Clinical Course of Nodular Regenerative Hyperplasia in Thiopurine Treated Inflammatory Bowel Disease Patients.

Nodular regenerative hyperplasia (NRH) is a poorly understood liver condition, which is increasingly recognized in thiopurine-treated patients with inflammatory bowel disease (IBD).1 It is difficult to establish an optimal approach to NRH patients, because its manifestations are highly variable (from asymptomatic to symptoms of noncirrhotic portal hypertension [NCPH]) and the prognosis is unknown.2 The aim of this study was to identify NRH cases in IBD patients treated with azathioprine, mercaptopurine, and/or thioguanine, and to describe its clinical course.

Prediction of fruit and vegetable intake from biomarkers using individual participant data of diet-controlled intervention studies.

Fruit and vegetable consumption produces changes in several biomarkers in blood. The present study aimed to examine the dose-response curve between fruit and vegetable consumption and carotenoid (α-carotene, ß-carotene, ß-cryptoxanthin, lycopene, lutein and zeaxanthin), folate and vitamin C concentrations. Furthermore, a prediction model of fruit and vegetable intake based on these biomarkers and subject characteristics (i.e. age, sex, BMI and smoking status) was established. Data from twelve diet-controlled intervention studies were obtained to develop a prediction model for fruit and vegetable intake (including and excluding fruit and vegetable juices). The study population in the present individual participant data meta-analysis consisted of 526 men and women. Carotenoid, folate and vitamin C concentrations showed a positive relationship with fruit and vegetable intake. Measures of performance for the prediction model were calculated using cross-validation. For the prediction model of fruit, vegetable and juice intake, the root mean squared error (RMSE) was 258.0 g, the correlation between observed and predicted intake was 0.78 and the mean difference between observed and predicted intake was - 1.7 g (limits of agreement: - 466.3, 462.8 g). For the prediction of fruit and vegetable intake (excluding juices), the RMSE was 201.1 g, the correlation was 0.65 and the mean bias was 2.4 g (limits of agreement: -368.2, 373.0 g). The prediction models which include the biomarkers and subject characteristics may be used to estimate average intake at the group level and to investigate the ranking of individuals with regard to their intake of fruit and vegetables when validating questionnaires that measure intake.

A review of vitamin A equivalency of ß-carotene in various food matrices for human consumption.

Vitamin A equivalency of ß-carotene (VEB) is defined as the amount of ingested ß-carotene in µg that is absorbed and converted into 1 µg retinol (vitamin A) in the human body. The objective of the present review was to discuss the different estimates for VEB in various types of dietary food matrices. Different methods are discussed such as mass balance, dose-response and isotopic labelling. The VEB is currently estimated by the US Institute of Medicine (IOM) as 12:1 in a mixed diet and 2:1 in oil. For humans consuming ß-carotene dissolved in oil, a VEB between 2:1 and 4:1 is feasible. A VEB of approximately 4:1 is applicable for biofortified cassava, yellow maize and Golden Rice, which are specially bred for human consumption in developing countries. We propose a range of 9:1-16:1 for VEB in a mixed diet that encompasses the IOM VEB of 12:1 and is realistic for a Western diet under Western conditions. For a 'prudent' (i.e. non-Western) diet including a variety of commonly consumed vegetables, a VEB could range from 9:1 to 28:1 in a mixed diet.

Food matrix effects on bioaccessibility of ß-carotene can be measured in an in vitro gastrointestinal model.

Since the food matrix determines ß-carotene availability for intestinal absorption, food matrix effects on the bioaccessibility of ß-carotene from two diets were investigated in vitro and compared with in vivo data. The "mixed diet" consisted of ß-carotene-rich vegetables, and the "oil diet" contained ß-carotene-low vegetables with supplemental ß-carotene. The application of extrinsically labeled ß-carotene was also investigated. The bioaccessibility of ß-carotene was 28 µg/100 µg ß-carotene from the mixed diet and 53 µg/100 µg ß-carotene from the oil diet. This ratio of 1.9:1 was consistent with in vivo data, where the apparent absorption was 1.9-fold higher in the oil diet than in the mixed diet. The labeled ß-carotene was not equally distributed over time. In conclusion, the food matrix effects on bioaccessibility of ß-carotene could be measured using an in vitro model and were consistent with in vivo data. The application of extrinsically labeled ß-carotene was not confirmed.

The role of antibiotic prophylaxis in endoscopic retrograde cholangiopancreatography; a retrospective single-center evaluation.

OBJECTIVE: Endoscopic retrograde cholangiopancreaticography (ERCP) can be complicated by post-ERCP cholangitis even when performed by experienced endoscopists. Therefore, antibiotic prophylaxis is recommended for certain patients, but controversy exists as to which patient groups really benefit from this strategy. We retrospectively evaluated the use of antibiotics in a primary teaching hospital in the Netherlands with regard to the incidence of post-ERCP cholangitis and cholecystitis. MATERIAL AND METHODS: Retrospective single-center evaluation in a primary teaching hospital. All consecutive ERCPs between 2000 and 2006 were studied. Primary end point was the incidence of post-ERCP cholangitis and cholecystitis, divided into four categories: definite, likely, possible and unlikely. Additionally, occurrence of complications such as pneumonia, post-ERCP pancreatitis, perforation of the duodenum, substantial bleeding and the need for re-ERCP within 5 days was scored. RESULTS: Five hundred forty ERCPs in 327 patients were screened. Of these, 292 ERCPs performed in 193 patients were included. Eight ERCPs (2.7%) of all ERCPs were followed by definite cholangitis and two ERCPs (0.7%) by likely cholangitis. The occurrence rate of ERCP-related complications remained low. CONCLUSIONS: This study shows that with our current policy of restricted use of antibiotic prophylaxis the overall incidence of biliary tract infections is low.

Vitamin A equivalency and apparent absorption of beta-carotene in ileostomy subjects using a dual-isotope dilution technique.

The objective was to quantify the vitamin A equivalency of beta-carotene in two diets using a dual-isotope dilution technique and the apparent beta-carotene absorption as measured by the oral-faecal balance technique. Seventeen healthy adults with an ileostomy completed the 4-week diet-controlled, cross-over intervention study. Each subject followed both diets for 2 weeks: a diet containing vegetables low in beta-carotene content with supplemental beta-carotene in salad dressing oil ('oil diet'; mean beta-carotene intake 3.1 mg/d) and a diet containing vegetables and fruits high in beta-carotene content ('mixed diet'; mean beta-carotene intake 7.6 mg/d). Daily each subject consumed a mean of 190 microg [13C10]beta-carotene and 195 microg [13C10]retinyl palmitate in oil capsules. The vitamin A equivalency of beta-carotene was calculated as the dose-corrected ratio of [13C5]retinol to [13C10]retinol in serum. Apparent absorption of beta-carotene was determined with oral-faecal balance. Isotopic data quantified a vitamin A equivalency of [13C10]beta-carotene in oil of 3.6:1 (95 % CI 2.8, 4.6) regardless of dietary matrices differences. The apparent absorption of (labelled and dietary) beta-carotene from the 'oil diet' (30 %) was 1.9-fold higher than from the 'mixed diet' (16 %). This extrinsic labelling technique can measure precisely the vitamin A equivalency of beta-carotene in oil capsules, but it does not represent the effect of different dietary matrices.

Vitamin A equivalency of beta-carotene in healthy adults: limitation of the extrinsic dual-isotope dilution technique to measure matrix effect.

Data on the vitamin A equivalency of beta-carotene in food are inconsistent. We quantified the vitamin A equivalency (microg) of beta-carotene in two diets using the dual-isotope dilution technique and the oral-faecal balance technique. A diet-controlled, cross-over intervention study was conducted in twenty-four healthy adults. Each subject followed two diets for 3 weeks each: a diet containing vegetables low in beta-carotene with supplemental beta-carotene in salad dressing oil ('oil diet') and a diet containing vegetables and fruits high in beta-carotene ('mixed diet'). During all 6 weeks, each subject daily consumed a mean of 55 (sd 0.5) microg [13C10]beta-carotene and 55 (sd 0.5) microg [13C10]retinyl palmitate in oil capsules. The vitamin A equivalency of beta-carotene was calculated as the dose-corrected ratio of [13C5]retinol to [13C10]retinol in serum and from apparent absorption by oral-faecal balance. Isotopic data quantified a vitamin A equivalency of [13C10]beta-carotene in oil of 3.4 microg (95 % CI 2.8, 3.9), thus the bio-efficacy of the beta-carotene in oil was 28 % in the presence of both diets. However, data from oral-faecal balance estimated vitamin A equivalency as 6:1 microg (95 % CI 4, 7) for beta-carotene in the 'oil diet'. beta-Carotene in the 'oil diet' had 2.9-fold higher vitamin A equivalency than beta-carotene in the 'mixed diet'. In conclusion, this extrinsic labelling technique cannot measure effects of mixed vegetables and fruits matrices, but can measure precisely the vitamin A equivalency of the beta-carotene in oil capsules.

Murine TNF(DeltaARE) Crohn's disease model displays diminished expression of intestinal Ca2+ transporters.

BACKGROUND: Patients suffering from Crohn's disease (CD) show increased incidence of low bone mineral density. Investigating this complication is difficult because the exact etiology of CD remains elusive. Mice carrying a deletion in the tumor necrosis factor (TNF) AU-rich elements (ARE) are reported as a model for human CD and are characterized by elevated TNF-alpha levels and inflammations in the terminal ileum. To evaluate whether these mice have a Ca(2+) handling problem, this study analyzed the Ca(2+) homeostasis in heterozygous TNF(DeltaARE) mice (TNF(DeltaARE/+)) in comparison to wildtype littermates. METHODS: Beside serum Ca(2+) and vitamin D levels, the expression of Ca(2+) transporters was analyzed in intestine, kidney and bone using quantitative real-time PCR, Western blot and immunohistochemistry. Bone scans were performed to measure bone parameters. RESULTS: Ca(2+) transporters in duodenum (TRPV6, calbindin-D(9K), PMCA1b) and kidney (TRPV5, calbindin-D(28K), NCX1) showed significantly reduced mRNA expression levels in TNP(DeltaARE/+) mice, except for renal TRPV5. In bone, only calbindin-D(9K) mRNA displayed a significant down-regulation. These findings were supported by declined duodenal calbindin-D(9K) and renal calbindin-D(28K) protein values. Likely, this down-regulation of Ca(2+) transporters in TNP(DeltaARE/+) mice is mediated by the 58 +/- 9% reduction in serum 1,25(OH)(2)D(3) levels. Diminished expression of Ca(2+) transporters combined with unchanged serum Ca(2+) levels assumes Ca(2+) loss from bone to compensate for the body's overall Ca(2+) shortage. Indeed, microcomputed tomography scanning demonstrated reduced trabecular and corticol bone thickness and volume in TNF(DeltaARE/+) mice. This finding is further supported by increased total deoxypyridinoline in serum. CONCLUSIONS: Our results imply that TNF(DeltaARE/+) mice have a disturbed Ca(2+) homeostasis characterized by reduced duodenal and renal Ca(2+) transporters, diminished 1,25(OH)(2)D(3) levels, and increased bone resorption associated with profound bone abnormalities.

Prednisolone-induced Ca2+ malabsorption is caused by diminished expression of the epithelial Ca2+ channel TRPV6.

Glucocorticoids, such as prednisolone, are often used in clinic because of their anti-inflammatory and immunosuppressive properties. However, glucocorticoids reduce bone mineral density (BMD) as a side effect. Malabsorption of Ca2+ in the intestine is supposed to play an important role in the etiology of low BMD. To elucidate the mechanism of glucocorticoid-induced Ca2+ malabsorption, the present study investigated the effect of prednisolone on the expression and activity of proteins responsible for active intestinal Ca2+ absorption including the epithelial Ca2+ channel TRPV6, calbindin-D(9K), and the plasma membrane ATPase PMCA1b. Therefore, C57BL/6 mice received 10 mg/kg body wt prednisolone daily by oral gavage for 7 days and were compared with control mice receiving vehicle only. An in vivo 45Ca2+ absorption assay indicated that intestinal Ca2+ absorption was diminished after prednisolone treatment. We showed decreased duodenal TRPV6 and calbindin-D(9K) mRNA and protein abundance in prednisolone-treated compared with control mice, whereas PMCA1b mRNA levels were not altered. Importantly, detailed expression studies demonstrated that in mice these Ca2+ transport proteins are predominantly localized in the first 2 cm of the duodenum. Furthermore, serum Ca2+ and 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] concentrations remained unchanged by prednisolone treatment. In conclusion, these data suggest that prednisolone reduces the intestinal Ca2+ absorption capacity through diminished duodenal expression of the active Ca2+ transporters TRPV6 and calbindin-D(9K) independent of systemic 1,25(OH)2D3.

Nucleotide-binding oligomerization domain-2 modulates specific TLR pathways for the induction of cytokine release.

The recognition of peptidoglycan by cells of the innate immune system has been controversial; both TLR2 and nucleotide-binding oligomerization domain-2 (NOD2) have been implicated in this process. In the present study we demonstrate that although NOD2 is required for recognition of peptidoglycan, this leads to strong synergistic effects on TLR2-mediated production of both pro- and anti-inflammatory cytokines. Defective IL-10 production in patients with Crohn's disease bearing loss of function mutations of NOD2 may lead to overwhelming inflammation due to a subsequent Th1 bias. In addition to the potentiation of TLR2 effects, NOD2 is a modulator of signals transmitted through TLR4 and TLR3, but not through TLR5, TLR9, or TLR7. Thus, interaction between NOD2 and specific TLR pathways may represent an important modulatory mechanism of innate immune responses.

NOD2 mediates anti-inflammatory signals induced by TLR2 ligands: implications for Crohn's disease.

Mutations of the NOD2 gene have been associated with an increased susceptibility to Crohn's disease, but the pathogenetic mechanisms mediated by NOD2 remain elusive. In the present study, we demonstrate that the 3020insC frameshift-mutation in the NOD2 gene associated with Crohn's disease results in defective release of IL-10 from blood mononuclear cells after stimulation with the Toll-like receptor (TLR)2 ligands, peptidoglycan and Pam3Cys-KKKK, but not with bacterial LPS, a TLR4 ligand. The potential pathophysiological significance of this finding in patients with Crohn's disease and who are homozygous for this NOD2 mutation was substantiated by the finding of decreased anti-inflammatory cytokine release when cells from these patients were stimulated with different species of Bacteroides, an enteric microorganism implicated in the pathogenesis of Crohn's disease. In conclusion, defective NOD2 function results in a pro-inflammatory cytokine bias after stimulation of mononuclear cells with TLR2 stimuli, and this could contribute to the overwhelming inflammation seen in Crohn's disease.

Side effects of azathioprine in patients with Crohn's disease.

OBJECTIVE: In clinical trials 0-15% of patients discontinued azathioprine due to side effects. The aim of this study was to assess the rate of side effects leading to discontinuation of azathioprine and to determine predictive factors for discontinuation. DESIGN: A retrospective cohort analysis of clinical data regarding adverse events of azathioprine in Crohn's disease. PATIENTS: Azathioprine had been prescribed for 54 of 112 consecutive patients with Crohn's disease. Because incomplete data were available in four patients, the data for 50 patients were analysed. RESULTS: In 15 of the 50 patients azathioprine was preliminary discontinued due to adverse events and in 11 of these patients (22%) adverse events were probably related to azathioprine. After the onset of therapy, a small, but significant, decrease in leucocyte count was observed within 6 weeks (median from 10.6 to 9.5 x 10(9)/l) and asymptomatic leucopenia (< 3.0 x 10(9)/l) occurred in two patients. Serious adverse events occurred in three patients who, as a result, required admission to hospital. All events were reversible after discontinuation of therapy. Patients who discontinued azathioprine due to adverse events used significantly lower initial doses of prednisone compared to patients who were able to continue azathioprine. The occurrence of side effects was not related to the initial dose of azathioprine or concomitant use of 5-aminosalicylates. CONCLUSION: Twenty-two per cent of patients discontinued azathioprine prematurely probably as a result of related adverse events. Patients who discontinued azathioprine prematurely used lower doses of prednisone initially. Therefore, concomitant use of prednisone may prevent some of the adverse events.

Parenteral administration of medium- but not long-chain lipid emulsions may increase the risk for infections by Candida albicans.

Intravenous administration to volunteers of an emulsion of medium-chain lipids, but not of an emulsion of pure long-chain lipids or a placebo, increased the growth of Candida albicans in serum and modulated Candida-induced cytokine production by mononuclear cells in a way suggesting that medium-chain, but not long-chain, triglycerides increase the risk for infections by Candida.