query: Titanium Dioxide & Inflammatory Bowel Disease

positive: Dietary microparticles and their impact on tolerance and immune responsiveness of the gastrointestinal tract Dietary microparticles are non-biological bacterial-sized particles of the gastrointestinal lumen that occur due to endogenous formation (calcium phosphate) or following oral exposure (exogenous microparticle). In the UK, about 40 mg (1012) of exogenous microparticles are ingested per person per day, through exposure to food additives, pharmaceutical/supplement excipients or toothpaste constituents. Once ingested, exogenous microparticles are unlikely to pass through the gastrointestinal tract without adsorbing to their surfaces some ions and molecules of the intestinal lumen. Both entropy and ionic attraction drive such interactions. Calcium ions are especially well adsorbed by dietary microparticles which then provide a positively charged surface for the attraction (adsorption) of other organic molecules such as lipopolysaccharides, peptidoglycans or protein antigen from the diet or commensal flora. The major (but not only) sites of microparticle entry into intestinal tissue are the M-cell rich lymphoid aggregates (termed Peyer’s patches in the small bowel). Indeed, it is well established that this is an efficient transport route for non-biological microparticles although it is unclear why. We hypothesise that this pathway exists for “endogenous microparticles” of calcium phosphate, with immunological and physiological benefit, and that “exogenous dietary microparticles”, such as titanium dioxide and the silicates, hijack this route. This overview focuses on what is known of these microparticles and outlines their potential role in immune tolerance of the gut (endogenous microparticles) or immune activation (exogenous microparticles) and inflammation of the gut.

positive: Lack of efficacy of a reduced microparticle diet in a multi-centred trial of patients with active Crohn's disease. BACKGROUND AND AIMS: Dietary microparticles, which are bacteria-sized and non-biological, found in the modern Western diet, have been implicated in both the aetiology and pathogenesis of Crohn's disease. Following on from the findings of a previous pilot study, we aimed to confirm whether a reduction in the amount of dietary microparticles facilitates induction of remission in patients with active Crohn's disease, in a single-blind, randomized, multi-centre, placebo controlled trial. METHODS: Eighty-three patients with active Crohn's disease were randomly allocated in a 2 x 2 factorial design to a diet low or normal in microparticles and/or calcium for 16 weeks. All patients received a reducing dose of prednisolone for 6 weeks. Outcome measures were Crohn's disease activity index, Van Hees index, quality of life and a series of objective measures of inflammation including erythrocyte sedimentation rate, C-reactive protein, intestinal permeability and faecal calprotectin. After 16 weeks patients returned to their normal diet and were followed up for a further 36 weeks. RESULTS: Dietary manipulation provided no added effect to corticosteroid treatment on any of the outcome measures during the dietary trial (16 weeks) or follow-up (to 1 year); e.g., for logistic regression of Crohn's disease activity index based rates of remission (P=0.1) and clinical response (P=0.8), in normal versus low microparticle groups. CONCLUSIONS: Our adequately powered and carefully controlled dietary trial found no evidence that reducing microparticle intake aids remission in active Crohn's disease.

positive: Biocompatibility of micro- and nano-particles in the colon. Part II. Pathological colonic tissues were investigated with an Environmental Scanning Electron Microscope technique to verify the presence of inorganic, non-biodegradable pollutants, i.e. micro- and nano-debris of exogenous origin, after debris in liver and kidney had been discovered. In all, 18 samples of colon tissues affected by cancer and Crohn's disease were evaluated and found in all the cases to contain micro- and nano-particles. Their chemistry, detected with an X-ray microprobe, indicated a heterogeneous nature, whereas the size of the particles was homogeneous. Three control samples of healthy, young, cadavers were analysed and showed the absence of debris within the normal, healthy colon mucosa. The study reveals the presence of particulate debris, generally considered as biocompatible, in pathological specimens of human colon. The findings suggest a possible link between the presence of such particles and the underlying pathology in the cases analysed.

positive: Dietary sources of inorganic microparticles and their intake in healthy subjects and patients with Crohn's disease. Dietary microparticles are non-biological, bacterial-sized particles. Endogenous sources are derived from intestinal Ca and phosphate secretion. Exogenous sources are mainly titanium dioxide (TiO2) and mixed silicates (Psil); they are resistant to degradation and accumulate in human Peyer's patch macrophages and there is some evidence that they exacerbate inflammation in Crohn's disease (CD). However, whether their intake differs between those with and without CD has not been studied. We aimed to identify dietary microparticle sources and intakes in subjects with and without CD. Patients with inactive CD and matched general practice-based controls (ninety-one per group) completed 7 d food diaries. Intake data for dietary fibre and sucrose were compared as positive controls. All foods, pharmaceuticals and toothpastes were examined for microparticle content, and intakes of Ca and exogenous microparticles were compared between the two groups. Dietary intakes were significantly different between cases and controls for dietary fibre (12 (SD 5) v. 14 (SD 5) g/d; P=0.001) and sucrose (52 (SD 27) v. 45 (SD 18) g/d; P=0.04) but not for Ca. Estimated median TiO2 and Psil intakes (2.5 and 35 mg/individual per d respectively, totalling 10(12)-10(13) microparticles/individual per d) were broadly similar to per capita estimates and while there was wide variation in intakes between individuals there was no significant difference between subjects with CD and controls. Hence, if exposure to microparticles is associated with the inflammation of CD, then the present study rules out excess intake as the problem. Nonetheless, microparticle-containing foods have now been identified which allows a low-microparticle diet to be further assessed in CD.

positive: Diet and risk of inflammatory bowel disease. BACKGROUND: A better understanding of the environmental factors leading to inflammatory bowel disease should help to prevent occurrence of the disease and its relapses. AIM: To review current knowledge on dietary risk factors for inflammatory bowel disease. METHODS: The PubMed, Medline and Cochrane Library were searched for studies on diet and risk of inflammatory bowel disease. RESULTS: Established non-diet risk factors include family predisposition, smoking, appendectomy, and antibiotics. Retrospective case-control studies are encumbered with methodological problems. Prospective studies on European cohorts, mainly including middle-aged adults, suggest that a diet high in protein from meat and fish is associated with a higher risk of inflammatory bowel disease. Intake of the n-6 polyunsaturated fatty acid linoleic acid may confer risk of ulcerative colitis, whereas n-3 polyunsaturated fatty acids may be protective. No effect was found of intake of dietary fibres, sugar, macronutrients, total energy, vitamin C, D, E, Carotene, or Retinol (vitamin A) on risk of ulcerative colitis. No prospective data was found on risk related to intake of fruits, vegetables or food microparticles (titanium dioxide and aluminium silicate). CONCLUSIONS: A diet high in protein, particular animal protein, may be associated with increased risk of inflammatory bowel disease and relapses. N-6 polyunsaturated fatty acids may predispose to ulcerative colitis whilst n-3 polyunsaturated fatty acid may protect. These results should be confirmed in other countries and in younger subjects before dietary counselling is recommended in high risk subjects. Copyright © 2011 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

positive: Efficacy and tolerability of a low microparticle diet in a double blind, randomized, pilot study in Crohn's disease. BACKGROUND: Ultrafine and fine particles are potent adjuvants in antigen-mediated immune responses, and cause inflammation in susceptible individuals. Following recent findings that microparticles accumulate in the phagocytes of intestinal lymphoid aggregates, this study is the first investigation of whether their reduction in the diet improves the symptoms of Crohn's disease. METHODS: In a double blind study, 20 patients with active corticosteroid-treated ileal or ileo-colonic Crohn's disease randomly received either a low microparticle diet (trial group; n = 10) or a control diet (n = 10) for 4 months. Crohn's disease activity index (CDAI) and corticosteroid requirements were compared. RESULTS: One patient in each group was withdrawn. In the trial group there was a progressive decrease in CDAI from entry (392 +/- 25) to month 4 (145 +/- 47) (P = 0.002 vs control group) and seven patients were in remission (CDAI <150). In contrast, the control group had returned to baseline levels (302 +/- 28 on entry and 295 +/- 25 at month 4), with none in remission. Corticosteroid intake was reduced more in the trial group although this did not reach significance. CONCLUSIONS: A low microparticle diet may be effective in the management of ileal Crohn's disease and could explain the efficacy of elemental diets, which similarly are low in microparticles.

positive: Fine and ultrafine particles of the diet: influence on the mucosal immune response and association with Crohn's disease. Crohn's disease is a modern Western disease characterised by transmural inflammation of the gastrointestinal tract. It is of unknown aetiology, but evidence suggests that it results from a combination of genetic predisposition and environmental factors. Bacterial-sized microparticles (0.1-1.0 microm) are potent adjuvants in model antigen-mediated immune responses and are increasingly associated with disease. Microparticles of TiO2 and aluminosilicate accumulate in macrophages of human gut-associated lymphoid tissue where the earliest signs of lesions in Crohn's disease are observed. Dietary microparticles are of endogenous or exogenous origin. Endogenous microparticles dominate and are calcium phosphate (most probably hydroxyapatite), which precipitates in the lumen of the mid-distal gastrointestinal tract due to secretion of Ca and phosphate in the succus entericus. Exogenous dietary microparticles are contaminants (soil and/or dust) and food additives. TiO2, for example, is a food colourant, and aluminosilicates are anti-caking agents, although some aluminosilicates occur as natural contaminants. Food additives alone account for ingestion of approximately 10(12) particles/person per d. Possible mechanisms for the role of exogenous and endogenous dietary microparticles in promoting toleragenic or immune responses of gastrointestinal mucosal phagocytosis are discussed. In a double-blind randomised pilot study we have shown that a diet low in Ca and exogenous microparticles appears to alleviate the symptoms of ileal Crohn's disease, with a significant (P= 0.002) improvement in the Crohn's disease activity index. A multi-centre trial and further mechanistic studies at the cellular level are underway.

positive: Dietary microparticles implicated in Crohn's disease can impair macrophage phagocytic activity and act as adjuvants in the presence of bacterial st... OBJECTIVE AND DESIGN: Western diets regularly expose the gastrointestinal tract (GI) to large quantities ( > 10(12)/day) of man-made, submicron-sized, particles derived from food additives and excipients. These are taken up by M cells, accumulate in gut macrophages, and may influence the aetiology of inflammatory bowel diseases (IBD). MATERIALS: We investigated the effects of common dietary microparticles on the function of macrophages from healthy donors or active Crohn's disease (CD) patients. METHODS: Macrophages were incubated for 24 h with microparticles before being assayed for cytokine production and phagocytic activity. RESULTS: Microparticles alone were non-stimulatory but, in the presence of bacterial antigens such as LPS, they could act as adjuvants to induce potent cytokine responses. Uptake of high concentrations of microparticles also impaired macrophage phagocytic capacity - but not their ability - to take up 2microM fluorescent beads. CONCLUSIONS: While dietary microparticles alone have limited effects on basic macrophage functions, their ability to act as adjuvants could aggravate ongoing inflammatory responses towards bacterial antigens in the GI tract.

positive: Origin and fate of dietary nanoparticles and microparticles in the gastrointestinal tract. Humans have evolved with oral exposure to dietary microparticles and nanoparticles as a normal occurrence but the ever-growing exploitation of nanotechnology is likely to increase exposure further, both qualitatively and quantitatively. Moreover, unlike the situation with respirable particles, relatively little is known about gastrointestinal intake and handling of nanoparticles. With a long term interest in gut exposure and responses to dietary microparticles, our group is now applying its expertise to nanoparticles in the gastrointestinal tract. Here we aim to address (i) the current challenges associated with the characterisation of particle-host or particle-cell interactions, (ii) the origin and mechanisms of uptake of particles in the gastrointestinal tract, especially via the Peyer's patch and (iii) potential cellular effects of nanoparticles in the generation of reactive oxygen species and inflammasome activation, or microparticles in their adjuvant activity in pro-inflammatory signalling and immune responsiveness. Copyright 2010 Elsevier Ltd. All rights reserved.

positive: Titanium Dioxide Nanoparticles in Food and Personal Care Products Titanium dioxide is a common additive in many food, personal care, and other consumer products used by people, which after use can enter the sewage system, and subsequently enter the environment as treated effluent discharged to surface waters or biosolids applied to agricultural land, incinerated wastes, or landfill solids. This study quantifies the amount of titanium in common food products, derives estimates of human exposure to dietary (nano-) TiO2, and discusses the impact of the nanoscale fraction of TiO2 entering the environment. The foods with the highest content of TiO2 included candies, sweets and chewing gums. Among personal care products, toothpastes and select sunscreens contained 1% to >10% titanium by weight. While some other crèmes contained titanium, despite being colored white, most shampoos, deodorants, and shaving creams contained the lowest levels of titanium (<0.01 μg/mg). For several high-consumption pharmaceuticals, the titanium content ranged from below the instrument detection limit (0.0001 μg Ti/mg) to a high of 0.014 μg Ti/mg. Electron microscopy and stability testing of food-grade TiO2 (E171) suggests that approximately 36% of the particles are less than 100 nm in at least one dimension and that it readily disperses in water as fairly stable colloids. However, filtration of water solubilized consumer products and personal care products indicated that less than 5% of the titanium was able to pass through 0.45 or 0.7 μm pores. Two white paints contained 110 μg Ti/mg while three sealants (i.e., prime coat paint) contained less titanium (25 to 40 μg Ti/mg). This research showed that while many white-colored products contained titanium, it was not a prerequisite. Although several of these product classes contained low amounts of titanium, their widespread use and disposal down the drain and eventually to WWTPs deserves attention. A Monte Carlo human exposure analysis to TiO2 through foods identified children as having the highest exposures because TiO2 content of sweets is higher than other food products, and that a typical exposure for a US adult may be on the order of 1 mg Ti per kilogram body weight per day. Thus, because of the millions of tons of titanium based white pigment used annually, testing should focus on food-grade TiO2 (E171) rather than that adopted in many environmental health and safety tests (i.e., P25), which is used in much lower amounts in products less likely to enter the environment (e.g., catalyst supports, photocatalytic coatings).

positive: Immune potentiation of ultrafine dietary particles in normal subjects and patients with inflammatory bowel disease. Various specific and non-specific environmental factors have been associated with the induction and/or exacerbation of disease activity in patients with Crohn's disease and ulcerative colitis. One such factor is the potential role of ingested ultrafine particles. In fact, based on a Western diet, recent data suggest that more than 10(12)ultrafine particles are ingested per person every day. These microparticles have been considered inert although they adsorb endogenous constituents of the intestinal lumen and are taken up by human intestinal lymphoid aggregates. Based on these observations, we determined whether one such dietary microparticle, titanium dioxide (TiO(2)), alters intestinal cell responsiveness to lipopolysaccharide (LPS) using colonic biopsy specimens from 28 patients with ulcerative colitis, 21 with Crohn's disease, and 36 healthy controls. These samples, as well as peripheral blood mononuclear cells when available, were incubated alone (control), or with either (a) LPS (1-2,000 ng/ml), (b) TiO(2)(5 microg/ml) or (c) LPS (1 ng/ml) adsorbed to TiO(2)(5 microg/ml). In each case, the levels of interleukin 1 (IL-1) produced in these assays were quantitated by bioassay and by ELISA. Interestingly, there was dramatic stimulation of peripheral blood mononuclear cells using the TiO(2)-LPS conjugate, with values 30-60-fold above controls and only minor stimulation with LPS or TiO(2)alone. In intestinal organ cultures there was no increase in IL-1 secretion when challenged with TiO(2)alone or with up to 2,000 ng/ml LPS. However, the TiO(2)-LPS conjugate produced a two-to-three-fold, significant increase in the intestinal secretion of IL-1. Our data demonstrate that ultrafine dietary particles are not immunologically inert and may be important adjuncts in overcoming normal gut cell hyporesponsiveness to endogenous luminal molecules. This may be particularly relevant to patients with inflammatory bowel disease where there is abnormal intestinal permeability. Copyright 2000 Academic Press.

positive: The cooked meat-derived mammary carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine promotes invasive behaviour of breast cancer cells. The cooked meat derived genotoxic carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) induces cancer of the colon, prostate and mammary gland when fed to rats. Epidemiology studies link these tumours to a Western diet and exposure to heterocyclic amines such as PhIP. We have shown that PhIP is also potently estrogenic and have proposed that this hormonal activity contributes to its target site carcinogenicity. We now postulate that the estrogenic properties of PhIP influence metastatic potential. We have used an in vitro assay for cell invasion based upon digestion and migration through a reconstituted basement membrane model. Zymography and immunoblotting were used to confirm PhIP-mediated changes associated with induction of the invasive phenotype. Treatment of the mammary cancer cell lines MCF-7 and T47D with PhIP induces cells to digest and migrate through a reconstituted basement membrane. The response was dose dependent, observed at sub-nanomolar concentrations of PhIP and was inhibited by the antiestrogen ICI 182,780. The PhIP-induced invasive phenotype was associated with expression of cathepsin D, cyclooxygenase-2 and matrix metalloproteinase activity. These findings emphasise the range and potency of the biological activities associated with this cooked meat product and mechanistically support the tissue-specific carcinogenicity of the chemical. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

positive: Meat, fat and risk of breast cancer: a case-control study from Uruguay. To examine whether meat intake modifies breast-cancer risk, a case-control study was conducted in Uruguay. Dietary patterns were assessed in detail (for cases, before diagnosis or symptoms occurred) using a food frequency questionnaire involving 64 food items, which allowed total energy intake to be calculated. Nutrient residuals were calculated through regression analysis. After adjustment for potential confounders (which included family history of breast cancer, menopausal status, body-mass index, total energy and total alcohol intake), an increased risk associated with consumption of total meat intake, red meat intake, total fat and saturated fat intake was observed. The strongest effect was observed for red meat intake (OR 4.2, 95% CL 2.3-7.7) for consumption in the upper quartile, after controlling for protein and fat intake. This suggests an independent effect for meat. Since experimental studies have shown a strong effect of heterocyclic amines in rat mammary carcinogenesis, further studies should be performed in human epidemiology, perhaps using biomarkers of heterocyclic amine exposure.

positive: Intake of fried meat and risk of cancer: a follow-up study in Finland. It has been suggested that mutagens in fried meat may be involved in the cancer process. Therefore the relationships between intake of fried meat and subsequent risk of cancers at different sites were studied among 9,990 Finnish men and women, 15-99 years of age and initially free of cancer. The baseline study was carried out in 1966-1972, and cases of cancer were identified through data linkage with the Finnish Cancer Registry. During a 24-year follow-up, 853 cancer cases were diagnosed. The intake of fried meat was estimated from a dietary history interview covering the total diet of the participants during the previous year. There was a positive association between fried meat intake and the risk of female-hormone-related cancers, i.e., cancer of the breast, endometrium and ovary combined. The relative risk of these cancers combined between persons in the highest and lowest tertiles of daily intake of fried meat adjusted for age, personal characteristics and intake of other main food groups was 1.77 (95% confidence interval = 1.11-2.84). Pancreatic and nervous system cancers also presented non-significant suggestive associations. No associations were observed with respect to other single cancer sites studied or to all sites of cancer combined. Further epidemiological efforts are needed to ascertain the potential link between fried-food mutagens and cancer risk.

positive: Detection of PhIP (2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine) in the milk of healthy women. An increased risk of breast cancer has been observed in women who consume "very well-done" meats. Heterocyclic amines are mutagenic and carcinogenic pyrolysis products formed during high temperature cooking of meats. In the present study, human milk samples were analyzed for PhIP, one of the most abundant dietary heterocyclic amine. A protocol was developed with a mixed-mode cation exchange sorbent for the extraction of heterocyclic amines from milk. Milk samples were acquired from healthy Canadian women. With LC/MS analysis and the method of isotope dilution for quantification, levels of PhIP were determined in human milk samples. PhIP was detected in 9 of the 11 milk samples, at levels as high as 59 pg/mL (ppt). No PhIP was detected in the milk of the vegetarian donor. Detection of PhIP in milk indicates that ductal mammary epithelial cells are directly exposed to this carcinogen, suggesting that heterocyclic amines are possible human mammary carcinogens.

positive: Dietary intake of meat and meat-derived heterocyclic aromatic amines and their correlation with DNA adducts in female breast tissue. It was the aim of this study to examine the association of the consumption of meat in general, meat prepared by different cooking methods and the dietary intake of heterocyclic aromatic amines (HCA) with the level of DNA adducts in the breast tissue of women undergoing reduction mammoplasty. Dietary intake of meat and HCA were assessed via questionnaire in 44 women undergoing reduction mammoplasty. DNA adduct analysis in breast tissue was performed by (32)P-postlabelling analysis. Spearman rank correlation coefficients (r) were calculated to examine the association of meat consumption and dietary HCA intake with tissue DNA adduct levels. A median DNA adduct level of 18.45 (interquartile range 12.81-25.65) per 10(9) nucleotides in breast tissue was observed; median HCA intake was 40.43 ng/day (interquartile range 19.55-102.33 ng/day). Total HCA intake (r = 0.33, P = 0.03), consumption of fried meat (r = 0.39, P = 0.01), beef (r = 0.32, P = 0.03) and processed meat (r = 0.51, P = 0.0004) were statistically significantly correlated with the level of DNA adducts in breast tissue. The detected DNA adducts could not be confirmed to be specific HCA-derived DNA adducts by comparison with external standards, using the (32)P-postlabelling assay. We observed strong correlations of dietary HCA intake and consumption of fried and processed meat with DNA adduct levels in breast tissue of 44 women. Since the detected DNA adducts were not necessarily specific only for HCA, it is possible that HCA intake is a surrogate of other genotoxic substances, such as polycyclic aromatic hydrocarbons, in meat prepared at high temperatures.

positive: The cooked food derived carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b] pyridine is a potent oestrogen: a mechanistic basis for its tissue-speci... The cooked meat carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) induces tumours of the breast, colon and prostate in rats. Here we show that in addition to its well-established genotoxicity, which can be detected at concentrations >10(-6) M, PhIP is also oestrogenic. In COS-1 cells transiently transfected with an oestrogen-responsive reporter gene, PhIP (10(-10)-10(-6) M) mediated transcription through oestrogen receptor (ER) alpha, but not ER-beta, and inhibition by the pure ER antagonist ICI 182 780 demonstrated a requirement for a functional ER. In contrast, the structurally related food-derived carcinogen 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) failed to induce reporter gene transcription. Additionally, we show that in a hormonally responsive breast cancer cell line (MCF-7 cells), PhIP induced transcriptional activation using endogenously expressed ER. Examination of the genotoxic potential of PhIP using a model mammalian cell mutation assay (hprt(-) locus) demonstrated that the genetic toxicology of PhIP was readily detectable, but separate, in terms of effective concentration, from its oestrogenic activity. To determine whether the oestrogenicity of PhIP could mediate oestrogen-dependent responses such as cell growth, we examined the growth of hormonally responsive cells (MCF-7 cells). We show that PhIP can stimulate cell proliferation and, again, this was dependent upon a functional ER. Using ligand blotting, we further show that PhIP can stimulate the expression of progesterone receptor (PR-A and PR-B) and c-MYC and activate the MAPK signal transduction pathway. These responses were similar to that produced by oestradiol, in terms of temporal aspects, potency and a requirement for a functional ER. Each of these dose-dependent mitogenic responses occurred at concentrations of PhIP ( approximately 10(-9)-10(-11)M) that are likely to be equivalent to systemic human exposure via consumption of cooked meat. Thus PhIP can induce cellular responses that encompass altered gene expression and mitogenesis. We suggest that the combination of genetic toxicology and oestrogen-like promotion of genomic and cellular events provide a mechanism for the tissue-specific tumorigenicity of this compound.

positive: Cooked meat and risk of breast cancer--lifetime versus recent dietary intake. BACKGROUND: Polycyclic aromatic hydrocarbons (PAHs) and heterocyclic amines (HCAs) are carcinogens formed in or on the surface of well-done meat, cooked at high temperature. METHODS: We estimated breast cancer risk in relation to intake of cooked meat in a population-based, case-control study (1508 cases and 1556 controls) conducted in Long Island, NY from 1996 to 1997. Lifetime intakes of grilled or barbecued and smoked meats were derived from the interviewer-administered questionnaire data. Dietary intakes of PAH and HCA were derived from the self-administered modified Block food frequency questionnaire of intake 1 year before reference date. Unconditional logistic regression was used to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Modest increased risk was observed among postmenopausal, but not premenopausal, women consuming the most grilled or barbecued and smoked meats over the life course (OR = 1.47; CI = 1.12-1.92 for highest vs. lowest tertile of intake). Postmenopausal women with low fruit and vegetable intake, but high lifetime intake of grilled or barbecued and smoked meats, had a higher OR of 1.74 (CI = 1.20-2.50). No associations were observed with the food frequency questionnaire-derived intake measures of PAHs and HCAs, with the possible exception of benzo(alpha)pyrene from meat among postmenopausal women whose tumors were positive for both estrogen receptors and progesterone receptors (OR = 1.47; CI = 0.99-2.19). CONCLUSIONS: These results support the accumulating evidence that consumption of meats cooked by methods that promote carcinogen formation may increase risk of postmenopausal breast cancer.

positive: Formation of a mutagenic heterocyclic aromatic amine from creatinine in urine of meat eaters and vegetarians. Liquid chromatography electrospray ionization mass spectrometry (MS) with a triple quadrupole MS was used to identify known and novel heterocyclic aromatic amines (HAAs) in human urine. The identities of 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (8-MeIQx) and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) were confirmed by their product ion spectra. The constant neutral loss scan mode was employed to probe for other analytes in urine that display the transition [M+H]+-->[M+H-CH3*]+*, which is common to HAAs containing an N-methylimidazo moiety, and led to the detection of a previously unreported isomer of 8-MeIQx [Holland, R., et al. (2004) Chem. Res. Toxicol. 17, 1121-1136]. We now report the identification of another novel HAA, 2-amino-1-methylimidazo[4,5-b]quinoline (IQ[4,5-b]), an isomer of the powerful animal carcinogen 2-amino-3-methylimidazo[4,5-f]quinoline (IQ). The amounts of IQ[4,5-b] measured in the urine of human volunteers who consumed grilled beef ranged from 15 to 135% of the ingested dose, while the amounts of 8-MeIQx and PhIP excreted in urine were on average <2% of the ingested dose. Base treatment of urine at 70 degrees C increased the concentrations of 8-MeIQx and PhIP by as much as 6-fold, indicating the presence of phase II conjugates; however, the amount of IQ[4,5-b] increased by more than 100-fold. IQ[4,5-b] was also detected in the urine of vegetarians following base hydrolysis. The formation of IQ[4,5-b], but not IQ, 8-MeIQx, or PhIP, also occurred in urine incubated at 37 degrees C. Creatinine and 2-aminobenzaldehyde are likely precursors of IQ[4,5-b]. The detection of IQ[4,5-b] in the urine of both meat eaters and vegetarians suggests that this HAA may be present in nonmeat staples or that IQ[4,5-b] formation may occur endogenously within the urinary bladder or other biological fluids.

positive: Effects of a very low-fat, vegan diet in subjects with rheumatoid arthritis. OBJECTIVE: To demonstrate the effects of a very low-fat, vegan diet on patients with rheumatoid arthritis (RA). DESIGN: Single-blind dietary intervention study. SUBJECTS AND STUDY INTERVENTIONS: This study evaluated the influence of a 4-week, very low-fat (approximately 10%), vegan diet on 24 free-living subjects with RA, average age, 56 +/- 11 years old. OUTCOME MEASUREMENTS: Prestudy and poststudy assessment of RA symptomatology was performed by a rheumatologist blind to the study design. Biochemical measures and 4-day diet data were also collected. Subjects met weekly for diet instruction, compliance monitoring, and progress assessments. RESULTS: There were significant (p < 0.001) decreases in fat (69%), protein (24%), and energy (22%), and a significant increase in carbohydrate (55%) intake. All measures of RA symptomatology decreased significantly (p < 0.05), except for duration of morning stiffness (p > 0.05). Weight also decreased significantly (p < 0.001). At 4 weeks, C-reactive protein decreased 16% (ns, p > 0.05), RA factor decreased 10% (ns, p > 0.05), while erythrocyte sedimentation rate was unchanged (p > 0.05). CONCLUSION: This study showed that patients with moderate-to-severe RA, who switch to a very low-fat, vegan diet can experience significant reductions in RA symptoms.

positive: Validation of a method for the detection of virulent Yersinia enterocolitica and their distribution in slaughter pigs from conventional and alterna... Various methods have been described in the literature for the detection of virulent Yersinia enterocolitica in pigs. The risk factors for pig herd contamination have yet to be determined. The objective of this study was to validate a sensitive method for the detection of Y. enterocolitica and to describe the distribution of the bacteria in pigs at slaughter from conventional and alternative ("organic") housing systems. First, samples were collected from tonsils, caecum with caecal contents, and the caecal lymph nodes of 60 slaughter pigs. These samples were used to compare the sensitivity of six different laboratory culture methods either in common use or described in the literature with that of a polymerase chain reaction with two primer pairs (multiplex PCR). Then, only PCR was used to examine tonsils, caecum and caecal lymph nodes from two groups of slaughter pigs: 210 from six conventional fattening farms and 200 from three with alternative housing. The results of the multiplex PCR were positive in 28 cases. All culture methods proved inferior to PCR in sensitivity. In the second part of the study, PCR detected 36 (18%) positive pigs from alternative housing and 60 (29%) from conventional housing (p<0.05). The highest rate of Y. enterocolitica contamination was found in tonsils (11% alternative, 22% conventional; p<0.05), followed by caecum (5%, 11%) and lymph nodes (2%, 7%). The housing system appears to be one important factor in the prevalence of this common pathogen in pig herds, as we found important differences between the two systems studied here. In the conventional system, the main risk factors appeared to be sourcing pigs from different pig suppliers, use of commercial feed and transportation to slaughter.

positive: Contamination of carcasses with human pathogenic Yersinia enterocolitica 4/O:3 originates from pigs infected on farms. Pigs are considered as a major reservoir of human pathogenic Yersinia enterocolitica and a source of human yersiniosis. However, the transmission route of Y. enterocolitica from farm to pork is still unclear. The transmission of pathogenic Y. enterocolitica from pigs to carcasses and pluck sets was investigated by collecting samples from 364 individual ear-tagged pigs on the farm and at the slaughterhouse. In addition, isolated strains were analyzed, using pulsed-field gel electrophoresis. Isolation of similar genotypes of pathogenic Y. enterocolitica 4/O:3 in animals on the farm and at the slaughterhouse and in carcasses shows that carcass contamination originates from the strains a pig carries during the fattening period. Direct contamination from the carrier pig to its subsequent pluck set is also the primary contamination route for pluck sets, but cross-contamination appears to have a larger impact on pluck set contamination than on carcasses. In this study, the within-farm prevalence of pathogenic Y. enterocolitica varied from 0% to 100%, indicating specific farm factors affect the prevalence of Y. enterocolitica in pigs. The association of farm factors with the high prevalence of pathogenic Y. enterocolitica on farms was studied for the first time, using correlation and two-level logistic regression analyses. Specific farm factors, i.e. drinking from a nipple, absence of coarse feed or bedding for slaughter pigs, and no access of pest animals to pig house, were associated with a high prevalence of pathogenic Y. enterocolitica 4/O:3.

positive: Prevalence of Yersinia enterocolitica shedding and bioserotype distribution in Ontario finisher pig herds in 2001, 2002, and 2004. We investigated characteristics of Yersinia enterocolitica infection in Ontario finisher pig herds. Our specific objectives were to estimate or test: prevalence of Y. enterocolitica shedding in finisher pigs, bioserotype distribution, agreement between the herd-level tests based on sampling pig and pooled fecal samples, whether bioserotypes cluster by farms, and whether Y. enterocolitica-positive herds cluster spatially. In total, 3747 fecal samples were collected from 100 farms over the years 2001, 2002, and 2004 (250 total herd visits). Fecal samples were tested by culture and positive isolates were biotyped and serotyped. Apparent pig-level prevalence of Y. enterocolitica was 1.8%, 3.2%, and 12.5% in 2001, 2002, and 2004, respectively. Estimated true pig-level prevalence of Y. enterocolitica was 5.1%, 9.1%, and 35.1% in 2001, 2002, and 2004, respectively. Herd-level prevalence was 16.3%, 17.9%, and 37.5% in 2001, 2002, and 2004, respectively. In all years, the most common bioserotype was 4, O:3, followed by bioserotype 2, O:5,27. Kappa between herd-level status based on pig and pooled samples ranged between 0.51 and 0.68 for biotype 1A and bioserotype 4, O:3, respectively. For 4, O:3, a significant bias in discordant pairs was detected, indicating that pig samples were more sensitive than pooled samples in declaring a herd as positive. Farms tended to be repeatedly positive with the same bioserotype, but positive study farms did not cluster spatially (suggesting lack of between herd transmission and lack of a common geographic risk factor). Copyright 2009 Elsevier B.V. All rights reserved.

positive: Annual cost of illness and quality-adjusted life year losses in the United States due to 14 foodborne pathogens. In this article we estimate the annual cost of illness and quality-adjusted life year (QALY) loss in the United States caused by 14 of the 31 major foodborne pathogens reported on by Scallan et al. (Emerg. Infect. Dis. 17:7-15, 2011), based on their incidence estimates of foodborne illness in the United States. These 14 pathogens account for 95 % of illnesses and hospitalizations and 98 % of deaths due to identifiable pathogens estimated by Scallan et al. We estimate that these 14 pathogens cause $14.0 billion (ranging from $4.4 billion to $33.0 billion) in cost of illness and a loss of 61,000 QALYs (ranging from 19,000 to 145,000 QALYs) per year. Roughly 90 % of this loss is caused by five pathogens: nontyphoidal Salmonella enterica ($3.3 billion; 17,000 QALYs), Campylobacter spp. ($1.7 billion; 13,300 QALYs), Listeria monocytogenes ($2.6 billion; 9,400 QALYs), Toxoplasma gondii ($3 billion; 11,000 QALYs), and norovirus ($2 billion; 5,000 QALYs). A companion article attributes losses estimated in this study to the consumption of specific categories of foods. To arrive at these estimates, for each pathogen we create disease outcome trees that characterize the symptoms, severities, durations, outcomes, and likelihoods of health states associated with that pathogen. We then estimate the cost of illness (medical costs, productivity loss, and valuation of premature mortality) for each pathogen. We also estimate QALY loss for each health state associated with a given pathogen, using the EuroQol 5D scale. Construction of disease outcome trees, outcome-specific cost of illness, and EuroQol 5D scoring are described in greater detail in a second companion article.

positive: Ranking the disease burden of 14 pathogens in food sources in the United States using attribution data from outbreak investigations and expert elic... Understanding the relative public health impact of major microbiological hazards across the food supply is critical for a risk-based national food safety system. This study was conducted to estimate the U.S. health burden of 14 major pathogens in 12 broad categories of food and to then rank the resulting 168 pathogen-food combinations. These pathogens examined were Campylobacter, Clostridium perfringens, Escherichia coli O157:H7, Listeria monocytogenes, norovirus, Salmonella enterica, Toxoplasma gondii, and all other FoodNet pathogens. The health burden associated with each pathogen was measured using new estimates of the cost of illness and loss of quality-adjusted life years (QALYs) from acute and chronic illness and mortality. A new method for attributing illness to foods was developed that relies on both outbreak data and expert elicitation. This method assumes that empirical data are generally preferable to expert judgment; thus, outbreak data were used for attribution except where evidence suggests that these data are considered not representative of food attribution. Based on evaluation of outbreak data, expert elicitation, and published scientific literature, outbreak-based attribution estimates for Campylobacter, Toxoplasma, Cryptosporidium, and Yersinia were determined not representative; therefore, expert-based attribution were included for these four pathogens. Sensitivity analyses were conducted to assess the effect of attribution data assumptions on rankings. Disease burden was concentrated among a relatively small number of pathogen-food combinations. The top 10 pairs were responsible for losses of over $8 billion and 36,000 QALYs, or more than 50 % of the total across all pairs. Across all 14 pathogens, poultry, pork, produce, and complex foods were responsible for nearly 60 % of the total cost of illness and loss of QALYs.

positive: Too early to dismiss Yersinia enterocolitica infection in the aetiology of Graves' disease: evidence from a twin case-control study. BACKGROUND: Yersinia enterocolitica (YE) infection has long been implicated in the pathogenesis of Graves' disease (GD). The association between YE and GD could, however, also be due to common genetic or environmental factors affecting the development of both YE infection and GD. This potential confounding can be minimized by investigation of twin pairs discordant for GD. AIM: To examine whether YE infection is associated with GD. DESIGN: We first conducted a classical case-control study of individuals with (61) and without (122) GD, and then a case-control study of twin pairs (36) discordant for GD. METHODS: Immunoglobulin (Ig)A and IgG antibodies to virulence-associated Yersinia outer membrane proteins (YOPs) were measured. MAIN OUTCOME MEASURES: The prevalence of YOP IgA and IgG antibodies. RESULTS: Subjects with GD had a higher prevalence of YOP IgA (49%vs. 34%, P = 0.054) and YPO IgG (51%vs. 35%, P = 0.043) than the external controls. The frequency of chronic YE infection, reflected by the presence of both IgA and IgG YOP antibodies, was also higher among cases than controls (49%vs. 33%, P = 0.042). Similar results were found in twin pairs discordant for GD. In the case-control analysis, individuals with GD had an increased odds ratio (OR) of YE infection: IgA 1.84 (95% CI 0.99-3.45) and IgG 1.90 (95% CI 1.02-3.55). In the co-twin analysis, the twin with GD also had an increased OR of YE infection: IgA 5.5 (95% CI 1.21-24.81) and IgG 5.0 (95% CI 1.10-22.81). CONCLUSION: The finding of an association between GD and YE in the case-control study and within twin pairs discordant for GD supports the notion that YE infection plays an aetiological role in the occurrence of GD, or vice versa. Future studies should examine the temporal relationship of this association in more depth.

positive: Prevalence of Pathogenic Yersinia enterocolitica Strains in Pigs in the United States Yersinia enterocolitica is considered an important food-borne pathogen impacting the pork production and processing industry in the United States. Since this bacterium is a commensal of swine, the primary goal of this study was to determine the prevalence of pathogenic Y. enterocolitica in pigs in the United Sates using feces as the sample source. A total of 2,793 fecal samples were tested for its presence in swine. Fecal samples were collected from late finisher pigs from 77 production sites in the 15 eastern and midwestern pork-producing states over a period of 27 weeks (6 September 2000 to 20 March 2001). The prevalence of ail-positive Y. enterocolitica was determined in samples using both a fluorogenic 5′ nuclease PCR assay and a culture method. The mean prevalence was 13.10% (366 of 2,793 fecal samples tested) when both PCR- and culture-positive results were combined. Forty-one of 77 premises (53.25%) contained at least one fecal sample positive for the ail sequence. The PCR assay indicated a contamination rate of 12.35% (345/2,793) compared to 4.08% (114/2,793) by the culture method. Of the 345 PCR-positive samples, 252 were culture negative, while of the 114 culture-positive samples, 21 were PCR negative. Among 77 premises, the PCR assay revealed a significantly (P < 0.05) higher percentage (46.75%, n = 36 sites) of samples positive for the pathogen (ail sequence) than the culture method (22.08%, n = 17 sites). Thus, higher sensitivity, with respect to number of samples and sites identified as positive for the PCR method compared with the culture method for detecting pathogenic Y. enterocolitica, was demonstrated in this study. The results support the hypothesis that swine are a reservoir for Y. enterocolitica strains potentially pathogenic for humans.

positive: Behavior of Yersinia enterocolitica in Foods Yersinia enterocolitica are ubiquitous, being isolated frequently from soil, water, animals, and a variety of foods. They comprise a biochemically heterogeneous group that can survive and grow at refrigeration temperatures. The ability to propagate at refrigeration temperatures is of considerable significance in food hygiene. Virulent strains of Yersinia invade mammalian cells such as HeLa cells in tissue culture. Two chromosomal genes, inv and ail, were identified for cell invasion of mammalian. The pathogen can cause diarrhoea, appendicitis and post-infection arthritis may occur in a small proportion of cases. The most common transmission route of pathogenic Y. enterocolitica is thought to be fecal-oral via contaminated food. Direct person-to-person contact is rare. Occasionally, pathogenic Y. enterocolitica has been detected in vegetables and environmental water; thus, vegetables and untreated water are also potential sources of human yersiniosis. However, the isolation rates of pathogenic Y. enterocolitica have been low, which may be due to the limited sensitivity of the detection methods. To identify other possible transmission vehicles, different food items should be studied more extensively. Many factors related to the epidemiology of Y. enterocolitica, such as sources, transmission routes, and predominating genotypes remain obscure because of the low sensitivity of detection methods.

positive: Vital signs: incidence and trends of infection with pathogens transmitted commonly through food--foodborne diseases active surveillance network, 10... BACKGROUND: In the United States, contaminated food causes approximately 1,000 reported disease outbreaks and an estimated 48 million illnesses, 128,000 METHODS: The Foodborne Diseases Active Surveillance Network (FoodNet) conducts surveillance among 15% of the U.S. population for laboratory-confirmed infections with nine pathogens transmitted commonly through food. Overall and pathogen-specific changes in incidence were estimated from 1996-1998 to 2010 and from 2006-2008 to 2010.hospitalizations, and 3,000 deaths annually. This report summarizes 2010 surveillance data and describes trends since 1996. RESULTS: A total of 19,089 infections, 4,247 hospitalizations, and 68 deaths were reported from FoodNet sites in 2010. Salmonella infection was the most common infection reported (17.6 illnesses per 100,000 persons) and was associated with the largest number of hospitalizations (2,290) and deaths (29); no significant change in incidence of Salmonella infection has occurred since the start of surveillance during 1996-1998. Shiga toxin-producing Escherichia coli (STEC) O157 infection caused 0.9 illnesses per 100,000. Compared with 1996-1998, overall incidence of infection with six key pathogens in 2010 was 23% lower, and pathogen-specific incidence was lower for Campylobacter, Listeria, STEC O157, Shigella, and Yersinia infection but higher for Vibrio infection. Compared with a more recent period, 2006--2008, incidence in 2010 was lower for STEC O157 and Shigella infection but higher for Vibrio infection. CONCLUSIONS: The incidence of STEC O157 infection has declined to reach the 2010 national health objective target of ≥1 case per 100,000. This success, as well as marked declines since 1996-1998 in overall incidence of six key foodborne infections, demonstrates the feasibility of preventing foodborne illnesses. IMPLICATIONS FOR PUBLIC HEALTH PRACTICE: Salmonella infection should be targeted because it has not declined significantly in more than a decade, and other data indicate that it is one of the most common foodborne infections, resulting in an estimated $365 million in direct medical costs annually. The prevention measures that reduced STEC O157 infection need to be applied more broadly to reduce Salmonella and other infections. Effective measures from farm to table include preventing contamination of meat during slaughter and of all foods, including produce, during processing and preparation; cooking meat thoroughly; vigorously detecting and investigating outbreaks; and recalling contaminated food.

positive: Prevalence of Yersinia enterocolitica in different phases of production on swine farms. Swine have been identified as the primary reservoir of pathogenic Yersinia enterocolitica (YE), but little research has focused on the epidemiology of YE at the farm level. The objective of this study was to describe the prevalence of YE in different production phases on swine farms. In this cross-sectional study, individual pigs on eight swine operations were sampled for the presence of YE. On each farm, both feces and oral-pharyngeal swabs were collected from pigs in five different production phases: gestating, farrowing, suckling, nursery, and finishing. A pig was considered positive if either sample tested positive. Samples were cultured with cold enrichment followed by isolation on selective media plates. Presumptive isolates were confirmed as YE and assayed for the presence of ail with a multiplex PCR. Of the 2,349 pigs sampled, 120 (5.1%) tested positive, and of those, 51 were ail positive (42.5% of YE isolates). On all farms, there was a trend of increasing prevalence as pigs mature. Less than 1% of suckling piglets tested positive for YE. Only 1.4% (44.4% of which were ail positive) of nursery pigs tested positive, but 10.7% (48.1% of which were ail positive) of finishing pigs harbored YE. Interestingly, gestating sows had the second highest prevalence of YE at 9.1% (26.7% of which were ail positive), yet YE was never detected from the farrowing sows. These results represent the first on-farm description of YE in U.S. herds and provide the initial step for designing future studies of YE.

positive: Yersinia enterocolitica: a brief review of the issues relating to the zoonotic pathogen, public health challenges, and the pork production chain. Yersinia enterocolitica is a zoonotic agent that causes gastrointestinal disease in humans, as well as reactive arthritis and erythema nodosum. Enteropathogenic Yersinia are the etiological agents for yersiniosis, which can be acquired through the consumption of contaminated foods. As porcine animals are the main carriers of Y. enterocolitica, food safety measures to minimize human infection are of increasing interest to the scientific and medical community. In this review, we examine why it is imperative that information on the reservoirs, prevalence, virulence, and ability of this pathogen to survive in different environments is further investigated to provide rational measures to prevent or decrease associated disease risks.

positive: Prevalence of Yersinia enterocolitica in market weight hogs in the United States. Pigs are the major animal reservoir for Yersinia enterocolitica strains, which are potentially pathogenic for humans. The goals of this study were (i) to estimate the individual animal and on-farm prevalences of Y. enterocolitica in hogs based on tonsil samples collected during National Animal Health Monitoring System Swine 2002 study and (ii) to use these data with data previously published for fecal samples to determine on-farm risk factors for Y. enterocolitica. Tonsil swabs (1,218) and fecal samples (2,847) were collected on 124 farms located in the top 17 pork-producing states. Ten percent of tonsils (122 of 1,218 samples) were positive in irgasan-tiracillin-chlorate (ITC) enrichment broth by real-time PCR, but only 5.6% of samples (68 of 1,218) were positive after subculture on the more selective cefsulodin-irgasan-novobiocin (CIN) agar. For tonsils, the on-farm prevalence based on real-time PCR detection of the ail gene in ITC enrichment broth cultures was 32% (32 of 100 premises sampled); the prevalence based on subculture in CIN agar was 19.6% (20 of 102 premises). Results of bacteriological isolation and real-time PCR analysis of tonsils and feces were combined to estimate prevalence (individual animal and farm), which was subsequently correlated with 40 farm management practices. Four factors and their accompanying odds ratios (ORs) were identified in the final regression model: location in a central state (OR = 0.3), vaccination for Escherichia coli (OR = 3.0), percentage of deaths due to scours (OR = 3.5), and presence of meat or bone meal in grower-finisher diet (OR = 4.1).

positive: Factors related to the prevalence of pathogenic Yersinia enterocolitica on pig farms. A survey of 788 pigs from 120 farms was conducted to determine the within-farm prevalence of pathogenic Yersinia enterocolitica and a questionnaire of management conditions was mailed to the farms afterwards. A univariate statistical analysis with carriage and shedding as outcomes was conducted with random-effects logistic regression with farm as a clustering factor. Variables with a P value <0·15 were included into the respective multivariate random-effects logistic regression model. The use of municipal water was discovered to be a protective factor against carriage and faecal shedding of the pathogen. Organic production and buying feed from a certain feed manufacturer were also protective against total carriage. Tonsillar carriage, a different feed manufacturer, fasting pigs before transport to the slaughterhouse, higher-level farm health classification, and snout contacts between pigs were risk factors for faecal shedding. We concluded that differences in management can explain different prevalences of Y. enterocolitica between farms.

positive: Piglets Are a Source of Pathogenic Yersinia enterocolitica on Fattening-Pig Farms To study the origin and spread of Yersinia enterocolitica among pigs, fecal and blood samples were repeatedly taken on a fattening farm. A few piglets were found to be already infected on breeding farms. After the piglets were mixed, the infection spread through the whole unit. Eventually, all the pigs excreted the pathogen.

positive: Human pathogens and tetracycline-resistant bacteria in bioaerosols of swine confinement buildings and in nasal flora of hog producers. Swine confinement buildings in eastern Canada are enclosed and equipped with modern production systems to manage waste. Bioaerosols of these swine confinement buildings could be contaminated by human pathogens and antimicrobial resistant bacteria which could colonize exposed workers. We therefore wanted to analyze bioaerosols of swine confinement buildings and nasal flora of Canadian hog producers to evaluate possible colonization with human pathogens and tetracycline-resistant bacteria. Culturable and non-culturable human pathogens and tet genes were investigated in the bioaerosols of 18 barns. The nasal passages of 35 hog producers were sampled and total DNA was extracted from the calcium-alginate swabs to detect, by PCR, Campylobacter, C. perfringens, Enterococcus, E. coli, Y. enterocolitica, tetA/tetC, tetG and ribosomal protection protein genes. Airborne culturable C. perfringens, Enterococcus, E. coli, and Y. enterocolitica were present in the bioaerosols of 16, 17, 11 and 6 of the 18 facilities. Aerosolized total (culturable/non culturable) Campylobacter, C. perfringens, Enterococcus, E. coli and Y. enterocolitica were detected in 10, 6, 15, 18 and 2 barns, respectively. Tet genes were found in isolates of culturable human pathogens. TetA/tetC, tetG and ribosomal protection protein genes were detected in the bioaerosols of all 18 studied buildings. Campylobacter, C. perfringens, Enterococcus, E. coli, and Y. enterocolitica were found respectively in 4, 9, 17, 14 and one nasal flora of workers. One and 10 workers were positive for tetA/tetC and tetG genes, respectively. In swine confinement buildings, hog producers are exposed to aerosolized human pathogens and tetracycline-resistant bacteria that can contaminate the nasal flora. Copyright © 2010 Elsevier GmbH. All rights reserved.

positive: Yersinia enterocolitica infection in diarrheal patients. In this study, we hoped to provide valuable clinical information on yersiniosis for clinicians. Two thousand six hundred stool samples were collected from in- and outpatients with diarrhea, which were tested with both culture method and real-time polymerase chain reaction (RT-PCR). In total, 188 positive samples were detected by RT-PCR (178) and culture method (160), while the incidence was about 7.23%. The detection rate of RT-PCR was significantly higher than culture method and a higher incidence in autumn-winter was also noticeably identified than in spring-summer. Infection sources mostly focused on unboiled foods (101) and pets (45), while clinical manifestation mainly presented as gastroenteritis (156), pseudoappendicitis (32), and extraintestinal complications (46). The morbidity of extraintestinal complications in adults was significantly higher than in children and it was the same for high-risk patients between adults over the age of 60 years (4.7%) and children under the age of 3 years (1.4%), whereas the constituent ratio of children versus adults with yersiniosis in different systems was not significant. Of 160 isolates tested for antimicrobial susceptibility, the majority were susceptible to third-generation cephalosporins, aminoglycosides, fluoroquinolones, and trimethoprim-sulfamethoxazole, whereas only a small portion was susceptible to the first-generation cephalosporins and penicillins. During autumn-winter months, clinicians should pay more attention to clinical manifestation, early diagnosis, and treatment with susceptible antibiotics of yersiniosis and its complications, targeting high-risk patients.

positive: Influence of water and food consumption on inadvertent antibiotics intake among general population. Antibiotic entry into the water environment has been of growing concern. However, few investigations have been performed to examine the potential for indirect human exposure to environmental antibiotic residues. We evaluated the contribution of drinking water and major food consumption to inadvertent intake of antibiotic residues among general human population in Korea. We estimated daily human intake of six antibiotics, i.e., sulfamethazine (SMZ), sulfamethoxazole (SMX), sulfathiazole (STZ), trimethoprim (TMP), enrofloxacin (EFX), and roxithromycin (RTM), by measuring the concentrations of the antibiotics and their major metabolites in urine from general population in Korea (n=541). In addition, we measured antibiotics from source water of drinking water as well as in tap water samples, and surveyed water consumption rates among the study population. To assess the contribution of dietary factor, we also surveyed consumption pattern for several major foods which are suspected of antibiotics residue. SMZ, Sulfamethazine-N4-acetyl (SMZ-N4), TMP, EFX, ciprofloxacin (CFX), and RTM were detected up to 448, 6210, 11,900, 6970, 32,400, and 151pg/ml in the urine samples, respectively. Estimates of daily intake of major antibiotics did not appear to be related with consumption of drinking water although antibiotics were frequently detected in source waters (10-67ng/l). Consumption of several foods correlated significantly with urinary excretion of several antibiotics. Daily intake estimates of EFX and CFX were associated with consumption of beef, pork, and dairy products; those of SMZ and TMP associated with pork and dairy products; and that of TMP related with raw fish. Daily antibiotics intake estimates however did not exceed the acceptable daily intake levels. Copyright 2010 Elsevier Inc. All rights reserved.

positive: Influence of a five-day vegetarian diet on urinary levels of antibiotics and phthalate metabolites: a pilot study with "Temple Stay" participants. Diet is purported to be means of exposure to many environmental contaminants. The purpose of this study is to understand the influence of dietary change on the levels of exposure to several environmental chemicals - in particular, antibiotics and phthalates. For this purpose, we examined the extent to which short-term changes in diet influenced the inadvertent exposure levels to these chemicals in an adult population. We recruited participants (n=25) of a five-day 'Temple Stay' program in Korea and collected urine samples before and after the program. We also conducted a questionnaire survey on participants' dietary patterns prior to their participation. During the program, participants followed the daily routines of Buddhist monks and maintained a vegetarian diet. Urinary levels of three antibiotics and their major metabolites, metabolites of four major phthalates, and malondialdehyde (MDA) as an oxidative stress biomarker were analyzed. The frequency and levels of detection for antibiotics and phthalates noticeably decreased during the program. Urinary MDA levels were significantly lower than before program participation (0.16 versus 0.27mg/g creatinine). Although the exposure to target compounds might be influenced by other behavioral patterns, these results suggest that even short-term changes in dietary behavior may significantly decrease inadvertent exposure to antibiotics and phthalates and hence may reduce oxidative stress levels. Copyright 2010 Elsevier Inc. All rights reserved.

positive: High Fat Intake Leads to Acute Postprandial Exposure to Circulating Endotoxin in Type 2 Diabetic Subjects OBJECTIVE To evaluate the changes in circulating endotoxin after a high–saturated fat meal to determine whether these effects depend on metabolic disease state. RESEARCH DESIGN AND METHODS Subjects (n = 54) were given a high-fat meal (75 g fat, 5 g carbohydrate, 6 g protein) after an overnight fast (nonobese control [NOC]: age 39.9 ± 11.8 years [mean ± SD], BMI 24.9 ± 3.2 kg/m2, n = 9; obese: age 43.8 ± 9.5 years, BMI 33.3 ± 2.5 kg/m2, n = 15; impaired glucose tolerance [IGT]: age 41.7 ± 11.3 years, BMI 32.0 ± 4.5 kg/m2, n = 12; type 2 diabetic: age 45.4 ± 10.1 years, BMI 30.3 ± 4.5 kg/m2, n = 18). Blood was collected before (0 h) and after the meal (1–4 h) for analysis. RESULTS Baseline endotoxin was significantly higher in the type 2 diabetic and IGT subjects than in NOC subjects, with baseline circulating endotoxin levels 60.6% higher in type 2 diabetic subjects than in NOC subjects (P < 0.05). Ingestion of a high-fat meal led to a significant rise in endotoxin levels in type 2 diabetic, IGT, and obese subjects over the 4-h time period (P < 0.05). These findings also showed that, at 4 h after a meal, type 2 diabetic subjects had higher circulating endotoxin levels (125.4%↑) than NOC subjects (P < 0.05). CONCLUSIONS These studies have highlighted that exposure to a high-fat meal elevates circulating endotoxin irrespective of metabolic state, as early as 1 h after a meal. However, this increase is substantial in IGT and type 2 diabetic subjects, suggesting that metabolic endotoxinemia is exacerbated after high fat intake. In conclusion, our data suggest that, in a compromised metabolic state such as type 2 diabetes, a continual snacking routine will cumulatively promote their condition more rapidly than in other individuals because of the greater exposure to endotoxin.

positive: The capacity of foodstuffs to induce innate immune activation of human monocytes in vitro is dependent on food content of stimulants of Toll-like r... The ingestion of fatty meals is associated with a transient, low-grade systemic inflammatory response in human subjects, involving the activation of circulating monocytes and the secretion of pro-inflammatory cytokines. However, it is not yet clear how different foodstuffs may promote inflammatory signalling. In a screen of forty filter-sterilised soluble extracts from common foodstuffs, seven were found to induce the secretion of TNF-α and IL-6 from human monocytes in vitro. To investigate what may differentiate inflammatory from non-inflammatory food extracts, stimulants of Toll-like receptor (TLR) 2 and TLR4 were quantified using human embryonic kidney-293 cells transfected with each TLR, and calibrated with defined bacterial lipopeptide (BLP) and lipopolysaccharide (LPS) standards. These assays revealed that while most foods contained undetectable levels of TLR2 or TLR4 stimulants, all TNF-α-inducing foods contained stimulants of either TLR2 (up to 1100 ng BLP-equivalent/g) or TLR4 (up to 2700 ng LPS-equivalent/g) in both the soluble and insoluble fractions. TLR stimulants were present mainly in meat products and processed foods, but were minimal or undetectable in fresh fruit and vegetables. The capacity of food extracts to induce TNF-α secretion in monocytes correlated with the content of both TLR2 (r 0·837) and TLR4 stimulants (r 0·748), and was completely abolished by specific inhibition of TLR2 and TLR4. LPS and BLP were found to be highly resistant to typical cooking times and temperatures, low pH and protease treatment. In conclusion, apparently unspoiled foodstuffs can contain large quantities of stimulants of TLR2 and TLR4, both of which may regulate their capacity to stimulate inflammatory signalling.

positive: Animal protein intake and risk of inflammatory bowel disease: The E3N prospective study. OBJECTIVES: Diet composition has long been suspected to contribute to inflammatory bowel disease (IBD), but has not been thoroughly assessed, and has been assessed only in retrospective studies that are prone to recall bias. The aim of the present study was to evaluate the role of dietary macronutrients in the etiology of IBD in a large prospective cohort. METHODS: The Etude Épidémiologique des femmes de la Mutuelle Générale de l'Education Nationale cohort consists of women living in France, aged 40-65 years, and free of major diseases at inclusion. A self-administered questionnaire was used to record dietary habits at baseline. Questionnaires on disease occurrence and lifestyle factors were completed every 24 months. IBDs were assessed in each questionnaire until June 2005, and subsequently validated using clinical and pathological criteria. We estimated the association between nutrients or foods and IBD using Cox proportional hazards models adjusted for energy intake. RESULTS: Among 67,581 participants (705,445 person-years, mean follow-up since completion of the baseline dietary questionnaire 10.4 years), we validated 77 incident IBD cases. High total protein intake, specifically animal protein, was associated with a significantly increased risk of IBD, (hazards ratio for the third vs. first tertile and 95% confidence interval being 3.31 and 1.41-7.77 (P trend=0.007), and 3.03 and 1.45-6.34 (P trend=0.005) for total and animal protein, respectively). Among sources of animal protein, high consumption of meat or fish but not of eggs or dairy products was associated with IBD risk. CONCLUSIONS: High protein intake is associated with an increased risk of incident IBD in French middle-aged women.

positive: Anti-inflammatory effects of plant-based foods and of their constituents. Inflammation is a pathological condition underlying a number of diseases including cardiovascular diseases, cancer, and chronic inflammatory diseases. In addition, healthy, obese subjects also express markers of inflammation in their blood. Diet provides a variety of nutrients as well as non-nutritive bioactive constituents which modulate immunomodulatory and inflammatory processes. Epidemiological data suggest that dietary patterns strongly affect inflammatory processes. Primarily the intake of fruit and vegetables as well as of whole wheat is inversely associated with the risk of inflammation. In addition to observational studies there are also data from human intervention studies suggesting an anti-inflammatory potential of these plant foods. At the level of bioactive compounds occurring in plant foods, primarily carotenoids and flavonoids seem to modulate inflammatory as well as immunological processes. In conclusion, there is convincing evidence that plant foods and non-nutritive constituents associated with these foods modulate immunological and inflammatory processes. By means of anti-inflammatory activities a plant-based diet may contribute to the lower risk of cardiovascular diseases and cancer. A high intake of vegetables, fruit, and whole wheat as recommended by all international nutrition authorities provides a wide spectrum of bioactive compounds at health-promoting concentrations.

positive: Red meat and colon cancer: should we become vegetarians, or can we make meat safer? The effect of meat consumption on cancer risk is a controversial issue. However, recent meta-analyses show that high consumers of cured meats and red meat are at increased risk of colorectal cancer. This increase is significant but modest (20-30%). Current WCRF-AICR recommendations are to eat no more than 500 g per week of red meat, and to avoid processed meat. Moreover, our studies show that beef meat and cured pork meat promote colon carcinogenesis in rats. The major promoter in meat is heme iron, via N-nitrosation or fat peroxidation. Dietary additives can suppress the toxic effects of heme iron. For instance, promotion of colon carcinogenesis in rats by cooked, nitrite-treated and oxidized high-heme cured meat was suppressed by dietary calcium and by α-tocopherol, and a study in volunteers supported these protective effects in humans. These additives, and others still under study, could provide an acceptable way to prevent colorectal cancer. Copyright © 2011 Elsevier B.V. All rights reserved.

positive: Epidemilogical trends strongly suggest exposures as etiologic agents in the pathogenesis of sporadic Alzheimer's disease, diabetes mellitus, and no... Nitrosamines mediate their mutagenic effects by causing DNA damage, oxidative stress, lipid peroxidation, and pro-inflammatory cytokine activation, which lead to increased cellular degeneration and death. However, the very same pathophysiological processes comprise the "unbuilding" blocks of aging and insulin-resistance diseases including, neurodegeneration, diabetes mellitus (DM), and non-alcoholic steatohepatitis (NASH). Previous studies demonstrated that experimental exposure to streptozotocin, a nitrosamine-related compound, causes NASH, and diabetes mellitus Types 1, 2 and 3 (Alzheimer (AD)-type neurodegeneration). Herein, we review evidence that the upwardly spiraling trends in mortality rates due to DM, AD, and Parkinson's disease typify exposure rather than genetic-based disease models, and parallel the progressive increases in human exposure to nitrates, nitrites, and nitrosamines via processed/preserved foods. We propose that such chronic exposures have critical roles in the pathogenesis of our insulin resistance disease pandemic. Potential solutions include: 1) eliminating the use of nitrites in food; 2) reducing nitrate levels in fertilizer and water used to irrigate crops; and 3) employing safe and effective measures to detoxify food and water prior to human consumption. Future research efforts should focus on refining our ability to detect and monitor human exposures to nitrosamines and assess early evidence of nitrosamine-mediated tissue injury and insulin resistance.

positive: The nitrate story--no end in sight. It has been demonstrated that nitrates are reduced to nitrites in humans, possibly through bacterial activity. Nitrites, together with ubiquitous amines, can lead to an in-vivo synthesis of carcinogenic nitrosamines. The average daily intake of nitrates depends upon the amount of vegetables consumed and on the nitrate concentration in drinking water. Agricultural practices play an important part in the concentration of nitrate in both water and vegetables. If nitrate is taken up by the plant and not metabolised to amino acids, proteins or nucleic acids, it is stored in cell vacuoles as a reserve. However, with an over-supply of nitrate relative to possible photosynthesis, this stored nitrate is still present at harvest and leads to high concentrations in plant tissue. The nitrate content in plants also depends upon other factors, such as plant variety (cultivar), kind and amount of fertiliser, time of harvest and environmental factors such as light intensity, temperature, etc. It is suggested that we should try to meet the recommendations of toxicologists who believe a dramatic reduction nitrate intake for humans is necessary. It has been demonstrated that modern biological-organic farming methods clearly lead both to lower leaching of nitrates and to lower nitrate content in vegetables. Since no synthetic fungicides are used in this farming method, problems with the reaction of metabolites of such products and nitrites e.g. to highly cancerogenic and multigenic nitroso-ethylenethiourea do not exist.

positive: A survey of feeding N-nitrosodimethylamine (NDMA) to domestic animals over an 18 year period. Sodium nitrite and formalin have been used as preservatives in the fish meal industry in Norway since 1953. In 1957, fur farms suffered losses of mink due to a new, malignant liver disease. Experimental feeding of herring meal to cows and sheep resulted in the death of some of the animals. Further studies showed that amines (TMAO) normally present in fish, can react with sodium nitrite used as preservative, or nitrogen oxides from the combustion of fuel oils used during processing, to produce the toxic agent, NDMA. Mink and fox may consume considerable amounts of fish meal in their diets. If the fish meal contains sufficient NDMA, the incidence of liver failure or tumours can be quite high. Long-term exposure to as little as 0.1 mg NDMA/kg b.w./day in the diet of mink, cows and sheep can produce fibro-occlusive changes in the hepatic vessels. These lesions can later cause capillary ectasies-like changes in cows, which are similar in appearance to hemangiomas seen in mink. The mink liver hemangiomas develop into hemangiosarcomas. We currently consider capillary ectasies-like changes in cows exposed to NDMA to represent pre-cancerous lesions.

positive: Nutritional composition of dry-cured ham and its role in a healthy diet. Dry-cured ham is a traditional product with a strong presence in markets in the Mediterranean area. It is very popular with European consumers and is of enormous economic importance for the meat industry in the Mediterranean area. Although the great palatability of ham largely outweighs other considerations, aspects relating to health and wellbeing are increasingly important factors in consumer decisions. The potential role of ham in a context of healthy nutrition has not been clearly elucidated, especially considering that origins and production methods of dry-cured hams can induce differences in composition. The object of this review was on the one hand to provide an analysis of the components of dry-cured ham and their role in a healthy diet, and on the other hand to suggest possible strategies for improving its nutritional composition. 2009 Elsevier Ltd. All rights reserved.

positive: A meta-analysis of maternal cured meat consumption during pregnancy and the risk of childhood brain tumors. OBJECTIVE: N-Nitroso compounds (NOCs) are recognized neural carcinogens in animal models and are suspected human carcinogens. A meta-analysis was performed examining the possible association of maternal intake of cured meat (an important source of dietary NOCs) during pregnancy and the risk of pediatric brain tumors. METHODS: Data from epidemiological studies were pooled using a general variance-based meta-analytic method employing confidence intervals described by Greenland in 1986. The outcome of interest was a summary relative risk (RR) reflecting the risk of childhood brain tumor (CBT) development associated with maternal intake of cured meats during pregnancy. Sensitivity analyses were performed when necessary to explain any observed statistical heterogeneity. RESULTS: Seven observational studies were found that met the protocol-specified inclusion criteria. Analysis for heterogeneity demonstrated a lack of statistical heterogeneity (p = 0.59), indicating that the data could be statistically combined. Pooling data from the 6 reports containing data on maternal cured meat intake of all types yielded an RR of 1.68 (1.30- 2.17), being a statistically significant result. Analyzing CBT risk by type of cured meat ingested showed that hot dog consumption increased CBT risk by 33% (1.08-1.66), with a similar increase shown by frequent ingestion of sausage, i.e. 44%. CONCLUSION: The data provide support for the suspected causal association between ingestion of NOCs from cured meats during pregnancy and subsequent CBT in offspring. Limitations in study design preclude definitive conclusions, but the relationship warrants exploration via additional observational and laboratory-based studies. Copyright 2004 S. Karger AG, Basel

positive: The comet assay with 8 mouse organs: results with 39 currently used food additives. We determined the genotoxicity of 39 chemicals currently in use as food additives. They fell into six categories-dyes, color fixatives and preservatives, preservatives, antioxidants, fungicides, and sweeteners. We tested groups of four male ddY mice once orally with each additive at up to 0.5xLD(50) or the limit dose (2000mg/kg) and performed the comet assay on the glandular stomach, colon, liver, kidney, urinary bladder, lung, brain, and bone marrow 3 and 24h after treatment. Of all the additives, dyes were the most genotoxic. Amaranth, Allura Red, New Coccine, Tartrazine, Erythrosine, Phloxine, and Rose Bengal induced dose-related DNA damage in the glandular stomach, colon, and/or urinary bladder. All seven dyes induced DNA damage in the gastrointestinal organs at a low dose (10 or 100mg/kg). Among them, Amaranth, Allura Red, New Coccine, and Tartrazine induced DNA damage in the colon at close to the acceptable daily intakes (ADIs). Two antioxidants (butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT)), three fungicides (biphenyl, sodium o-phenylphenol, and thiabendazole), and four sweeteners (sodium cyclamate, saccharin, sodium saccharin, and sucralose) also induced DNA damage in gastrointestinal organs. Based on these results, we believe that more extensive assessment of food additives in current use is warranted.

positive: Genotoxicity and cell transformation studies with sorbates in Syrian hamster embryo fibroblasts. Sorbic acid, sodium sorbate and potassium sorbate were tested for their genotoxic potential in the Syrian hamster embryo (SHE) fibroblast micronucleus assay and the SHE cell transformation test in vitro. Sorbic acid and potassium sorbate showed no activity in either test system. When freshly prepared sodium sorbate solutions were used, no genotoxic or cell-transforming activity was detected. However, sodium sorbate as stored solution, which previously had been heated and sonicated to facilitate solubilization, yielded a positive response in both test systems. It is concluded that oxidation products of sodium sorbate that possess genotoxic and cell-transforming properties are formed under conditions of heating, sonication and storage.

positive: Does potassium sorbate induce genotoxic or mutagenic effects in lymphocytes? The present study evaluates the genotoxic potential of potassium sorbate (PS) in cultured and isolated human lymphocytes. To assess the damage caused by PS in humans, we designed in vitro experiments by measuring chromosomal aberrations (CAs), sister-chromatid exchanges (SCEs), micronucleus (MN) and comet assays. Lymphocytes were treated with negative control (sterile distilled water), positive control (MMC for cultured lymphocytes, and H(2)O(2) for isolated lymphocytes) and four concentrations (125, 250, 500, and 1000 microg/ml) of PS. According to the results, PS treatment significantly increases the CAs (with or without gaps at 500 and 1000 microg/ml concentrations) and SCEs (at 250, 500, 1000 microg/ml for 24h and 125, 250, 500, 1000 microg/ml for 48h) compared with vehicle control. Following treatment of the isolated lymphocytes for 1h, significant PS-induced DNA strand breaks were observed, at all concentrations. However, PS failed to significantly affect the MN assay. On the contrary, PS does not cause cell cycle delay as noted by the non-significant decrease in the cytokinesis-block proliferation index (CBPI) and replicative index (RI). Only a slight decrease was observed in the mitotic index (MI) at the highest concentration for both treatment times. From the results, PS is clearly seen to be genotoxic to the human peripheral blood lymphocytes in vitro. Copyright (c) 2009 Elsevier Ltd. All rights reserved.

positive: Effects of sorbic acid and its salts on chromosome aberrations, sister chromatid exchanges and gene mutations in cultured Chinese hamster cells. The ability of sorbic acid and its potassium and sodium salts to induce chromosome aberrations, sister chromatid exchanges (SCE) and gene mutations in cultured Chinese hamster V79 cells was examined. Sodium sorbate caused significant induction of chromosome aberrations and SCE, and also induced 6-thioguanine-resistant mutations in a dose-dependent manner. The clastogenic potency of sodium sorbate was found to be less than one hundredth of that of the potent clastogen N-methyl-N'-nitro-N-nitrosoguanidine. The induction of SCE by sodium sorbate was twice the control level, whereas that by methyl methanesulphonate, a potent inducer of SCE, was 14 times the control level. The mutagenic potency of sodium sorbate was less than one-tenth that of ethyl methanesulphonate, a potent inducer of mutation, when compared at an equitoxic level. Sorbic acid and its potassium salt induced chromosome aberrations, but only at the highest doses tested. These compounds also induced 1.2 times the control level of SCE, but neither compound induced 6-thioguanine-resistant mutations. The cytogenetic activity of sodium sorbate was concluded not to be due to the effect of osmotic pressure or an impurity. These results indicate that sodium sorbate is a genotoxic agent, although its potency seems to be weak, and that sorbic acid and potassium sorbate are less genotoxic than the sodium salt.

positive: Diet and inflammation. The emerging role of chronic inflammation in the major degenerative diseases of modern society has stimulated research into the influence of nutrition and dietary patterns on inflammatory indices. Most human studies have correlated analyses of habitual dietary intake as determined by a food frequency questionnaire or 24-hour recall with systemic markers of inflammation like high-sensitivity C-reactive protein (HS-CRP), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-α). An occasional study also includes nutrition analysis of blood components. There have been several controlled interventions which evaluated the effect of a change in dietary pattern or of single foods on inflammatory markers in defined populations. Most studies reveal a modest effect of dietary composition on some inflammatory markers in free-living adults, although different markers do not vary in unison. Significant dietary influences have been established for glycemic index (GI) and load (GL), fiber, fatty acid composition, magnesium, carotenoids, and flavonoids. A traditional Mediterranean dietary pattern, which typically has a high ratio of monounsaturated (MUFA) to saturated (SFA) fats and ω-3 to ω-6 polyunsaturated fatty acid (PUFAs) and supplies an abundance of fruits, vegetables, legumes, and grains, has shown anti-inflammatory effects when compared with typical North American and Northern European dietary patterns in most observational and interventional studies and may become the diet of choice for diminishing chronic inflammation in clinical practice.

positive: Aluminium and lead: molecular mechanisms of brain toxicity. The fact that aluminium (Al) and lead (Pb) are both toxic metals to living organisms, including human beings, was discovered a long time ago. Even when Al and Pb can reach and accumulate in almost every organ in the human body, the central nervous system is a particular target of the deleterious effects of both metals. Select human population can be at risk of Al neurotoxicity, and Al is proposed to be involved in the etiology of neurodegenerative diseases. Pb is a widespread environmental hazard, and the neurotoxic effects of Pb are a major public health concern. In spite of the numerous efforts and the accumulating evidence in this area of research, the mechanisms of Al and Pb neurotoxicity are still not completely elucidated. This review will particularly address the involvement of oxidative stress, membrane biophysics alterations, deregulation of cell signaling, and the impairment of neurotransmission as key aspects involved Al and Pb neurotoxicity.

positive: Aluminum bioavailability from basic sodium aluminum phosphate, an approved food additive emulsifying agent, incorporated in cheese Oral aluminum (Al) bioavailability from drinking water has been previously estimated, but there is little information on Al bioavailability from foods. It was suggested that oral Al bioavailability from drinking water is much greater than from foods. The objective was to further test this hypothesis. Oral Al bioavailability was determined in the rat from basic [26Al]-sodium aluminum phosphate (basic SALP) in a process cheese. Consumption of ~ 1 gm cheese containing 1.5 or 3% basic SALP resulted in oral Al bioavailability (F) of ~ 0.1 and 0.3%, respectively, and time to maximum serum 26Al concentration (Tmax) of 8 to 9 h. These Al bioavailability results were intermediate to previously reported results from drinking water (F ~ 0.3%) and acidic-SALP incorporated into a biscuit (F ~ 0.1%), using the same methods. Considering the similar oral bioavailability of Al from food vs. water, and their contribution to the typical human’s daily Al intake (~ 95 and 1.5%, respectively), these results suggest food contributes much more Al to systemic circulation, and potential Al body burden, than does drinking water. These results do not support the hypothesis that drinking water provides a disproportionate contribution to total Al absorbed from the gastrointestinal tract.

positive: Algal-oil capsules and cooked salmon: nutritionally equivalent sources of docosahexaenoic acid. Food and nutrition professionals question whether supplement-sourced nutrients appear to be equivalent to those derived from natural food sources. We compared the nutritional availability of docosahexaenoic acid (DHA) from algal-oil capsules to that from assayed cooked salmon in 32 healthy men and women, ages 20 to 65 years, in a randomized, open-label, parallel-group study. In this 2-week study comparing 600 mg DHA/day from algal-oil capsules to that from assayed portions of cooked salmon, mean change from baseline in plasma phospholipids and erythrocyte DHA levels was analyzed and DHA levels were compared by Student's t tests. In post-hoc analyses to determine bioequivalence, least-squares mean ratios of percent change from baseline in plasma phospholipid and erythrocyte DHA levels were compared. DHA levels increased by approximately 80% in plasma phospholipids and by approximately 25% in erythrocytes in both groups. Changes in DHA levels in plasma phospholipids and erythrocytes were similar between groups. As measured by delivery of DHA to both plasma and erythrocytes, fish and algal-oil capsules were equivalent. Both regimens were generally well-tolerated. These results indicate that algal-oil DHA capsules and cooked salmon appear to be bioequivalent in providing DHA to plasma and red blood cells and, accordingly, that algal-oil DHA capsules represent a safe and convenient source of non-fish-derived DHA.

positive: Aquaculture practices and potential human health risks: current knowledge and future priorities. Annual global aquaculture production has more than tripled within the past 15 years, and by 2015, aquaculture is predicted to account for 39% of total global seafood production by weight. Given that lack of adequate nutrition is a leading contributor to the global burden of disease, increased food production through aquaculture is a seemingly welcome sign. However, as production surges, aquaculture facilities increasingly rely on the heavy input of formulated feeds, antibiotics, antifungals, and agrochemicals. This review summarizes our current knowledge concerning major chemical, biological and emerging agents that are employed in modern aquaculture facilities and their potential impacts on public health. Findings from this review indicate that current aquaculture practices can lead to elevated levels of antibiotic residues, antibiotic-resistant bacteria, persistent organic pollutants, metals, parasites, and viruses in aquacultured finfish and shellfish. Specific populations at risk of exposure to these contaminants include individuals working in aquaculture facilities, populations living around these facilities, and consumers of aquacultured food products. Additional research is necessary not only to fully understand the human health risks associated with aquacultured fish versus wild-caught fish but also to develop appropriate interventions that could reduce or prevent these risks. In order to adequately understand, address and prevent these impacts at local, national and global scales, researchers, policy makers, governments, and aquaculture industries must collaborate and cooperate in exchanging critical information and developing targeted policies that are practical, effective and enforceable.

positive: Food additives and hyperactive behaviour in 3-year-old and 8/9-year-old children in the community: a randomised, double-blinded, placebo-controlled... BACKGROUND: We undertook a randomised, double-blinded, placebo-controlled, crossover trial to test whether intake of artificial food colour and additives (AFCA) affected childhood behaviour. METHODS: 153 3-year-old and 144 8/9-year-old children were included in the study. The challenge drink contained sodium benzoate and one of two AFCA mixes (A or B) or a placebo mix. The main outcome measure was a global hyperactivity aggregate (GHA), based on aggregated z-scores of observed behaviours and ratings by teachers and parents, plus, for 8/9-year-old children, a computerised test of attention. This clinical trial is registered with Current Controlled Trials (registration number ISRCTN74481308). Analysis was per protocol. FINDINGS: 16 3-year-old children and 14 8/9-year-old children did not complete the study, for reasons unrelated to childhood behaviour. Mix A had a significantly adverse effect compared with placebo in GHA for all 3-year-old children (effect size 0.20 [95% CI 0.01-0.39], p=0.044) but not mix B versus placebo. This result persisted when analysis was restricted to 3-year-old children who consumed more than 85% of juice and had no missing data (0.32 [0.05-0.60], p=0.02). 8/9-year-old children showed a significantly adverse effect when given mix A (0.12 [0.02-0.23], p=0.023) or mix B (0.17 [0.07-0.28], p=0.001) when analysis was restricted to those children consuming at least 85% of drinks with no missing data. INTERPRETATION: Artificial colours or a sodium benzoate preservative (or both) in the diet result in increased hyperactivity in 3-year-old and 8/9-year-old children in the general population.

positive: Food additives and hyperactivity Evidence supports a trial period of eliminating colourings and preservatives from the diet

negative: Dietary intake and risk of developing inflammatory bowel disease: a systematic review of the literature. OBJECTIVES: The incidence of inflammatory bowel disease (IBD) is increasing. Dietary factors such as the spread of the "Western" diet, high in fat and protein but low in fruits and vegetables, may be associated with the increase. Although many studies have evaluated the association between diet and IBD risk, there has been no systematic review. METHODS: We performed a systematic review using guideline-recommended methodology to evaluate the association between pre-illness intake of nutrients (fats, carbohydrates, protein) and food groups (fruits, vegetables, meats) and the risk of subsequent IBD diagnosis. Eligible studies were identified via structured keyword searches in PubMed and Google Scholar and manual searches. RESULTS: Nineteen studies were included, encompassing 2,609 IBD patients (1,269 Crohn's disease (CD) and 1,340 ulcerative colitis (UC) patients) and over 4,000 controls. Studies reported a positive association between high intake of saturated fats, monounsaturated fatty acids, total polyunsaturated fatty acids (PUFAs), total omega-3 fatty acids, omega-6 fatty acids, mono- and disaccharides, and meat and increased subsequent CD risk. Studies reported a negative association between dietary fiber and fruits and subsequent CD risk. High intakes of total fats, total PUFAs, omega-6 fatty acids, and meat were associated with an increased risk of UC. High vegetable intake was associated with a decreased risk of UC. CONCLUSIONS: High dietary intakes of total fats, PUFAs, omega-6 fatty acids, and meat were associated with an increased risk of CD and UC. High fiber and fruit intakes were associated with decreased CD risk, and high vegetable intake was associated with decreased UC risk.

negative: The aryl hydrocarbon receptor in inflammatory bowel disease: linking the environment to disease pathogenesis. PURPOSE OF REVIEW: The aryl hydrocarbon receptor (AhR), a transcription factor activated by a large number of environmental agents, modulates the activity of immune and nonimmune cells in the gut, and may represent an important link between the environment and the immune perturbations which underlie the pathogenesis of inflammatory bowel disease. This review will summarize the current knowledge of the role of AhR in regulation of intestinal immune homeostasis and inflammation. RECENT FINDINGS: Activation of AhR by dietary ligands is necessary for the maintenance or expansion of innate immune cells in the gut, such as intraepithelial lymphocytes (IELs) and interleukin (IL)-22-producing lymphoid cells (ILC22). AhR-deficient mice lack IELs, have reduced number of ILC22 cells, and are more susceptible to bacterial infections and experimental colitis. In animal models, AhR activators inhibit proinflammatory cytokine synthesis and attenuate colitis by a pathway that involves IL-22. Analysis of AhR in the human gut reveals that intestinal T cells and natural killer cells isolated from Crohn's disease patients express low levels of AhR and respond to AhR ligands by downregulating inflammatory cytokines and upregulating IL-22. SUMMARY: These novel findings may help explain how environmental factors may regulate mucosal immune responses.

negative: Pro-inflammatory NF-κB and early growth response gene 1 regulate epithelial barrier disruption by food additive carrageenan in human intestinal epi... The widely used food additive carrageenan (CGN) has been shown to induce intestinal inflammation, ulcerative colitis-like symptoms, or neoplasm in the gut epithelia in animal models, which are also clinical features of human inflammatory bowel disease. In this study, the effects of CGN on pro-inflammatory transcription factors NF-κB and early growth response gene 1 product (EGR-1) were evaluated in terms of human intestinal epithelial barrier integrity. Both pro-inflammatory transcription factors were elevated by CGN and only NF-κB activation was shown to be involved in the induction of pro-inflammatory cytokine interleukin-8. Moreover, the integrity of the in vitro epithelial monolayer under the CGN insult was maintained by both activated pro-inflammatory transcription factors NF-κB and EGR-1. Suppression of NF-κB or EGR-1 aggravated barrier disruption by CGN, which was associated with the reduced gene expression of tight junction component zonula occludens 1 and its irregular localization in the epithelial monolayer. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

negative: Anti-Gal titers in healthy adults and inflammatory bowel disease patients. INTRODUCTION: ALPHA-GAL is a glycoconjugate present on cell membranes of mammals and bacteria but not humans who display anti-Gal antibodies (AB) in high titers provoked by the commensal gut flora. In the present study, we sought to determine the longitudinal course of alpha-Gal specific AB titers of all isotypes over 8 weeks among healthy adult subjects. Furthermore, we hypothesized that inflammatory bowel disease (IBD) patients display increased anti-Gal titers. MATERIALS AND METHODS: We drew serum from healthy probands (n=20) weekly for 8 weeks and obtained plasma samples of from patients suffering from Crohn's disease (n=20) and ulcerative colitis (n=20). We measured anti-Gal ABs of all isotypes and total immunoglobulin (Ig) content using an enzyme-linked immunosorbent assay technique. For statistical evaluation of the longitudinal titers, we calculated confidence intervals for the slopes of a random intercept model, comparing variances between and within the probands. For group comparisons, we performed paired student t-tests and Pearson correlations. RESULTS: Alpha-Gal specific IgG, IgM, IgD, and IgA titers remained unvaried within a narrow range upon longitudinal observation. Most probands did not display alpha-Gal specific IgE ABs. Crohn's disease patients showed highly increased alpha-Gal-specific IgA titers compared with control subjects (P<.01). CONCLUSION: Apart from IgE, alpha-Gal-specific ABs of all isotypes remained constant over longer time periods in healthy subjects. Thus, significant titer changes actually represent increased antigen exposure and a specific anti-alpha-Gal response. Crohn's disease patients display increased anti-Gal IgA titers compared with healthy controls, which reflects a chronically impaired mucosal gut barrier in this patient cohort. Copyright © 2011 Elsevier Inc. All rights reserved.

negative: Curcumin, an active component of turmeric in the prevention and treatment of ulcerative colitis: preclinical and clinical observations. Inflammatory bowel disease (IBD) comprising of ulcerative colitis (UC) and Crohn's disease (CD) is a major ailment affecting the small and large bowel. In clinics, IBD is treated using 5-amninosalicylates, antibiotics, the steroids and immunomodulators. Unfortunately, the long term usages of these agents are associated with undue side effects and compromise the therapeutic advantage. Accordingly, there is a need for novel agents that are effective, acceptable and non toxic to humans. Preclinical studies in experimental animals have shown that curcumin, an active principle of the Indian spice turmeric (Curcuma longa Linn) is effective in preventing or ameliorating UC and inflammation. Over the last few decades there has been increasing interest in the possible role of curcumin in IBD and several studies with various experimental models of IBD have shown it to be effective in mediating the inhibitory effects by scavenging free radicals, increasing antioxidants, influencing multiple signaling pathways, especially the kinases (MAPK, ERK), inhibiting myeloperoxidase, COX-1, COX-2, LOX, TNF-α, IFN-γ, iNOS; inhibiting the transcription factor NF-κB. Clinical studies have also shown that co-administration of curcumin with conventional drugs was effective, to be well-tolerated and treated as a safe medication for maintaining remission, to prevent relapse and improve clinical activity index. Large randomized controlled clinical investigations are required to fully understand the potential of oral curcumin for treating IBD.

negative: Dietary suppression of colonic cancer. Fiber or phytate? The incidence of colonic cancer differs widely between various human populations. It has been suggested that dietary fiber content is of utmost importance and is inversely related to the occurrence of colonic cancer. However, high-fiber diets are not always correlated with low frequency of colonic cancer, suggesting the involvement of additional dietary constituents. Inositol hexaphosphate (phytic acid) is an abundant plant seed component present in many, but not all, fiber-rich diets. The authors have found that phytic acid is a potent inhibitor of iron-mediated generation of the hazardous oxidant, hydroxyl radical. Herein, the authors propose that inhibition of intracolonic hydroxyl radical generation, via the chelation of reactive iron by phytic acid, may help explain the suppression of colonic carcinogenesis and other inflammatory bowel diseases by diets rich in phytic acid.

negative: A Prospective Study of Long-term Intake of Dietary Fiber and Risk of Crohn’s Disease and Ulcerative Colitis Background & Aims Increased intake of dietary fiber has been proposed to reduce risk of inflammatory bowel diseases (Crohn’s disease [CD], ulcerative colitis [UC]). However, few prospective studies have examined associations between long-term intake of dietary fiber and risk of incident CD or UC. Methods We collected and analyzed data from 170,776 women, followed over 26 y, who participated in the Nurses’ Health Study, followed for 3,317,425 person-y. Dietary information was prospectively ascertained via administration of a validated semi-quantitative food frequency questionnaire every 4 y. Self-reported CD and UC were confirmed through review of medical records. Cox proportional hazards models, adjusting for potential confounders, were used to calculate hazard ratios (HRs). Results We confirmed 269 incident cases of CD (incidence 8/100,000 person-y) and 338 cases of UC (incidence 10/100,000 person-y). Compared to the lowest quintile of energy-adjusted cumulative average intake of dietary fiber, intake of the highest quintile (median of 24.3 g/day) was associated with a 40% reduction in risk of CD (multivariate HR for CD, 0.59; 95% confidence interval [CI], 0.39–0.90). This apparent reduction appeared to be greatest for fiber derived from fruits; fiber from cereals, whole grains, or legumes did not modify risk. In contrast, neither total intake of dietary fiber (multivariate HR, 0.82; 95% CI 0.58–1.17) nor intake of fiber from specific sources appeared to be significantly associated with risk of UC. Conclusion Based on data from the Nurses’ Health Study, long-term intake of dietary fiber, particularly from fruit, is associated with lower risk of CD but not UC. Further studies are needed to determine the mechanisms that mediate this association.

negative: Antagonistic effects of sulfide and butyrate on proliferation of colonic mucosa: a potential role for these agents in the pathogenesis of ulcerativ... It has been shown that feces of patients with ulcerative colitis uniformly contain sulfate reducing bacteria. Sulfide produced by these bacteria interferes with butyrate-dependent energy metabolism of cultured colonocytes and may be involved in the pathogenesis of ulcerative colitis. Mucosal biopsies from the sigmoid rectum of 10 patients (no caner, polyps, inflammatory bowel disease) were incubated with either NaCl, sodium hydrogen sulfide (1 mmol/L), a combination of both sodium hydrogen sulfide and butyrate (10 mmol/L), or butyrate. Mucosal proliferation was assessed by bromodeoxyuridine labeling of cells in S-phase. Compared to NaCl, sulfide increased the labeling of the entire crypt significantly, by 19% (p < 0.05). This effect was due to an expansion of the proliferative zone to the upper crypt (compartments 3-5), where the increase in proliferation was 54%. Sulfide-induced hyperproliferation was reversed when samples were coincubated with sulfide and butyrate. The study shows that sodium hydrogen sulfide induces mucosal hyperproliferation. Our data support a possible role of sulfide in the pathogenesis of UC and confirm the role of butyrate in the regulation of colonic proliferation and in the treatment of UC.

negative: Non-nutrient causes of low-grade, systemic inflammation: support for a 'canary in the mineshaft' view of obesity in chronic disease. A form of low-grade, systemic inflammation ('metaflammation') is linked to many types of chronic disease. Initially, this was thought to be causally related to weight gain and obesity and a possible explanation of the link between obesity and disease. However, several lifestyle-related inducers of such inflammation, some of which are associated with obesity, but some of which are not, have now been identified. The most common of these have been nutritive related, suggesting that there could still be a relationship, either directly or indirectly, with obesity. Here we provide evidence for non-nutritive inflammatory inducers, providing further support for an earlier suggestion that while obesity, beyond a point, may have a direct link with disease, this may be neither necessary nor sufficient to explain the current epidemic of chronic disease. A more ubiquitous cause encompassing all inflammatory inducers is the modern, post-industrial environment and lifestyles emanating from this. Obesity may thus be more of 'a canary in the mineshaft', warning of bigger global problems, than just a single pathway to modern environmentally driven disease. © 2010 The Authors. obesity reviews © 2010 International Association for the Study of Obesity.

negative: Lipotoxicity: Effects of Dietary Saturated and Transfatty Acids The ingestion of excessive amounts of saturated fatty acids (SFAs) and transfatty acids (TFAs) is considered to be a risk factor for cardiovascular diseases, insulin resistance, dyslipidemia, and obesity. The focus of this paper was to elucidate the influence of dietary SFA and TFA intake on the promotion of lipotoxicity to the liver and cardiovascular, endothelial, and gut microbiota systems, as well as on insulin resistance and endoplasmic reticulum stress. The saturated and transfatty acids favor a proinflammatory state leading to insulin resistance. These fatty acids can be involved in several inflammatory pathways, contributing to disease progression in chronic inflammation, autoimmunity, allergy, cancer, atherosclerosis, hypertension, and heart hypertrophy as well as other metabolic and degenerative diseases. As a consequence, lipotoxicity may occur in several target organs by direct effects, represented by inflammation pathways, and through indirect effects, including an important alteration in the gut microbiota associated with endotoxemia. Interactions between these pathways may perpetuate a feedback process that exacerbates an inflammatory state. The importance of lifestyle modification, including an improved diet, is recommended as a strategy for treatment of these diseases.

negative: Dioxin May Promote Inflammation-Related Development of Endometriosis Laboratory and population-based studies suggest that exposure to environmental toxicants may be one of several triggers for the development of endometriosis. We discuss evidence that modulation of the endometrial endocrine-immune interface could mechanistically link toxicant exposure to the development of this disease. Capsule Summary: Environmental toxicant exposure induces an inflammatory-like endometrial response that may promote the development of endometriosis.

negative: Inflammatory bowel disease in rural sub-Saharan Africa: rarity of diagnosis in patients attending mission hospitals. One hundred and eighteen missionaries working on 75 mission stations or hospitals in 24 sub-Saharan African countries provided information about their medical practice in the preceding year of 1981. Details were collected of the total number of patients seen and admitted during the year, and the number of cases of bloody diarrhoea, typhoid and inflammatory bowel disease. Over 1 million outpatients and about 190,000 inpatients were treated. These included 12,859 cases of bloody diarrhoea, of whom 1,914 had typhoid. Twenty-two cases of inflammatory bowel disease were also reported. Histological support was least available in West Africa and only 25% of hospitals had access to this facility. Nevertheless, the frequency with which inflammatory bowel disease in sub-Saharan Africa is difficult and limited by access to diagnostic facilities. It is likely to be some time before reliable estimates of the incidence and prevalence of Crohn's disease and ulcerative colitis in the rural African population can be made.

negative: Between Celiac Disease and Irritable Bowel Syndrome: The “No Man’s Land” of Gluten Sensitivity The repertoire of gastrointestinal (GI) symptoms is finite; however, the etiologies and mechanisms underlying symptom generation and perception are diverse and, in many cases, unknown. This review examines the clinical and experimental evidence exploring the putative relationship between gluten sensitivity (GS) and the generation of GI symptoms. It explores the hypothesis that, in a proportion of patients, GS causes functional bowel disorder (FBD)-like symptoms. We propose a model for investigating and understanding the induction of GI symptoms and dysfunction by gluten in FBD and organic disease. We hypothesize that, even in the absence of fully developed celiac disease, gluten can induce symptoms similar to FBD. We discuss the hypothesis that GS and post-infectious irritable bowel syndrome (IBS) provide two triggers that can explain at least part of the spectrum that constitutes IBS, further advancing an understanding of the role of mucosal responses to luminal factors in FBDs. We propose that the animal model of GS in human leukocyte antigen (HLA)-DQ8 mice allows investigation of mucosal pathophysiological changes that occur before the onset of full-blown inflammation in a GS host. A better understanding of how gluten can cause symptoms in sensitive individuals will illuminate the interaction between host genotype, diet, and intestinal microbiota in generating one of the most common GI conditions.

negative: Curcumin: an orally bioavailable blocker of TNF and other pro-inflammatory biomarkers TNFs are major mediators of inflammation and inflammation-related diseases, hence, the United States Food and Drug Administration (FDA) has approved the use of blockers of the cytokine, TNF-α, for the treatment of osteoarthritis, inflammatory bowel disease, psoriasis and ankylosis. These drugs include the chimeric TNF antibody (infliximab), humanized TNF-α antibody (Humira) and soluble TNF receptor-II (Enbrel) and are associated with a total cumulative market value of more than $20 billion a year. As well as being expensive ($15 000–20 000 per person per year), these drugs have to be injected and have enough adverse effects to be given a black label warning by the FDA. In the current report, we describe an alternative, curcumin (diferuloylmethane), a component of turmeric (Curcuma longa) that is very inexpensive, orally bioavailable and highly safe in humans, yet can block TNF-α action and production in in vitro models, in animal models and in humans. In addition, we provide evidence for curcumin's activities against all of the diseases for which TNF blockers are currently being used. Mechanisms by which curcumin inhibits the production and the cell signalling pathways activated by this cytokine are also discussed. With health-care costs and safety being major issues today, this golden spice may help provide the solution. Linked Articles This article is part of a themed section on Emerging Therapeutic Aspects in Oncology. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2013.169.issue-8

negative: Carrageenan induces interleukin-8 production through distinct Bcl10 pathway in normal human colonic epithelial cells. Carrageenan is a high molecular weight sulfated polygalactan used to improve the texture of commercial food products. Its use increased markedly during the last half century, although carrageenan is known to induce inflammation in rheumatological models and in intestinal models of colitis. We performed studies to determine its direct effects on human intestinal cells, including normal human intestinal epithelial cells from colonic surgeries, the normal intestinal epithelial cell line NCM460, and normal rat ileal epithelial cells. Cells were treated with high molecular weight lambda-carrageenan at a concentration of 1 mug/ml for 1-96 h. IL-8, IL-8 promoter activity, total and nuclear NF-kappaB, IkappaBalpha, phospho-IkappaBalpha, and Bcl10 were assessed by immunohistochemistry, Western blot, ELISA, and cDNA microarray. Increased Bcl10, nuclear and cytoplasmic NF-kappaB, IL-8 promoter activation, and IL-8 secretion were detected following carrageenan exposure. Knockdown of Bcl10 by siRNA markedly reduced the increase in IL-8 that followed carrageenan exposure in the NCM460 cells. These results show, for the first time, that exposure of human intestinal epithelial cells to carrageenan triggers a distinct inflammatory pathway via activation of Bcl10 with NF-kappaB activation and upregulation of IL-8 secretion. Since Bcl10 contains a caspase-recruitment domain, similar to that found in NOD2/CARD15 and associated with genetic predisposition to Crohn's disease, the study findings may represent a link between genetic and environmental etiologies of inflammatory bowel disease. Because of the high use of carrageenan as a food additive in the diet, the findings may have clinical significance.

negative: Evaluation of certain food additives. Seventy-first report of the Joint FAO/WHO Expert Committee on Food Additives. This report represents the conclusions of a Joint FAO/WHO Expert Committee convened to evaluate the safety of various food additives, with a view to recommending acceptable daily intakes (ADIs) and to preparing specifications for identity and purity. The first part of the report contains a general discussion of the principles governing the toxicological evaluation and assessment of intake of food additives. A summary follows of the Committee's evaluations of technical, toxicological and intake data for certain food additives: branching glycosyltransferase from Rhodothermus obamensis expressed in Bacillus subtilis, cassia gum, cyclamic acid and its salts (dietary exposure assessment), cyclotetraglucose and cyclotetraglucose syrup, ferrous ammonium phosphate, glycerol ester of gum rosin, glycerol ester of tall oil rosin, lycopene from all sources, lycopene extract from tomato, mineral oil (low and medium viscosity) class II and class III, octenyl succinic acid modified gum arabic, sodium hydrogen sulfate and sucrose oligoesters type I and type II. Specifications for the following food additives were revised: diacetyltartaric acid and fatty acid esters of glycerol, ethyl lauroyl arginate, glycerol ester of wood rosin, nisin preparation, nitrous oxide, pectins, starch sodium octenyl succinate, tannic acid, titanium dioxide and triethyl citrate. Annexed to the report are tables summarizing the Committee's recommendations for intakes and toxicological evaluations of the food additives considered.

negative: When can we cure Crohn's? Crohn's disease is a life-long idiopathic inflammatory disease which affects the entire gastrointestinal tract and occasionally extra-intestinal organs. CD is thought to result from complex interactions between environmental factors, the gut microbes, and the genetic background and the immune system of the host. In the last decades research on these pathogenetic components, and especially on mucosal immunity, has led to the development of biologic agents and therapeutic strategies that have improved dramatically the treatment of CD but we are still far away from curing the disease. If there is a treatment for CD that will probably evolve through methodical steps towards integrating research on all the components involved in the pathogenesis of CD. This holistic and global approach may aid at unravelling the mysteries of CD and developing novel agents and therapeutic strategies which by targeting multiple pathogenetic pathways and at different stages of disease may lead hopefully to cure. Copyright © 2014 Elsevier Ltd. All rights reserved.

negative: Evolution of Inflammatory Diseases The association of inflammation with modern human diseases (e.g. obesity, cardiovascular disease, type 2 diabetes mellitus, cancer) remains an unsolved mystery of current biology and medicine. Inflammation is a protective response to noxious stimuli that unavoidably occurs at a cost to normal tissue function. This fundamental tradeoff between the cost and benefit of the inflammatory response has been optimized over evolutionary time for specific environmental conditions. Rapid change of the human environment due to niche construction outpaces genetic adaptation through natural selection, leading increasingly to a mismatch between the modern environment and selected traits. Consequently, multiple tradeoffs that affect human physiology are not optimized to the modern environment, leading to increased disease susceptibility. Here we examine the inflammatory response from an evolutionary perspective. We discuss unique aspects of the inflammatory response and its evolutionary history that can help explain the association between inflammation and modern human diseases.

negative: Asthma induced by sulphur dioxide, benzoate and tartrazine contained in orange drinks. Of 272 patients with asthma, thirty (11%) gave a history of exacerbations occurring after ingestion, solutions of orange orange drinks. Fourteen of these were given provocation tests by drinking, on separate occasions of sulphur dioxide, sodium benzoate and tartrazine, which are present in all orange drinks. Eight reacted to sulphur dioxide with a fall in FEV1, four to sodium benzoate and one to tartrazine, and four did not react to any of these agents. Three of the benzoate patients were also sensitive to sulphur dioxide. The sulphur dioxide sensitive patients were predominantly young, with extrinsic asthma. The benzoate sensitive patients were predominantly middle-aged and the proportion with intrinsic asthma was higher. Prior inhalation of sodium cromoglycate by four patients inhibited the reaction to these substances. Sulphur dioxide has not previously been reported to cause exacerbations of asthma when ingested as a food preservative. It is used as a preservative in a wide range of acidic beverages and foods, and should be considered as possibly causal in patients suffering from apparently cryptogenic asthma, and asthma seemingly due to food allergy.

negative: Dietary clues to the pathogenesis of Crohn's disease. Crohn's disease is a complex inherited disorder of unknown pathogenesis with environmental, genetic and microbial factors involved in the development of the disease. A remarkable feature of this disease in childhood is the effective response to exclusive enteral nutrition (EEN) therapy and the need for complete exclusion of normal diet required for success (principle of exclusivity). EEN or dietary interventions might act through removal of dietary components, which affect microbial composition, decrease a proinflammatory response and promote restitution of the epithelial barrier, likewise allowing termination of this vicious disease-forming cycle before a critical threshold is reached. Multiple traditional and nontraditional dietary components may affect the microbiome, mucous layer, intestinal permeability, or adherence and translocation of pathobionts. We review the epidemiological data, as well as data from animal models and cell lines, and propose a model for pathogenesis we have termed the 'bacterial penetration cycle', whereby dietary components such as animal fat, high sugar intake and gliadin, and consumption of emulsifiers, maltodextrin as well as low-fiber diets may be able to cause a localized acquired bacterial clearance defect, leading to bacterial adhesion and penetration, and subsequently inflammation in the gut. © 2014 S. Karger AG, Basel.

negative: Bowel obsession syndrome in a patient with ulcerative colitis. Gastroenterologists are often faced with the diagnostic problem of differentiating acute symptoms of ulcerative colitis from functional intestinal disorders. Bowel obsession syndrome (BOS) is an OCD-like, functional syndrome characterized by fear of fecal incontinence and compulsive behaviors of evacuation-checking. Only sparse case studies on treatment of BOS with antidepressants have been published. This is the first study on successful psychotherapy of a male patient with ulcerative colitis overlapping functional bowel symptoms and marked symptoms of BOS. Clinical recognition of BOS may help clinicians in differential diagnosis, prevent unnecessary investigations, and give patients the most appropriate treatment.

negative: Regulatory T-cell abnormalities and the global epidemic of immuno-inflammatory disease. The incidence of autoimmune, allergic and inflammatory disease is increasing due to as yet unidentified environmental factors related to western living conditions. Here, I propose that alterations in the gut microbiome, acting via regulatory T cells (Tregs), may be responsible for this epidemic. Tregs control the threshold for peripheral antigen recognition via tonic downregulation of dendritic cell (DC) costimulation, and are also implicated in maintaining the tolerogenic function of DCs. In this model, minor perturbations in Treg number or function are predicted to lower the activation threshold, allowing proliferation and differentiation of self-reactive CD4T cells of too low an affinity to have undergone negative selection in the thymus. Failure to maintain the tolerogenic commitment of DCs exposed to commensal microbes and allergens could result in potentially pathogenic, allergic and inflammatory responses at epithelial surfaces.

negative: Diverticular disease: Epidemiology and management Diverticular disease of the colon is among the most prevalent conditions in western society and is among the leading reasons for outpatient visits and causes of hospitalization. While previously considered to be a disease primarily affecting the elderly, there is increasing incidence among individuals younger than 40 years of age. Diverticular disease most frequently presents as uncomplicated diverticulitis, and the cornerstone of management is antibiotic therapy and bowel rest. Segmental colitis associated with diverticula shares common histopathological features with inflammatory bowel disease and may benefit from treatment with 5-aminosalicylates. Surgical management may be required for patients with recurrent diverticulitis or one of its complications including peridiverticular abscess, perforation, fistulizing disease, and strictures and/or obstruction. Résumé La maladie diverticulaire du côlon est l’une des pathologies les plus prévalentes de la société occidentale et des principales causes de consultations ambulatoires et d’hospitalisations. On croyait qu’elle touchait surtout les personnes âgées, mais son incidence est en croissance auprès des personnes de moins de 40 ans. La maladie diverticulaire se manifeste surtout sous forme de diverticulite sans complication, et la pierre angulaire du traitement est l’antibiothérapie et le repos intestinal. La colite segmentaire associée aux diverticules partage des caractéristiques histopathologiques avec les maladies inflammatoires de l’intestin et peut profiter d’un traitement aux 5-aminosalicylates. Une prise en charge chirurgicale peut s’imposer en présence de diverticulite récurrente ou de l’une de ses complications, y compris un abcès péridiverticulaire, une perforation, une fistulisation et des sténoses ou des obstructions.

negative: Curcumin as "Curecumin": from kitchen to clinic. Although turmeric (Curcuma longa; an Indian spice) has been described in Ayurveda, as a treatment for inflammatory diseases and is referred by different names in different cultures, the active principle called curcumin or diferuloylmethane, a yellow pigment present in turmeric (curry powder) has been shown to exhibit numerous activities. Extensive research over the last half century has revealed several important functions of curcumin. It binds to a variety of proteins and inhibits the activity of various kinases. By modulating the activation of various transcription factors, curcumin regulates the expression of inflammatory enzymes, cytokines, adhesion molecules, and cell survival proteins. Curcumin also downregulates cyclin D1, cyclin E and MDM2; and upregulates p21, p27, and p53. Various preclinical cell culture and animal studies suggest that curcumin has potential as an antiproliferative, anti-invasive, and antiangiogenic agent; as a mediator of chemoresistance and radioresistance; as a chemopreventive agent; and as a therapeutic agent in wound healing, diabetes, Alzheimer disease, Parkinson disease, cardiovascular disease, pulmonary disease, and arthritis. Pilot phase I clinical trials have shown curcumin to be safe even when consumed at a daily dose of 12g for 3 months. Other clinical trials suggest a potential therapeutic role for curcumin in diseases such as familial adenomatous polyposis, inflammatory bowel disease, ulcerative colitis, colon cancer, pancreatic cancer, hypercholesteremia, atherosclerosis, pancreatitis, psoriasis, chronic anterior uveitis and arthritis. Thus, curcumin, a spice once relegated to the kitchen shelf, has moved into the clinic and may prove to be "Curecumin".

negative: Recurrent monoarthritis in an 11-year-old boy with occult coeliac disease. Successful and stable remission after gluten-free diet. A case of occult coeliac disease (CD) presenting with recurrent monoarthritis in a boy aged 11 years is reported. The case is unique due to the association of occult untreated CD and arthritis in childhood. Peripheral or axial arthritis as a first manifestation of occult CD has been described in adult patients, with an interval between the arthritis and CD of up to 15 years. In our case the interval between the appearance of arthritis and the diagnosis of CD was 2 years. The boy was asymptomatic for bowel disease and his nutritional status was normal. The diagnosis of CD was established using anti-gliadin (AGA) and anti-endomysium (EMA) antibody tests and was confirmed by small bowel biopsy. The introduction of a gluten-free diet resulted in the persistent remission of arthritis. As the treatment of CD-associated arthritis is based on dietary therapy, physicians should be alert to the possibility of occult CD in any child with arthritis of unclear origin.

negative: The reactive oxygen species-total antioxidant capacity score is a new measure of oxidative stress to predict male infertility. The imbalance between reactive oxygen species (ROS) production and total antioxidant capacity (TAC) in seminal fluid indicates oxidative stress and is correlated with male infertility. A composite ROS-TAC score may be more strongly correlated with infertility than ROS or TAC alone. We measured ROS, TAC, and ROS-TAC scores in semen from 127 patients and 24 healthy controls. Of the patients, 56 had varicocele, eight had varicocele with prostatitis, 35 had vasectomy reversals, and 28 had idiopathic infertility. ROS levels were higher among infertile men, especially those with varicocele with prostatitis (mean +/- SE, 3.25 +/- 0.89) and vasectomy reversals (2.65 +/- 1.01). All infertile groups had significantly lower ROS-TAC scores than control. ROS-TAC score identified 80% of patients and was significantly better than ROS at identifying varicocele and idiopathic infertility. The 13 patients whose partners later achieved pregnancies had a mean ROS-TAC score of 47.7 +/- 13.2, similar to controls but significantly higher than the 39 patients who remained infertile (35.8 +/- 15.0; P < 0.01). ROS-TAC score is a novel measure of oxidative stress and is superior to ROS or TAC alone in discriminating between fertile and infertile men. Infertile men with male factor or idiopathic diagnoses had significantly lower ROS-TAC scores than controls, and men with male factor diagnoses that eventually were able to initiate a successful pregnancy had significantly higher ROS-TAC scores than those who failed.

negative: Gut inflammation in chronic fatigue syndrome Chronic fatigue syndrome (CFS) is a debilitating disease characterized by unexplained disabling fatigue and a combination of accompanying symptoms the pathology of which is incompletely understood. Many CFS patients complain of gut dysfunction. In fact, patients with CFS are more likely to report a previous diagnosis of irritable bowel syndrome (IBS), a common functional disorder of the gut, and experience IBS-related symptoms. Recently, evidence for interactions between the intestinal microbiota, mucosal barrier function, and the immune system have been shown to play a role in the disorder's pathogenesis. Studies examining the microecology of the gastrointestinal (GI) tract have identified specific microorganisms whose presence appears related to disease; in CFS, a role for altered intestinal microbiota in the pathogenesis of the disease has recently been suggested. Mucosal barrier dysfunction promoting bacterial translocation has also been observed. Finally, an altered mucosal immune system has been associated with the disease. In this article, we discuss the interplay between these factors in CFS and how they could play a significant role in GI dysfunction by modulating the activity of the enteric nervous system, the intrinsic innervation of the gut. If an altered intestinal microbiota, mucosal barrier dysfunction, and aberrant intestinal immunity contribute to the pathogenesis of CFS, therapeutic efforts to modify gut microbiota could be a means to modulate the development and/or progression of this disorder. For example, the administration of probiotics could alter the gut microbiota, improve mucosal barrier function, decrease pro-inflammatory cytokines, and have the potential to positively influence mood in patients where both emotional symptoms and inflammatory immune signals are elevated. Probiotics also have the potential to improve gut motility, which is dysfunctional in many CFS patients.

negative: Postprandial anti-inflammatory and antioxidant effects of extra virgin olive oil. High postprandial serum lipid concentrations are associated with increased oxidative stress which, in turn, increases the risk of atherosclerosis. Epidemiological studies correlate lower incidence of cardiovascular disease with adherence to the Mediterranean diet. The aim of this study was to evaluate changes in inflammatory (TXB(2) and LTB(4)) and oxidative stress markers (urinary hydrogen peroxide levels and serum antioxidant capacity), in addition to classic lipid parameters, after a fat-rich meal administered to 12 normolipemic, healthy subjects. Following a Latin square design, subjects were divided into three groups, each one receiving a different kind of oil (extra virgin olive oil; EVOO, olive oil; OO or corn oil; CO, together with 150g of potatoes), with 2-week washout periods between treatments. Blood samples were drawn at baseline and after 1, 2, and 6h after the meal. A significant decrease in inflammatory markers, namely TXB(2) and LTB(4), after 2 and 6h after EVOO (but not OO or CO) consumption and a concomitant increase of serum antioxidant capacity were recorded. These data reinforce the notion that the Mediterranean diet reduces the incidence of coronary heart disease partially due to the protective role of its phenolic components, including those of extra virgin olive oil.

negative: Therapeutic Roles of Curcumin: Lessons Learned from Clinical Trials Extensive research over the past half century has shown that curcumin (diferuloylmethane), a component of the golden spice turmeric (Curcuma longa), can modulate multiple cell signaling pathways. Extensive clinical trials over the past quarter century have addressed the pharmacokinetics, safety, and efficacy of this nutraceutical against numerous diseases in humans. Some promising effects have been observed in patients with various pro-inflammatory diseases including cancer, cardiovascular disease, arthritis, uveitis, ulcerative proctitis, Crohn’s disease, ulcerative colitis, irritable bowel disease, tropical pancreatitis, peptic ulcer, gastric ulcer, idiopathic orbital inflammatory pseudotumor, oral lichen planus, gastric inflammation, vitiligo, psoriasis, acute coronary syndrome, atherosclerosis, diabetes, diabetic nephropathy, diabetic microangiopathy, lupus nephritis, renal conditions, acquired immunodeficiency syndrome, β-thalassemia, biliary dyskinesia, Dejerine-Sottas disease, cholecystitis, and chronic bacterial prostatitis. Curcumin has also shown protection against hepatic conditions, chronic arsenic exposure, and alcohol intoxication. Dose-escalating studies have indicated the safety of curcumin at doses as high as 12 g/day over 3 months. Curcumin’s pleiotropic activities emanate from its ability to modulate numerous signaling molecules such as pro-inflammatory cytokines, apoptotic proteins, NF–κB, cyclooxygenase-2, 5-LOX, STAT3, C-reactive protein, prostaglandin E2, prostate-specific antigen, adhesion molecules, phosphorylase kinase, transforming growth factor-β, triglyceride, ET-1, creatinine, HO-1, AST, and ALT in human participants. In clinical trials, curcumin has been used either alone or in combination with other agents. Various formulations of curcumin, including nanoparticles, liposomal encapsulation, emulsions, capsules, tablets, and powder, have been examined. In this review, we discuss in detail the various human diseases in which the effect of curcumin has been investigated.

negative: Cytological abnormalities in nipple aspirates of breast fluid from women with severe constipation. The relation between epithelial dysplasia in nipple aspirates of breast fluid and frequency of bowel movements was studied in 1481 white women. There was a significant positive association with dysplasia (risk ratio 4.5; 95% confidence interval 1.9-11.9) in women reporting severe constipation, i.e., two or fewer bowel movements weekly, which was not seen in women reporting more than one bowel movement daily. Women who had one bowel movement daily or one every other day had increased risk ratios. Cytological abnormalities in breast epithelium associated with severe constipation may be relevant to studies of diet and breast disease since the intestinal flora has been reported to metabolism bile salts and oestrogens secreted by the liver into the gastrointestinal tract-a process which may be enhanced by severe constipation.

negative: Clinical utility of curcumin extract. Turmeric root has been used medicinally in China and India for thousands of years. The active components are thought to be the curcuminoids, primarily curcumin, which is commonly available worldwide as a standardized extract. This article reviews the pharmacology of curcuminoids, their use and efficacy, potential adverse effects, and dosage and standardization. Preclinical studies point to mechanisms of action that are predominantly anti-inflammatory and antineoplastic, while early human clinical trials suggest beneficial effects for dyspepsia, peptic ulcer, inflammatory bowel disease, rheumatoid arthritis, osteoarthritis, uveitis, orbital pseudotumor, and pancreatic cancer. Curcumin is well-tolerated; the most common side effects are nausea and diarrhea. Theoretical interactions exist due to purported effects on metabolic enzymes and transport proteins, but clinical reports do not support any meaningful interactions. Nonetheless, caution, especially with chemotherapy agents, is advised. Late-phase clinical trials are still needed to confirm most beneficial effects.

negative: Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis Intestinal microbiota metabolism of choline/phosphatidylcholine produces trimethylamine (TMA), which is further metabolized to a proatherogenic species, trimethylamine-N-oxide (TMAO). Herein we demonstrate that intestinal microbiota metabolism of dietary L-carnitine, a trimethylamine abundant in red meat, also produces TMAO and accelerates atherosclerosis. Omnivorous subjects are shown to produce significantly more TMAO than vegans/vegetarians following ingestion of L-carnitine through a microbiota-dependent mechanism. Specific bacterial taxa in human feces are shown to associate with both plasma TMAO and dietary status. Plasma L-carnitine levels in subjects undergoing cardiac evaluation (n = 2,595) predict increased risks for both prevalent cardiovascular disease (CVD) and incident major adverse cardiac events (MI, stroke or death), but only among subjects with concurrently high TMAO levels. Chronic dietary L-carnitine supplementation in mice significantly altered cecal microbial composition, markedly enhanced synthesis of TMA/TMAO, and increased atherosclerosis, but not following suppression of intestinal microbiota. Dietary supplementation of TMAO, or either carnitine or choline in mice with intact intestinal microbiota, significantly reduced reverse cholesterol transport in vivo. Intestinal microbiota may thus participate in the well-established link between increased red meat consumption and CVD risk.