The chronic rat studies provide a limited amount of evidence for neoplastic or preneoplastic changes in tissues other than the liver antibiotics for uti during pregnancy cheap 600 mg linezolid with mastercard. Incidences of preneoplastic lesions in the biliary tract were increased in both sexes by exposure to Aroclor 1260 (Norback and Weltman 1985) virus headache linezolid 600mg lowest price, although the response was greater in females antibiotics for ear infection buy cheap linezolid 600mg online. There was a suggestive indication of Aroclor 1254induced precancerous intestinal metaplasia and adenocarcinomas in the stomach of rats in one study (Morgan et al antibiotic dosage for uti purchase linezolid 600mg otc. The preneoplastic lesions in the biliary tract and stomach have not been reported in other studies antibiotic to treat mrsa buy cheap linezolid 600mg line, particularly Mayes et al antibiotic prophylaxis for endocarditis 600 mg linezolid otc. Statistically significant increases in thyroid gland follicular cell adenomas were induced by Aroclors 1242 treatment for dogs cold linezolid 600mg for sale, 1254 virus under a microscope 600mg linezolid with mastercard, and 1260 in males, but not females (Mayes et al. Before the comprehensive four-Aroclor comparative carcinogenicity study was conducted by Mayes et al. Health effects in wildlife that were cited in the support document included the following: mortality in piscivorous birds; reproductive impairment in monkeys, minks, ring doves, and American kestrels; immunotoxicity in monkeys and birds; and endocrine and neurobehavioral effects in birds. A variety of other health effects have since been evaluated in wildlife, some of which may be relevant to human health. Since Table 3-6 is intended for hazard identification, data concerning effects from parenteral exposures were included, as well as oral, inhalation, and dermal routes that are more directly relevant to human environmental exposures. Table 3-6 distinguishes between correlational evidence from field observations and experimental evidence. Correlational evidence from field studies inherently has multiple sources of uncertainty, many of which are controlled in experimental studies. Effects that were observed in experimental studies under controlled or closely monitored exposure conditions were included in the table as experimental observations. However, no entry was made in Table 3-6 for responses that were reported in an experimental study to be equivocal, ambiguous, or not statistically significant. Information contained in the reviews was supplemented by individual studies that were not otherwise represented, such as more recent studies. The number of sources identified for an individual Table 3-6 entry does not necessarily reflect the number of studies showing that effect for the following reasons: (1) several reviews may have reported the same results from a single study, or (2) a single source document may report effects in multiple studies, but the source is represented only once for a given entry. Information included in Table 3-6 was limited to effects in fish and birds, and in mammals that had not been bred to reduce genetic variability. No data concerning effects in fungi, invertebrates, microbes, or terrestrial or aquatic plants were included. Among the classes of organisms represented in Table 3-6, mustelids (primarily minks and ferrets), galliform birds (primarily domestic fowl and quail), and freshwater fish were the most frequently studied (see Table 3-6). Additional categories of end points that were relatively frequently addressed were immunological, neurological/behavioral, and hepatic effects. Effects in wildlife that are potentially related to neurological impairment included alterations in central nervous system neurotransmitter levels, retarded learning, increased activity, and behavioral changes. Significantly reduced dopamine levels were observed in certain regions of the brain in adult pigtailed macaques provided Aroclor 1016 or Aroclor 1260 orally at 0. Similarly, retarded learning, increased locomotor activity, impaired discrimination reversal learning, and increased hyperactivity were observed in monkeys provided Aroclor 1248 for an unspecified duration (Safe 1994). Doves provided an unspecified Aroclor mixture showed altered brain catecholamine levels (Hansen 1987). Positive findings in wild mammals, birds, or fish that contribute to the weight of evidence for immunological effects included morphological changes in organs related to the immune system, as well as functional impairment of humoral- and cell-mediated immune responses. Increased disease susceptibility was observed in pinfish and spot fish (marine/estuarine species) exposed to Aroclor 1254 at concentrations as low as 0. Wildlife findings that contribute to the weight of evidence for dermal/ocular effects include dermal changes in several taxa. Dose- and time-dependent increases in chloracne and histological changes in the sebaceous glands were observed in Rhesus macaques fed diets containing 0. Scaly skin, hair loss, and abnormal nail growth were observed in cotton top marmoset monkeys orally administered 0. The wildlife database outlined in Table 3-6 includes observations of increased postimplantation embryo/fetal loss in several taxa. This supplemental information is considered necessary since most of the current knowledge regarding biotransformation of chlorinated biphenyls in experimental animals has been derived from such studies. Mainly metabolites are found in urine and bile, although small amounts of parent compound may appear in the feces. In general, the model predicted the experimental data well, although some deviations were apparent. From data summarized by Wolff (1985), a maximum of 80% of the levels commonly seen in adipose tissue of exposed capacitor workers may have been absorbed by the inhalation route. Further information regarding tissue levels in occupationally-exposed subjects can be found in Section 3. It must be also mentioned that since exposure was not nose-only, the dermal route may have contributed to absorption. In contrast, the congener profile in adipose tissue resembles that of most exposed or unexposed animals, with hexa- and hepta-substituted congeners being the major congeners present. Furthermore, oral exposure through ingestion of contaminated water or soil represents a possible additional source of exposure for populations in the vicinity of hazardous waste sites. Blood samples obtained during a period of 260 days after dosing revealed the presence of mostly penta- and hexachlorobiphenyls and smaller amounts of heptachlorobiphenyls. From data presented in the report, it appears that the maximum concentration in blood was reached within 2 days of dosing (the first time point examined). This was attributed to changes in blood lipids, which depended on factors such as diet, physical activity, and time of day. A more recent study in a 19-week-old nursing infant provided quantitative data on absorption (McLachlan 1993). Indirect evidence of absorption results from studies regarding ingestion of contaminated food by the general population. The net absorption is calculated as the difference between contaminant input with food and contaminant output with feces, normalized to the contaminant intake. Positive values in Table 3-7 indicate net absorption and negative values indicate net excretion, with absorption or excretion expressed as a percentage of daily intake. Table 3-7 illustrates that compounds showing nearly complete net absorption had low levels in the serum lipids, and for other congeners, there was a trend for decreasing net absorption/increasing net excretion with increasing congener concentration in serum lipids. Positive values indicate net absorption and negative values indicate net excretion with absorption or excretion expressed as a percentage of daily intake. In rats, individual congeners (mono- to hexachlorobiphenyls) were readily absorbed when administered by gavage (vehicle not reported) in doses between 5 and 100 mg/kg (Albro and Fishbein 1972). Retention was >90% of the administered dose over a 4-day period, and was apparently dose independent. No relationship between substitution pattern and degree of absorption could be established due to the low levels of excretion, although a later study reported that absorption efficiency decreased in rats as the number of chlorine atoms increased such that dichlorobiphenyls were absorbed with a 95% efficiency, whereas octachlorobiphenyls had an absorption efficiency of only 75% (Tanabe et al. Results similar to those obtained in rats were reported in monkeys administered a single dose of 1. In mature ewes receiving 30 mg/kg of the same Aroclor in a single oral dose, absorption was slower and maximum blood levels of 2. The concentration in dissectable backfat was about 15 ppm on day 7 and 10 ppm on day 14; however, the body composition was determined by noninvasive means so that the actual amount in body fat was estimated at 70 mg on day 7 and 60 mg on day 14. The slower decline in amount than in concentration was due to disproportionate expansion of the fat compartment in these rapidly growing animals (Hansen and Welborn 1977). The total amount of tetrachlorobiphenyl declined linearly through 118 days, but the amount of hexachlorobiphenyl estimated in total fat based on backfat concentration increased gradually so that the 118-day amount was only slightly lower than the 7-day amount (Hansen and Welborn 1977). These studies utilized 14C-labeled Aroclor 1242 and 1254 (mixtures containing 42 or 54% chlorine by mass) in soil, mineral oil, and water. Following iv administration, the 30-day cumulative excretion was 55% of the administered dose (39% urine, 16% feces) for Aroclor 1242 and 27% (7% urine, 20% feces) for Aroclor 1254. The percentage of the dose absorbed following topical administration to abdominal skin (after light clipping of hair) was estimated from the ratio of the total urinary and fecal excretion following topical and iv administration. Topical administration of Aroclor 1242 in soil, mineral oil, trichlorobenzene, or acetone resulted in 14, 20, 18, and 21% absorption of the administered dose, respectively. The effectiveness of methods for decontaminating or removing Aroclor 1242 from Rhesus monkey skin was also investigated by Wester et al. Use of soap and water was similar in effectiveness to washing with trichlorobenzene, mineral oil, or ethanol. At 15 minutes following dermal exposure, 93% of the applied dose was removed from skin by washing with soap and water. The application sites were washed with water and acetone after 24 hours, and radioactivity was monitored in the urine for several weeks postdosing. Dermal penetration rate constants have been measured in male Fischer 344 rats after single 0. Penetration rate and degree of penetration (defined as penetration through the stratum corneum into the viable epidermis) were inversely related to degree of chlorination. Rate constants correlated strongly with the logarithm of the octanol-water partition coefficient. Cumulative penetration at 48 hours was near 100% for the mono-, 95% for the di-, 75% for the tetra-, and 30% for the hexachlorinated forms. Absorption of the tetra- and hexachlorinated forms continued after washing the site with acetone at 48 hours, indicating that the viable epidermis served as a reservoir for these higher chlorinated forms. The rate of systemic absorption of radioactivity was kinetically complex and not a first-order process like penetration into the skin. The treatment area was then occluded, and urine and feces were collected and analyzed for radioactivity. The levels of several di-ortho-substituted congeners in human milk (on a lipid basis) ranged from not detected to >300 ppb (Schecter et al. On a wet weight basis, the adipose/plasma partition ratio for Aroclor 1248 residues was 185/1; the partition ratio for Aroclor 1254 residues was 190/1. In a study of 173 workers of the same population, adipose/plasma partition ratios of 210/1, 190/1, and 200/1 were determined for residues of Aroclors 1242, 1254, and 1260, respectively (Brown and Lawton 1984). The partition ratios were significantly dependent on the levels of lipids in the serum, but not on albumin content. Among all exposure categories, the homolog groups present in the highest concentrations were the hexa- and heptachlorobiphenyls, both in sera and adipose tissue, as expected from the highly chlorinated Aroclor 1260. Mono-, di-, tri-, and nonachlorobiphenyls were found at very low levels in adipose tissue, as expected, and no differences were observed among the exposure categories. Currently exposed workers had significantly higher levels of penta-, hepta-, and octachlorobiphenyls than those in both formerly exposed and control groups. The concentration of tetrachlorobiphenyls was significantly higher among currently exposed individuals than among the other groups. Mono-, tri-, penta-, hexa-, hepta-, and octachlorobiphenyls were found at significantly higher concentrations (p<0. The relative distribution of individual congeners was similar in the three groups, but the amounts varied. The seven major peaks in serum and adipose tissue were mainly penta-, hexa-, hepta-, and octachlorobiphenyls. More standards became available after the study was published and some congener (but not homolog) identifications were corrected (see Hansen 1999). The large differences observed in isomer distribution within a given tissue and between the various tissues of the donors do not allow generalizations to be made on general population isomer distribution. However, if a more complete profile of congeners is considered, the correlations are lower (Bachour et al. The difference in accumulation may be due to the nature of more polar brain lipids, which are mainly phospholipids. The higher levels of the lower chlorinated congeners in the lung may be related to the greater volatility and greater direct pulmonary exposure to these congeners. Steady-state concentrations in adipose tissue were much higher than in liver and thymus. Liver concentrations increased from steadystate levels for 2 hours after the final dose before beginning to decline. The distribution ratio of the 3,3N,4,4N-isomer for adipose tissue was 2-fold higher than that of the 2,2N,5,5N-isomer, and the ratios for thymus and liver were 3- and 10-fold higher, respectively. The decline in concentration of both isomers in the three tissues followed first-order kinetics. Tissue elimination half-lives for adipose tissue, thymus, and liver ranged from 1. No apparent relationship between a substitution pattern and biological half-life could be observed. No selective tissue retention was observed over a 30-day period that followed dosing. The blood levels of Aroclor 1254 increased rapidly in monkeys during 10 months of treatment (from approximately 1. When the data were expressed as relative concentration, it appeared that absorption and bioaccumulation were dose-dependent. Throughout the treatment period the monkeys were bred to untreated males and the resulting offspring were nursed by their mother. Following a 7-day total dose of 15 mg/kg Aroclor 1254 to growing pigs, lower chlorinated congeners reached peripheral fat (dissectable backfat) more rapidly than did higher chlorinated congeners; however, redistribution (from more central fat) between 35 and 80 days resulted in total estimated amounts of higher chlorinated congeners (Hansen and Welborn 1977). The highest concentration of chlorinated hydrocarbon residues 24 hours following administration by gavage of a single dose of 1,600 mg/kg Aroclor 1254 or 3,200 mg/kg Aroclor 1260 to female Sherman rats was found in fat tissue, followed by kidney, liver, and brain; plasma and muscle contained the least (Curley et al. Despite the difference in administered doses, the concentration of residues in tissues, derived from both Aroclors, were comparable. When male and female rats were given an oral dose of 73 mg/kg/day Aroclor 1254 for 98 days, fat tissue again had the highest concentration, followed by muscle and liver (Curley et al. Results such as these have led to the conclusion that suckling may account for higher exposure of young offspring than does placental transfer; the fetus, however, may be more sensitive. Total tissue radioactivity has been measured in male Fischer 344 rats after single 0. Peak total radioactivity in the tissues (excised dose site, samples of blood, adipose tissue, muscle, skin [ears], and the entire liver and kidney) occurred at progressively later times depending on the degree of chlorination. For example, the monochlorinated form reached maximal concentrations (37% of the absorbed dose) in blood and other tissues at 4 hours postadministration and was almost absent (0. In contrast, peak tissue concentrations of the tetrachlorinated form (80% of the absorbed dose) occurred at 72 hours and approximately 45% remained in the tissues after 2 weeks. Absorption of the tetra- and hexachlorinated forms continued after washing the site with acetone at 48 hours, indicating that the viable epidermis retained these forms and served as a reservoir. This may be due to partitioning into lipophilic sites in the skin or adsorption to epithelial proteins. This differential distribution is probably due to differences in maternal metabolism for the tetra- and pentachlorobiphenyls (see Section 3. Some congeners induce P-450s from the 3A and 4A families, but the structureactivity relationships are incomplete (Huang and Gibson 1992; Schuetz et al. Arene oxides are mainly transformed to hydroxylated aromatic compounds but also to sulfur-containing metabolites via the mercapturic acid pathway (Haraguchi et al. Unsubstituted meta and para carbon atoms are the preferred site for oxidation (Borlakoglu and Wilkins 1993b). Comparison of the molecular structures of the biologically persistent congeners reveals different molecular weights, substitution patterns, feasibility to rotate on the phenyl-phenyl bond, and intramolecular distances determined by nonelectrostatic forces (Borlakoglu and Walker 1989). The results of in vitro metabolism with human liver microsomes entirely support the conclusions drawn above. The major metabolites identified, 2,2N,3,3N,6,6N-hexachloro-4-biphenylol, and 2,2N,3,3N,6,6N-hexachloro-5-biphenylol, suggest that this congener is metabolized through an arene oxide. The decreased excretion rate with increasing chlorination was directly related to the decreased rate of metabolism of the more highly chlorinated congeners. Not only does the number of chlorines affect the rate of biotransformation, but the position of the chlorines on the phenyl rings is also critical. This was demonstrated in rats, which excreted four symmetrical hexachlorobiphenyls at different rates depending on the chlorine positions (Kato et al. As the number of unsubstituted meta positions or adjacent unsubstituted carbon atoms increases, the percentage of the dose excreted increases. Hydroxylation is favored at the para position in the least chlorinated phenyl ring unless this site is sterically hindered. In the lower chlorinated biphenyls, the para position of both biphenyl rings and carbon atoms that are para to the chloro substituent are all readily hydroxylated. As the degree of chlorination increases on both phenyl rings, the rate of metabolism decreases. Arene oxides are potential electrophiles, and have been implicated in cellular necrosis, mutagenicity, and carcinogenicity (Safe 1989b). The reactive metabolites may result for arene oxides and/or catechol and p-hydroquinone species, which are oxidized to semiquinones and/or quinones. The thiols formed are methylated, reabsorbed, and further oxidized on the sulfur to the corresponding methyl sulfones, which are distributed by the blood (Brandt et al.
Iron absorption in breast-fed infants: effects of age bacteria 4 billion years ago cheap 600mg linezolid otc, iron status can you get antibiotics for acne linezolid 600 mg discount, iron supplements virus pro buy linezolid 600 mg overnight delivery, and complementary foods treatment for recurrent uti in dogs buy linezolid 600 mg. Gastrointestinal causes of refractory iron deficiency anemia in patients without gastrointestinal symptoms antimicrobial washcloths purchase linezolid 600mg online. Prevalence of celiac disease in a sample of Turkish children and adolescents with type 1 diabetes mellitus infection journal purchase 600mg linezolid free shipping. Genotypic and phenotypic heterogeneity of African Americans with primary iron overload antimicrobial agents examples buy linezolid 600 mg visa. Roetto A antibiotics for sinus infection penicillin discount linezolid 600 mg amex, Papanikolaou G, Politou M, Alberti F, Girelli D, Christakis J, Loukopoulos D, Camaschella C. Mutant antimicrobial peptide hepcidin is associated with severe juvenile hemochromatosis. Screening hepcidin for mutations in juvenile hemochromatosis: identification of a new mutation (C70R). Homozygosity for transferrin receptor-2 Y250X mutation induces early iron overload. Resistance to hepcidin is conferred by hemochromatosis-associated mutations of ferroportin. Aceruloplasminemia: molecular characterization of this disorder of iron metabolism. The role of iron in bacterial infections, with special consideration of host-tubercle bacillus interaction. Synthetic hepcidin causes rapid dose-dependent hypoferremia and is concentrated in ferroportin-containing organs. He is currently Professor of Human Nutrition at the Swiss Federal Institute of Technology, Zurich, Switzerland. She has also worked in the Nutrition Department of the World Health Organization in the area of micronutrient deficiencies with a special focus on iron, iodine, and vitamin A. Phytic acid and phenolic compounds, commonly present in cereal and legume foods, are the major inhibitors of iron absorption, whereas ascorbic acid from fruits, vegetables and muscle tissue are the major enhancers of iron absorption. Ascorbic acid is commonly added to iron fortified foods to optimize iron absorption. The World Health Organization (1) has recently published guidelines on food fortification with micronutrients, which include recommendations for iron fortification compounds and a method to define the iron fortification level. Recent efficacy studies, which have to a large extent followed these guidelines, have shown good efficacy of iron fortified salt, fish sauce, wheat flour and rice in improving the iron status of target populations. Additionally, specific recommendations are given detailing which iron compounds are most appropriate to add to the different food vehicles. There are recommendations for cereal flours and different cereal based foods, rice, milk products, cocoa products, and condiments. Ferrous bisglycinate or micronized dispersible ferric pyrophosphate (2) are recommended for liquid milk products and other beverages. Electrolytic iron is the only elemental iron powder recommended for cereal flour and breakfast cereal fortification. Hydrogenreduced (H-reduced) iron and carbonyl iron powders may be recommended at a later date as more information becomes available on these compounds. Ferrous sulfate and ferrous fumarate encapsulated with hydrogenated lipids can also be used for the fortification of cereal flours and cereal based complementary foods. The resulting iron absorption is generally believed to be as good as the nonencapsulated compounds, provided that the capsule to iron compound ratio does not exceed 60:40 (4). The addition of ascorbic acid is recommended for complementary foods, dried milks and cocoa products. In addition, it is necessary to have detailed information on the iron intake of the target population. In reality, there is a wide range of iron intakes within each population subgroup, and the goal of the fortification program is to shift the iron intake distribution in the target population upwards, so that only a small proportion of that population is at risk of inadequate intake. For most nutrients, the process is to calculate the amount of extra daily nutrient required so that only 2. These groups would be the expected target populations of an iron fortification program. For such population groups, it is recommended to use the full probability approach to define the iron fortification level. By combining these values with a detailed knowledge of iron intake in the target population, it is possible to calculate the prevalence of inadequate intakes within the population subgroup (Table 7. For each intake range, a prevalence of inadequacy is obtained by multiplying the percentage of the group with intakes in that range by the probability of inadequacy. The next step is to calculate the amount of extra daily iron intake necessary to decrease the esti- Table 7. Usual mean iron intake mg <5 5-10 10-15 15-20 20-25 25-30 30-35 35-40 40-45 45-50 50-55 55-60 >60 Probability of inadequacy for women consuming diets of different iron bioavailability* 15% 1. This is an extreme example of women consuming a whole grain cereal diet and, because of the very low iron bioavailability of this diet, large amounts of fortification iron are necessary to bring iron intake in line with iron requirements. Care should be taken that other population groups do not exceed the upper limit of iron intake at these high levels of fortification (7). The ranking is based either on the ability of the iron compound to replete hemoglobin in anemic rats (11) or more recently, directly in relation to fractional iron absorption in humans as measured by either radioactive or stable isotope techniques (12, 13). These rat and human studies have subdivided the iron fortification compounds into four categories. Category 2 contains the poorly water soluble iron compounds, which readily dissolve in the dilute acid of the gastric juice. Because they are poorly soluble in water, these compounds cause far fewer adverse organoleptic changes than ferrous sulfate (12). Category 3 contains those iron compounds which are insoluble in water and poorly soluble in dilute acid. Included in this category are two of the most widely used iron fortification compounds, the different elemental iron powders and ferric pyrophosphate. Usual daily iron intake mg <15 15-20 20-25 25-30 30-35 35-45 45-60 >60 * from Table 7. The physical characteristics of the five different elemental iron powders vary according to their method of manufacture. They are, however, more susceptible to adverse sensory changes than Category 2 or Category 3 compounds. It has been successfully used to fortify infant formula, Bioavailability of iron compounds for food fortification 83 dried milk, bread and pasta (9) and can be used to fortify low extraction wheat flour that is stored for no more than a few months (18). It may, however, provoke fat oxidation and rancidity in cereal flours stored for longer periods (9) and has been reported to cause unacceptable color changes in cocoa products (19), infant cereals (20), salt (21) and extruded rice (22). It often causes a metallic taste in liquid products and can precipitate peptides from soy sauce and fish sauce. Dried ferrous sulfate is somewhat less soluble, and is preferred to the heptahydrate form as it is less prooxidant (12). It is soluble in water, so would be expected to cause similar sensory problems as ferrous sulfate. It has been less frequently used in food fortification, as it costs about five times more than ferrous sulfate. It has been used to fortify infant formula (24), grape juice and malt extract (25), but rapidly causes fat oxidation and off colors in stored cereal based complementary foods (20). Recently it has been shown to be a highly efficacious iron fortificant for whole milk powder reconstituted for consumption. After six months feeding, the prevalence of anemia decreased from 41% to 12%, with no change in control children receiving nonfortified milk (26). In this study, volunteer subjects were fed a meal of rice and vegetable soup seasoned with fish sauce fortified with 57Fe-labeled ferrous lactate. The authors suggested that ferrous lactate was unstable in the aqueous fish sauce and degraded in a few days to less well absorbed ferric compounds. Ferrous lactate this water soluble iron compound has been reported to give slight off flavors in liquid whole milk and skim milk (27) and to cause a darkening of color of chocolate milks (19). In rats, it has Ferric ammonium citrate this iron compound has been used to fortify infant formula and fruit flavored beverages (18) and has been reported to be organoleptically acceptable in fluid skim milk (30). Although ferric ammonium citrate has been reported to be as well absorbed as ferrous sulfate by anemic rats (31), several studies in human volunteers have shown it to be less well absorbed than ferrous sulfate when fed either as pharmacological preparations or used to fortify foods. Using erythrocyte incorporation of radioiron to measure iron absorption, Hahn et al. Similarly, when ferric ammonium citrate was used to fortify fish sauce, which was fed to volunteers with rice and vegetable soup, iron was only 50% as well absorbed as from the same meal fortified with ferrous sulfate (13). The lower absorption of soluble ferric iron compared to soluble ferrous iron is presumably related to the more ready formation of insoluble, unabsorbable ferric hydroxides in the duodenum. This may perhaps be prevented by the addition of ascorbic acid to the iron fortified food. Category 2: Poorly water soluble iron compounds which are soluble in dilute acid Ferrous fumarate Ferrous fumarate has been used mostly to fortify cereal based complementary foods for young children, but it has also been added to maize flour in Venezuela with some success (36) and to chocolate drinks (9). It is, however, a dark red color and may cause sensory problems in some applications. Because of its insolubility in water it causes fewer sensory changes than ferrous sulfate. It does not cause fat oxidation during storage of cereal based complementary foods, but may cause color changes during preparation for feeding, particularly if fruits are present. Similarly, if added to chocolate drink powders, which are reconstituted with boiling water, sufficient iron may dissolve to cause color changes (37). When making the recommendations for the choice of iron fortificant for infant foods, it has been assumed that ferrous fumarate will also be as well absorbed as ferrous sulfate. Two recent studies in infants and young children, however, have cast doubt on the use of ferrous fumarate for complementary food fortification (41, 42), at least at the currently used fortification level. The reasons for lower iron absorption from ferrous fumarate than from ferrous sulfate in young children are unclear. Lower gastric acid secretion has been suggested (41) although poor iron status is another possibility (15), with iron absorption from ferrous sulfate being upregulated to a greater extent than from ferrous fumarate. In a recent stable isotope study from Mexico, iron absorption from ferrous fumarate and ferrous sulfate were similar in women, preschool children and infants fed a maize based complementary food (Harrington et al. Ferrous succinate Ferrous succinate, like ferrous fumarate, is insoluble in water but readily soluble in dilute acids. It has the advantage of being a pale brownish yellow color but, unlike ferrous fumarate, it has not been widely used for food fortification. It has been suggested for fortification of infant cereals and chocolate drinks (12, 37) and has shown equivalent bioavailability to ferrous sulfate in both rats and humans (12). Category 3: Water insoluble compounds which are poorly soluble in dilute acid Ferric pyrophosphate this iron compound is an off-white, water insoluble powder which causes few if any sensory changes when added to different food vehicles. It is widely used to fortify chocolate drink powders and has been used extensively to fortify cereal based complementary foods. These include the physical characteristics of the compound and the composition of the meal. In addition, it has been proposed that ferrous sulfate absorption may be more influenced by phytate and ascorbic acid than ferric pyrophosphate absorption (15, 43), and that iron deficient individuals may upregulate absorption from ferrous sulfate to a greater extent than from ferric pyrophosphate (15). Despite these uncertainties, and despite a lower absorption than from ferrous sulfate, ferric pyrophosphate has proven efficacious in improving the iron status of schoolchildren fed iron fortified salt (45) and iron fortified extruded rice (46) when added at an increased level of fortification. A breakthrough in food fortification was the iron fortification of extruded rice grains with small particle size ferric pyrophosphate, without causing adverse color formation (22). The extruded grains were not detectable from normal rice grains, and were mixed 1:50 with normal grains and fed as part of a school lunch program to children in Bangalore, India (46). A seven month long randomized double blind efficacy trial was made in two groups of 90 schoolchildren. All the children were dewormed, and the prevalence of iron deficiency in the dewormed control children decreased from around 80% to 50%. The prevalence of iron deficiency in the dewormed children receiving the iron fortified rice decreased from 80% to 25%, significantly lower (P<0. In the same study, micronized, dispersible ferric pyrophosphate with a particle size of 0. By adding emulsifiers, the formation of agglomerates is prevented and the aqueous form can be added to liquid food products such as milks and beverages with few sensory problems. Ferric orthophosphate this compound would appear to be similar to ferric pyrophosphate both in color and solubility, and has been used to fortify infant foods, chocolate drinks and salt (8). Elemental iron compounds Even though elemental iron powders have been used to fortify wheat flour for more than 50 years, it was not until recently that certain forms of elemental iron were shown to be efficacious fortificants in this vehicle (52). This study, made in Thailand, was the first fortification efficacy trial to use the body iron method of Cook et al. The study was a randomized double blind controlled trial in 330 women of child bearing age with serum ferritin <25 g/L. The women, working in clothing factories, were divided into four groups and, at break time six days per week over 35 weeks, they consumed a wheat flour snack fortified with 12 mg iron as either ferrous sulfate, electrolytic iron, H-reduced iron, or with no iron. There was no change in the body iron status in the women consuming the non iron fortified snack. The quantity of iron added to a fortified food is fundamental to the success of a program. Adding too little iron will not lead to an improvement of iron status, as will not conducting the efficacy study for a sufficient length of time. This is demonstrated by a recent study in which iron deficient schoolchildren (serum ferritin <20 g/L) were fed electrolytic iron fortified bread containing an average of 3. The length of the study Bioavailability of iron compounds for food fortification 87 was shorter than previous studies and the amount of iron per day about one third that fed in studies which reported an improvement in iron status (45, 52, 55). The authors failed to take into account that electrolytic iron is only about half as well absorbed as ferrous sulfate, and that its level of fortification should be increased accordingly (10). There are many elemental iron powders, manufactured by five different manufacturing procedures. These powders are mostly used for molding components of cars, such as gear wheels, and those supplied to the food industry have not been specifically manufactured for the purpose of food fortification. Food manufactures should therefore check carefully the origin of the elemental iron powders supplied for food fortification. H-reduced iron and carbonyl iron powders were considered to require further study. This report was based a review of in vitro studies, rat assays, human bioavailability studies with isotopically labeled compounds, and efficacy studies monitoring iron status in human subjects. It was concluded that, at the present time, only electrolytic iron powder can be recommended as an iron fortificant. As it is only approximately half as well absorbed as ferrous sulfate, it was recommended that the amount added should provide double the amount of iron. As with ferric pyrophosphate, ascorbic acid enhances iron absorption from electrolytic iron to a lesser extent than from ferrous sulfate (59). Category 4: Iron chelates Amino acid chelates Ferrous bisglycinate is the major amino acid chelate produced commercially, although ferrous trisglycinate and ferric glycinate are also available. The chelate is reported to be formed by two glycine molecules combining with ferrous iron in a double heterocyclic ring structure (60). Evidence would suggest that iron is protected from inhibitors by the structure, since iron absorption is one to 3. Four non controlled efficacy studies with ferrous bisglycinate fortified foods have reported a marked decrease in the prevalence of anemia or iron deficiency anemia in children or adolescents. Three studies made in Brazil reported good efficacy in fortified liquid milk (64), sweetened bread rolls (65) and a whey based beverage (66), and a fourth study in Saudi Arabia reported good efficacy in an iron fortified flavored milk drink (67). Egli rous bisglycinate fortified bread made from high extraction flour resulted in small but significant increases in both hemoglobin and serum ferritin when fed in a randomized controlled design to South African schoolchildren (54). A longer feeding period with higher iron concentrations would probably have given more impressive results. The influence of ferrous bisglycinate on stored flour was not investigated in this study. It can, however be degraded in some liquid products by ultraviolet rays from the sun. It has, however, been consistently shown to improve the iron status of targeted populations when added to a variety of condiments. These include fish sauce in Thailand (73) and Vietnam (74, 75), sugar in Guatemala (76), curry powder in South Africa (77) and soy sauce in China (78), although there has been no demonstration yet of its efficacy when added to cereal flours. In this way, it protects iron from phytate and polyphenol binding in the stomach and releases it for absorption in the duodenum (69). In addition, it is highly useful in fermented sauces such as fish or soy, where most soluble compounds cause peptide precipitation in storage. Its main advantage is that it should allow the addition of iron compounds of high relative bioavailability, such as ferrous sulfate and ferrous fumarate, to difficult Bioavailability of iron compounds for food fortification 89 food vehicles such as cereal flours or salt without causing any adverse sensory changes. Encapsulated iron compounds are suitable for most dry products such as infant foods, dry beverage mixes, condiment sachets and Sprinkles sachets for mixing with complementary foods. As they protect against fat oxidation, they are recommended for cereal flour fortification (1), however, widespread use in wheat flour fortification is prevented at the present time by the large size of the capsules, which are removed during the final sieving process.
Blood was collected from one group of mice 20 min after challenge to measure histamine levels bacteria normally carried by about a third of the population purchase 600 mg linezolid amex, and 24 hr after challenge in another group to measure the IgG1 and IgE xylitol antibiotics purchase 600mg linezolid with visa. Histamine levels were 2 to 17 times higher in the allergen challenged mice compared to the control mice infection during pregnancy buy linezolid 600 mg mastercard. Lastly treatment for dogs eating grapes purchase linezolid 600 mg on line, levels of IgG1 and IgE in the allergen challenged mice were 2 to 6 times higher than the control mice virus 90 mortality rate 600 mg linezolid with visa. Allergic contact dermatitis antibiotics types cheap linezolid 600 mg line, caused by metallic ions such as nickel antibiotic lock therapy idsa linezolid 600mg without prescription, is a T cell-mediated inflammatory skin disease antibiotic resistant bacteria india purchase linezolid 600mg amex. These cell lines show few changes in the expression of the 29 genes following allergen treatment. In U937 cells the few positive responses observed were minimal with only 2-6 fold changes over control except for a maximal response of 8. Human bronchial cells are one of the first cell types exposed to inhalable environmental toxins. The loss of E-cadherin was specific since other cellular markers remained unchanged. BaP at 30 M significantly altered the normal structure of cytokeratin, another marker of epithelial functional integrity, as asessed by immunostaining. The molecular basis for the shift toward mesenchymal phenotype is currently under investigation. Moreover, micronucleated cells in the peripheral blood are increased in Ogg1-deficient but not in wildtype mice indicating that while strand breaks are repaired in wildtype mice, they seem less easily repaired in Ogg1-deficient mice. The expression of p53 was examined by western blot analysis and cellular localization of p53 was evaluated by immunocytochemistry. This suggests that the lung has very effective adaptive responses to limit the potential damaging effects of chronic smoking. Although extensive studies have shown that benzo[a]pyrene (BaP), a ubiquitous environmental carcinogen, is closely associated with multiple human pulmonary diseases, molecular mechanisms of BaP toxicity are still not fully understood. Endothelial dysfunction due to acrolein was prevented by pretreating the isolated aorta with N-acetylcysteine. These animals were also co-exposed to arsenite (10 mg/kg) or saline via gavage for 10 days. All animals, in groups of 3, were housed in metabolic cages for urine collections. Significant increased hepatic Cyp2a enzyme expression and activity were found in all arsenic treated animals. Our findings also provide the needed scientific base for the epidemiological observations. Preclinical toxicity contributes to ~ 70% of compound failure during the drug discovery process, suggesting that approaches that reduce attrition due to pharmacology or chemistry can lead to successful selection of candidate drugs. The use of animal disease models to test for toxicity presents a unique opportunity for toxicologists to explore liabilities early in the drug discovery process. Rodent models, including tumor xenograft, metabolic, and inflammation models are especially attractive for combined efficacy/toxicology testing due to their repeat-dose testing paradigm and study duration. Thus, this forum will highlight the successes and challenges in the use of nonclinical disease models to evaluate safety endpoints. In addition, information obtained from such studies can often be applied toward a biomarker strategy or dose-scheduling plan for nonclinical and clinical development. Metabolic and chronic inflammatory disease models have altered physiology needs to be considered, as this may modulate the toxicological response. Mounting epidemiological evidences indicated that interaction between cigarette smoke and arsenic increased lung and liver cancer risks among cigarette smokers in arseniasis areas. Collaboration among all food safety bodies, including state, federal and global partners provides a robust system for continued protection and preparedness of the food protection system. The chemical and microbial risk assessment communities benefit from this on-going collaboration and cooperation. Collaboration has led to advancements in the food safety information infrastructure, data mining, data sharing and the development of sophisticated risk assessment models (risk assessments, vulnerability assessments, etc. Leaders from state, federal and international bodies will discuss cooperative and innovative approaches for chemical and microbiological risk assessments in order to provide the safest food supply to the consumer. Some of the federal agencies, such as the National Science Foundation, support research in the areas of environmental biology. Drug-related injury to cardiac and/or skeletal muscle is a common cause of safetyrelated attrition in drug development, and has resulted in the withdrawal of several efficacious pharmaceutical agents from the market. Scientific challenges that limit the broader application of these biomarkers are also addressed in a presentation on the changes in muscle structure and biochemistry that are driven by physiological and pathological processes, including those related to exercise, muscle atrophy, and drug toxicity in human muscle. Chemicals interact with biological targets ultimately at the molecular level producing key, necessary and causative events. Nanomaterials, typically defined as manufactured materials that have at least 1 dimension <100 nanometers, are being increasingly produced worldwide. Nanomaterials have been used or proposed for use in a variety of products, ranging from computers, clothing, cosmetics, medical devices, coatings and fuel cells, to new technologies for environmental clean up. Use is expected to increase and it is estimated that by 2015 about 10% of output from the chemicals sector will have some influence from nanotechnology, greatly increasing opportunities for human exposures. There has been some evaluation of potential health risks from nanomaterials, but to date, but these have not been pursued in a systematic way. Nanomaterials pose new challenges and opportunities to the regulatory and policy structure. There is an increasing number of regulatory and policy decisions being discussed or made at the state, federal and international level. Given that this is still a new and emerging technology, there are opportunities to consider how to address potential health risks in the regulatory and policy framework prior to widespread use and adoption. This symposium will present an overview of nanomaterials, the current state of regulations and policies for addressing nanomaterials and a discussion of how various entities propose the government move forward to address nanomaterials. Toxicology research at academic institutions is supported by various extramural research funding mechanisms, of which the most common are research grants and fellowships. Identification of possible health hazards has been the basis of toxicological research with an examination of possible reproductive effects, immunotoxicity, hepatic effects, cancer and a number of endpoints. However, because of regulatory and voluntary efforts subsequently introduced, the levels of dioxin in the environment and food chain have significantly declined. The margin of exposures should continue to increase as additional controls on dioxin emissions are enacted and environmental levels dissipate. The available scientific data have improved our understanding of the strengths and weaknesses of toxicity equivalency factors used in dioxin risk assessment. This session will focus on the research that has been reported over the last 40+ years, the principles of mechanistic toxicology learned from this research and what the future of research into the human health and environmental effects of this particularly toxic compound. Manganese (Mn) exposure in primates has been recently shown to result in diffuse beta-amyloid plaques in the frontal cortex of young non-human primates. Experts in metal toxicology, neurotoxicology, and environmental epidemiology, who have performed pioneering work to address this newly emerging research area in metal neurotoxicology will address these issues. Lead is well-known to toxicologists and the public health community as a potent neurobehavioral toxicant in children. More recently, a critical mass of studies has developed using molecular and biomarker epidemiology to demonstrate that, if the dose received is chronic over many years, lead is both a potent neurobehavioral toxicant in community-exposed adults as well as a trans-generational neurotoxicant resulting from the mobilization of maternal skeletal lead stores during pregnancy. The Exposure Biology Program aims to develop a new generation of tools for comprehensive exposure assessment. These tools stem from the efforts of four complementary program areas focused on improving detection of individual exposures to traditional environmental toxicants, assessing psychosocial stress and addictive substances, assessing diet and physical activity, and measuring biological responses to these factors. This activity is focused on the development and validation of new tools, approaches, and biomarkers that will enable fundamentally new directions in environmental epidemiology and the exploration of gene environment interactions. The evolution of these new biomarkers and biosensors and how they may be used to assess early but persistent changes in key physiological pathways known to be involved in disease pathogenesis will be the primary focus. Furthermore, the epigenetic mechanisms involved as well as potential novel therapeutic approaches will be discussed. Excess amounts of extracellular Abeta may result from an overproduction, inadequate metabolic clearance, and/or imbalanced import and export of Abeta by brain barrier systems. Water insoluble nickel (Ni) compounds are carcinogenic due to delivery of high concentrations of Ni ions into cells by phagocytosis and dissolution. The major target of Ni ions in cells is the iron-, ascorbate-, oxoglutarate-dependent dioxygenase enzymes. Since Fe binding to this domain is required for catalytic activity and Ni ions readily displace Fe from all of these enzymes, Ni exposure results in essentially inactive enzyme. A ratio of Ni ions to enzyme molecules of ~1:1 was required for complete inhibition. Since Ni ions are one of the least toxic metal ions, this ratio was easily achievable at non-toxic levels. The genes most stably downregulated by Ni ion exposure had greater H3K9 Dimethylation changes in their promoter based upon Chip assays. Chip on chip using H3K9 di me and H3K4 tri me antibodies mapped the coordinates on the promoter of genes that were up or down regulated and these changes were correlated with down regulation (H3K9 di me) or up regulation (H3K4 tri me) marks in their promoters. In addition to genes, environmental factors, including diet, metals and life style, play an important role in the development of disease phenotype. This model integrates both the neuropathological features and environmental factors associated with the disease. This presentation will be in two parts: 1) present data on a recently development computer-learning algorithm that predicts 600 imprinted genes in mice versus 156 in humans with a mere 30% overlap between the two; and, 2) show data on how in utero maternal dietary supplementation with various compounds causes an alteration in expression of the metastable Avy allele as a sensor for epigenetic changes. Epigenetics can be defined as heritable changes in gene expression that do not involve genetic mutations and are propagated without continued stimulus. Discrete chemical modifications of the chromatin can regulate gene expression or repression and can be transmitted to daughter cells or future generations due to epigenetic memory. Although potentially reversible, these heritable changes may be classified as transgenerational, mitotic, or meiotic, implicating the wide-ranging impact of epigenetic control in cellular function. These epigenetic processes play fundamental roles in cell proliferation, differentiation, cancer development and toxicities. Understanding how these modifications are inherited from mother cells to daughter cells or from an organism to its progeny remains a major scientific challenge. Recently, there has been a growing concern that epigenetic events may play a role in chemically and/or nutritionally driven adverse health effects, with particular focus toward reproductive toxicity and non-genotoxic carcinogenesis. Overall, although the current literature consists of relatively few studies, there has been considerable interest by the popular press, government agencies, and the scientific community. Therefore, it is important to provide an introduction to epigenetic mechanisms and to highlight the current state-of-the-science in epigenetic toxicology. Estrogen and estrogen mimics are now known to have distinct epigenetic effects on various reproductive end organs. The effects of estradiol-17beta, bisphenol A, diethylstilbestrol, soy-estrogens were investigated for their epigenetic effects on the prostate, uterus, and breast to determine if an "e-epigenome" could be identified and/or constructed. Infection and chronic inflammation contribute to about 1 in 4 of all cancer cases. In vitro studies on the mechanism of action revealed that resveratrol triggered high levels of apoptosis in activated T cells and to a lesser extent in unactivated T cells. Moreover, resveratrol-induced apoptosis was mediated through up-regulation of AhR, Fas, and FasL expression. In vivo, resveratrol was also found to decrease the induction of Th17 cells while increasing the generation of FoxP3+ Tregs. Resveratrol was also effective on a wide range of inflammatory disorders including colitis, bacterial super antigen-induced lung injury and graft-versus-host disease. However, there is lack of sufficient experimental and clinical proof that they are safe and effective. On the other hand, the immunosuppressive properties of plant products, if found safe, can also be used to develop new therapeutic modality against inflammatory and autoimmune diseases. Herbal and plant-derived compounds are widely available in the market that claim to sustain, restore or enhance immunity. Responses to gut mucosal infection by reovirus were used to gauge n-3 suppression of the normal IgA response. Cannabinoids are a group of more than 60 plant-derived compounds from the plant Cannabis sativa, more commonly known as marijuana. Use of marijuana for medicinal purposes is an ongoing debate in the United States, although the mechanisms by which it exerts any therapeutic benefits are not fully elucidated. The objective of these studies was to characterize the molecular mechanisms by which plantderived cannabinoid compounds modulate immune function. However, unlike conventional macroscale dosage forms where excipients are either not absorbed into the body or are readily eliminated, the biological fate of the materials comprising nanoscale delivery systems is not fully understood. The physical, chemical and biological properties of biocompatible materials that are known or suspected to influence elimination from the body will be briefly reviewed and several case studies will be discussed. Following this, our efforts to design biodegradable dimeric nanocarriers will be described. Several features will be discussed including target cell uptake, blood and target cell persistence, toxicity and effectiveness in in vitro and in vivo models. Finally, a detailed analysis of the "enhanced elimination" design elements relating to the selective intracellular degradation of the dimeric nanocarriers will be presented followed by results supporting our hypothesis. Eosinophilic inflammation plays an important role in pathological mechanisms of asthma. There is an increasing interest in investigating botanical products for treatment of allergy and asthma. Here we report the structure and biological activities of flavonoids isolated from G. Studies on pure compounds will enhance our understanding of the pharmacological mechanisms G. Nanotechnology-based drug delivery platforms offer the potential to rejuvenate traditional chemotherapeutics by improving safety and efficacy profiles. For example, nanotechnology platforms can target drugs to tumor sites via passive mechanisms, resulting from the inherent leakiness of the tumor vasculature, and via active ligand-receptor dependent targeting mechanisms. Nanotechnology can also eliminate the need for the toxic vehicles required for administration of hydrophobic drug entities. Platforms presently undergoing evaluation include nanoemulsions, nanoliposomes, and metal, polymeric and carbon-based nanoparticles. Critical parameters that can influence the success of nanotechnology platforms include stability, clearance and tissue permeability. This presentation will specifically address the importance and challenges of monitoring the disposition and in vivo integrity of nanotechnology platforms, using preclinical and clinical case studies to demonstrate the analytical methodologies and the pharmacokinetic models employed. The biopharmaceutical industry is looking at the rapidly developing, multifaceted field of nanotechnology as an opportunity for improved approaches to drug development. A good example is the ongoing effort to exploit the unique physical and chemical properties of nanoscale materials for the purpose of improved drug delivery. Using nanoparticles with targeting ligands to precisely deliver a drug payload to a specific diseased tissue, while by-passing all other parts of the body, would clearly represent a game changing approach to drug development. However, before that future vision can be realized, significant unknowns and gaps in our understanding of the toxicology of nanoscale drug delivery platforms will need to be addressed. Academic and industry researchers, as well as government regulators, interested in the unique safety issues confronting drug developers will explore the use of nanomaterials for improved drug delivery. The program will consider the design and development of nanomaterials compatible with the unique requirements for drug delivery and therapy, focusing on material distribution and safety when intentionally delivered into physiologic systems. Special emphasis will be placed on properties that influence absorption, distribution, metabolism and excretion of nanomaterials, including immune system interactions, and properties that influence the toxicity of nanomaterials and their degradation products. Particle chemistries for imaging vary from metals and metalloids to polymer/metal or polymer/metal chelate composites. Therapeutic nanoparticles include nanometer-sized crystals of drug, dendrimer polymers containing drugs and/or photosensitizers and other polymers housing combinations of drug and/or photosenitizers. The surfaces of each of these nanoparticle formulations may be further modified to enable targeting (peptides, antibodies, nucleotide polymers, etc. Each of these modifications may have unintended biological, pharmacological and toxicological consequences. The unique physicochemical properties of nanosized particles make them attractive candidate drugs or drug carriers. Products containing nanomaterials are being investigated for potential applications as therapeutics. While some of these nanomaterials are nanoscale versions of larger materials used in approved products, other nanomaterials are novel and have never been used in drug products. Meanwhile, the regulatory requirements to ensure preclinical safety for products containing such novel materials, remain identical to those requirement for products that do not contain nanoparticles. There are various reasons why there are no "nano-specific" requirements at this time. One reason is that the preclinical studies currently required of sponsors are very comprehensive, and include many studies that measure endpoints that should pick up injury in most organs. Another reason is that, while some have suggested that the current preclinical screening tests might need to be tailored for nanomaterial-containing products, no one has clearly communicated in what respect the current requirements might be lacking in their capacity to assess safety concerns from nanomaterial-containing products, and what are other available tests that might improve the predictive value of the current regulatory preclinical requirements. Nevertheless, it is widely accepted that there are unique features associated with nanotherapeutic products, and these unique features may lead to future challenges for the development, manufacturing, safety evaluation and review of these products. These challenges are both for the sponsor of nanotechnology-based products, as well as for regulatory agencies, who must regulate these products. With this goal in mind, the Agency is working on future guidance documents to help industry bring to fruition the promise of nanotechnology in drug applications. In this presentation, we describe the application of benchmark dose analysis to gene expression microarray data collected following ninety day exposures to five different lung and liver carcinogens. The benchmark dose methods were used to estimate doses at which different cellular processes are altered and showed that benchmark dose values for certain processes mirrored the tumor response in a two-year rodent bioassay. The results show that dose-response changes in gene expression, when related to higher-order biological processes and pathways, reflect the dose dependent changes in key events in the carcinogenic process and can support nonlinear modeling of the events in the low dose region within the framework of a mode of action risk assessment. The nature of the dose-response curve at levels below the no-observed adverse effect level is a contentious issue in risk assessment. Resolution of the debate has been difficult because the resolving power of most experimental methods is too limited to support conclusions about response at very low doses. One controversy has been the possibility of non-monotonic dose-response curves for estrogens on the developing male reproductive system.
Hepcidin production has been reported to be decreased despite elevated serum ferritin levels (indicative of increased iron stores) in the presence of accelerated erythropoiesis (120 virus journal order linezolid 600 mg mastercard, 121) antibiotic resistance obama linezolid 600mg with visa, leading to continued iron accumulation antibiotics for uti for pregnancy purchase 600 mg linezolid overnight delivery. Repeated blood transfusions also contribute significantly to the iron overload in these patients infection signs best 600mg linezolid. They include atransferrinemia as well as conditions that lead to organ/tissue specific iron overload antibiotics for dogs ear infection order 600 mg linezolid with amex. Examples include abnormalities of iron trafficking in the mitochondrion (122) and aceruloplasminemia (123 antibiotic resistance hsc biology buy discount linezolid 600mg line, 124) antibiotic resistance rates linezolid 600 mg generic. Anemia of inflammation (anemia of chronic disease) the anemia of inflammation is a mild or moderate anemia that is characterized by decreased iron release from macrophage stores antibiotic 4 days buy discount linezolid 600 mg, reduced absorption, restriction of the supply available for red cell production and reduced plasma iron and transfer- Iron metabolism 71 rin concentrations (125). Many investigators have postulated that it is a vital host response that evolved to deprive pathogens of iron, and that it is one of the mechanisms that constitute "nutritional immunity" (126, 127). Although the former name of the anemia of inflammation, "anemia of chronic disease," suggested slow evolution of the characteristic laboratory findings, the fall in plasma iron concentration was well known to occur rapidly after the onset of infection or inflammation. Recent studies demonstrate that synthetic hepcidin administered to mice causes hypoferremia within hours of a single intraperitoneal injection (130). The scientific knowledge base has provided a sound foundation for approaches to combating nutritional iron deficiency. I have provided only a brief overview of some of the highlights that are relevant to nutrition and nutritional anemia. Model of reticuloendothelial iron metabolism in humans: abnormal behavior in idiopathic hemochromatosis and in inflammation. A new mouse liverspecific gene, encoding a protein homologous to human antimicrobial peptide hepcidin, is overexpressed during iron overload. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Presence of the iron exporter ferroportin at the plasma membrane of macrophages is enhanced by iron loading and downregulated by hepcidin. Role of the ferroportin iron-responsive element in iron and nitric oxide dependent gene regulation. Response of monocyte iron regulatory protein activity to inflammation: abnormal behavior in genetic hemochromatosis. Nitric oxide-mediated induction of ferritin synthesis in J774 macrophages by inflammatory cytokines: role of selective iron regulatory protein-2 downregulation. Cellular and molecular mechanisms of senescent erythrocyte phagocytosis by macrophages. Microcytic anaemia mice have a mutation in Nramp2, a candidate iron transporter gene. An iron-regulated ferric reductase associated with the absorption of dietary iron. Isolation and function of a receptor for human lactoferrin in human fetal intestinal brush-border membranes. Iron in ferritin or in salts (ferrous sulfate) is equally bioavailable in nonanemic women. The transcytosis of divalent metal transporter 1 and apo-transferrin during iron uptake in intestinal epithelium. Copper repletion enhances apical iron uptake and transepithelial iron transport by Caco-2 cells. Cellular and subcellular localization of the Nramp2 iron transporter in the intestinal brush border and regulation by dietary iron. Intestinal mucosal uptake of iron and iron retention in idiopathic haemochromatosis as evidence for a mucosal abnormality. Range and consistency of menstrual blood loss in and iron requirements of menstruating Egyptian women. Dietary reference intakes for vitamin A, vitamin K, arsenic, boron, chromium, copper, iodine, iron, manganese, molybdenum, nickel, silicon, vanadium, and zinc. The potential impact of iron supplementation during adolescence on iron status in pregnancy. Effect of iron supplementation on the iron status of pregnant women: consequences for newborns. Iron and ascorbic Acid: proposed fortification levels and recommended iron compounds. Effects of iron intake on iron stores in elderly men and women: longitudinal and cross-sectional results. A comparison of iron absorption in adults and infants consuming identical infant formulas. The coatings are commonly hydrogenated palm oil or hydrogenated soy bean oil, although maltodextrin and celluloses have also been used. Maltodextrin and the celluloses are water soluble, and offer less protection against adverse color reactions or against lipid oxidation during storage if moisture is present. When the ratio of the coating material to the iron compound is close to 1:1, there is no change in the bioavailability of ferrous sulfate in rat assays (12). Ferrous sulfate encapsulated in hydrogenated soy bean oil added to salt (1:1) was efficacious in improving the iron status of Moroccan schoolchildren (55) and 57Fe-labeled ferrous fumarate added (40:60) with Sprinkles to a maize based complementary food was well absorbed by infants (80). Amounts of coating material greater than 60:40, or the inclusion of other compounds, such as waxes, into the coating, may decrease bioavailability (4). It enhances the absorption of fortification iron (with the exception of the chelates) and intrinsic food iron in a dose dependent way (81). The enhancing effect has been attributed to its reducing and chelating properties during the digestion of the food (82). The addition of ascorbic acid overcomes the negative effects of all major inhibitors of iron absorption, including phytate, polyphenols (83), calcium and casein from milk products (84), and can increase iron absorption two to threefold, although recent studies indicate that insoluble iron compounds such as elemental iron and ferric pyrophosphate are less enhanced by ascorbic acid than ferrous sulfate (43, 59). A 2:1 molar ratio of ascorbic acid to iron is recommended for low phytate products and powdered milk, and a 4:1 ratio is recommended for high phytate products (85). The use of ascorbic acid as an enhancing agent is limited by its instability in aqueous solutions, during storage of powdered foods, and during prolonged heat processing or cooking. Adequate packaging to exclude oxygen can help preserve ascorbic acid during storage, however, almost all will be destroyed during heat treatments such as baking or during preparation for consumption if extensive cooking is required. A possible solution is the use of ascorbyl palmitate, a synthetic ester composed of palmitic acid and ascorbic acid. This compound is thermostable and its reductive and vitamin properties are reported to be maintained during baking (86). When baked with ferrous sulfate into bread, it increased iron absorption in women from 10. It is routinely added to Addition of erythorbic acid Erythorbic acid is a stereoisomer of ascorbic acid which appears to have a better enhancing effect on iron absorption but to be more sensitive to oxidation (88). Egli is a common additive in processed foods (89), but has limited antiscorbutic activity in guinea pigs (90). When added to a ferrous sulfate fortified cereal porridge, iron absorption by women increased from 4. The addition of ascorbic acid to the same meal at a 4:1 molar ratio increased iron absorption from 4. Addition of other organic acids With the possible exception of fruit drinks, the addition of other organic acids does not appear to be an option, as the large quantities of organic acids which are required to enhance iron absorption will cause unacceptable flavor changes in most vehicles (92). Although citric, lactic, tartaric and malic acids do enhance iron absorption and are commonly used food additives, they effectively enhance iron absorption only at molar ratios in excess of 100:1. One gram or more of citric, malic or tartaric acid was necessary to increase iron absorption by two to threefold, from 3 mg ferrous sulfate iron added to a rice meal (93). Phytic acid degradation Phytic acid in cereal and legume based foods is a potent inhibitor of iron absorption from iron fortification compounds and from native food iron (96). It can, however, be degraded in an aqueous environment by the addition of exogenous phytases or by the activation of native phytases in the cereal grains under controlled pH and temperature conditions (97). To obtain a meaningful increase in iron absorption, it is necessary to achieve near complete degradation of phytate from meals containing few or no enhancers of iron absorption (98, 99) although, when enhancers of iron absorption are present in a meal, even a 50% phytate reduction can considerably improve iron absorption (100). Low cost cereal and legume based complementary foods would be appropriate foods for dephytinization, as it is usually not possible to add ascorbic acid to these products without expensive packaging. In single meal studies, complete dephytinization of cereal porridges with added phytase under controlled temperature and pH conditions increased fractional iron absorption from two to twelvefold (101). In such porridges, with no enhancers of iron absorption, it has been recommended that the phytate to iron molar ratio should be reduced to <1:1 and, if possible, to <0. When commercial phytases are not available, native cereal phytases can be activated by a similar wet processing methodology. Rye, triticale, wheat, buckwheat and barley had the highest phytase levels and whole wheat, whole rye and buckwheat were considered useful sources of phytase for dephytinizing complementary foods. When 10% whole wheat or rye was added to a cereal and legume based complementary food mixture, phytate could be degraded completely after one to two hours of wet processing (103). While sophisticated industrial processing methods may be too expensive and complicated for developing countries, phytate degradation by traditional fermentation processes (104) or germination processes (105) would seem to be a possibility. In industrialized countries, it is probably simpler and less expensive to add ascorbic acid than to degrade phytate. Cost may be an issue, and sensory trials checking for off colors and off flavors during storage of the fortified food or during the preparation of the meal should confirm the suitability of the compound. The level of fortification should be based on the needs of the consumer, the estimated or measured iron absorption and the consumption of the food vehicle by the target population. If the level of absorption is considered too low due to the presence of inhibitors such as phytic acid or polyphenols, ascorbic acid is the most suitable enhancer of iron absorption that can be added to iron fortified foods. With only one exception, the iron fortified foods tested greatly improved the iron status of the target population. Two studies in Morocco with fortified salt clearly demonstrate how relative bioavailability of the iron compound can be linked to the efficacy of the iron fortified food (45, 55). In the first study (55), sensory studies demonstrated that ferrous sulfate encapsulated in hydrogenated soy bean oil was an acceptable fortification compound for the local salt. The salt was provided monthly to individual households and was added primarily to bread, bean paste and olives. Hemoglobin, serum ferritin, serum transferrin receptor and zinc protoporphyrin were measured at baseline, 20 weeks and 40 weeks. Although the Moroccan salt fortified with encapsulated ferrous sulfate was satisfactory from a sensory viewpoint during the dry season, it deve-loped a slight yellow color during the wet season. To overcome the color formation, the salt was fortified with ferric pyrophosphate, which 92 R. In a randomized double blind controlled trial, two groups of 60 anemic women factory workers consumed rice or noodles with vegetables and 10 mL fish sauce with or without iron six times per week for six months. Based on these studies, we can now claim that we know technically how to design an effective iron fortified food. It depends on an efficient manufacturing and distribution system with well planned quality control and monitoring procedures, good social marketing, and especially on the nutritional status and general health of the target population. Efficacy may be blunted by other micronutrient deficiencies (107, 108) and by widespread infections such as malaria or intestinal worms (109). In these situations, multiple micronutrient fortification and other public health measures to control infections may be necessary before the iron fortification program is successful. A micronised, dispersible ferric pyrophosphate with high relative bioavailability in man. Bioavailability of elemental iron powders to rats is less than bakery-grade ferrous sulfate and predicted by iron solubility and particle surface area. Dietary reference intakes for vitamin A, vitamin K, arsenic, boron, chromium, copper, iodine, iron, manganese, molybdenum, nickel, silicon, vanadium and zinc. Iron fortification of infant cereals: a proposal for the use of ferrous fumarate or ferrous succinate. Iron absorption by human subjects from different iron fortification compounds added to Thai fish sauce. Low bioavailability of carbonyl iron in man: studies on iron fortification of wheat flour. Iron status and food matrix strongly affect the relative bioavailability of ferric pyrophosphate in humans. Bioavailability of different iron compounds used to fortify formulas and cereals: technological problems. A method for comparative studies on iron absorption in man using two radioiron isotopes. Fortifying milk with ferrous gluconate and zinc oxide in a public nutrition program reduced the prevalence of anemia in toddlers. Effects on flavor of fortifying milk with iron and absorption of the iron from intestinal tract of rats. Effect of processing on availability of iron salts in liquid infant formula products. Effect of processing on availability of iron salts in liquid infant cereal formula products. Egli Application of the animal hemoglobin repletion test to measurement of iron availability in foods. The relative absorption and utilization of ferrous and ferric iron in anemia as determined with the radioactive isotope. Absorption of unlabeled reduced iron of small particle size from a commercial source. Iron bioavailability from iron-fortified Guatemalan meals based on corn tortillas and black bean paste. Helicobacter pylori infection, iron absorption, and gastric acid secretion in Bangladeshi children. Effect of ascorbic acid and particle size on iron absorption from ferric pyrophosphate in adult women. Iron bioavailability in infants from an infant cereal fortified with ferric pyrophosphate or ferrous fumarate. Extruded rice fortified with micronized ground ferric pyrophosphate reduces iron deficiency in Indian schoolchildren: a double-blind randomized controlled trial. Particle size reduction and encapsulation affect the bioavailability of ferric pyrophosphate in rats. Iron absorption and bioavailability in rats of micronized dispersible ferric pyrophosphate. Comparison of the efficacy of wheat-based snacks fortified with ferrous sulfate, electrolytic iron, or hydrogen-reduced elemental Bioavailability of iron compounds for food fortification 95 iron: randomized, double-blind, controlled trial in Thai women. The efficacy of ferrous bisglycinate and electrolytic iron as fortificants in bread in iron-deficient schoolchildren. Effectiveness of iron-fortified infant cereal in prevention of iron deficiency anemia. Comparison of in vitro, animal, and clinical determinations of iron bioavailability: International Nutritional Anemia Consultative Group Task Force report on iron bioavailability. Iron absorption from ferrous bisglycinate and ferric trisglycinate in whole maize is regulated by iron status. Repleting hemoglobin in iron deficiency anemia in young children through liquid milk fortification with bioavailable iron amino acid chelate. The use of sweet rolls fortified with iron bis-glycinate chelate in the prevention of iron deficiency anemia in preschool children. Effect of long-term fortification of whey drink with ferrous bisglycinate on anemia prevalence in children and adolescents from deprived areas in Londrina, Parana, Brazil. A model for calculating the cost of employing iron absorption enhancement strategies in fortification programs. Determination of iron absorption from intrinsically labeled microencapsulated ferrous fumarate (Sprinkles) in infants with different iron and hematologic status by using a dual-stable-isotope method. Ascorbic acid prevents the dose-dependent inhibitory effects of polyphenols and phytates on nonheme-iron absorption. Determination of a surfactant (sodium 6-0-palmotylL-ascorbate) in bread by high performance liquid chromatography. The effects of organic acids, phytates and polyphenols on the absorption of iron from vegetables. Influence of vegetable protein sources on trace element and mineral bioavailability. Soy protein, phytate, Bioavailability of iron compounds for food fortification 97 and iron absorption in humans. Degradation of phytic acid in cereal porridges improves iron absorption by human subjects. The influence of soaking and germination on the phytase activity and phytic acid content of grains and seeds potentially useful for complementary feeding. Phytic acid degradation in complementary foods using phytase naturally occurring in whole grain cereals. Levels of antinutritional factors in pearl millet as affected by processing treatments and various types of fermentation. The antinutritional factors in weaning foods prepared from germinated legumes and cereals.
