CONCLUSION: L johnsonii LA1 (4 x 10(9) cfu/day) did not have a sufficient effect, if any, to prevent endoscopic recurrence of Crohn's disease.

Environmental risk factors in paediatric inflammatory bowel diseases: a population based case control study.

BACKGROUND: Environmental exposures in early life have been implicated in the aetiology of inflammatory bowel disease. OBJECTIVE: To examine environmental risk factors prior to the development of inflammatory bowel disease in a paediatric population based case control study. METHODS: A total of 222 incident cases of Crohn's disease and 60 incident cases of ulcerative colitis occurring before 17 years of age between January 1988 and December 1997 were matched with one control subject by sex, age, and geographical location. We recorded 140 study variables in a questionnaire that covered familial history of inflammatory bowel disease, events during the perinatal period, infant and child diet, vaccinations and childhood diseases, household amenities, and the family's socioeconomic status. RESULTS: In a multivariate model, familial history of inflammatory bowel disease (odds ratio (OR) 4.3 (95% confidence interval 2.3-8)), breast feeding (OR 2.1 (1.3-3.4)), bacille Calmette-Guerin vaccination (OR 3.6 (1.1-11.9)), and history of eczema (OR 2.1 (1-4.5)) were significant risk factors for Crohn's disease whereas regular drinking of tap water was a protective factor (OR 0.56 (0.3-1)). Familial history of inflammatory bowel disease (OR 12.5 (2.2-71.4)), disease during pregnancy (OR 8.9 (1.5-52)), and bedroom sharing (OR 7.1 (1.9-27.4)) were risk factors for ulcerative colitis whereas appendicectomy was a protective factor (OR 0.06 (0.01-0.36)). CONCLUSIONS: While family history and appendicectomy are known risk factors, changes in risk based on domestic promiscuity, certain vaccinations, and dietary factors may provide new aetiological clues.

[Pancreas divisum and the dominant dorsal duct syndrome]. / Pancréas divisum et syndrome du canal pancréatique dorsal dominant.

Pancreas divisum, the most frequent congenital malformation of the pancreas, results from the absence of embryologic fusion of the dorsal and ventral pancreatic ducts which keep an autonomy of drainage. The dorsal pancreatic duct is dominant and drains the major part of the pancreatic fluid through a non adapted accessory papilla. The high prevalence of pancreas divisum in patients presenting recurrent acute pancreatitis, the presence of obstructive pancreatitis electively located on the dorsal pancreatic duct and the results of the treatments targeted on the accessory papilla are the arguments pleading for the pathogenic character of the pancreas divisum. Currently, the diagnosis of pancreas divisum is based on magnetic resonance imaging. For symptomatic patients (after exclusion of patients with intestinal functional disorders), results of endoscopic sphincterotomy or surgical sphincteroplasty are favourable in 75% of patients with recurrent acute pancreatitis. They are worse in patients with chronic pain. Surgical sphincteroplasty must be discussed in the same manner as the endoscopic treatment for sometimes avoiding multiplication of the procedures.