Early Transmural Response Assessed Using Magnetic Resonance Imaging Could Predict Sustained Clinical Remission and Prevent Bowel Damage in Patients with Crohn's Disease Treated with Anti-Tumour Necrosis Factor Therapy.

BACKGROUND: Magnetic resonance imaging [MRI] is a promising tool to evaluate therapeutic efficacy in ileocolonic Crohn's disease [CD]. AIMS: We aimed to assess the feasibility of early MRI evaluation (week 12 [W12]) to predict corticosteroid-free remission [CFREM] at W52 and prevent long-term bowel damage. METHODS: All patients with active CD needing anti-tumour necrosis factor [anti-TNF] therapy were consecutively enrolled in this multicentre prospective study. MRI was performed before starting therapy, at W12 and W52. CFREM was defined as Crohn's Disease Activity Index < 150, C-reactive protein < 5 mg/L and faecal calprotectin < 250 µg/g, with no switch of anti-TNF agents, no bowel resection and no therapeutic intensification between W12 and W52. RESULTS: Among 46 patients, 22 [47.8%] achieved CFREM at W52. Anti-TNF agents were able to heal almost all CD lesions as soon as W12 [p < 0.05]. Early transmural response defined as a 25% decrease of either Clermont score (odds ratio [OR] = 7.7 [1.7-34.0], p < 0.001) or Magnetic Resonance Index of Activity (OR = 4.2 [1.3-13.3], p = 0.015) was predictive of CFREM at W52. Achieving at least two items on W12-MRI among ulceration healing, disappearance of enlarged lymph nodes or sclerolipomatosis, ΔADC [apparent diffusion coefficient] > +10% or ΔRCE [relative contrast enhancement] > -30% was associated with a likelihood of CFREM at W52 of 84.6% vs 37.5% in patients without transmural response [p < 0.001]. Early transmural response could prevent bowel damage progression over time using Clermont score (hazard ratio = 0.21 [0.0-0.9]; p = 0.037). CONCLUSION: Evaluation of early transmural response by MRI is feasible and is a promising end point to monitor therapeutic efficacy in patients with CD.

Estrogens control inflammation in experimental colitis.

There is now a wealth of experimental evidence indicating that the deficit in endogenous estrogen facilitates the onset of inflammation that can be antagonized by estrogen replacement therapy. This work investigated the role of estrogen in the control of intestinal inflammation in a panel of colitis models, focusing on the morphological changes, the activity of mast cells, the expression of cytokines (IL-1beta, IL-6, and TNF-alpha), fibronectin and reactive oxygen species. Two hundred adult male rats were divided into 4 groups: colitis was induced in Group I and Group II but only the latter was treated with estrogen; Group III received estrogen only, and Group IV saline. Colitis was induced in 4 models using: iodoacetamide; iodoacetamide + enteropathogenic E. coli; 2, 4, 6-Trinitrobenzene sulfonic acid; and dextran sulfate sodium salt. Macroscopic and microscopic evaluations of abdominal structures as well as molecular analysis were made on days 7, 14, 28 and 56. There was a significant improvement in the health condition of the estrogen-treated rats: the inflammation scores were reduced by at least 10-15%, the number of mast cells in the colon decreased by 30%, fibronectin expression was only 50% and reactive oxygen species decreased by 30%. In addition, there was a significant decrease in TNF-alpha, IL-6 and IL-1beta expression by about 25%. In conclusion, there was an improvement in the inflammatory status in all estrogen-treated groups through the duration of the experiment at all-time points. In addition, there was less tissue necrosis as depicted by less fibronectin and a marked antioxidant effect.

Enteropathogenic e.coli sustains iodoacetamide-induced ulcerative colitis-like colitis in rats: modulation of IL-1ß, IL-6, TNF-α, COX-2, and apoptosisi.

Pathogenic or non-pathogenic bacteria from flora may play a key role in inflammatory bowel disease (IBD) pathogenesis. However, a specific infectious agent causing IBD has not been identified. This study assessed the impact of enteropathogenic E. coli (EPEC) on the modulation of IL-1beta, IL-6, TNF- alpha, COX-2, BAX and Bcl-2 expression, in sustaining inflammation of a rat colitis model. Two hundred male Sprague-Dawley rats (4 groups) were inoculated weekly or bi-weekly for 70 days, with 1 percent methylcellulose (MC), (b) 6 percent iodoacetamide (IA) in 1 percent MC, (c) 4x108 CFU of EPEC, and (d) IA+EPEC. After a month, treatment was stopped in half of the animals in each group. IL-1beta, IL-6, TNF-alpha, COX-2, BAX and Bcl-2 expression were measured in colonic mucosa scrapings. IL-1beta, IL-6, TNF-alpha, and COX-2 were significantly increased in colonic mucosa of the IA+EPEC group and to a lesser but significant level in the IA group compared to controls, or EPEC alone, both in continued and discontinued treatment groups. Additionally, the BAX/Bcl-2 ratio decreased, indicating less apoptosis in the IA+EPEC group which exhibited more necrosis. These effects increased with experiment duration. This work provides new arguments favouring the role of bacteria in IBD pathogenesis.

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.

Pancreatic cancer: incidence, treatment and survival trends--1175 cases in Calvados (France) from 1978 to 2002.

AIM: To assess the trends in incidence, therapeutic modalities and survival of pancreatic cancer between 1978 and 2002 in a well-defined population, as recorded in the Calvados digestive cancer registry database. PATIENTS AND METHODS: All patients living in Calvados with a diagnosis of pancreatic cancer were registered. Clinical data and treatment modalities were prospectively recorded. This 25-year database was divided into five 5-year periods. Data were compared using log-rank tests and the Cox model. RESULTS: A total of 1175 cases of pancreatic cancer (617 men, 558 women) were registered. Its incidence increased with an average annual coefficient of +2.8% in men and +5.1% in women. Therapeutic modalities changed over the five time periods: surgical resection increased from 6.8 to 13.4% (median survival 15 months) while radiation therapy and/or chemotherapy also increased from 5.5 to 13.2%. Palliative surgery decreased from 54.6 to 32.0% and favored interventional endoscopic techniques. Postoperative mortality decreased significantly. Survival increased significantly over the five time periods, although the median survival time remained stable (4 months). CONCLUSION: From 1978 to 2002, pancreatic cancer incidence increased in Calvados (France). Therapeutic modalities changed, with endoscopic treatments preferred over palliative surgery. The improvement in survival could be explained by the decrease in postoperative mortality.

Colon cancer in inflammatory bowel disease: recent trends, questions and answers.

Patients with chronic colitis (ulcerative colitis or colonic Crohn's disease) have an increased risk of colorectal cancer (CRC). Although most of the molecular alterations reported in sporadic CRC have also been observed in colitis-associated CRC, they do not occur at the same timing and frequency, indicating a different pathophysiology. In particular, recent work highlighted the importance of chronic mucosal inflammation as a key factor favouring colorectal carcinogenesis in these patients. This may also be one of the reasons explaining the role of 5-aminosalicylates as chemopreventive agents for CRC in inflammatory bowel disease (IBD) patients with colonic involvement. Beside chemoprevention, colonoscopic screening and surveillance have been shown to be the cornerstone for CRC prevention and early detection in this particular patients' population. Periodic surveillance colonoscopy to detect dysplasia has been shown to decrease the mortality attributed to CRC. More recently, progress in imaging techniques increased our ability to identify dysplasia, and should probably now be considered to be an integral part of surveillance colonoscopy. In the future, further improvement of our knowledge of CRC biology, refinement of imaging techniques, as well as molecular discovery (e.g. identification of specific mutations in stool DNA extracts), might lead to develop more accurate diagnostic strategies to reduce the morbidity and mortality related to CRC in patients with ulcerative colitis or colonic Crohn's disease.

Urinary neopterin is a valuable tool in monitoring Crohn's disease activity.

BACKGROUND: The aim was to investigate the relation between urinary neopterin and the Crohn's Disease Activity Index (CDAI) and to compare its ability to discriminate active versus inactive CD with serum C-reactive protein (CRP). METHODS: In all, 217 urinary samples for neopterin measurement were obtained in a cohort of 93 consecutive patients with CD and 66 samples in 33 healthy volunteers. Clinical parameters were recorded and blood samples for CRP were collected as well. RESULTS: Whereas patients with inactive CD showed similar levels of urinary neopterin excretion than healthy volunteers (163 +/- 8 versus 142 +/- 7 nmol/mol of creatinine, respectively; P = 0.1), urinary neopterin excretion from mild to severe active CD was significantly higher (302 +/- 15 nmol/mol of creatinine; P < 0.001). Serum CRP levels were higher in active CD (14.8 +/- 2.1 mg/L) compared with inactive CD (5.6 +/- 0.8 mg/L; P < 0.001). Urinary neopterin excretion, and to a lesser degree CRP, were positively and significantly correlated with CDAI (r = 0.64 and 0.43, respectively, P < 0.001). Based on the cutoff of 183 nmol/mol of creatinine for urinary neopterin, the sensitivity and specificity of urinary neopterin to discriminate between active and inactive CD were 73% and 82%, respectively, and the positive and negative predictive values were 80% and 78%, respectively. CONCLUSIONS: Urinary neopterin excretion is an objective, valuable, simple, and noninvasive biomarker to detect and follow fluctuations of CD activity. Further work is warranted to study its clinical value and relation to mucosal healing.

Immune activation and nutritional status in adult Crohn's disease patients.

BACKGROUND: Recent attention focused on the effect of inflammatory cytokines on intermediary metabolism contributing to the nutritional disturbances observed in acute or chronic inflammatory diseases. AIMS: To examine the interactions between immune activation and nutritional parameters in adult Crohn's disease patients. PATIENTS AND METHODS: We analysed anthropometric and biochemical nutritional parameters in 40 Crohn's disease patients and 26 healthy controls, and related them to inflammatory and immune markers. RESULTS: Weight, body mass index, mid-arm circumference, triceps skinfold thickness, as well as albumin, transthyretin, retinol binding protein, insulin growth factor-I and Vitamin A were significantly decreased in Crohn's disease patients and negatively correlated to disease activity. By contrast, erythrocyte sedimentation rate, fibrinogen, C-reactive protein, alpha1-acylglycoprotein, soluble receptor of interleukin-2, blood neopterin, tumour necrosis factor-alpha and interleukin-1beta concentrations were significantly higher in patients and positively correlated to disease activity. Nutritional parameters and acute phase reactants were linked to tumour necrosis factor-alpha and interleukin-1beta concentrations, and markers of nutritional status were negatively correlated to positive acute phase reactants. CONCLUSIONS: In Crohn's disease, inflammatory cytokines appear partly responsible for decreased nutritional status. Thus, nutritional intervention to correct nutritional (in particular protein) depletion, and/or therapeutic intervention reducing inflammation and therefore restoring adequate nutritional proteins synthesis, appears a major therapeutic goal in active Crohn's disease.

Thymidine phosphorylase gene mutations in patients with mitochondrial neurogastrointestinal encephalomyopathy syndrome.

The mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) syndrome is characterized by the association of gastrointestinal and neurological symptoms. It is a rare autosomal recessive mitochondrial disorder with multiple mitochondrial DNA deletions and/or depletion. It is caused by thymidine phosphorylase (TP) gene mutations resulting in a complete abolition of TP activity. We tested 31 unrelated patients presenting either with a complete MNGIE syndrome (8 patients), a severe intestinal pseudo-obstruction (10 patients), and multiple deletions and/or depletion of mitochondrial DNA (13 patients). All the tested patients presenting with a complete MNGIE had increased thymidine levels in plasma and urine, and no TP activity. The group with pseudo-obstruction syndrome had normal or partial reduction of TP activity. We found pathogenic mutations on TP gene only in the MNGIE syndrome group: all the MNGIE patients were compound heterozygous or homozygous for mutations in the TP gene. Eight of these mutations are yet unreported, confirming the lack of genotype/phenotype correlation in this syndrome. Enzymatic activity and thymidine level are thus rapid diagnosis tests to detect MNGIE affected patients prior to genetic testing for patients with gastrointestinal symptoms.

Efficacy and safety of an olive oil-based intravenous fat emulsion in adult patients on home parenteral nutrition.

BACKGROUND: The most frequently used intravenous lipid emulsions are composed of 100% long chain triacylglycerols from soybean oil or of 50% long chain triacylglycerols-50% medium chain triacylglycerols. A newer emulsion, ClinOleic 20% containing 80% olive oil and 20% soybean oil, was suggested to reduce lipid peroxidation and immune function impairment. AIM: To assess ClinOleic 20%'s efficacy, safety and effect upon systemic inflammatory parameters in adults on home parenteral nutrition. METHODS: In stable home parenteral nutrition patients, the initial intravenous lipid emulsion was changed for ClinOleic 20%. Nutritional status, clinical and biological tolerance, and systemic inflammatory markers were analysed before and after 1 and 3 months of home parenteral nutrition, with ClinOleic 20% as intravenous lipid emulsion. RESULTS: Clinical and biological nutritional markers and inflammatory parameters did not differ between day 0 and month +3. There was no essential fatty acids deficiency. No side-effects were reported. Three of five patients presenting with migraine during home parenteral nutrition infusion at day 0 felt consistently better at month +3. CONCLUSIONS: ClinOleic 20% is safe and efficient in adult home parenteral nutrition. It maintains normal essential fatty acids status and did not influence inflammatory parameters. In contrast to studies in preterm infants or paediatric patients, no effect on vitamin E concentration or lipid peroxidation was observed.

[How to test at once six cytokines in samples as small as 25 microl?]. / Comment doser simultanément par cytométrie en flux six cytokines sécrétées dans seulement 25 microL d'échantillon ?

Inflammatory and regulatory or anti-inflammatory cytokines (TNFalpha, IL-1beta, -6, -8, -10 and -12) regulate both the humoral and cellular immune responses. Cytokines have diverse peripheral and central functions. They are critical mediators of protective host responses, including defense against microbial invasion and tumorigenesis. However, the production of specific proinflammatory cytokines must be tightly regulated and compartmentalized to prevent the overexpression of these molecules that can end in chronic inflammation and tissue injury. Many diseases like autoimmune disease (rheumatoid arthritis, multiple sclerosis, arteriosclerosis, Crohn's disease), neurodegenerative disease (Alzheimer's and Parkinson's disease), tumor invasion and metastasis correlate with a deregulation in cytokine action. Thus, cytokines network provides an attractive and intensely competitive area of potential targets for therapeutic intervention. To monitor such secretion patterns in presence of putative drugs obtained by high throughput screening (HTS) some new techniques recently appeared on the market. We here compared results obtained by CBA (BD Cytometric Bead Array) to IC50 values obtained by classical sandwich Elisa. The complexity and cost of this new method is largely compensated by simultaneous testing of 6 cytokines in only 25 micro L of cell supernatant.

Catheter-related infection in patients on home parenteral nutrition: results of a prospective survey.

BACKGROUND & AIMS: Central venous catheter (CVC) infection is the most frequent complication during home parenteral nutrition (HPN). We prospectively assessed incidence and catheter-related sepsis (CRS)-associated factors in the 42 adult patients enrolled in our HPN centre since its opening. METHODS: Age, frequency of infusions, CVC type, autonomy or nurse/family aid, underlying disease, involved infectious organism(s), hospital stay, efficacy of antibiotic-lock and other infectious complications, were studied. RESULTS: CRS occurred 39 times (3/1000 days of HPN). In 37/39 cases, it was proven by both peripheral and central blood cultures. In 56% of patients, clinical signs were discrete, delaying diagnosis. Individual factors like learning potency, underlying disease (especially chronic intestinal obstruction with bacterial overgrowth), and length of remaining colon and small intestine, were slightly associated with higher CRS incidence. Usually, one organism (S. epidermidis; 51%) was detected. A total of 14 CVC were immediately removed. In the others, antibiotic-lock was more effective in patients having tunnelled catheters (TC, 50%) than implanted devices (25%; P<0.05). Mean hospital stay was 22+/-15 days, which was influenced by 3 patients presenting associated osteomyelitis. CONCLUSIONS: CRS incidence was 3/1000 days of HPN. Clinical symptoms were often discrete, suggesting importance of rigorous survey. Individual apprenticeship and risk for higher bacterial translocation seem associated to higher CRS incidence. CVC sterilization was more frequent in patients with TC.

The phosphodiesterase inhibitor, pentoxifylline, alters rat intestinal epithelial cell proliferation via changes in the expression of transforming growth factors.

BACKGROUND: Phosphodiesterase (PDE) inhibitors, among which pentoxifylline (PTX), are candidate molecules for the treatment of TNF-alpha-dependent inflammatory diseases. Based on the controversial effects of PTX observed in experimentally-induced colitis, the aim of this work was to analyse its influence on intestinal epithelial cell proliferation and growth factor expression using the well-established IEC18 cell line. METHODS: The effects of PTX, and of an activation (addition of dibutyryl-cAMP, db-cAMP) or inhibition (by a specific cAMP-protein kinase inhibitor, PKI) of the cAMP pathway, were examined after 3 days of culture. The IEC18 cell proliferation and [3H] thymidine incorporation, as well as the expression of TGF-alpha, TGF-beta1 and -beta2 mRNAs, were analysed in basal culture conditions and in the presence of the pro-inflammatory cytokine, TNF-alpha. RESULTS: PTX, like exogenous db-cAMP, inhibited in a dose-dependent manner the basal and TNF-alpha-modulated IEC18 cell proliferation; this effect was partly prevented by PKI. We confirmed that PTX induced a dose-related increase in intracellular cAMP. Concomitantly, the expression of TGF-alpha mRNA dropped and that of TGF-beta2 increased. Addition of db-cAMP instead of PTX also decreased TGF-alpha mRNA, but did not change TGF-beta2 transcripts. The decrease in the expression of TGF-alpha mRNA caused by PTX and db-cAMP was completely abolished by PKI; in contrast, TGF-beta2 remained unaltered. Yet, anti-TGF-beta2 antibodies partially restored the PTX-inhibited cell proliferation. CONCLUSION: The phosphodiesterase inhibitor, PTX, inhibits IEC18 cell proliferation via a differential modulation of TGF-alpha and TGF-beta2 expression. The drop in TGF-alpha mRNA is related to increasing intracellular cAMP, whereas the effect upon TGF-beta2 appears cAMP-independent.

Anti-TNF-alpha properties of new 9-benzyladenine derivatives with selective phosphodiesterase-4- inhibiting properties.

In inflammatory cells, intracellular cAMP concentration is regulated by cyclic nucleotide phosphodiesterases 4. Therefore, PDE4 inhibition appears as a rational goal for treating acute or chronic inflammatory diseases. Selective PDE4 inhibitors have been developed, but due to unwanted side effects, search for new selective PDE4-inhibitors had to be pursued. Recently, Boichot et al. (J. Pharmacol. Exp. Ther. (2000) 292, 647-653) showed that 9-benzyladenine derivatives are selective PDE4 inhibitors. In vivo data in animals suggested that they may induce fewer side effects (emesis). We examined the effects of new 9-benzyladenines on TNF-alpha, interleukin (IL)-1beta, IL-6 and IL-8 production by lipopolysaccharide-activated peripheral blood mononuclear cells, and compared them to other PDEs inhibitors. Selected potent 9-benzyladenines, strongly inhibited TNF-alpha production. Interleukin-1beta, IL-6, and IL-8 production was not significantly affected. Our results suggest that some of these new adenines (i.e., NCS 675 and NCS 700), may be potential therapeutic candidates for the treatment of inflammatory diseases.

Persistent inflammation and immune activation contribute to cholestasis in patients receiving home parenteral nutrition.

Liver disease is frequent in patients taking home parenteral nutrition (HPN), but its cause remains unclear. Ongoing inflammation was implicated in HPN-associated cholestasis, so we examined the relation between liver-enzyme concentrations and circulating inflammatory and immune markers in these patients. In 17 HPN patients and 10 age- and sex-matched control subjects, we examined erythrocyte sedimentation rate, blood neopterin, soluble interleukin (IL)--2 receptors, circulating tumor necrosis factor-alpha, IL-6, aspartate and alanine aminotransferases, alkaline phosphatases, and gamma-glutamyltranspeptidase (GGT) concentrations. Fourteen of 17 patients had abnormal liver function tests with an increase in alkaline phosphatases (P < 0.001), gamma-glutamyltranspeptidase (P < 0.01), and aspartate aminotransferase (P < 0.01). Alkaline phosphatases were positively correlated to erythrocyte sedimentation rate, neopterin, tumor necrosis factor-alpha, and IL-6. gamma-Glutamyltranspeptidase was positively linked to tumor necrosis factor-alpha and soluble IL-2 receptors. There was no link between aminotransferases and inflammatory parameters. Liver-enzyme concentrations were correlated to the amount of total intravenous calories and calories originating from carbohydrates but not to infused lipids (median infused lipids x kg(-1) body weight x d(-1) = 0.62 g) in contrast to recently published data. Our results confirmed that the number of infused calories contributes to liver toxicity in HPN patients and strongly suggested that sustained inflammation is probably a key factor in worsening HPN-associated cholestasis.

Factors associated to hypermanganesemia in patients receiving home parenteral nutrition.

BACKGROUND: Home parenteral nutrition (HPN) patients often present hypermanganesamia. AIM: To examine which factors may be associated to hypermanganesemia in HPN patients. METHODS: Plasma manganese (Mn), liver function tests, C-reactive protein concentrations, erythrocyte sedimentation rate (ESR), tumor necrosis factor-alpha (TNF- alpha), interleukin-6, soluble receptors of interleukin-2, and blood neopterin concentrations were determined in 21 HPN patients and 10 healthy controls. Brain magnetic resonance imaging (MRI) and careful neurologic clinical examination were performed in 11 patients. RESULTS: Mn concentration was higher in HPN patients than controls (1.96+/-1.1 vs 0.81+/- 0.4 microg/L;P<0.001) and positively correlated to the amount of parenteral nutrition (PN) supply, transaminases and alkaline phosphatase (r=0.53, P<0.0001) concentrations, as well as to ESR (r=0.61, P<0.0001), TNF- alpha and blood neopterin. The amount of calories provided by PN was positively correlated to inflammatory markers and liver parameters. All patients investigated by MRI showed hyperintense basal ganglia on T1-weighted images suggesting brain Mn deposition. Only one had slight clinical extrapyramidal symptoms. CONCLUSION: In HPN patients, sustained inflammation may facilitate hypermanganesemia through 1. cholestatic liver disease and thereby decreased Mn biliary excretion, 2. high nutritional requirements (responsible for increased Mn supply), and/or 3. modified Mn metabolism or body distribution. Neurologic complications appeared marginal whereas Mn brain deposition seems frequent.

Cytokine gene expression during postnatal small intestinal development: regulation by glucocorticoids.

BACKGROUND: In the intestinal mucosa, numerous cytokines produced by the epithelium, fibroblasts, and immune cells were shown to affect epithelial differentiation and proliferation through epithelial-mesenchymal and epithelial-immune cell interactions. To date, the importance of cytokines in postnatal development of the rat small intestine has not been established. AIM: To investigate the developmental changes in expression of mucosal cytokines in the postnatal maturation of the rat small intestinal epithelium and their regulation by glucocorticoids (GC). METHODS: Mucosal maturation was assessed by the onset of sucrase-isomaltase (SI) mRNA, analysed by in situ hybridisation. The amount of transforming growth factor beta1 (TGF-beta1), beta2 (TGF-beta2), tumour necrosis factor alpha (TNF-alpha), interleukin 1beta (IL-1beta), and TGF-alpha was analysed by reverse transcription-polymerase chain reaction (RT-PCR) in mucosal extracts from weaning (14-21 days old) and adult rats, or one day after an injection of hydrocortisone (HC) in 11 day old rats. Similarly, expression of cytokines and the regulatory effect of GC were studied on cultured subepithelial myofibroblasts cloned from postnatal jejunum and ileum cultured in the absence or presence of dexamethasone (DX). RESULTS: TGF-beta1, TGF-beta2, and IL-1beta decreased during the third week of life while levels of TNF-alpha increased and TGF-alpha remained constant. In parallel, SI transcripts increased and showed a progressive accumulation in the apical part of the enterocytes first localised at the base of the villi from 18 days onwards. Interestingly, precocious induction of SI mRNA by HC paralleled the decrease in expression of TGF-beta isoforms and of IL-1beta. All cytokines were expressed in the myofibroblast cell lines. In addition, the results showed that TNF-alpha was differentially expressed in basal culture conditions and after DX stimulation in jejunal and ileal myofibroblasts. DX decreased IL-1beta but not the TGF-beta isoforms, similar to that in vivo. CONCLUSIONS: This study shows that mucosal cytokines are developmentally regulated and that GC are potentially involved in this regulation in parallel with maturation of the gut mucosa at weaning.

Vitamins and trace elements in home parenteral nutrition patients.

AIMS: to study the micronutrient status in home parenteral nutrition (HPN) patients and its relationship to inflammatory markers, and clinical outcome. METHODS: Vitamins (A, 25OH D3, E, B12), serum folic acid, as well as trace elements (selenium, zinc, copper, iron and manganese) were measured in 22 adult HPN patients and 14 controls. They were compared to serum malondialdehyde (MDA) concentration (as a marker of lipid peroxidation), erythrocyte superoxide dismutase (SOD) and gluthatione peroxidase (GSHPx), inflammatory markers, and clinical outcome. RESULTS: In HPN patients MDA concentration was increased whereas vitamin E concentrations were decreased, and significantly negatively correlated to MDA. Erythrocyte GSHPx and plasma selenium were decreased in the patients and positively correlated to each other. By contrast, manganese concentration was significantly increased in HPN patients and correlated to inflammatory markers. CONCLUSIONS: Adult HPN patients showed increased lipid peroxidation. This seems principally the result of low vitamin E status. In addition, these patients presented often a decrease in plasma selenium responsible for low GSHPx activity. These combined antioxidant system deficiencies contribute probably to peroxidative damage in HPN patients. Increased manganese concentrations, in view of their potential neurotoxicity have to be closely surveyed. In HPN patients micronutrient status needs regular monitoring in regard to the possibility of vitamin and/or trace element abnormalities.

Antioxidant and immune status in active Crohn's disease. A possible relationship.

BACKGROUND AND AIMS: As reactive oxygen has been demonstrated to participate in immune genes transcription, the aim of this study was to examine the relationship between systemic concentrations of several antioxidants and markers of inflammatory and immune activation in patients with Crohn's disease (CD). METHODS: In 26 CD patients and 15 controls we compared plasma selenium and zinc concentrations, erythrocyte glutathione peroxidase (GSHPx) and superoxide dismutase activities, as well as erythrocyte sedimentation rate (ESR), C-reactive protein, tumor necrosis factor-alpha, interleukin-6, blood neopterin and soluble receptors of interleukin-2 (sIL-2R), and examined the link between these parameters. RESULTS: Selenium concentration and GSHPx activity were decreased in CD patients (54.5 +/- 3.2 vs 79 ± 2.2 microg/l, P<< 0.05; 28 +/- 1.6 vs 38 +/- 2.6 IU/g Hb, P<< 0.05) and positively correlated to each other's (r= 0.59, P<< 0.01). TNF-alpha was significantly increased in patients (18 +/- 2.6 vs 5 +/- 0.6 pg/ml;P<< 0.001), negatively correlated to GSHPx activity (r= -0.56, P<< 0.05) and selenium concentration (r= -0.72, P<< 0.001), and positively to neopterin and sIL-2R concentrations. Selenium showed negative correlation with sIL-2R (r= -0.83, P<< 0.0001) and ESR. CONCLUSIONS: In CD patients low selenium concentration may participate in reduced GSHPx activity facilitating inflammatory and immune activation. In these patients, selenium monitoring and, if needed, supplementation may be of therapeutical interest.

[Diagnostic value of high resolution sonography in Crohn's disease and ulcerative colitis]. / Valeur diagnostique de l'échographie de haute fréquence au cours de la maladie de Crohn et de la rectocolite hémorragique.

OBJECTIVE: To evaluate the diagnostic accuracy of high resolution sonography in patients with inflammatory bowel disease (MICI). PATIENTS AND METHODS: In patients with Crohn's disease (n = 48), ulcerative colitis (n = 23), indeterminate colitis (n = 3), inflammatory (n = 21) and non-inflammatory (n = 23) controls, high resolution sonography was performed and compared to colonoscopy (+/- retrograde ileoscopy) and/or baryum studies of the small bowel and the colon. RESULTS: Diagnosis of intestinal inflammation or not was correct in 69/74 MICI patients (sensitivity: 94.4%, specificity: 66.7%, global accuracy: 93.2%). Segment location was accurate in 58/74 (sensitivity: 80.3%, specificity: 66.7%, global accuracy: 79.7), more frequently in Crohn's disease, than in ulcerative colitis. Five out of six complications of Crohn's disease were diagnosed. In Crohn's disease, the method was more accurate in case of colonic or ileocolonic involvement. CONCLUSION: High resolution sonography is a reliable diagnostic tool for the detection of intestinal inflammation and related complications in MICI. In can be of value in the follow-up and seems particularly interesting in the case of temporary contraindication of invasive methods.