Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery datasets from genome-wide association studies of European subjects (n=2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n=3,716 cases and 4261 controls). We discover and validate six previously unknown risk loci for PBC (Pcombined<5×10−8) and used pathway analysis to identify JAK-STAT/IL12/IL27 signaling and cytokine-cytokine pathways, for which relevant therapies exist.
Macrophages at the base of human gut associated lymphoid tissue (GALT), become loaded early in life with dark granular pigment that is rich in aluminium, silicon, and titanium. The molecular characteristics, intracellular distribution, and source of this pigment is described. Laser scanning and electron microscopy showed that pigmented macrophages were often closely related to collagen fibres and plasma cells in GALT of both small and large intestine and contained numerous phagolysosomes, previously described as granules, that are rich in electron dense submicron sized particles. Morphological assessment, x ray microanalysis, and image electron energy loss spectroscopy showed three distinct types of microparticle: type I -spheres of titanium dioxide, 100-200 nm diameter, characterised as the synthetic food-additive polymorph anatase; type II -aluminosilicates, <100-400 nm in length, generally of flaky appearance, often with adsorbed surface iron, and mostly characteristic of the natural clay mineral kaolinite; and type III -mixed environmental silicates without aluminium, 100-700 nm in length and of variable morphology. Thus, this cellular pigment that is partly derived from food additives and partly from the environment is composed of inert inorganic microparticles and loaded into phagolysosomes of macrophages within the GALT of all human subjects. These observations suggest that the pathogenicity of this pigment should be further investigated since, in susceptible individuals, the same intracellular distribution of these three types of submicron particle causes chronic latent granulomatous inflammation. (Gut 1996; 38: 390-395)
INTRODUCTIONIron de®ciency anaemia is a common haematological problem but current treatment remains unsatisfactory. Intravenous iron supplementation has been withdrawn and intramuscular iron has signi®cant side-effects. Oral iron supplementation, typically with ferrous sulphate, is associated with a high incidence of gastrointestinal sideeffects, 1 and so compliance with treatment is often poor and treatment is ineffective. Although different ferrous preparations are available, there is no signi®cant difference in their side-effects or ef®cacy. 1±3 Ferrous iron preparations have more side-effects than ferric preparations, probably due to the initiation and propagation of potentially damaging hydroxyl free radicals 4, 5 at the gastrointestinal mucosa:However, iron is poorly absorbed from ferric preparations, because ferric salts are rapidly converted to poorly absorbed iron hydroxide polymers when passing from the acidic environment of the stomach to the more neutral pH of the duodenum. These polymers have high af®nity for intestinal mucus 6 and so absorption of the metal is further limited. Inhibition of this hydroxide polymer formation and a more rapid transit through the mucus layer and mucosa would facilitate ferric iron absorption.Maltol (3-hydroxy-2-methyl-4-pyrone) is a naturally occurring sugar derivative formed during caramelization SUMMARY Background: Oral iron supplements, which are usually in the form of ferrous (Fe 2+ ) salts, are toxic to the gastrointestinal mucosa, and so intolerance is common, resulting in poor compliance and failure of treatment. The sugar derivative maltol strongly chelates iron, rendering it available for absorption and stabilized in the less toxic ferric (Fe 3+ ) form. Aim: To test whether ferric trimaltol could correct iron de®ciency anaemia in patients intolerant of ferrous sulphate. Methods: Twenty-three patients were recruited from gastroenterology clinics, of whom 15 had in¯ammatory
Our adequately powered and carefully controlled dietary trial found no evidence that reducing microparticle intake aids remission in active Crohn's disease.
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