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.

The prevalence of malnutrition and its predictive value for the incidence of complications were determined in 155 patients hospitalized for internal or gastrointestinal diseases. At admission, 45% of the patients were malnourished according to the Subjective Global Assessment (physical examination plus questionnaire), 57% according to the Nutritional Risk Index [(1.5 X albumin) + (41.7 X present/usual weight)], and 62% according to the Maastricht Index [(20.68 -(0.24 X albumin) -(19.21 X transthyretin (prealbumin) -(1.86 X lymphocytes) -(0.04 X ideal weight)]. Crude odds ratios for the incidence of any complication in malnourished compared with well-nourished pa tients during hospitalization were 2.7 (95% Cl: 1

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.See Mini-review in this issue http://dx

Huybers S, Naber TH, Bindels RJ, Hoenderop JG. Prednisolone-induced Ca 2ϩ malabsorption is caused by diminished expression of the epithelial Ca 2ϩ channel TRPV6. Am J Physiol Gastrointest Liver Physiol 292: G92-G97, 2007. First published August 10, 2006; doi:10.1152/ajpgi.00317.2006.-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 Ca 2ϩ in the intestine is supposed to play an important role in the etiology of low BMD. To elucidate the mechanism of glucocorticoid-induced Ca 2ϩ malabsorption, the present study investigated the effect of prednisolone on the expression and activity of proteins responsible for active intestinal Ca 2ϩ absorption including the epithelial Ca 2ϩ channel TRPV6, calbindin-D9K, 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 45 Ca 2ϩ absorption assay indicated that intestinal Ca 2ϩ absorption was diminished after prednisolone treatment. We showed decreased duodenal TRPV6 and calbindin-D9K 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 Ca 2ϩ transport proteins are predominantly localized in the first 2 cm of the duodenum. Furthermore, serum Ca 2ϩ and 1,25-dihydroxyvitamin D 3 [1,25(OH)2D3] concentrations remained unchanged by prednisolone treatment. In conclusion, these data suggest that prednisolone reduces the intestinal Ca 2ϩ absorption capacity through diminished duodenal expression of the active Ca 2ϩ transporters TRPV6 and calbindin-D 9K independent of systemic 1,25(OH)2D3.1,25-dihydroxyvitamin D3; duodenum; epithelial calcium channel 2; calcium transporter 1 REDUCED BONE MINERAL DENSITY (BMD) is particularly present in the elderly and women, which implies that age and gender are important risk factors for developing low BMD. However, in clinical practice low BMD is frequently observed in several patient groups, including inflammatory bowel disease (IBD) patients. Estimates of osteopenia in IBD range from 31 to 59% and osteoporosis from 5 to 41%. Various studies exploring the cause of low BMD in IBD found a significant correlation between glucocorticoid treatment and decreased BMD (3,5,17,28,29). Glucocorticoids, such as prednisolone, are wellknown drugs for their potent anti-inflammatory and immunosuppressive properties. As a consequence, glucocorticoids are widely used in clinic as drugs to treat inflammatory conditions such as IBD. To date, glucocorticoids are generally accepted to reduce BMD, despite the fact that in a number of studies an effect on bone mass could not be observed (5, 11) or could be observed only in male glucocorticoid users (31).This effect of glucocorticoids on BMD is caused by the c...

Vitamin A equivalency of b-carotene (VEB) is defined as the amount of ingested b-carotene in mg that is absorbed and converted into 1 mg 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 b-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.Key words: Vitamin A equivalency: b-Carotene: Bioconversion: Human studies Vitamin A equivalency of b-carotene (VEB) is defined as the amount of ingested b-carotene in mg that is absorbed and converted into 1 mg retinol (vitamin A) in the human body. A certain amount of the ingested b-carotene is excreted in the faeces and the remaining part is absorbed, but not all of the absorbed b-carotene will be converted into retinol and enter the lymph, blood and finally the liver and other tissues.Vitamin A can be obtained from animal-derived foods as preformed vitamin A, or from vegetables and fruits as provitamin A carotenoids, mainly b-carotene, a-carotene and b-cryptoxanthin. In the Western diet, about 20 to 34 % of the habitual intake of vitamin A originates from provitamin A carotenoids (1 -3) . In contrast, the majority of individuals in developing countries require . 70 % of provitamin A carotenoids in the diet (4) . The effect of food matrices of vegetables and fruits in which b-carotene is incorporated has been found to exert a major influence on measured VEB.The objective of the present review was to discuss the different estimates for VEB in various types of dietary food matrices.The question is which VEB should be used for humans in general good health.For this purpose, first, the currently used VEB are described. Second, a brief overview of the main influencing factors on the assessment of VEB is given. Third, the habitual daily intake of dietary vitamin A and b-carotene in humans is described. Fourth, different methods for estimating VEB are discussed to evaluate the reliability of the different studies. The studies are grouped by the different types of dietary food matrices in which b-carotene is incorporated, which are the oil matrix, the complex mixed diet matrix with various vegetables and fruits and the single vegetable or fruit matrix. Currently used vitamin A equivalency of b-caroteneCurrently, two estimates of VEB for the oil matrix and two estimates ...